CN117279908A - Heteroaryl compounds for the treatment of cognitive disorders - Google Patents

Abstract

The present invention provides compounds of formula (I): wherein X is ¹ 、X ² 、X ³ 、R ³ Ring a and ring B are as described herein. The compound is used for GABA containing alpha 5 subunit _A The receptor has affinity. The invention further provides for the preparation of compounds of formula (I), pharmaceutical compositions comprising these compounds and their use as medicaments for the treatment of and/or prevention of alpha 5-GABA _A Use of receptor-related diseases and disorders, including depression and cognitive disorders, such as cognitive disorders associated with mental disorders such as schizophrenia.

Description

Heteroaryl compounds for the treatment of cognitive disorders

The present invention relates to a gamma-aminobutyric acid (GABA) type A receptor (GABA) _A R) Negative Allosteric Modulator (NAM) compounds, in particular for GABA containing an alpha 5 subunit _A R(α5-GABA _A R) optionally those, their preparation, pharmaceutical compositions comprising these compounds and their use as medicaments. The compounds of the invention are useful in the treatment of and alpha 5-GABA _A R-related diseases and medical conditions, including, for example, cognitive disorders, alzheimer's disease, or huntington's disease.

Background

GABA is the primary inhibitory neurotransmitter in the mammalian central nervous system. Receptors for this neurotransmitter fall into three general classes: type A and type C receptors (GABA) _A R and GABA _C R) which are related members of the ligand-gated ion channel superfamily (there is no mention of distinguishing GABA) _A R and GABA _C The pharmacological conditions of R are also often collectively referred to asGABA), and B-type receptor (GABA) _B R), which are a family of G protein-coupled receptors.

GABA _A R is a membrane bound heteropentamer consisting of 19 known subunits. Most GABA _A R comprises two alpha subunits, two beta subunits and one gamma subunit, and two GABA binding sites are formed at the interface of the alpha and beta subunits. Despite the presence of different GABA _A A large number of theoretical heteropentamer assemblies of the R protein, but only about 25 are believed to be present in the brain (Olsen R.W. and Sieghart W.20088 Pharmacology Review [ pharmacological reviews ]]60243-260)。GABA _A The pharmacology of R can be based on its terephthalamideSensitivity (or insensitivity) of a class of drugs is defined as benzodiazepine +.>Class of drugs as GABA comprising beta and gamma 2 subunits with alpha 1, alpha 2, alpha 3 or alpha 5 (but excluding alpha 4 or alpha 6) subunits _A Positive Allosteric Modulators (PAMs) of R. These different alpha-containing GABA _A R mediates different physiological and pharmacological functions and may have different expression levels at different parts of the body.

GABA _A R PAM and action on benzodiazepinesNegative Allosteric Modulators (NAMs) of drug-like recognition sites have opposite pharmacological effects at the molecular and whole animal level in preclinical species and humans (Atack J.201110urrent Topics in Medicinal Chemistry [ current subject of pharmaceutical chemistry) ]11 1176-1202; atack J.201110urrent Topics in Medicinal Chemistry [ Current subject of pharmaceutical chemistry ]]11 1203-1214). For example, there is evidence that nonselective GABA _A R PAM (with benzodiazepine +)>The class of drugs diazepam is representative) generally has anxiolytic, sedative, anticonvulsant, and cognitive impairment effects (Atack j.201110urren)t Topics in Medicinal Chemistry [ present of pharmaceutical chemistry study ]]11 1176-1202) but not the selective GABAAR NAM causes anxiety, convulsions and enhances cognition, e.g. B-carboline FG7142 causes anxiety and produces a convulsive-like precursor in normal volunteers (Dorrow, r. Et al 1983Lancet]2 98-99). On the other hand, α5-GABAAR NAMs, such as α5ia, MRK016 and RG1662, do not have convulsive-like side effects nor cause anxiety in humans (Atack, j.2010 pharmacology)&Therapeutics [ pharmacology and Therapeutics ]]125 11-26)。

Although alpha 5-GABA _A R GABA throughout the brain _A The R population is relatively few but they are highly expressed in the hippocampus, presumably related to cognition and other hippocampal functions. Alpha 5-GABA _A R is involved in the pathophysiology and treatment of a variety of diseases, including: down syndrome (Mart I nez-Cu C. Et al 2013Journal of Neuroscience journal of neuroscience ]33 3953-3966), depression (Zanos p. Et al 2017eNeuro 4ENEURO [ neurological ]]0285-16.2017), cognitive dysfunction due to anaesthesia (Zurek A.A. et al 2014Journal of Clinical Investigation journal of clinical research]124 5437-5441), stroke (Gacsa lyi, I.2018European Journal of Pharmacology [ J.European pharmacology)]834 118-125), mild cognitive impairment and/or alzheimer's disease (Atack j. Et al 2009Journal of Pharmacology and Experimental Therapeutics journal of pharmacology and experimental therapeutics]331 470-484; ballard T et al 2009Psychopharmacology [ pharmacology ]]202 207-223; kawaharada S.et al 2018Journal of Pharmacology and Experimental Therapeutics journal of pharmacology and experimental therapeutics]366 58-65), alcohol-related diseases (Platt D.2005 et al Journal of Pharmacology and Experimental Therapeutics journal of pharmacology and experimental theraphy)]313 658-667) and impaired brain function associated with neuroinflammation (Eimerbrink M. Et al 2015Behavioural Brain Research [ behavioural brain research)]288 50-53) or viral infections such as bacteria or HIV (Green and Thayer 2019Neuropharmacology [ Neuropharmacology ]]149161-168, and Jacob,2019Frontiers in Molecular Neuroscience [ molecular neuroscience front edge ] ],12179)。

α5-GABA _A R modulators have entered the clinic for a variety of indicationsTrials including Down syndrome (RG 1662/bar Mi Shani (basmsil), NCT 02024789), schizophrenia (RG 1662/bar Mi Shani, NCT 02953639), stroke (S44819, NCT 02877615) and Dup15q syndrome (NCT 05307679).

Certain alpha 5-GABA _A R modulators are 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 (small field pharmaceutical (Ono Pharmaceuticals)); WO 2014/001279 (san niona); WO 2019/046300 (university of maryland (University of Maryland)); and WO 2022/029170.

There remains a need for new alpha 5-GABA _A R modulators, in particular alpha 5-GABA _A R NAM。

Disclosure of Invention

According to the present invention there is provided a compound of formula (I):

wherein the method comprises the steps of

Ring a is selected from: a1, A2 and A3:

R ¹ selected from: phenyl and 5-or 6-membered heteroaryl, wherein R ¹ Optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 ；

R ² Selected from: H. halo, C _1-4 Alkyl and C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2

Wherein C is _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a3 、-SR ^a3 and-NR ^a3 R ^b3 ；

R ³ Selected from: c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-;

R ⁴ and R is ⁵ Independently selected from: H. c (C) _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl-, 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms-C _1-3 Alkyl-;

R ⁶ selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ³ 、R ⁴ 、R ⁵ Or R is ⁶ Any C in any of (3) _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 ；

X ¹ 、X ² And X ³ Independently selected from: n and CR ⁷ ；

R ⁷ Independently at each occurrence selected from: H. halo, -CN, 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 is ⁹ Each independently selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

Wherein R is ⁷ 、R ⁸ Or R is ⁹ Any C in any of (3) _1-4 Alkyl radicalOptionally substituted with one or more substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 ；

Ring B is selected from the group consisting of optionally one or more R ¹⁰ Substituted C _6-10 Aryl and 5-to 12-membered heteroaryl, wherein when ring B is heteroaryl, ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the aromatic ring of the heteroaryl;

R ¹⁰ independently at each occurrence selected from: 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 ，

Wherein said C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with 1 or more R ¹² Substitution;

R ¹¹ independently selected from: H. c (C) _1-6 Alkyl and C _1-6 Haloalkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more R ¹³ Substitution;

Q ¹ independently at each occurrence selected from: c (C) _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-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-,

wherein 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-optionally substituted with one or more R ¹⁴ Substituted, and

Wherein the phenyl, phenyl-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁵ Substitution;

L ¹ is a bond or is selected from-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 -；

R ¹² 、R ¹³ And R is ¹⁴ Each occurrence is independently selected from: 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 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a9 、-NR ^a9 R ^b9 and-SO ₂ R ^a9 ；

R ¹⁵ Independently at each occurrence selected from: 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 NR ^a10 R ^b10 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a11 、-NR ^a11 R ^b11 and-SO ₂ R ^a11 ；

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 is ^b11 Independently at each occurrence selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

or any-NR within a 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 A 4-to 6-membered heterocyclyl can be formed, wherein the 4-to 6-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

the conditions are (i) and (ii):

(i) When ring A is A2 and R ² When H is H, then R ³ not-NR ⁵ R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the And

(ii) The compound of formula (I) is not:

also provided are pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Also provided are compounds of the invention, or pharmaceutically acceptable salts thereof, for use as a medicament. In some embodimentsIn the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof is used for the treatment of a disease selected from the group consisting of alpha 5-GABA _A R-mediated diseases or medical conditions.

Also provided are methods of treating a disorder caused by alpha 5-GABA in a subject in need thereof _A A method of treating a disease or medical condition mediated by R, the method comprising administering to a subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of disorders resulting from the administration of alpha 5-GABA _A R-mediated neurological or neuropsychiatric disorders. In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of conditions involving alpha 5-GABA _A R or a cognitive dysfunction associated with a neuropsychiatric disorder. The neurological disorder may be a neurological disorder such as down's syndrome or a neurodegenerative disease such as alzheimer's disease or huntington's disease. Thus also provided are compounds of the invention, or pharmaceutically acceptable salts thereof, for use in the treatment of neurological disorders such as Down syndrome. Also provided are compounds of the invention, or pharmaceutically acceptable salts thereof, for use in the treatment of neurodegenerative disorders (e.g., alzheimer's disease or huntington's disease).

From alpha 5-GABA _A The R-mediated disease or medical disorder may be selected from: alzheimer's disease, parkinson's disease, huntington's disease, cognitive dysfunction (e.g., cognitive dysfunction associated with chemotherapy, narcotics, bacterial or viral infections (e.g., HIV)), memory deficits, age-related cognitive dysfunction (i.e., mild cognitive impairment, MCI), bipolar disorder, autism, down's syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, amyotrophic Lateral Sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorders, schizophreniform disorders, substance-induced psychotic disorders or paranoid disorders), psychosis, post-traumatic stress disorders, anxiety disorders, generalized anxiety disorders, panic disorders, delusional disorders, obsessive-compulsive disorders, acute stress disorders, drug addiction, alcohol disorders (e.g., alcohol addiction), drug withdrawal symptoms, movement disordersRestless leg syndrome, cognitive deficit disorder, multi-infarct dementia, vascular dementia, mood disorder, depression, neuropsychiatric conditions, attention deficit/hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive dysfunction associated with stroke, cognitive dysfunction associated with brain injury or trauma, cognitive dysfunction associated with brain tumors, attention disorder, and Dup15q syndrome.

In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, are useful for treating or preventing depression, e.g., treating refractory depression.

In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, are used to treat or prevent post-operative cognitive dysfunction in a subject.

In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, are used to treat or prevent a neurological symptom or a psychotic symptom induced by neuroinflammation. For example, the compounds of the invention, or pharmaceutically acceptable salts thereof, are useful for treating neuroinflammation-induced cognitive disorders.

In embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, are used to treat or prevent a cognitive disorder associated with a bacterial or viral infection in a subject.

Drawings

Embodiments of the invention are further described below with reference to the accompanying drawings, in which:

FIG. 1 shows expression of α5β3γ2GABA using the in vitro electrophysiological recording assay described herein before and after addition of the compound described in example 1 (1. Mu.M) _A The same cells of the receptor were recorded as raw whole cell current traces on the QPatch system.

Figure 2 shows the rescue of etomidate-mediated long-term potentiation (LTP) defects by the compound of example 1 in the mouse hippocampal brain slice LTP assay described herein. The Y-axis in FIG. 2A shows the slope of the field excitatory postsynaptic potential (fEPSP), expressed as% of control fEPSP prior to 4- θ burst stimulation (4-TBS). The Y-axis in FIG. 2B shows the fEPSP slope from 50 to 60 minutes after 4-TBS delivery.

FIG. 3 shows the process described hereinIn vivo brain receptor occupancy assays, compound example 1 was used at doses ranging from 3 to 30mg/kg (oral) on rat brain benzodiazepinesOccupancy of drug-like (BZ) binding sites.

Detailed Description

Definition of the definition

The following terms, as used in the specification and claims, have the meanings listed below unless otherwise indicated.

Reference herein to "a compound of the invention" refers to any compound disclosed herein, including compounds of formulae (I) to (XXXI), compounds selected from compound list 1, or compounds described in any example, or any pharmaceutically acceptable salt, solvate, or salt of a solvate thereof.

Mention of "alpha 5-GABA _A R' means GABA comprising at least one alpha 5 subunit, e.g. one or two alpha 5 subunits _A R。

The term "negative allosteric modulator" or "NAM" refers to acting on alpha 5-GABA _A An allosteric site on R and indirectly reduces the responsiveness of the receptor to endogenous ligands (GABA).

The term "treatment" refers to any beneficial effect of treating or ameliorating a lesion, disease, pathology, or disorder, including any objective or subjective parameter, such as alleviation; relief; impair symptoms or make patients more tolerant of injury, pathology or condition; the rate of denaturation or decay is slowed; altering the progression of the disease or condition such that the final point of degeneration is no longer so debilitating; improving physical or mental health of the patient. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of physical examination, neuropsychiatric examination, and/or psychiatric assessment. The term "treating" and variations thereof includes preventing injury, pathology, condition or disease (i.e., preventing or arresting). For example, the term "treatment" and variants thereof include prophylaxis against alpha 5-GABA _A R-associated pathology, disorder or disease (e.g., reducing or preventing cognitive dysfunction associated with the disorder or disease).

The term "cognitive dysfunction" or "cognitive dysfunction" refers to a deficit in cognitive function as defined in Diagnostic and Statistical Manual of Mental Disorders [ manual for diagnosis and statistics of mental disorders ] (DSM-5). Examples of cognitive dysfunction include deficiencies in performing one or more of function, learning, memory, perception, problem solving, language, or social cognition. Cognitive dysfunction may be associated with neurocognitive dysfunction with reduced cognitive ability (e.g., alzheimer's disease, huntington's disease, parkinson's disease, or dementia). Cognitive dysfunction may also be associated with neurological disorders such as Down syndrome, autism, or attention deficit/hyperactivity disorder (ADHD).

In the case of disease-related alpha 5-GABA _A In the context of R, the terms "associated" or "associated with" … … "," related "or" mediated "mean that the disease is caused (in whole or in part) or that the symptoms of the disease are caused (in whole or in part) by alpha 5-GABA _A Receptor or receptor activity or function. For example, with alpha 5-GABA _A The symptoms of a disease or disorder associated with R-pathway activity may be (in whole or in part) a disease or disorder associated with R-pathway activity mediated by alpha 5-GABA _A Symptoms caused by increased levels of R protein pathway activity. As used herein, a substance described as being associated with a disease, if it is a causative agent, may be a target for treating the disease. For example, with alpha 5-GABA _A Diseases associated with increased levels of R activity may be treated with compounds effective in reducing alpha 5-GABA _A R activity levels (e.g., compounds described herein).

An "effective amount" is an amount sufficient to achieve the intended purpose. For example, sufficient to effect its administration, treat a disease, reduce enzyme activity, increase enzyme activity, decrease receptor signaling, increase receptor signaling, decrease one or more symptoms of a disease or disorder, or provide a disease modifying effect (i.e., alter the underlying pathophysiology of a disease). An example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease or alter the progression of a disease, which may also be referred to as a "therapeutically effective amount". "alleviation" of one or more symptoms refers to a reduction in the severity or frequency of one or more symptoms, or elimination of one or more symptoms. A "prophylactically effective amount" of a drug is an amount of a drug that has an intended prophylactic effect (preventing or delaying the onset (or recurrence) of a lesion, disease, pathology, or disorder, or reducing the likelihood of the onset (or recurrence) of a lesion, disease, pathology, or disorder, or symptom thereof, when administered to a subject. Complete prevention does not necessarily occur by administration of one dose, but may only occur after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on The purpose of The treatment and will be determined by one skilled in The Art using known techniques (see, e.g., lieberman, pharmaceutical Dosage Forms [ pharmaceutical dosage form ] (volumes 1-3, 1992); lloyd, the Art, science and Technology of Pharmaceutical Compounding [ Art of drug compounding, science and technology ] (1999); pickar, dosage Calculations [ dose calculation ] (1999); and Remington: the Science and Practice of Pharmacy [ Lemington: pharmaceutical sciences and practices ], 20 th edition, 2003, gennaro editions, lippincott, williams & Wilkins).

The therapeutically effective amount of the compounds of the present invention can be estimated initially by cell culture assays. The target concentration will be the concentration of the active compound or compounds that is capable of achieving the therapeutic effects described herein (as measured using the methods described herein or methods known in the art).

The therapeutically effective amount for humans can also be determined from animal models using known methods. For example, a dose for humans may be formulated to achieve a concentration that has been found to be effective in animals. As described above, the dose in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dose up or down. It is well within the ability of the ordinarily skilled artisan to adjust dosages based on the methods described above and other methods to achieve maximum efficacy in humans.

The dosage may vary depending on the needs of the patient and the compound used. In the context of the present invention, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also depend on the presence, nature and extent of any adverse side effects. It is within the skill of the practitioner to determine the appropriate dosage for a particular situation. Generally, treatment is initiated at a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the best effect is achieved under the particular circumstances.

The dosage and interval may be adjusted individually to provide a level of administered compound that is effective for the particular clinical indication being treated, or in response to a biomarker or other relevant or alternative endpoint of the disease. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

A prophylactic or therapeutic treatment regimen is suitably one that does not cause significant toxicity but is still effective in treating clinical symptoms exhibited by a particular patient. The determination of the dosage regimen is generally based on an assessment of the active compound, taking into account a number of factors, such as the potency of the compound, the relative bioavailability, the weight of the patient, the presence and severity of adverse side effects, the preferred mode of administration and the toxicity profile of the selected agent.

The term "halo" or "halogen" refers to one of the halogens of group 17 of the periodic table of elements. The term refers in particular to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

Term C _m-n Refers to groups having m to n carbon atoms.

The term "C _1-6 Alkyl "means a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. "C _1-4 Alkyl "similarly refers to groups containing up to 4 carbon atoms. The alkylene group is a divalent alkyl group and may likewise be linear or branched and have two points of attachment to the rest of the molecule. Furthermore, the alkylene group may for example correspond to one of the alkyl groups listed in this paragraph. For example, C _1-6 The alkylene group may be-CH ₂ -、-CH ₂ CH ₂ -、-CH ₂ CH(CH ₃ )-、-CH ₂ CH ₂ CH ₂ -or-CH ₂ CH(CH ₃ )CH ₂ -. The alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Herein describeAnd (3) an optional substituent. For example, substituents of the alkyl or alkylene groups may be halogen (e.g., fluorine, chlorine, bromine and iodine), OH, C ₁ -C ₄ Alkoxy, -NR 'R "amino, wherein R' and R" are independently H or alkyl. Other substituents of the alkyl group may alternatively be used.

The term "C _1-6 Haloalkyl ", e.g." C _1-4 Haloalkyl "refers to a hydrocarbon chain substituted with at least one halogen atom (e.g., fluorine, chlorine, bromine, and iodine) independently selected at each occurrence. Halogen atoms may be present at any position on the hydrocarbon chain. For example, C _1-6 Haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1, 2-trichloroethyl, 2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1, 2-trifluoroethyl and 2, 2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. Haloalkyl groups can be, for example, -CX ₃ 、-CHX ₂ 、-CH ₂ CX _3、 -CH ₂ CHX ₂ or-CX (CH) ₃ )CH ₃ Wherein X is halogen (e.g., F, cl, br or I). Fluoroalkyl groups, i.e. hydrocarbon chains substituted with at least one fluorine atom (e.g. -CF ₃ 、-CHF ₂ 、-CH ₂ CF ₃ or-CH ₂ CHF ₂ )。

The term "C _2-6 Alkenyl "includes branched or straight hydrocarbon chains containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. One or more double bonds may be present as E or Z isomers. The double bond may be located at any possible position of the hydrocarbon chain. For example, "C _2-6 Alkenyl "may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. Alkenylene groups are divalent alkenyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, the alkenylene group may for example correspond to one of those alkenyl groups listed in this paragraph. For example, alkenylene may be-CH=CH-, -CH ₂ CH＝CH-、-CH(CH ₃ ) ch=ch-or-CH ₂ Ch=ch-. Alkenyl groupsAnd the alkenylene group may be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, substituents may be those described above as substituents for the alkyl group.

The term "C _2-6 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 located at any possible position of the hydrocarbon chain. For example, "C _2-6 Alkynyl "may be ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynylene group is a divalent alkynyl group and may likewise be linear or branched and have two points of attachment to the rest of the molecule. Furthermore, an alkynylene group may for example correspond to one of those alkynyl groups listed in this paragraph. For example, the alkynylene group may be-C.ident.C-, -CH ₂ C≡C-、-CH ₂ C≡CCH ₂ -、-CH(CH ₃ ) CH≡C-or-CH ₂ C＝CCH ₃ . Alkynyl and alkynylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, substituents may be those described above as substituents for the alkyl group.

The term "C _3-6 Cycloalkyl "includes saturated hydrocarbon ring systems containing 3, 4, 5 or 6 carbon atoms. For example, "C ₃ -C ₆ Cycloalkyl "can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.1.1]Hexane or bicyclo [1.1.1]Pentane. Suitably, "C ₃ -C ₆ Cycloalkyl "may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "heterocyclyl", "heterocyclic" or "heterocycle" includes non-aromatic saturated or partially saturated monocyclic or fused, bridged or spiro bicyclic heterocyclic systems. The monocyclic heterocycle may contain about 3 to 12 (suitably 3 to 7) ring atoms with 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles may contain 7 to 12 membered atoms in the ring. The one or more bicyclic heterocycles may be fused, spiro, or bridged ring systems. The heterocyclyl group may be 3-12 membered, for example 3-to 9-membered (e.g. 3-to 7-membered) non-aromatic monocyclic or bicyclic saturated or partially Saturated groups comprising 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 applies in particular to monocyclic rings having 5 to 7 members. The double bond is typically located between two carbon atoms, but may also be located between a carbon atom and a nitrogen atom. The bicyclic ring system may be spiro-fused, i.e. the rings are connected to each other by a single carbon atom; ortho-condensed, i.e. the rings are linked to each other by two adjacent carbon and/or nitrogen atoms; or they may share bridgeheads, i.e. the rings are connected to each other by 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. Heterocyclic rings 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]Heptyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1, 3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiopyran. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrothiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, dioxanyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, SO or SO-containing ₂ Sulfur oxide heterocycles of the radicals. Examples include sulphoxide and sulphone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiophene 1, 1-dioxide and thiomorpholinyl 1, 1-dioxide. Suitable values for the heterocyclic groups with 1 or 2 oxo (=o) groups are, for example, 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2, 5-dioxopyrrolidinyl, 2, 5-dioxoimidazolidinyl or 2, 6-dioxopiperidinyl. Specific heterocyclyl groups are saturated monocyclic 3-to 7-membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, e.g. azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl 1,1-Dioxide, thiomorpholinyl 1, 1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocyclic ring may be attached to another group through any suitable atom, for example through a carbon or nitrogen atom. For example, the term "piperidino" or "morpholino" refers to piperidin-1-yl or morpholin-4-yl rings that are linked through a ring nitrogen.

The term "bridged ring system" includes ring systems in which two rings share more than two atoms, see, e.g., advanced Organic Chemistry [ advanced organic chemistry ], the authors Jerry March, 4 th edition, wiley Interscience [ wili international scientific press ], pages 131-133, 1992. Suitably, a bridge is formed between two non-adjacent carbon or nitrogen atoms in the ring system. The bridge connecting the bridgehead atoms may be a bond or contain one or more atoms. Examples of bridged Lian Zahuan-based 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.

The term "spirobicyclic ring system" includes ring systems in which two ring systems share a common spirocarbon atom, i.e., a heterocycle is attached to another carbocyclic or heterocyclic ring through a single common spirocarbon atom. Examples of spiro 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.

"heterocyclyl-C _m-n Alkyl "includes covalent attachment to C _m-n Heterocyclyl groups of alkylene groups, both defined herein; and wherein heterocyclyl-C _m-n The alkyl group is attached to the remainder of the molecule through a carbon atom in the alkylene group. The radical "aryl-C _m-n Alkyl "," heteroaryl-C _m-n Alkyl "and" cycloalkyl-C _m-n Alkyl "is defined in the same manner.

"substituted with-NRR-C _m-n Alkyl "and" C substituted by-OR _m-n Alkyl "similarly refers to covalent attachment to C _m-n an-NRR "OR-OR" group of an alkylene group, and wherein the group is attached to the remainder of the molecule through a carbon atom in the alkylene group.

The term "aromatic" when applied to an entire substituent includes a single or multiple ring system having 4n+2 electrons in the conjugated pi system within the ring, or a ring system in which all atoms contributing to the conjugated pi system are in the same plane.

The term "aryl" includes aromatic hydrocarbon ring systems. The ring system has 4n+2 electrons in the conjugated pi system within the ring (where all atoms contributing to the conjugated pi system are in the same plane). For example, "aryl" may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

The term "heteroaryl" includes aromatic mono-or bi-cyclic rings incorporating one or more (e.g. 1-4, especially 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulphur. The ring or ring system has 4n+2 electrons in the conjugated pi system (where all atoms contributing to the conjugated pi system are in the same plane).

Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, more typically five to ten ring members. Heteroaryl groups may be, for example, 5-or 6-membered monocyclic or 9-or 10-membered bicyclic, for example, a bicyclic structure formed by a fused five-membered ring and a six-membered ring or two fused six-membered rings. Bicyclic heteroaryl groups may be ortho-fused, i.e. wherein the rings are connected to each other by two adjacent carbon and/or nitrogen atoms. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, a heteroaryl ring will contain up to 4, e.g., up to 3 heteroatoms, more typically up to 2, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) will be less than five.

Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazolyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurepentayl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno [2,3-b ] furanyl, 2H-furo [3,2-b ] -pyranyl, 1H-pyrazolo [4,3-d ] -oxazolyl, 4H-imidazo [4,5-d ] thiazolyl, imidazo [2,3-d ] pyridazinyl, and imidazo [1,2-b ] thiazolyl. Examples of heteroaryl groups containing at least one nitrogen at a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazene, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurol, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnamyl and pteridinyl.

"heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems wherein at least one ring is aromatic and one or more 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. The partially aromatic heteroaryl bicyclic ring system may be ortho-fused, i.e., the rings are connected to each other by 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, dihydrobenzothienyl, dihydrobenzofuranyl, 2, 3-dihydro-benzo [1,4] dioxinyl, benzo [1,3] dioxolyl, 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.

When ring B is heteroaryl and the heteroaryl ring system includes aromatic rings and non-aromatic, saturated or partially saturated rings, ring B is bonded to a group of the formula:

the bond is through a ring atom in the aromatic ring of ring B. For example, when ring B is a bicyclic heteroaryl group of the formula:

Ring B is bonded to the remainder of the compound of formula (I) by a carbon atom in the pyridine ring (i.e. one of the ring carbon atoms marked below)

Examples of five membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furoxanyl, oxazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

Examples of six membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

Specific examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenine, guanine), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

Specific examples of bicyclic heteroaryl groups containing two fused six membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromene, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

The term "oxo" or "=o" as used herein refers to an oxygen double bonded to a carbon atom.

The term "optionally substituted" includes both substituted and unsubstituted groups, structures or molecules.

When an optional substituent is selected from "one or more" groups, it is to be understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more specified groups, which may be the same or different. For example, "one or more optional substituents" may refer to 1 or 2 or 3 substituents (e.g., 1 substituent or 2 substituents).

When a moiety is substituted, it may be substituted at any point on the moiety where it is chemically possible and meets the valence requirements. The moiety may be substituted with one or more substituents, for example, 1, 2, 3 or 4 substituents; optionally, there are 1 or 2 substituents on the group. When two or more substituents are present, the substituents may be the same or different.

Substituents are present only at chemically possible positions and the person skilled in the art will be able to decide (experimentally or theoretically) which substitutions are chemically possible and which are not.

Ortho, meta and para substitution are terms well known in the art. Undoubtedly, "ortho" substitution is a substitution pattern in which adjacent carbons have substituents, whether simple groups, such as fluoro groups in the examples below, or other portions of the molecule, such as inThe key at the end shows:

"meta" substitution is a substitution pattern in which two substituents are on a carbon, one carbon being separated from the other, i.e., having a single carbon atom between the substituted carbons. In other words, there is a substituent on a second atom that is remote from the atom having another substituent. For example, the following groups are meta-substituted:

/>

"para" substitution is a substitution pattern in which two substituents are located on carbons that are two carbons apart 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 that is remote from the atom having another substituent. For example, the following groups are substituted in para-position:

references to-NRR 'groups forming 4-to 6-membered heterocyclyl means that R and R' together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclyl group. For example, -NRR' e.g. -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 The group may form:

similarly, the-NRR 'group within the substituent may form a carbonyl-linked 4-to 6-membered heterocyclyl, e.g., -C (O) NRR' group may form:

-NRR 'groups within the substituents, e.g. -OC (O) NRR', -SO ₂ NRR 'or-NRC (O) NRR' may similarly form a 4-to 6-membered heterocyclyl within such substituents.

To be used forOr the ending bond indicates that the bond is attached to another atom not shown in the structure. A bond that terminates inside the ring structure and does not terminate at an atom of the ring structure means that the bond can be attached to any atom in the ring structure as valency permits.

Throughout the description and claims of this specification the words "comprise" and "contain" and variations thereof mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, features, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (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, unless at least some of such features and/or steps in such combinations are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The reader is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

The various functional groups and substituents constituting the compounds of the invention are generally selected so that the molecular weight of the compounds does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, such as less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 585, for example less than 575.

Suitable or preferred features of any of the compounds of the invention may also be suitable features of any other aspect.

The invention encompasses pharmaceutically acceptable salts of the compounds of the invention. These may include acid addition salts and base salts of the compounds. These may be acid addition salts and base salts of the compounds.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, dextromethorsulfonate, citrate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyparate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, napthalamate, 1, 5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, sucrose, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts. Semi-salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a review of suitable salts, see "Handbook of Pharmaceutical Salts:properties, selection and Use [ handbook of pharmaceutically acceptable salts: properties, choices and uses ] "(Wiley-VCH [ John Wei Lignia publication Co., ltd. ], weinheim, germany [ Wei Yinhai mu ], 2002).

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) Ring opening of suitable cyclic precursors, such as lactones or lactams, by removing acid or base labile protecting groups from suitable precursors of the compounds of the present invention, or by using the desired acid or base; or alternatively

(iii) One salt of the compound of the invention is converted to another salt by reaction with an appropriate acid or base or by passage through an appropriate ion exchange column.

These processes are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

Compounds that have the same molecular formula but differ in the nature or order of their bonding of atoms or their arrangement of atoms in space are referred to as "isomers". Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and those that are not overlapping mirror images of each other are referred to as "enantiomers". For example, when a compound has an asymmetric center, it is bonded to four different groups, and a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and by the R-and S-order rules of Cahn and Prelog, or by the way the molecules rotate the plane of polarized light and are designated as either dextrorotatory or levorotatory (i.e., designated as (+) or (-) -isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". When the compounds of the present invention have two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a mixture of diastereomers or a single diastereomer. The compounds of the invention may exist as single stereoisomers or may be mixtures of stereoisomers, such as racemic mixtures and other enantiomeric mixtures as well as 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 still contain other diastereomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have 100% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), but may have about at least 85% e.e. or d.e., for example at least 90%, at least 95% or at least 99%.

The compounds of the invention may have one or more asymmetric centers; thus, such compounds may be produced as the (R) or (S) stereoisomers alone or as mixtures thereof. Unless otherwise indicated, descriptions or designations of particular compounds in the specification and claims are intended to include individual enantiomers and mixtures, racemates or other forms thereof. Methods for determining stereochemistry and isolating stereoisomers are well known in the art (see "Advanced Organic Chemistry [ advanced organic chemistry ]", 4 th edition j. March, john Wiley and Sons [ john wili parent-child publishing company ], new york, chapter 4 of 2001), e.g., by synthesis from optically active starting materials or by resolution in racemic form. Some compounds of the invention may have geometric isomerism centers (E and Z isomers). It is to be understood that the present invention encompasses all optical, diastereomers and geometric isomers, as well as mixtures thereof

The Z/E (e.g., cis/trans) isomer may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for preparing/separating individual enantiomers as necessary include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). Thus, the chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by: using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of: hydrocarbons, typically heptane or hexane, contain 0-50% isopropyl alcohol, typically 2-20% by volume, and for particular examples 0-5% alkylamine, e.g. 0.1% diethylamine, by volume. Concentrating the eluate to obtain an enriched mixture.

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol, or in the case of compounds of the present invention containing an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization, and one or both diastereomers may be converted to the corresponding pure enantiomers by means well known to those skilled in the art.

When any racemate is crystallized, two different types of crystals may be formed. The first type is the racemic compound (true racemate) mentioned above, in which crystals are produced in a homogeneous form containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or aggregate in which two forms of crystals are produced in equimolar amounts, each form comprising a single enantiomer.

Although the two crystal forms present in the racemic mixture have the same physical properties, they may have different physical properties compared to the actual racemate. The racemic mixture can be separated by conventional techniques known to those skilled in the art-see, for example, "Stereochemistry of Organic Compounds [ stereochemistry of organic compounds ]" (Wiley [ Wili company ], 1994) of E.L.Eliel and S.H.Wilen.

The compounds and salts described in this specification 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), a, ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ¹³ N、 ¹⁵ N、 ¹⁸ F、 ³⁶ Cl、 ¹²³ I、 ²⁵ I、 ³² P、 ³⁵ S, etc. The radionuclide used will depend on the specific application of the radiolabeled derivative. For example, for in vitro competition assays, ³ h or ¹⁴ C is generally useful. For radiological imaging applications, ¹¹ c or ¹⁸ F is generally useful. In some embodiments, the radionuclide is ³ H. In some embodiments, the radionuclide is ¹⁴ C. In some embodiments, the radionuclide is ¹¹ C. And in some embodiments the radionuclide is ¹⁸ F。

Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labeled reagent in place of the unlabeled reagent previously used.

Selective substitution of deuterium in a compound for hydrogen 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 of the compound in vivo or decrease clearance. Deuteration can also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It is to be understood that the present invention encompasses deuterated derivatives of the compounds of formula (I). As used herein, the term deuterated derivative refers to a compound of the invention wherein at least one hydrogen atom is replaced by deuterium at a particular position. For example, C _1-4 One or more hydrogen atoms in the alkyl group may beSubstitution by deuterium to form deuterated C _1-4 -an alkyl group. For example, if R ² Methyl, the invention also covers-CD ₃ 、-CHD ₂ and-CH ₂ D。

Certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the present invention encompasses all such solvated forms.

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

The compounds of the present invention may exist in a variety of different tautomeric forms, and reference to the compounds of the present invention includes all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all other forms are still included within the compounds of the invention. Examples of tautomeric forms include ketone forms, enol forms, and enolate forms, such as the following tautomeric pairs: ketone/enol (shown below), imine/enamine, amide/iminoalcohol, amidine/amidine, nitroso/oxime, thioketone/enamine, and nitro/acyl nitro.

For example

The in vivo effects of the compounds of the invention may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compounds of the invention.

It will also be appreciated that suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) also form an aspect of the invention. Thus, the compounds of the present invention include prodrug forms of the compounds, and the compounds of the present invention may be administered in the form of prodrugs (i.e., compounds that decompose to release the compounds of the present invention in the human or animal body). Prodrugs can be used to alter the physical and/or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when compounds of the invention contain suitable groups or substituents that can attach property modifying groups. Examples of prodrugs include in vivo cleavable ester derivatives that may be formed at the carboxy or hydroxy groups of the compounds of the invention, and in vivo cleavable amide derivatives that may be formed at the carboxy or amino groups of the compounds of the invention.

Thus, the present invention includes those compounds of the invention as defined herein obtained by organic synthesis and obtained in the human or animal body by cleavage of a prodrug thereof. Thus, the present invention includes those compounds of formula (I) produced by organic synthetic methods, and also includes such compounds produced in the human or animal body via metabolism of precursor compounds, i.e., the compounds of formula (I) may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of the compounds of the invention are those which are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity, based on sound medical judgment.

Various forms of prodrugs have been described, for example in the following documents: -

a) Methods in Enzymology [ methods of enzymology ], vol.42, pages 309-396, K.Widder et al (Academic Press [ Academic Press ], 1985);

b) Design of Pro-drugs [ prodrug Design ], H.Bundgaard editions, (Elsevier [ Esculer Press ], 1985);

c) A Textbook of Drug Design and Development [ textbook of drug design and development ], krogsgaard-Larsen and H.Bundgaard editions, chapter 5, "Design and Application of Pro-drugs [ prodrug design and application ]", author H.Bundgaard pages 113-191 (1991);

d) Bundegaard, advanced Drug Delivery Reviews [ advanced drug delivery reviews ],8,1-38 (1992);

e) Bundgaard, et al, journal of Pharmaceutical Sciences [ journal of pharmaceutical science ],77,285 (1988);

f) N. Kakeya, et al, chem.Pharm.Bull. [ chemical and pharmaceutical bulletins ],32,692 (1984);

g) Higuchi and V.stella, "Pro-Drugs as Novel Delivery Systems [ prodrug as novel delivery system ]", volume 14, A.C.S. symposium Series [ A.C.S. seminar Series ]. And

h) Roche (eds.), "Bioreversible Carriers in Drug Design [ bioreversible vehicle in drug design ]", pergamon Press [ Pegamon Press ],1987.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxyl group are, for example, in vivo cleavable esters thereof. An in vivo cleavable ester of a compound of the invention containing a carboxyl group is a pharmaceutically acceptable ester that is cleaved, e.g., in a human or animal body, to yield the parent acid. Pharmaceutically acceptable esters of suitable carboxyl groups include C _1-6 Alkyl esters, e.g. methyl, ethyl and tert-butyl, C _1-6 Alkoxymethyl esters, e.g. methoxymethyl esters, C _1-6 Alkanoyloxymethyl esters, e.g. pivaloyloxymethyl ester, 3-phthalate, C _3-8 cycloalkyl-carbonyloxy-C _1-6 Alkyl esters, such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl, 2-oxo-1, 3-dioxolylmethyl esters, such as 5-methyl-2-oxo-1, 3-dioxol-4-ylmethyl ester and C _1-6 alkoxycarbonyloxy-C _1-6 Alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl.

Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having a hydroxyl group are, for example, esters or ethers thereof which are cleavable in vivo. The in vivo cleavable ester or ether of the compound of the invention containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether which cleaves in the human or animal body to yield the parent hydroxyl compound. Suitable pharmaceutically acceptable ester forming groups for the hydroxyl groups include inorganic esters, such as phosphate esters (including phosphoramidate cyclic esters). Other suitable pharmaceutically acceptable ester forming groups of the hydroxyl group include C _1-10 Alkanoyl groups, e.g. acetyl, benzoyl, phenylacetyl and substituted benzoylRadicals and phenylacetyl radicals, C _1-10 Alkoxycarbonyl groups, e.g. ethoxycarbonyl, N- (C) _1-6 Alkyl group ₂ Carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C) _1-4 Alkyl) piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for the hydroxyl groups include α -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having a carboxyl group are, for example, amides which are cleavable in vivo, for example amides with amines (e.g. ammonia), C _1-4 Alkylamines, e.g. methylamine, (C) _1-4 Alkyl group ₂ Amines, e.g. dimethylamine, N-ethyl-N-methylamine or diethylamine, C _1-4 alkoxy-C _2-4 Alkylamines, e.g. 2-methoxyethylamine, phenyl-C _1-4 Alkylamines, such as benzylamine, and amino acids, such as glycine or esters thereof.

Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having an amino group are, for example, amide or carbamate derivatives which are cleavable in vivo. Suitable pharmaceutically acceptable amides from amino groups include, for example, those derived from C _1-10 Alkanoyl groups (e.g., acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl). Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4- (C) _1-4 Alkyl) piperazin-1-ylmethyl. Suitable pharmaceutically acceptable carbamates from amino groups include, for example, acyloxyalkoxycarbonyl and benzyloxycarbonyl.

Compounds of formula (I)

The following paragraphs apply to the compounds of the invention.

In certain embodiments, the compound of formula (I) is a compound of formula (II):

in certain embodiments, the compound of formula (I) is a compound of formula (III):

in certain embodiments, the compound of formula (I) is a compound of formula (IV):

in certain embodiments, the compound of formula (I) is a compound of formula (V):

wherein X is ⁴ Is CH or N; and is also provided with

R ¹⁰¹ Selected from H and halo.

In certain embodiments, the compound of formula (I) is a compound of formula (VI):

In certain embodiments, the compound of formula (I) is a compound of formula (VII):

in certain embodiments, the compound of formula (I) is a compound of formula (VIII):

in certain embodiments, the compound of formula (I) is a compound of formula (IX):

in certain embodiments, the compound of formula (I) is a compound of formula (X):

wherein X is ⁴ Is CH or N; and is also provided with

R ¹⁰¹ Selected from H and halo.

In certain embodiments, the compound of formula (I) is a compound of formula (XI):

in certain embodiments, the compound of formula (I) is a compound of formula (XII):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XIII):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XIV):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XV):

Wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XVI):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl);

X ⁴ is CH or N; and is also provided with

R ¹⁰¹ Selected from H and halo.

In certain embodiments, the compound of formula (I) is a compound of formula (XVII):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XVIII):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XIX):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XX):

/>

R ⁴¹ is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXI):

wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl);

wherein X is ⁴ Is CH or N; and

R ¹⁰¹ selected from H and halo.

In certain embodiments, the compound of formula (I) is a compound of formula (XXII):

Wherein R is ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXIII):

wherein p is 0, 1, 2 or 3.

In certain embodiments, the compound of formula (I) is a compound of formula (XXIV):

wherein p is 0, 1, 2 or 3; and is also provided with

R ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXV):

/>

wherein p is 0, 1, 2 or 3; and is also provided with

R ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXVI):

wherein p is 0, 1, 2 or 3; and is also provided with

X ⁵ Is CH or N.

In certain embodiments, the compound of formula (I) is a compound of formula (XXVII):

wherein p is 0, 1, 2 or 3;

X ⁵ is CH or N; and is also provided with

R ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXVIII):

wherein p is 0, 1, 2 or 3;

X ⁵ is CH or N; and is also provided with

R ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXIX):

Wherein X is ⁵ Is CH or N.

In certain embodiments, the compound of formula (I) is a compound of formula (XXX):

wherein X is ⁵ Is CH or N; and is also provided with

R ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compound of formula (I) is a compound of formula (XXXI):

wherein X is ⁵ Is CH or N; and is also provided with

R ⁴¹ Is C _1-3 Alkyl (e.g. R ⁴¹ Methyl).

In certain embodiments, the compounds of the present invention include, for example, compounds of formulas (I) through (XXXI) or pharmaceutically acceptable salts thereof, wherein, unless otherwise specified, ring A, ring B, R ¹ 、R ² 、R ³ 、R ¹⁰ 、X ₁ 、X ₂ 、X ₃ Has any of the meanings defined in any of the following statements in paragraphs (1) to (203) above or below. These statements are independent and interchangeable. In other words, any feature described below by any one Chen Shuzhong may be combined (where chemically permitted) with features described in one or more other statements below. In particular, when compounds are exemplified or described in this specification, any two or more of the following statements describing the characteristics of the compounds expressed at any general level may be combined to represent subject matter intended to form part of the disclosure of the invention in this specification:

1. Ring a is A1 of the structure:wherein->Represents the attachment point defined in formula (I).

2. Ring A is formed byA2 of the following structure:wherein->Represents the attachment point defined in formula (I).

3. Ring a is A3 and has the following structure:wherein->Represents the attachment point defined in formula (I).

4.R ¹ Is phenyl.

5.R ¹ Is phenyl substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 . For example, R ¹ May be substituted with one OR more substituents selected from halo and-OR ^a1 Phenyl substituted by substituents of (2), wherein R ^a1 May be C _1-4 A haloalkyl group. Thus, R is ¹ May be a phenyl group substituted by a halo group. For example, R ¹ May be phenyl substituted by-F or-Cl. R is R ¹ May be a quilt-OR ^a1 A substituted phenyl group. R is R ¹ May be a quilt-OC _1-4 Haloalkyl-substituted phenyl. Thus, R is ¹ May be a quilt-OCF ₃ A substituted phenyl group.

6.R ¹ Is 4-fluorophenyl.

7.R ¹ Is a 5-or 6-membered heteroaryl group containing at least one ring nitrogen atom, wherein the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

8.R ¹ Is a 5 membered heteroaryl group containing at least one ring nitrogen, wherein the heteroaryl group is optionally selected from one ofOr multiple substituents: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

9.R ¹ Is a 6 membered heteroaryl group containing at least one ring nitrogen, wherein the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

10.R ¹ Is a heteroaryl selected from the group consisting of: isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

11.R ¹ Is a heteroaryl selected from the group consisting of: isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

12.R ¹ Is a heteroaryl selected from the group consisting of: a pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl group, wherein the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

13.R ¹ Is a heteroaryl selected from pyridinyl, wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

14.R ¹ Is a heteroaryl group as defined in any of numbered paragraphs 7 to 13, wherein the heteroaryl group is unsubstituted。

15.R ¹ Is a heteroaryl group as defined in any of numbered paragraphs 7 to 13, wherein the heteroaryl group is substituted with one or two substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

16.R ¹ Is a heteroaryl group as defined in any of numbered paragraphs 7 to 13, wherein the heteroaryl group is substituted with one or two substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl and-OR ^a1 。

17.R ¹ Is a heteroaryl group as defined in any of numbered paragraphs 7 to 13, wherein the heteroaryl group is substituted with one or two substituents selected from the group consisting of: and (3) halogenating.

18.R ¹ Is a heteroaryl group as defined in any of numbered paragraphs 7 to 13, wherein the heteroaryl group is substituted with one fluoro substituent.

19.R ¹ Selected from:

wherein:

X ⁴ is CH or N;

R ¹⁰¹ is H or halo; and is also provided with

R ¹⁰² is-OC _1-4 A haloalkyl group.

20.R ¹ The structure is as follows:

wherein R is ¹⁰¹ Is H or halo. Thus, R is ¹⁰¹ May be F or Cl.

21.R ¹ Selected from:

/>

wherein->Indicating the point of attachment to ring a.

22. Ring A is A1 and R ¹ Selected from the group consisting of:

wherein->Indicating the point of attachment to ring a.

23. Ring A is A1 and R ¹ Selected from the group consisting of: wherein->Indicating the point of attachment to ring a.

24. Ring A is A2 and R ¹ Is unsubstituted phenyl.

25. Ring A is A3 and R ¹ Selected from the group consisting of:

wherein the method comprises the steps ofIndicating the point of attachment to ring a.

26.R ² Selected from: halo, C _1-4 Alkyl groupC _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 Wherein C _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a3 、-SR ^a3 and-NR ^a3 R ^b3 。

27.R ² Selected from: H. halo, C _1-4 Alkyl and C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 。

28.R ² Selected from: halo, C _1-4 Alkyl and C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 。

29.R ² Is H.

30.R ² Is C _1-4 An alkyl group.

31.R ² Is C _1-3 Alkyl group

32.R ² Is methyl.

33.R ² Methyl and ring A is A1.

34.R ² Methyl and ring a is A2.

35.R ² Methyl and ring a is A3.

36.R ² Is methyl and R ¹ As defined in any of numbered paragraphs 4 through 25.

37. Ring a is selected from the group consisting of: wherein->The expression is shown as [ (]I) An attachment point as defined in (a).

38. Ring a is selected from:

39.R ³ selected from: c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-, wherein said C _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 Any of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 。

40.R ³ Selected from: c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-, wherein said C _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 Any of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 and-SR ^a4 。

41.R ³ Selected from: c (C) _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl-, -OR ⁴ 、-SR ⁵ 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-, wherein said C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 Any of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of: halogenated radical,-OR ^a4 and-SR ^a4 。

42.R ³ Selected from: 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms, 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-, and-OR ⁴ 。

43.R ³ Selected from: 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms, 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-.

44.R ³ Is a 4-to 7-membered heterocyclic group containing 1 or 2 epoxy atoms. Preferably, R ³ May be a 4-to 7-membered heterocyclic group containing 1 epoxy atom. Thus, R is ³ May be selected from oxetanyl, tetrahydrofuranyl and pyranyl.

45.R ³ Is a 4-to 7-membered heterocyclyl-C containing 1 or 2 epoxide atoms _1-3 An alkyl group. Preferably, R ³ Can be a 4-to 7-membered heterocyclyl-C containing 1 epoxide atom _1-3 An alkyl group. Thus, R is ³ Can be selected from oxetanyl-C _1-3 Alkyl-, tetrahydrofuranyl-C _1-3 Alkyl-and pyranyl-C _1-3 Alkyl-.

46.R ³ Selected from: c (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 Wherein said C _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 Any of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 。

47.R ³ Selected from: -OR ⁴ and-NR ⁵ R ⁶ 。

48.R ³ Selected from: -OR ⁴ and-NR ⁵ R ⁶ Wherein R is ⁴ Selected from: is-NR ^a4 R ^b4 Substituted C _3-6 Cycloalkyl, C _1-4 Alkyl and C _2-4 An alkyl group; r is R ^a4 And R is ^b4 Independently selected from: h and C _1-4 An alkyl group; and R is ⁵ And R is ⁶ Independently selected from: h and C _1-4 An alkyl group.

49.R ³ is-NR ⁵ R ⁶ 。

50.R ³ is-NH ₂ 。

51.R ³ May not be-NR ⁵ R ⁶ . Thus, R is ³ May not be-NH ₂ 。

52.R ³ May not be C _1-4 An alkyl group. R is R ³ May not be C _1-4 Alkyl or-NR ⁵ R ⁶ 。

53.R ³ is-OR ⁴ 。

54.R ³ is-OR ⁴ Wherein R is ⁴ Selected from 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 1 or 2 epoxy atoms, 4-to 7-membered heterocyclyl-C containing 1 or 2 epoxy atoms _1-3 Alkyl-, wherein R ⁴ The C in (a) _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 Alkyl-optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 。

55.R ³ is-OR ⁴ Wherein R is ⁴ Is a 4-to 7-membered heterocyclic group containing 1 or 2 epoxy atoms, or a 4-to 7-membered heterocyclic group containing 1 or 2 epoxy atoms-C _1-3 Alkyl-.

56.R ³ is-OR ⁴ Wherein R is ⁴ Is a 4-to 6-membered heterocyclic group containing 1 or 2 epoxy atoms. Preferably, R ³ is-OR ⁴ Wherein R is ⁴ Is a 4-to 6-membered heterocyclic group containing 1 epoxy atom. Thus, R is ³ May be-OR ⁴ Wherein R is ⁴ Selected from the group consisting of oxetanyl, tetrahydrofuranyl and pyranyl.

57.R ³ is-OR ⁴ Wherein R is ⁴ Is a compound containing 4 to 6 members containing 1 or 2 epoxy atomsMembered heterocyclyl-C _1-3 Alkyl-. R is R ³ May be-OR ⁴ Wherein R is ⁴ Is a 4-to 6-membered heterocyclyl-C containing 1 epoxy atom _1-3 Alkyl-. Thus, R is ³ May be-OR ⁴ Wherein R is ⁴ Selected from oxetanyl-C _1-3 Alkyl-, tetrahydrofuranyl-C _1-3 Alkyl-and pyranyl-C _1-3 Alkyl-.

58.R ³ The method comprises the following steps:wherein->Represents the point of attachment to the remainder of the compound of formula (I).

59.R ³ is-OR ⁴ Wherein R is ⁴ Selected from C _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl and C _3-6 cycloalkyl-C _1-3 Alkyl-, wherein R ⁴ The C in (a) _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 Alkyl-optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 。

60.R ³ is-OR ⁴ Wherein R is ⁴ Selected from: c (C) _1-4 Alkyl, C _1-4 Haloalkyl and C _3-6 Cycloalkyl groups.

61.R ³ is-OR ⁴ Wherein R is ⁴ Selected from: c (C) _1-4 Alkyl and C _1-4 A haloalkyl group.

62.R ³ is-OR ⁴ Wherein R is ⁴ Is C _1-4 An alkyl group.

63.R ³ is-OR ⁴ Wherein R is ⁴ Is C _2-4 Alkyl substituted with one or more substituents selected from the group consisting of: -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 。

64.R ³ is-OR ⁴ Wherein R is ⁴ Is C _2-4 Alkyl, by-OR ^a4 Substitution, wherein R ^a4 Selected from H and C _1-4 An alkyl group. R is R ⁴ May be C _2-4 Alkyl, by-OR ^a4 Substitution, wherein R ^a4 Is H. R is R ³ Can be-O (CH) ₂ ) ₂ OH。R ⁴ May be C _2-4 Alkyl, by-OR ^a4 Substitution, wherein R ^a4 Is C _1-4 An alkyl group. Thus, R is ³ Can be-O (CH) ₂ ) ₂ OCH ₃ 。

65.R ³ is-OR ⁴ Wherein R is ⁴ Is quilt-NR ^a4 R ^b4 Substituted C _2-4 Alkyl, wherein R is ^a4 And R is ^b4 Independently selected from H and C _1-4 An alkyl group. R is R ⁴ May be C _2-4 Alkyl, covered by-NR ^a4 R ^b4 Substitution, wherein R ^a4 Is H, and R ^b4 Is C _1-4 An alkyl group. Thus, R is ³ Can be-O (CH) ₂ ) ₂ NHCH ₃ 。

66.R ³ is-OR ⁴ Wherein R is ⁴ Is C _3-6 Cycloalkyl groups.

67.R ³ Selected from: cyclopropyloxy, cyclobutoxy and cyclopentyloxy.

68.R ³ Is a cyclobutoxy group.

69.R ³ Selected from: -OC _1-3 Alkyl and-OC _3-4 Cycloalkyl groups.

70.R ³ Selected from: methoxy and-OCH (CH) ₃ ) ₂ 。

71.R ³ Selected from methoxy and-O-cyclobutyl.

72.R ³ Is methoxy.

73.R ³ is-OCH (CH) ₃ ) ₂ 。

74.R ³ is-O-cyclobutyl.

75.R ³ is-OH.

76.R ³ is-NR ⁵ R ⁶ 。R ⁵ And R is ⁶ Can be independently selected from H and C _1-4 An alkyl group. R is R ⁵ May be H and R ⁶ May beC _1-4 An alkyl group. R is R ⁵ May be H and R ⁶ Is methyl. R is R ⁵ And R is ⁶ May be C _1-4 An alkyl group. R is R ⁵ May be methyl and R ⁶ May be methyl.

77.R ³ Selected from: -OR ⁴ and-NR ⁵ R ⁶ ，

Wherein R is ⁴ Selected from: is-NR ^a4 R ^b4 Substituted C _3-6 Cycloalkyl, C _1-4 Alkyl and C _2-4 An alkyl group, a hydroxyl group,

R ^a4 and R is ^b4 Independently selected from H and C _1-4 An alkyl group; and is also provided with

R ⁵ And R is ⁶ Independently selected from H and C _1-4 An alkyl group.

78.R ³ The method comprises the following steps: -OR ⁴ ，

Wherein R is ⁴ Selected from: optionally by-OR ^a4 Substituted C _3-6 Cycloalkyl, C _1-4 Alkyl and C _2-4 An alkyl group. R is R ³ May be-OR ⁴ And R is ⁴ Selected from: c (C) _3-6 Cycloalkyl, C _1-4 An alkyl group.

79.R ³ Selected from: methoxy group, Wherein->Represents the point of attachment to the remainder of the compound of formula (I).

80.R ³ Selected from: methoxy group, Wherein->Represents the point of attachment to the remainder of the compound of formula (I).

81.R ³ Selected from: methoxy group, Wherein->Represents the point of attachment to the remainder of the compound of formula (I). R is R ³ May be selected from: methoxy group,/- >

82.X ¹ Is N.

83.X ¹ Is CR (CR) ⁷ 。

84.X ¹ Is CH.

85.X ¹ Is CR (CR) ⁷ Wherein R is ⁷ Is C _1-4 Alkyl optionally substituted with one or more substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 。

86.X ₁ Is CR (CR) ⁷ Wherein R is ⁷ Is C _1-3 Alkyl, covered by-NR ^a5 R ^b5 And (3) substitution.

87.X ₁ Is CR (CR) ⁷ Wherein R is ⁷ Is C _1-3 Alkyl, covered by-NR ^a5 R ^b5 Substitution, wherein R ^a5 And R is ^b5 Selected from: h and C _1-3 An alkyl group.

88.X ¹ Is CR (CR) ⁷ Wherein R is ⁷ is-CH ₂ N(CH ₃ ) ₂ 。

89.X ² Is N.

90.X ² Is CR (CR) ⁷ 。

91.X ² Is CH.

92.X ³ Is N.

93.X ³ Is CR (CR) ⁷ 。

94.X ³ Is CH.

95.X ³ Is N, and X ¹ And X ² Is CR (CR) ⁷ 。

96.X ³ Is N, X ¹ Is CR (CR) ⁷ And X is ² Is CH.

97.X ³ Is N, X ¹ Is CH and X ² Is CR (CR) ⁷ 。

98.X ³ Is N, and X ¹ And X ² Is CH.

99.X ² And X ³ Is N and X ¹ Is CR (CR) ⁷ 。

100.X ² And X ³ Is N, and X ¹ Is CR (CR) ⁷ Wherein R is ⁷ is-CH ₂ N(CH ₃ ) ₂ 。

101.X ² And X ³ Is N, and X ¹ Is CH.

102.X ¹ And X ² Is N, and X ³ Is CR (CR) ⁷ 。

103.X ¹ And X ² Is N, and X ³ Is CH.

104.X ¹ Is N, and X ² And X ³ Is CR (CR) ⁷ 。

105.X ¹ Is N, X ² Is CH and X ³ Is CR (CR) ⁷ 。

106.X ¹ Is N, X ² Is CR (CR) ⁷ And X is ³ Is CH.

107.X ¹ Is N, X ² X is X ³ Is CH.

108.X ² Is N, and X ¹ And X ³ Is CR (CR) ⁷ 。

109.X ² Is N, X ¹ Is CR (CR) ⁷ And X is ³ Is CH.

110.X ² Is N, X ¹ Is CH and X ³ Is CR (CR) ⁷ 。

111.X ² Is N, and X ¹ And X ³ Is CH.

112.X ₁ 、X ₂ And X ₃ Is CH.

113.R ⁷ Independently at each occurrence selected from: H. c (C) _1-4 Haloalkyl and C _1-4 Alkyl optionally substituted with one or more substituents selected from the group consisting of: -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 。

114.R ⁷ Independently at each occurrence selected from: H. c (C) _1-3 Haloalkyl and C _1-3 Alkyl optionally substituted with one substituent selected from the group consisting of: -OR ^a5 、-S(O) ₂ R ^a5 and-NR ^a5 R ^b5 。

115.R ⁷ Independently at each occurrence selected from: H. c (C) _1-4 Haloalkyl and C _1-4 An alkyl group.

116.R ⁷ Is H.

117. Ring B is selected from: phenyl and a monocyclic or bicyclic 5-to 12-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ And (3) substitution.

118. Ring B is selected from: phenyl and mono-or bicyclic 5-to 11-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ And (3) substitution.

119. Ring B is selected from: phenyl, monocyclic 5-or 6-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ And (3) substitution.

120. Ring B is selected from: 5-or 6-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ And (3) substitution.

121. 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 ¹⁰ And (3) substitution. Ring B may be selected from: monocyclic 5-or 6-membered heteroaryl and 9-or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one or more R ¹⁰ And (3) substitution.

122. Ring B is selected from: optionally by one or more R ¹⁰ Substituted phenyl and bicyclic 8-to 10-membered heteroaryl.

123. Ring B is selected from: optionally by one or more R ¹⁰ Substituted monocyclic or bicyclic 5-to 11-membered heteroaryl.

124. Ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 8-, 9-or 10-membered heteroaryl.

125. Ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 9-or 10-membered heteroaryl.

126. Ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 9 membered heteroaryl.

127. Ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 10 membered heteroaryl.

128. Ring B is selected from: optionally by one or more R ¹⁰ Substituted 5 membered heteroaryl.

129. Ring B is selected from: optionally by one or more R ¹⁰ Substituted 6 membered heteroaryl.

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

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

132. Ring B is as defined in any of numbered paragraphs 117 to 129 wherein the heteroaryl contains 1 ring nitrogen atom and optionally 1 or 2 ring heteroatoms selected from O, S and N.

133. Ring B is as defined in any of numbered paragraphs 117 to 129, wherein the heteroaryl contains 1 to 4 ring nitrogen atoms. Thus, heteroaryl groups may contain 1 to 3 ring nitrogen atoms. For example, heteroaryl groups contain 1 or 2 ring nitrogen atoms.

134. Ring B is as defined in any of numbered paragraphs 117 to 133, wherein when ring B is heteroaryl, the heteroaryl is bonded to the remainder of the compound of formula (I) through a ring carbon atom in the aromatic ring of ring B.

135. Ring B is as defined in any of numbered paragraphs 117 to 133, wherein when ring B is heteroaryl, the heteroaryl is bonded to the remainder of the compound of formula (I) through a ring nitrogen atom in the aromatic ring of ring B.

136. Ring B is as defined in any of numbered paragraphs 117 through 135, wherein ring B is optionally substituted with 1 or 2R ¹⁰ And (3) substitution. Thus, ring B can be substituted with 1R ¹⁰ And (3) substitution. Ring B may be substituted with 1R ¹⁰ And (3) substitution.

137. Ring B is selected from:

wherein p' is 0 or 1;

p "is 0, 1 or 2;

p' "is 0, 1, 2 or 3; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I). p ', p "and p'" may be 0 or 1.p ', p "and p'" may be 0.

138. Ring B is selected from:

wherein p' is 0 or 1;

p "is 0, 1 or 2;

p' "is 0, 1, 2 or 3; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I). p ', p "and p'" may be 0 or 1.p ', p "and p'" may be 0.

139. Ring B is selected from:

/>

wherein p "is 0, 1 or 2;

p' "is 0, 1, 2 or 3; and is also provided with

Represents 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.

140. Ring B is:

wherein p "is 0, 1 or 2; and is also provided withRepresents the point of attachment to the remainder of the compound of formula (I).

141. Ring B is:

wherein the method comprises the steps ofRepresents the point of attachment to the remainder of the compound of formula (I).

142. Ring B is selected from:

/>

wherein p' is 0 or 1; and is also provided with

p' is 0, 1 or 2; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I). p' and p "may be 0 or 1.p' and p "may be 0.

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

144. Ring B has the following structure:

wherein:

X ¹⁰ 、X ¹¹ 、X ¹² 、X ¹³ and X ¹⁴ Independently selected from CH and N, wherein X ¹⁰ 、X ¹¹ 、X ¹² 、X ¹³ And X ¹⁴ At least one of which is N;

p is 0, 1, 2, 3 or 4 (where chemically possible); and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I).

Suitably, X ¹⁰ 、X ¹¹ 、X ¹² 、X ¹³ And X ¹⁴ Not more than two of which are N.

145. Ring B is selected from:

wherein p is 0, 1, 2 or 3, and wherein +.>Representation ofAttachment point 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.

146. Ring B has the following structure:

wherein:

X ¹⁰ 、X ¹¹ 、X ¹³ and X ¹⁴ Independently selected from CH and N, wherein X ¹⁰ 、X ¹¹ 、X ¹³ And X ¹⁴ At least one of which is N;

p is 0, 1, 2 or 3 (where chemically possible); and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I).

Suitably, X ¹⁰ 、X ¹¹ 、X ¹² 、X ¹³ And X ¹⁴ Not more than two of which are N

147. Ring B is selected from:

wherein p is 0 or 1; and is also provided withRepresents the point of attachment to the remainder of the compound of formula (I). Optionally, p is 1, so ring B may be selected from: />

148. Ring B is selected from:

wherein p is 0 or 1; and is also provided withRepresents the point of attachment to the remainder of the compound of formula (I). Optionally, p is 1, so ring B may be selected from:

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

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

151. Ring B is a fused bicyclic heteroaryl selected from: phenyl or 5-or 6-membered heteroaryl ring fused to a ring 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 Cycloalkyl wherein ring B is optionally substituted with one or more R ¹⁰ The group is substituted and wherein at least one ring atom in ring B is N, and wherein ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the aromatic ring of ring B.

152. Ring B is a fused bicyclic heteroaryl selected from: a benzene ring fused to a ring selected from the group consisting of: 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 optionally substituted with one or more R ¹⁰ The group is substituted and wherein at least one ring atom in ring B is N. Ring B may be a bicyclic heteroaryl selected from: a benzene ring fused to a ring selected from the group consisting of a 5-or 6-membered heteroaryl, a 5-or 6-membered saturated heterocyclyl and a 5-or 6-membered partially saturated heterocyclyl, wherein ring B is optionally substituted with one or more R ¹⁰ The group is substituted and wherein at least one ring atom in ring B is N. At the position ofIn each of the above cases, the ring B group is bonded to the remainder of the compound of formula (I) through a ring carbon atom in the benzene ring of the bicyclic B group.

153. Ring B has the following structure:

/>

wherein:

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 possible);

wherein at least one ring atom in ring B' is N; and is also provided with

Wherein ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the benzene ring of ring B, byAnd (3) representing. Suitably, p '+q' +.ltoreq.4, e.g. p '+q' is 0, 1 or 2.

154. Ring B is selected from:

wherein the method comprises the steps ofRepresents the point of attachment of a carbon atom in the benzene ring of ring B to the remainder of the compound of formula (I); and is also provided with

p 'and q' are independently selected from 0, 1, 2 or 3 (where chemically possible). Suitably, p '+q'. Ltoreq.4. For example, p '+q' is 0, 1 or 2.

155. Ring B is selected from:

wherein the method comprises the steps ofRepresents the point of attachment of ring B to the remainder of the compound of formula (I); and is also provided with

p 'and q' are independently selected from 0, 1, 2 or 3 (where chemically possible). Suitably, p '+q'. Ltoreq.4. For example, p '+q' is 0, 1 or 2.

156. Ring B is a fused bicyclic heteroaryl selected from: and is selected from the group consisting of 4-to 7-membered saturated heterocyclic groups, 4-to 7-membered partially saturated heterocyclic groups, and C _3-6 A ring-fused 6 membered heteroaryl ring of cycloalkyl, wherein the bicyclic group is optionally substituted with one or more R ¹⁰ The group is substituted and wherein at least one ring atom in ring B is N. Ring B may be a fused bicyclic heteroaryl selected from 6 membered heteroaryl rings fused to a ring selected from the group consisting of: 5-or 6-membered saturated heterocyclic group, partially saturated 5-or 6-membered heterocyclic group and C _5-6 Cycloalkyl wherein the bicyclic group is optionally substituted with one or more R ¹⁰ The group is substituted and wherein at least one ring atom in ring B is N. In each 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.

157. Ring B has the following structure:

wherein:

ring B' is a 5-or 6-membered saturated heterocyclic group, a partially saturated 5-or 6-membered heterocyclic group, or C _3-6 Cycloalkyl;

X ¹⁵ 、X ¹⁶ 、X ¹⁷ and X ¹⁸ Is independently selected from CH and N, provided that X ¹⁵ 、X ¹⁶ 、X ¹⁷ And X ¹⁸ At least one but not more than two of which are N, and wherein ring B is via a ring consisting of X ¹⁵ 、X ¹⁶ 、X ¹⁷ And X ¹⁸ One of which represents a ring carbon bonded to the remainder of the compound of formula (I);

p' is 0, 1 or 2; q' is 0, 1, 2 or 3 (where chemically possible). Suitably, p '+q' +.ltoreq.4, e.g. 0, 1 or 2.

158. Ring B is selected from:

wherein;

p' is 0, 1 or 2 (where chemically possible); and q' is 0, 1, 2 or 3 (where chemically possible); and is also provided withRepresents the point of attachment of the ring carbon in the pyridyl ring of ring B to the remainder of the compound of formula (I). Suitably, p '+q' +.ltoreq.4, e.g. 0, 1 or 2.

159. Ring B is selected from:

wherein the method comprises the steps of

p' is 0, 1 or 2 (where chemically possible); and q' is 0, 1, 2 or 3 (where chemically possible); and is also provided with Represents an attachment point to the remainder of the compound of formula (I); suitably, p '+q' +.ltoreq.4, e.g. 0, 1 or 2.

160. Ring B is a fused bicyclic heteroaryl selected from 5 membered heteroaryl rings fused to a ring selected from the group consisting of: 4-to 7-membered saturated heterocyclic group, partially saturated 4-to 7-membered heterocyclic group and C _3-6 Cycloalkyl wherein ring B is optionally substituted with one or more R ¹⁰ The group is substituted and wherein at least one ring atom in ring B is N. Ring B may be a fused bicyclic heteroaryl selected from: with a member selected from the group consisting of 5-or 6-membered heterocyclyl, partially saturated 5-or 6-membered heterocyclyl and C _5-6 A cycloalkyl ring fused 5 membered heteroaryl ring wherein ring B is optionally substituted with one or more R ¹⁰ Group substitution, and wherein at least one ring in ring BThe atom is N. In each of the fused bicyclic heteroaryl ring B groups described above, ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the 5-membered heteroaryl ring of the ring B group.

161. Ring B has the following structure:

wherein:

ring B contains at least one ring nitrogen;

ring B' is selected from: a 5-or 6-membered saturated heterocyclic ring, a 5-or 6-membered partially saturated heterocyclic ring and C _5-6 Cycloalkyl;

from X ¹⁹ 、X ²⁰ 、X ²¹ 、X ²² And X ²³ The ring formed is a 5 membered heteroaryl ring;

X ¹⁹ and X ²³ Independently selected from C and N;

X ²⁰ 、X ²¹ And X ²² Independently selected from CH, N, NH, O and S, provided that X ²⁰ 、X ²¹ And X ²² Not more than one of which is O, S or NH;

ring B is formed by X ²⁰ 、X ²¹ And X ²² One of which represents a ring carbon or nitrogen atom bound to the remainder of the compound of formula (I)

p' is 0, 1 or 2; and is also provided with

q' is 0, 1, 2, 3 or 4.

Suitably, p '+q' +.ltoreq.4, e.g. p '+q' is 0, 1 or 2.

162. Ring B is selected from:

wherein the method comprises the steps ofPoints representing ring B to the remainder of the compound of formula (I); and wherein ring B is through a 5 membered heteroaryl ring in ring BIs bonded to the remainder of the compound;

p' is 0 or 1; and is also provided with

q' is 0, 1, 2, 3 or 4.

Suitably, p '+q' +.ltoreq.4, e.g. p '+q' is 0, 1 or 2.

163. Ring B is selected from:

wherein the method comprises the steps ofPoints representing ring B to the remainder of the compound of formula (I);

p' is 0 or 1; and is also provided with

q' is 0, 1, 2, 3 or 4.

Suitably, p '+q' +.ltoreq.4, e.g. p '+q' is 0, 1 or 2.

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

165. Ring B is a fused bicyclic heteroaryl selected from: a 5 membered heteroaryl group fused to a 6 membered heteroaryl group, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring carbon or ring nitrogen atom in the 5 membered heteroaryl group, and wherein ring B contains at least one ring nitrogen atom (e.g., 1,2,3, or 4 ring nitrogen atoms) and optionally one or two ring atoms selected from O and S; and wherein ring B is optionally substituted with one or more R ¹⁰ And (3) group substitution.

166. Ring B is a fused bicyclic heteroaryl selected from: a 5 membered heteroaryl fused to a 6 membered heteroaryl, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring carbon or ring nitrogen atom in the 5 membered heteroaryl;

wherein the 5-membered heteroaryl is selected from pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2, 3-triazole and 1,2, 4-triazole; and is also provided with

The 6 membered heteroaryl is selected from pyridine, pyrimidine, pyridazine and pyrazine; and is also provided with

Wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ And (3) group substitution.

167. Ring B is a fused bicyclic heteroaryl selected from 6 membered heteroaryl fused to 5 membered heteroaryl, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring carbon or ring nitrogen atom in the 6 membered heteroaryl, and wherein ring B contains at least one ring nitrogen atom (e.g., 1,2,3, or 4 ring nitrogen atoms) and optionally one or two ring atoms selected from O and S; and wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ And (3) group substitution.

168. Ring B is a fused bicyclic heteroaryl selected from: a 6 membered heteroaryl fused to a 5 membered heteroaryl, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the 6 membered heteroaryl;

wherein the 5-membered heteroaryl is selected from: pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2, 3-triazole and 1,2, 4-triazole; and is also provided with

The 6 membered heteroaryl is selected from pyridine, pyrimidine, pyridazine and pyrazine; and is also provided with

Wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ And (3) group substitution.

169. Ring B is a fused bicyclic heteroaryl selected from 6 membered heteroaryl fused to another 6 membered heteroaryl, wherein ring B contains at least one ring nitrogen atom (e.g., 1,2,3, or 4 ring nitrogen atoms) and optionally one or two ring atoms selected from O and S; and wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ Radical extractionAnd (3) replacing.

170. Ring B is a fused bicyclic heteroaryl group selected from 6 membered heteroaryl groups fused to another 6 membered heteroaryl group, wherein each of said 6 membered heteroaryl groups is independently selected from: pyridine, pyrimidine, pyridazine and pyrazine; and is also provided with

Wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ And (3) group substitution.

171. Ring B is a fused bicyclic heteroaryl selected from 5 membered heteroaryl fused to a benzene ring, wherein the 5 membered heteroaryl has 1,2 or 3 ring heteroatoms selected from O, S and N; and wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ Group substitution; wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ And (3) group substitution. Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in a 5-membered heteroaryl ring. Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in the benzene ring.

172. Ring B is a fused bicyclic heteroaryl selected from 5 membered heteroaryl groups fused to a benzene ring, wherein the 5 membered heteroaryl is selected from the group consisting of: pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2, 3-triazole and 1,2, 4-triazole; and is also provided with

Wherein ring B is optionally substituted with one or more (e.g., 1,2,3 or 4) R ¹⁰ And (3) group substitution.

Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in a 5-membered heteroaryl ring. Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in the benzene ring.

173. Ring B is a fused bicyclic heteroaryl selected from: a 6 membered heteroaryl group fused to a benzene ring, wherein the 6 membered heteroaryl group has 1, 2 or 3 ring heteroatoms selected from O, S and N; and wherein ring B is optionally substituted with one or more (e.g., 1, 2, 3 or 4) R ¹⁰ And (3) group substitution. Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in a 6 membered heteroaryl ring. Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in the benzene ring.

174. Ring B is a fused bicyclic group selected from 6 membered heteroaryl groups fused to a benzene ring, wherein the 6 membered heteroaryl groups are selected from: pyridine, pyrimidine, pyridazine and pyrazine; and is also provided with

Wherein ring B is optionally substituted with one or more (e.g., 1, 2, 3 or 4) R ¹⁰ And (3) group substitution.

Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in a 6 membered heteroaryl ring. Ring B may be bonded to the remainder of the compound of formula (I) through a ring atom in the benzene ring.

175. Ring B is selected from:

the method comprises the steps of,

Wherein the method comprises the steps of

p' is 0, 1, 2 or 3;

q' is 0, 1 or 2 (where chemically possible); and is also provided with

Represents the point of attachment of the ring atom in the 5-membered heteroaryl ring of ring B to the remainder of the compound in formula (I).

176. Ring B is selected from:

wherein the method comprises the steps of

p' is 0, 1, 2 or 3;

q' is 0, 1 or 2 (where chemically possible); and is also provided withRepresents the point of attachment to the remainder of the compound of formula (I). 177. Ring B is selected from:/>

/>

p' is 0, 1, 2 or 3;

q' is 0, 1 or 2 (where chemically possible); and is also provided with

Represents the point of attachment of the ring carbon atom in the 6-membered heteroaryl ring of ring B to the remainder of the compound of formula (I)

178. Ring B is selected from:

/>

p' is 0, 1, 2 or 3;

q' is 0, 1 or 2 (where chemically possible);

q "is 0 or 1; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I).

179. Ring B is C _6-10 Aryl, optionally substituted with one or more (e.g., 1, 2, 3 or 4) R ¹⁰ And (3) substitution.

180. Ring B is optionally substituted with one or more (e.g., 1, 2, 3 or 4) R ¹⁰ A substituted phenyl group.

Ring B is covered by one R ¹⁰ A substituted phenyl group. Thus, ring B may be selected from: wherein the method comprises the steps of

Represents the point of attachment to the remainder of the compound of formula (I). Preferably, ring B may be +. >

181. Ring B is unsubstituted. Thus R is ¹⁰ May not be present.

182. Ring B is as defined in any one of numbered paragraphs 117 through 180, wherein R ¹⁰ Is not present.

183. Ring B is substituted with one or more R ¹⁰ And (3) substitution. For example ring B is substituted by 1 or 2R ¹⁰ And (3) substitution. Thus ring B can be substituted by one R ¹⁰ And (3) substitution.

184. Ring B is as defined in any of numbered paragraphs 117 through 180, and ring B is defined by 1 or 2R ¹⁰ And (3) substitution.

185.R ¹⁰ Independently at each occurrence selected from: 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 ^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 Wherein said C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with 1 or more R ¹² And (3) substitution. Ring B may be as defined in any of numbered paragraphs 117 to 184.

186.R ¹⁰ Independently at each occurrence selected from: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, -SC _1-6 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 -；

Wherein Q is ¹⁰¹ Selected from C _3-6 Cycloalkyl, 4-to 6-membered heterocyclyl, 5-or 6-membered heteroaryl,

wherein said C _3-6 Cycloalkyl and 4-to 6-membered heterocyclyl are optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 、-C(O)R ^a8 and-S (O) ₂ R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, C _1-4 Alkyl, -OR ^a10 、-NR ^a10 R ^b10 、-C(O)R ^a10 and-S (O) ₂ R ^a1 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

L ¹⁰¹ Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 -。

Ring B may be as defined in any of numbered paragraphs 117 to 184.

187.R ¹⁰ Independently at each occurrence selected from: 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 -；

Wherein Q is ¹⁰² Selected from 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

wherein the 4-to 6-membered heterocyclyl is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is selected from: pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolylA pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, C _1-4 Alkyl, -OR ^a10 and-NR ^a10 R ^b10 ；

L ¹⁰² Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 -。

Ring B may be as defined in any of numbered paragraphs 117 to 184.

188.R ¹⁰ Independently at each occurrence selected from: 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 _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 -；

Wherein Q is ¹⁰³ Is a 4-to 6-membered heterocyclyl group, wherein the 4-to 6-membered heterocyclyl group is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ；

L ¹⁰³ Is a bond or is selected from: methylene, -O-, -NH-, and-NMe-. Ring B may be as defined in any of numbered paragraphs 117 to 184.

189.R ¹⁰ Independently at each occurrence selected from: 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 may be as defined in any of numbered paragraphs 117 to 184.

190.R ¹⁰ Independently at each occurrence selected from: 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 R ^a61 ；

Wherein said C _1-6 Alkyl is optionally substituted with 1 or more R ¹² Substitution;

R ¹¹ independently selected from: H. c (C) _1-6 Alkyl and C _1-6 Haloalkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more R ¹³ Substitution;

Q ¹ independently at each occurrence selected from: c (C) _3-6 Cycloalkyl, 4-to 7-membered heterocyclyl, 4-to 9-membered heterocyclyl-C _1-3 Alkyl, 5-or 6-membered heteroaryl,

wherein said C _3-6 Cycloalkyl, 4-to 7-membered heterocyclyl and 4-to 9-membered heterocyclyl-C _1-3 Alkyl is optionally substituted with one or more R ¹⁴ Substituted, and

wherein the 5-or 6-membered heteroaryl is optionally substituted with one or more R ¹⁵ Substitution;

L ¹ is a bond or is selected from-O-or-NR ^a71 ；

R in each occurrence ¹² Selected from: -NR ^a81 R ^b81 、-C(O)OR ^a81 、-OR ^a81 ；

R in each occurrence ¹³ Selected from: -NR ^a81 R ^b81 and-OR ^a81 ；

R in each occurrence ¹⁴ Selected from: halo, = O, C _1-4 Alkyl, -NR ^a81 R ^b81 OR-OR ^a81 ；

R in each occurrence ¹⁵ Selected from: halo, C _1-4 Alkyl, -NR ^a81 R ^b81 OR-OR ^a81 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ^a61 、R ^a71 、R ^a81 And R is ^b81 Independently selected from H and C _1-4 An alkyl group.

Ring B may be as defined in any of numbered paragraphs 117 to 184. In this embodiment, Q at each occurrence ¹ May be independently selected from: c (C) _3-6 Cycloalkyl, 4-to 7-membered heterocyclyl-C _1-3 Alkyl-, 5-or 6-membered heteroaryl,

wherein said C _3-6 Cycloalkyl, 4-to 7-membered heterocyclyl and 4-to 7-membered heterocyclyl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁴ Substituted, and

wherein the 5-or 6-membered heteroaryl is optionally substituted with one or more R ¹⁵ And (3) substitution.

191.R ¹⁰ Independently at each occurrence selected from: c (C) _1-6 Alkyl or Q ¹ -L ¹ -，

Wherein said C _1-6 Alkyl is optionally substituted with 1 or more R ¹² Substitution;

Q ¹ independently at each occurrence selected from: 4-to 7-membered heterocyclyl, wherein the heterocyclyl has 1 ring nitrogen atom and optionally one ring atom selected from O, S and N, and wherein Q ¹ Optionally substituted with one or two substituents selected from the group consisting of: halo, C _1-4 Alkyl, -NR ^a81 R ^b81 and-OR ^a81 ；

L ¹ Is a bond or-O-;

r in each occurrence ¹² Selected from: -NR ^a81 R ^b81 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ^a81 And R is ^b81 Independently selected from H and C _1-4 An alkyl group.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

192.R ¹⁰ Independently at each occurrence selected from: q (Q) ¹ -L ¹ -，

Q ¹ Independently at each occurrence selected from: 4-to 9-membered heterocyclyl-C _1-3 Alkyl-, wherein the heterocyclyl has 1 ring nitrogen atom and optionally one ring atom selected from O, S and N; and is also provided with

L ¹ Is a key.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

193.R ¹⁰ Selected from: -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 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

194.R ¹⁰ is-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

195.R ¹⁰ Selected from: -NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group. R is R ¹⁰ Can be-C _1-3 alkyl-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

196.R ¹⁰ Selected from:

fluorine (F),Chloro, cyano, nitro, oxo, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, -NH ₂ 、-NH(Me)、-N(Me) ₂ 、/>/>

Wherein the method comprises the steps ofIndicating the point of attachment to ring B.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

197. Ring B is substituted with one member selected from Q ¹ -L ¹ R of- ¹⁰ A substituent, and ring B is optionally substituted with one or two additional substituents selected from the group consisting of: halo, C _1-3 Alkyl and C _1-3 A haloalkyl group. Ring B may be as defined in any of numbered paragraphs 117 to 184.

198. Ring B is substituted with one member selected from Q ¹⁰¹ -L ¹⁰¹ R of- ¹⁰ A substituent, and ring B is optionally substituted with one or two additional substituents selected from the group consisting of: halo, C _1-3 Alkyl and C _1-3 A haloalkyl group, a halogen atom,

wherein Q is ¹⁰¹ Selected from C _3-6 Cycloalkyl, 4-to 6-membered heterocyclyl, 5-or 6-membered heteroaryl,

wherein said C _3-6 Cycloalkyl and 4-to 6-membered heterocyclyl are optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 、-C(O)R ^a8 and-S (O) ₂ R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is optionally selected from one or more (e.g. 1 or 2) groupsThe following substituents are substituted: halo, C _1-4 Alkyl, -OR ^a10 、-NR ^a10 R ^b10 、-C(O)R ^a10 and-S (O) ₂ R ^a1 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

L ¹⁰¹ Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 -。

Ring B may be as defined in any of numbered paragraphs 117 to 184.

199. Ring B is substituted with one member selected from Q ¹⁰² -L ¹⁰² R of- ¹⁰ A substituent, and ring B is optionally substituted with one or two additional substituents selected from the group consisting of: halo, C _1-3 Alkyl and C _1-3 A haloalkyl group, a halogen atom,

wherein Q is ¹⁰² Selected from 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

wherein the 4-to 6-membered heterocyclyl is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is selected from: pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, C _1-4 Alkyl, -OR ^a10 and-NR ^a10 R ^b10 ；

L ¹⁰² Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 。

Ring B may be as defined in any of numbered paragraphs 117 to 184.

200. Ring B is substituted with one member selected from Q ¹⁰³ -L ¹⁰³ R of- ¹⁰ A substituent, and ring B is optionally substituted with one or two additional substituents selected from the group consisting of: halo, C _1-3 Alkyl and C _1-3 A haloalkyl group, a halogen atom,

wherein Q is ¹⁰³ Is a 4-to 6-membered heterocyclyl group, wherein the 4-to 6-membered heterocyclyl group is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ；

L ¹⁰³ Is a bond or is selected from: methylene, -O-, -NH-, and-NMe-.

Ring B may be as defined in any of numbered paragraphs 117 to 184.

201. Ring B is selected from:

/>

/>

/>

wherein represents the point of attachment to the remainder of the compound of formula (I).

202. Ring B is selected from:

wherein the method comprises the steps ofRepresents the point of attachment to the remainder of the compound of formula (I).

203. Ring B is selected from:

wherein the method comprises the steps ofRepresents the point of attachment to the remainder of the compound of formula (I).

204. In the compounds of formula (I), X ¹ And X ³ Is N, and X ² Is CH.

In certain embodiments, the compounds of the present invention are compounds of formula (I), (II), (III), (IV), (VII), (VIII), (IX), (XII), (XIII), (XIV), (XV), (XVIII), (XIX), (XX), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI) or pharmaceutically acceptable salts thereof, wherein R ¹ Selected from: phenyl and 5-or 6-membered heteroaryl containing at least one ring nitrogen, wherein R ¹ Optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 。

In certain embodiments, the compounds of the present invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or pharmaceutically acceptable salts thereof, wherein R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ . Thus, R is ³ OR-OR ⁴¹ May be-OMe. R is R ³ OR-OR ⁴¹ Can be-OCH (CH) ₃ ) ₂ 。

In certain embodiments, the compounds of the present invention are 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 pharmaceutical thereofSalts of the above acceptable, wherein X ¹ Is CR (CR) ⁷ And X is ² Is N. For example, X ¹ Is CR (CR) ⁷ Wherein R is ⁷ Selected from: H. halo and C _1-4 An alkyl group; and X is ² Is N. For example, wherein X ¹ Is CH. And X is ² Is N. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the present invention are of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI) or pharmaceutically acceptable salts thereof, wherein X ¹ Is N, and X ² Is CR (CR) ⁷ . For example, wherein X ¹ Is N and X ² Is CR (CR) ⁷ Wherein R is ⁷ Selected from: H. halo and C _1-4 An alkyl group. For example, wherein X ¹ Is N and X ² Is CH. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the present invention are of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI) or pharmaceutically acceptable salts thereof, wherein X ¹ And X ² Is CR (CR) ⁷ . In these embodiments, X ¹ May be CH and X ² Is CR (CR) ⁷ 。X ¹ Can be CR ⁷ And X is ² Is CH. In these embodiments, R ⁷ May be selected from: H. halo and C _1-4 An alkyl group. Thus, X is ¹ And X ² May be CH. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the present invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XXIII), (XXIV), (XXVI), (XXVII), (XXIX) or (XXX), or pharmaceutically acceptable salts thereof, wherein X ¹ 、X ² And X ³ Is CH. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) or (XXII), or pharmaceutically acceptable salts thereof, wherein ring B is as defined in any one of numbered paragraphs 117 to 184, 201 or 202.

In certain embodiments, the compounds of the invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) or (XXII), or pharmaceutically acceptable salts thereof, wherein ring B is as defined in any one of numbered paragraphs 117 to 184, 201 or 202; and is also provided with

R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) or (XXII), or pharmaceutically acceptable salts thereof, wherein ring B is as defined in any one of numbered paragraphs 117 to 184, 201 or 202; and X is ¹ And X ² Are CH. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) or (XXII), or pharmaceutically acceptable salts thereof, wherein ring B is as defined in any one of numbered paragraphs 117 to 184, 201 or 202; and X is ¹ Is N, and X ² Is CH. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the invention are compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) or (XXII), or pharmaceutically acceptable salts thereof, wherein ring B is as defined in any one of numbered paragraphs 117 to 184, 201 or 202; and X is ¹ Is CH and X ² Is N. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the present invention are compounds of formula (I), (XII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), or (XXXI), or a pharmaceutically 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-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe). In these embodiments, X ¹ And X ² May be CH. In these embodiments, X ¹ May be CH and X ² Is N. In these embodiments, X ¹ May be N and X ² Is CH.

In certain embodiments, the compounds of the present invention are of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), a compound of formula (I), (II), (VI) and (VI),A compound of formula (XX), (XXI) or (XXII), or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with one or two R ¹⁰ Substituted, and wherein R ¹⁰ As defined in any of numbered paragraphs 185 through 196. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe). Thus, in this embodiment, ring B may be unsubstituted. In this embodiment, ring B may be substituted with one or two R ¹⁰ Substitution, wherein R ¹⁰ As defined in any of numbered paragraphs 185 through 196.

In certain embodiments, the compounds of the present invention are compounds of formula (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ As defined in any of numbered paragraphs 185 through 196. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe). Suitably, in these embodiments, p (when present) is 0, 1 or 2.

In certain embodiments, the compounds of the present invention are compounds of formula (I), (II), (III), (IV), (VII), (VIII), (IX), (XIII), (XIV), (XV), (XVIII), (XIX) or (XX) or a pharmaceutically acceptable salt thereof, wherein R ¹ As defined in any of numbered paragraphs 4 through 21; and R is ² Is methyl. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

In certain embodiments, the compounds of the present invention are compounds of formula (I), (II), (III), (IV), (V), (VII), (VIII), (IX), (X), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX) or (XXI) or a pharmaceutically acceptable salt thereof, wherein R ² Is not H. Thus, R is ² May be as defined in one of numbered paragraphs 26, 28 or 30 through 32.

In certain embodiments, the compounds of the present invention are of formula (I), (XII), (XXIII), (XXIV), (XXV)A compound of (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharmaceutically acceptable salt thereof, wherein ring a is as defined in numbered paragraphs 37 or 38. Ring A may be as defined in numbered paragraph 37 and R ³ As defined in any of numbered paragraphs 39 through 81. For example, wherein ring A is as defined in numbered paragraph 37 and R ³ Is methoxy.

In certain embodiments, the compounds of the present invention are compounds of formula (I), (II), (III), (IV), (VII), (VIII), (IX), (XIII), (XIV), (XV), (XVIII), (XIX) or (XX) or a pharmaceutically acceptable salt thereof, wherein R ² As defined in any of numbered paragraphs 26 through 32; and R is ¹ Selected from phenyl or 4-fluorophenyl. Suitably, in these embodiments, R ³ OR-OR ⁴¹ Selected from-OMe and-OCH (CH) ₃ ) ₂ (e.g. R ³ OR-OR ⁴¹ is-OMe).

Suitably are compounds of formula (I), (IV), (IX), (XII), (XV), (XX), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) and (XXXI) or pharmaceutically acceptable salts thereof, when ring a has formula A3 then R ² not-OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 . For example, in these embodiments, when ring A is A3, R ² Can be selected from halogenated, C _1-4 Alkyl and C _1-4 A haloalkyl group. When ring A is A3, R ² May be H.

In certain embodiments, the compounds of the present invention are compounds of formula (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is-NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group. R is R ¹⁰ Can be-CH ₂ -NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group. In this embodiment, R ³ OR-OR ⁴¹ May be selected from: -OMe, -OCH (CH) ₃ ) ₂ and-O-cyclobutyl. For example, the number of the cells to be processed,R ³ OR-OR ⁴¹ Selected from: OMe and OCH (CH) ₃ ) ₂ 。

In certain embodiments, the compounds of the invention are compounds 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 pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of-NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 R of (2) ¹⁰ Substituted with substituents wherein R ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group; and optionally one or two selected from halo and C _1-4 Substituents of alkyl groups. Ring B may be selected from only one of-NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 R of (2) ¹⁰ Substituted with substituents wherein R ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group. R is R ¹⁰ Can be-CH ₂ -NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group. In this embodiment, R ³ OR-OR ⁴¹ May be selected from: -OMe, -OCH (CH) ₃ ) ₂ and-O-cyclobutyl. For example, R ³ OR-OR ⁴¹ Selected from: OMe and OCH (CH) ₃ ) ₂ 。

In another embodiment, the compound of formula (I) is a compound of formula (II):

Or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from: phenyl and 5-or 6-membered heteroaryl containing at least one nitrogen atom, wherein R ¹ Optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 ；

R ² Selected from: H. halo, C _1-4 Alkyl and C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2

Wherein C is _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a3 、-SR ^a3 and-NR ^a3 R ^b3 ；

R ³ Selected from: c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-;

R ⁴ and R is ⁵ Independently selected from: H. c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-;

R ⁶ selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

X ¹ 、X ² and X ³ Independently selected from: n and CR ⁷ ；

R ⁷ Independently at each occurrence selected from: H. halo, -CN, 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 is ⁹ Each independently selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ⁷ 、R ⁸ Or R is ⁹ Any C in any of (3) _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 ；

Ring B is selected from the group consisting of optionally one or more R ¹⁰ Substituted phenyl and 5-to 12-membered heteroaryl, wherein

R ¹⁰ Independently at each occurrence selected from: 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 ，

Wherein said C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with 1 or more R ¹² Substitution;

R ¹¹ independently selected from: H. c (C) _1-6 Alkyl and C _1-6 Haloalkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more R ¹³ Substitution;

Q ¹ independently at each occurrence selected from: c (C) _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-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-,

wherein 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-optionally substituted with one or more R ¹⁴ Substituted, and

wherein the phenyl, phenyl-C _1-3 Alkyl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl is optionally substituted with one or more R ¹⁵ Substitution;

L ¹ is a bond or is selected from-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 -；

R ¹² 、R ¹³ And R is ¹⁴ Each occurrence is independently selected from: 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 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a9 、-NR ^a9 R ^b9 and-SO ₂ R ^a9 ；

R ¹⁵ Independently at each occurrence selected from: 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 NR ^a10 R ^b10 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a11 、-NR ^a11 R ^b11 and-SO ₂ R ^a11 ；

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 is ^b11 Independently at each occurrence selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

or any-NR within a 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 A 4-to 6-membered heterocyclyl can be formed, wherein the 4-to 6-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl and C _1-4 A haloalkyl group.

In this embodiment, R ³ May be selected from: c (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 May be-OR ⁴ 。

In this embodiment, R ⁴ May be selected from: H. c (C) _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl, 4-to 6-membered heterocyclic group containing 1 epoxy atom, and 4-to 6-membered heterocyclic group-C containing 1 epoxy atom _1-3 An alkyl group; .

In this embodiment, Q at each occurrence ¹ May be independently selected from: c (C) _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-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-,

wherein 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-optionally substituted with one or more R ¹⁴ Substituted, and

wherein the phenyl, phenyl-C _1-3 Alkyl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁵ And (3) substitution.

In this embodiment, ring B may be as defined in any of numbered paragraphs 117 to 184, 201 or 202.

In this embodiment, R ³ May be selected from: -OMe, -OCH (CH) ₃ ) ₂ and-O-cyclobutyl. Thus, R is ³ May be-OMe. R is R ³ Can be-OCH (CH) ₃ ) ₂ 。R ³ May be-O-cyclobutyl.

In this embodiment, R ³ May be selected from: -OMe, -OCH (CH) ₃ ) ₂ And oxetan-3-yloxy-.

In another embodiment, the compound of formula (I) is a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is phenyl optionally substituted with one or two substituents selected from halo;

R ² Is C _1-4 An alkyl group;

R ³ is-OR ⁴ ；

R ⁴ Selected from: c (C) _1-4 Alkyl and C _3-6 Cycloalkyl;

X ¹ and X ² Is CH;

X ³ is N;

ring B is selected from:

R ¹⁰¹ independently selected from: H. c (C) _1-4 Alkyl, -C _1-3 alkyl-NR ^a82 R ^b82 、-NR ^a82 R ^b82 And Q ¹ -L ¹ -，

Q ¹ Selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with 1 or 2 substituents selected from: halo, C _1-4 Alkyl and = O;

L ¹ is a bond or is selected from: -O-, -NH-and-N (C) _1-3 Alkyl) -; and is also provided with

R ^a82 And R is ^b82 Independently selected from: h and C _1-4 An alkyl group.

In this embodiment, R ³ May be selected from: -OMe, -OCH (CH) ₃ ) ₂ and-O-cyclobutyl. Thus, R is ³ May be-OMe. R is R ³ Can be-OCH (CH) ₃ ) ₂ 。R ³ May be-O-cyclobutyl.

In this embodiment, R ¹⁰¹ May be selected from: -NR ^a82 R ^b82 、-C _1-3 alkyl-NR ^a82 R ^b82 And Q ¹ -L ¹ -, wherein Q ¹ Is azetidinyl, optionally substituted with 1 substituent selected from the group consisting of: c (C) _1-4 An alkyl group; and L is ¹ Is a bond or is selected from: -O-and-NH-. Thus, R is ¹⁰¹ May be selected from: -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 Can be-CH ₂ -NH ₂ 。

In this embodiment, it may be:

R ¹ is phenyl or 4-fluorophenyl;

R ² is methyl;

R ³ is-OMe or-CH (CH) ₃ ) ₂ ；

X ¹ And X ² Is CH;

X ³ Is N;

ring B is selected from:

R ¹⁰¹ independently selected from: selected from: -NR ^a82 R ^b82 、-C _1-3 alkyl-NR ^a82 R ^b82 And Q ¹ -L ¹ -；

Q ¹ Is azetidinyl, optionally substituted with 1 substituent selected from the group consisting of: c (C) _1-4 An alkyl group;

L ¹ is a bond or is selected from: -O-and-NH-; and is also provided with

R ^a82 And R is ^b82 Independently selected from: h and C _1-4 An alkyl group.

In another embodiment, there is provided a compound selected from the group consisting of compound list 1, or a pharmaceutically acceptable salt thereof:

list of compounds 1

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Or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound selected from any of the examples herein, or a pharmaceutically acceptable salt thereof, is provided.

In another embodiment, a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

Specific compounds of the invention are those compounds that have an affinity (Ki) for a 5-GABAAR of less than 30nM (e.g., 10nM or less) when measured in the in vitro radioligand binding assays described herein. Preferred compounds of the invention are directed against GABA containing the alpha 1, alpha 2 or alpha 3 subunit _A The receptor has a ligand binding to alpha 5-GABA _A R selective binding affinity and/or efficacy.

Pharmaceutical composition

According to another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs [ science of pharmaceutical formulation ]", m.e. olton (m.e. aulton), churchill Livingstone [ churnier liston publishing ], 1988.

The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a fine powder or liquid aerosol), for administration by insufflation (e.g., as a fine powder) or for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intraperitoneal administration or as a suppository for rectal administration).

The compositions of the present invention may be obtained by conventional procedures using conventional pharmaceutically acceptable excipients well known in the art. Thus, compositions for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

An effective amount of a compound of the invention for use in the treatment of a disorder is an amount sufficient to symptomatically relieve symptoms of the disorder in a warm-blooded animal, especially a human, or to slow the progression of the disorder.

The amount of active ingredient combined with one or more excipients to produce a single dosage form will vary as necessary depending upon the host treated and the particular route of administration. For example, formulations for oral administration to humans typically contain, for example, from 0.1mg to 0.5g (more suitably from 0.5 to 100mg, for example from 1 to 30 mg) of active agent compounded with a suitable and convenient amount of excipient, which may be in an amount of from about 5% to about 98% by weight of the total composition.

The dosage size of the compounds of the present invention for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration, according to well known medical principles.

In using the compounds of the invention for therapeutic or prophylactic purposes, the compounds of the invention will generally be administered such that a daily dose in the range selected from, for example, 0.1mg/kg to 100mg/kg, 1mg/kg to 75mg/kg, 1mg/kg to 50mg/kg, 1mg/kg to 20mg/kg or 5mg/kg to 10mg/kg of body weight is accepted, if administration in divided doses is required. Generally, lower doses will be administered when the parenteral route is employed. Thus, for example, for intravenous, subcutaneous, intramuscular or intraperitoneal administration, a dose in the range of, for example, 0.1mg/kg to 30mg/kg body weight may be suitable. Similarly, for administration by inhalation, a dose in the range of, for example, 0.05mg/kg to 25mg/kg body weight may be suitable. When administered orally, the total daily dose of the compounds of the invention may be selected, for example, from: 1mg to 1000mg, 5mg to 1000mg, 10mg to 750mg or 25mg to 500mg. Typically, unit dosage forms will contain from about 0.5mg to 0.5g of the compound of the invention. In certain embodiments, the compounds of the invention are administered parenterally, for example by intravenous administration. In another particular embodiment, the compounds of the invention are administered orally.

Therapeutic uses and applications

According to another aspect, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disorder selected from the group consisting of alpha 5-GABA _A R-mediated diseases or medical disorders.

Also provided are methods of preventing or treating a disorder caused by alpha 5-GABA in a subject _A A method of treating a disease or medical disorder mediated by R, the method comprising administering to a subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of a disorder resulting from the administration of alpha 5-GABA _A Use in medicine of R-mediated diseases or medical disorders.

In the following sections of the present application, reference is made to the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the prevention or treatment of certain diseases or medical disorders. It will be appreciated that any reference herein to a compound for a particular use is also intended to refer to the use of (i) a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of the disease or disorder; and (ii) a method for preventing or treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of disorders associated with alpha 5-GABA _A R-mediated diseases or cognitive dysfunction associated with medical disorders.

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of disorders resulting from the administration of alpha 5-GABA _A R-mediated neurological or neuropsychiatric disorders. In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of disorders associated with alpha 5-GABA _A R-mediated neurological or neuropsychiatric disorders. The neurological disorder may be a neurological developmental disorder (e.g., attention deficit disorder (ADHD), down's syndrome, learning disorder, cerebral palsy, autism, or speech disorder). The neurological condition 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).

From alpha 5-GABA _A The R-mediated disease or medical disorder may be selected from: alzheimer's disease, parkinson's disease, huntington's disease, cognitive dysfunction (e.g., cognitive dysfunction associated with chemotherapy, narcotics, bacterial or viral infections (e.g., HIV), memory deficits, age-related cognitive dysfunction (i.e., mild cognitive impairment, MCI), bipolar disorder, autism, down's syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, amyotrophic Lateral Sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorders, schizophreniform disorders, substance-induced psychotic disorders or paranoid disorders), psychosis, post-traumatic stress disorders, anxiety disorders, generalized anxiety disorders, panic disorders, delusional disorders, obsessive-compulsive disorders, acute stress disorders, drug addiction, alcohol disorders (e.g., alcohol addiction), drug withdrawal symptoms, movement disorders, restless leg syndrome, cognitive deficit disorders, multi-infarct dementia, vascular dementia, mood disorders, depression, neuropsychiatric conditions, notes Italic deficit/hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive dysfunction associated with stroke, cognitive dysfunction associated with brain injury or trauma, cognitive dysfunction associated with brain tumors, and attention deficit.

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of Alzheimer's disease, parkinson's disease, huntington's disease, cognitive dysfunction (e.g., cognitive dysfunction associated with chemotherapy, narcotics or bacterial or viral infections (e.g., HIV), memory deficits, age-related cognitive dysfunction (e.g., mild cognitive dysfunction, MCI), bipolar disorder, autism, down's syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, amyotrophic Lateral Sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorders, schizophreniform disorders, substance-induced psychotic disorders or paranoid disorders), psychosis, post-traumatic stress disorders, anxiety disorders, generalized anxiety disorders, panic disorders, delusional disorders, obsessive-compulsive disorders, acute stress disorders, drug addiction, alcohol disorders (e.g., alcohol addiction), drug withdrawal symptoms, movement disorders, restless leg syndrome, cognition deficit disorder, multi-infarct dementia, vascular dementia, cognitive dementia, neurological disorders, cognitive impairment, cognitive dysfunction or cognitive impairment associated with cognitive dysfunction, stroke-related pain, cognitive impairment and cognitive dysfunction.

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of cognitive dysfunction associated with alzheimer's disease.

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of cognitive dysfunction associated with huntington's disease.

Chromosome 15q11.2-13.1 repeat syndrome (Dup 15q syndrome) is a rare disease caused by 15q11.2-13.1 chromosome partial repeats. Dup15q syndrome is characterized by hypomyotonia, coarse and coarse symptomsFine motor retardation, varying degrees of intellectual disability, autism spectrum disorders, and epilepsy (including infantile spasticity). Excessive amounts of alpha 5-GABA have been identified in Dup15q syndrome _A Receptor function (potential mechanism of the Dup15q syndrome EEG biomarker by Frohlich et al Mechanisms underlying the EEG biomarker in Dup q syndrome.)]Molecular Autism]10,29 (2019)). One use of Ba Mi Shani (α5-GABA) was also proposed _A R NAM) phase II clinical trial for children with Dup15q syndrome (NCT 05307679).

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the treatment of Dup15q syndrome. The compounds of the invention may be used to treat children suffering from DUP15g syndrome, for example children aged 2 to 11. The compounds of the invention may reduce or eliminate one or more neurological characteristics associated with Dup15q syndrome, such as hypomyosis, bradykinesia, or mental development (e.g., speech or language retardation, cognitive impairment, or social interaction problems).

In certain embodiments, compounds of the invention, or pharmaceutically acceptable salts thereof, are provided for use in the prevention or treatment of chemotherapy-induced cognitive dysfunction in a subject in need thereof. Examples of chemotherapies that can induce cognitive dysfunction include amphetamines, dopamine agonists, ketamine, corticosteroids, and anticonvulsants.

In certain embodiments, the compounds of the invention are useful for treating depression, e.g., treating refractory depression.

Neuroinflammation can induce psychotic and neurological symptoms, such as cognitive dysfunction, and use of alpha 5-GABA _A Treatment with R NAM may be beneficial (Jacob, 2019Frontiers in Molecular Neuroscience [ molecular neuroscience front edge ]],12 179). Thus, in certain embodiments, compounds of the invention are provided for use in the prevention or treatment of psychotic and/or neurological symptoms associated with neuroinflammation. In certain embodiments, the compounds of the invention are useful for treating or preventing cognitive dysfunction associated with neuroinflammation. The neuroinflammation may be chronic neuroinflammation. Neuroinflammation can be caused, for example, by stroke, bacterial infection, viral infection, traumaTraumatic brain injury or autoimmune diseases (e.g., systemic lupus erythematosus) caused by or associated with.

It is well known that bacterial or viral infections can lead to acute and chronic cognitive dysfunction in subjects who are or have been infected with the bacteria or viruses. In particular, viral infection can lead to a so-called "post-viral syndrome", wherein a subject infected with a virus experiences chronic symptoms after viral infection. These symptoms include chronic fatigue, joint soreness, cognitive disorders, or influenza-like symptoms. There is growing evidence that certain subjects infected with SARS-CoV-2 virus may develop chronic symptoms, including cognitive dysfunction in so-called "long-term-COVID" or "post-COVID syndrome" (ravendran et al, 2021Diabetes&metabolic syndrome [ diabetes and metabolic syndrome ],15 (3), 869-875. Thus, the compounds of the invention are useful in treating or preventing cognitive dysfunction caused by or associated with viral or bacterial infection.

In certain embodiments, compounds of the invention are provided for use in the treatment or prevention of psychotic and/or neurological symptoms (particularly cognitive dysfunction) caused by or associated with a viral or bacterial infection.

In some embodiments, the psychotic and/or neurological symptoms (e.g., cognitive dysfunction) are caused by or associated with infection with a bacterium (e.g., a bacterium selected from the group consisting of Chlamydia pneumoniae, helicobacter pylori, borrelia species (e.g., borrelia burgdorferi, ma Yaoshi borrelia, avzeylaria or Gardnerella), treponema, streptococcus pneumoniae, neisseria meningitidis, haemophilus influenzae, listeria monocytogenes, brucella species, mycobacterium tuberculosis, salmonella species and Rickettsia species).

In some embodiments, the mental symptoms and/or neurological symptoms (e.g., cognitive dysfunction) are caused by or associated with a viral infection. In some embodiments, the psychotic symptoms and/or neurological symptoms (e.g., cognitive dysfunction) are caused by or associated with an infection with a virus selected from the group consisting of: coronaviridae (e.g., alphacoronavirus, betacoronavirus, gamma coronavirus, and delta coronavirus), picornaviridae (e.g., enteroviruses such as rhinovirus, human Rhinovirus (HRV)), flaviviridae (e.g., zika virus (ZIKV), dengue (e.g., DENV 1-4), west Nile Virus (WNV), yellow fever virus (YFV such as yellow fever 17D virus), japanese Encephalitis Virus (JEV), hepatitis C Virus (HCV), filoviridae (e.g., ebola virus)), togaviridae (e.g., alphavirus such as chikungunya virus (CHIKV), sindbis virus, and ross river virus), herpesviruses (e.g., gamma-herpesvirus, human herpesvirus 8, herpesvirus 1, herpesvirus 2, varicella zoster virus, cytomegalovirus (CMV), and EB virus (EBV)), adenoviridae (e.g., human adenovirus (HAdV)), lentiviruses (e.g., HIV), and influenza viruses.

In certain embodiments, the psychotic and/or neurological symptoms (e.g., cognitive dysfunction) are caused by or associated with a virus selected from the group consisting of: cytomegalovirus (CMV); herpes simplex virus 1 (HSV-1), HIV, hepatitis, varicella zoster virus, zika virus, EB virus or coronavirus (e.g., SARS-CoV-2) or variants thereof.

In certain embodiments, the mental symptoms and/or neurological symptoms (e.g., cognitive dysfunction) are caused by or associated with: coronaviruses (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 variants thereof.

In certain embodiments, the mental symptoms and/or neurological symptoms (e.g., cognitive dysfunction) are caused by or associated with: coronaviruses causing Severe Acute Respiratory Syndrome (SARS), such as SARS virus or MERS virus, such as SARS-CoV, SARS-CoV-2 or MERS-CoV. Preferably, the viral infection is caused by or associated with: SARS-CoV-2 or variants thereof.

In certain embodiments, the compounds of the invention are useful for treating or preventing cognitive dysfunction caused by or associated with respiratory viral infections, such as Severe Acute Respiratory Syndrome (SARS). In particular embodiments, the compounds of the invention are useful for treating or preventing cognitive dysfunction caused by or associated with covd-19.

In certain embodiments, the compounds of the invention are useful for treating or preventing psychotic and/or neurological symptoms (particularly cognitive dysfunction) in a subject suffering from a viral or bacterial infection. In this embodiment, the psychotic 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.

In certain embodiments, the compounds of the invention are useful for preventing or treating a psychotic and/or neurological symptom (particularly cognitive dysfunction) in a subject suffering from post-viral or post-bacterial infection syndrome. In this embodiment, the subject may have post-viral infection syndrome. In this embodiment, the subject may have post-bacterial infection syndrome. In this embodiment, the compound is administered to the subject after the initial acute bacterial or viral infection, e.g., when the subject has recovered from the initial acute symptoms of the viral or bacterial infection, and/or when the subject is substantially free of infectious bacteria or viruses (e.g., the subject has substantially no viral/bacterial load or very low viral/bacterial load after the initial infection). Bacterial/viral loads in a subject can be determined using well known methods, such as bacterial culture methods and/or suitable diagnostic tests, such as PCR-based methods. The initial (acute) infection may be, for example, an infection by any of the bacteria or viruses described herein. The initial acute bacterial or viral infection may be a symptomatic bacterial or viral infection. Alternatively, the initial infection may be an asymptomatic bacterial or viral infection.

In a particular embodiment, the compounds of the invention are used to treat cognitive dysfunction in a subject, wherein the subject exhibits cognitive dysfunction following SARS-CoV-2 infection. Thus, the compounds of the invention may be used to treat or prevent cognitive dysfunction caused by or associated with covd-19. For example, the compounds of the invention may be used to treat subjects suffering from cognitive dysfunction following a covd-19 infection.

Postoperative cognitive dysfunction (POCD)

Post-operative cognitive dysfunction refers to cognitive dysfunction that occurs after anesthesia and surgery. POCD is a widely accepted clinical phenomenon that involves acute or persistent deficits in post-operative attention, concentration, learning and memory that are not caused by obvious complications or injuries caused by surgery.

POCD is a transient disorder that young patients typically disappear within 3 months. However, POCD occurs much more frequently in elderly patients, 41% of patients over 60 years old showing symptoms 7 days post-surgery. POCD may also last for a long time in elderly patients, >10% of patients show symptoms within 3 months after surgery. POCD is associated with an increased risk of death within 3 months and 1 year after surgery. POCD may also be a risk factor for dementia progression or acceleration (rank et al Anesthesiology [ Anesthesiology ]2008,108 (1), 18-30; moller et al The Lancet [ Lancet ]1998,351 (9106), 857-861; and needle et al British Journal of Anaesthesia [ UK J.Anaesthetic ], volume 2017, volume 119, i115-i 125). Cardiopulmonary bypass (CPB) surgery is most closely tied to POCD, especially because it is one of the most common medical conditions and procedures worldwide. CPB surgery is performed approximately 200,000 times per year in the United states alone, with an average incidence of 62 per 100,000 residents in Western European countries (Melly et al J.Thorac.Dis. [ J.pectoral disease ]2018,10 (3), 1960-1967).

General anesthetics are considered to be responsible for POCD by observing that the duration of anesthesia is positively correlated with the incidence of cognitive deficits in patients post-surgery (Moller 1998 supra). Single exposure to anesthetics can lead to retrograde and retrograde memory deficits that persist in rodent models for days to weeks (cross et al, anesth. Analg. [ anesthesia and analgesia ],2005,101 (5), 1389-92; and Culley et al, anesth. Analg. [ anesthesia and analgesia ],2003,96 (4), 1004-9).

Many general anesthetics act as inhibitory gamma-aminobutyric acid type a receptors (GABA) _A Positive allosteric modulators of R)(Antkowiak et al, curr. Opin. Anaethesiosiol. [ current view of anesthesiology)]2016,29 (4),447-453). During anesthesia, GABA _A The increase in R activity helps the anesthetic drug achieve the desired, profound neurological suppression properties. GABA after stopping administration of anesthetic _A Positive allosteric modulation of R function is rapidly reversed, thus assuming that receptor activity is restored to baseline, and GABA _A R does not lead to poor long-term cognitive dysfunction after anaesthesia (Belelli et al, br. J. Pharmacol. [ J. Pharmacol., UK.)]1996,118 (3),563-76). However, this assumption has recently been challenged by the following observations: alpha 5-GABA _A The R-deleted mice did not exhibit symptoms of cognitive deficit in new object recognition experiments following exposure to isoflurane. In contrast, wild-type mice exhibited reduced cognitive ability, meaning that α5-GABA _A R plays a role in cognitive deficits caused by anesthetics (Zurek et al anesth]2012,114 (4),845-855). Changes in Long-term potentiation of rat amygdala brain sections were also observed following repeated, rather than single doses of isoflurane (Long et al, neural Plast. [ neuroplasticity]2016,8524560-8524560)。

Single treatment of mice with etomidate, an injection anesthetic, increased alpha 5-GABA _A Stress-suppressing current and alpha 5-GABA produced by R _A Cell surface expression of R lasted for at least 1 week (Zurek 2012, supra). Alpha 5-GABA _A Sustained increases in R activity impair the memory performance and synaptic plasticity of the hippocampus. Also, inhalation of the anesthetic isoflurane induces tension currents and cell surface α5-GABA _A The R expression increases continuously. Thus, after anesthetic elimination, alpha 5-GABA _A The R function does not return to baseline, indicating that there is a mechanism to account for persistent memory deficit following general anesthesia. The study also showed that the memory performance of mice was impaired up to 72 hours after a single etomidate treatment in the new object recognition task. However, although the stress current still increased, the memory performance recovered after 1 week. Given the wide demonstration of hippocampal homeostasis plasticity, a sustained increase in tension current may trigger compensatory changes that contribute to memory performance recovery. Use of alpha 5-GABA _A Inhibition of alpha by R NAM L-655,7085-GABA _A R completely reversed etomidate-induced memory deficit. Further studies showed that, although no other anesthetic was evaluated, alpha 5-GABA on non-pyramidal cells _A R probably most important for the effect on LTP seen with etomidate (Rodgers et al The Journal of Neuroscience: the official journal of the Society for Neuroscience [ journal of neuroscience: journal of the official journal of the neuroscience society)]2015,35(26),9707-9716)。

L-655,708 was able to prevent but not reverse cognitive deficit in isoflurane anesthetized aged rats in the Morris-Water Maze (Morris-Water Maze) experiment. This is in sharp contrast to young rats where the compound is able to prevent and reverse cognitive effects (Zhao et al, nerve regen. Res. [ nerve regeneration study ]2019,14 (6), 1029-1036).

In addition, benzodiazepines are usedThe quasi-drug is associated with increased risk of developing POCD, and studies indicate that 2.5mg of midazolam doubles the risk of developing POCD. Due to benzodiazepine->The drug is GABA _A Nonspecific positive allosteric modulators of R, suggesting that overdriving these receptors may lead to or exacerbate POCD.

POCD may also be associated with surgery-induced inflammation. A comprehensive overview of the underlying mechanisms of POCD inflammatory hypothesis has recently been published by Safavynia and Goldstein (Frontiers in psychiatry [ psychiatric front ]2019,9,752-752). It is thought that the disruption of the peripheral surgical wound through the Blood Brain Barrier (BBB) leads to CNS inflammation, which in turn leads to disruption of neuroactive function, leading to POCD. In addition, TNFα can suppress inhibitory neurotransmission through down-regulation of GABA receptors, disrupting the subtle balance of excitatory and inhibitory neurotransmission, ultimately favoring glutamate toxicity (Pribiag et al, J. Neurosci. [ J. Neuroscience ]2013,33 (40), 15879-93).

Acute inflammation reduces the hippocampus of wild-type miceLong-term enhancement (memory synaptic correlation) in slices and this decrease can be achieved by inhibition of alpha 5-GABA _A R function is reversed (Wang et al, cell reports [ Cell report ]]2012,2 (3),488-496). Alpha 5-GABA in hippocampal neurons _A The tone-suppressing current produced by R is increased by the key pro-inflammatory cytokine interleukin-1 beta through the p38 mitogen-activated protein kinase signaling pathway. Interleukin-1 beta also increases alpha 5-GABA in the hippocampus _A Surface expression of the receptor (Wang et al, supra).

By pretreatment with the inflammatory cytokine interleukin-1 beta, current induced by GABA was increased in cultured hippocampus and cortical neurons using etomidate or isoflurane. Lipopolysaccharide also increases the immobilization properties of etomidate (rather than isoflurane) in vivo, suggesting that inflammation increases sensitivity to some anesthetics (Avramescu et al, anesthesiology [ Anesthesiology ]2016,124 (2), 417-27).

In comparison with mice treated with vehicle, in the presence of benzodiazepineDrug-like site modulators (diazepam and brotizolam) and GABA _A In R agonist (musculol) treated mice, LPS treatment significantly increased the duration of pentobarbital-induced loss of eversion (LORR). These effects are mediated by dicentraine (GABA) _A R antagonists) blocking (Kitamura et al European Journal of Pharmacology [ J. European Pharmacol.)]2019,842,231-238)。Gabra5 ^-/- There was no inflammation-induced defect of contextual fear memory with LPS in mice, and alpha 5-GABA could be inhibited by L-655,708 in wild-type mice _A R for prophylaxis (Wang et al, cell reports]2012,2 (3),488-496). Extracellular levels of GABA and GABA were also observed in the neuroinflammatory rat model _A Increased expression levels of the α5 subunit membrane of the receptor (Agusti et al, CNS neurosci. Ther. [ CNS neuroscience and therapeutics.)]2017,23(5),386-394)。

According to another aspect, there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of POCD in a subject.

In certain embodiments, the subject has or will undergo a significant surgical procedure, such as a surgical procedure that lasts at least one hour. Examples of surgical procedures include the heart; a blood vessel; ear, nose and throat; shaping; gynaecology; orthopedics department; urology department; or ophthalmic surgery. In certain embodiments, the subject has or is about to undergo a cardiac procedure, such as a coronary bypass procedure. In certain embodiments, the subject has or will be subjected to an orthopedic procedure, such as a hip or knee replacement procedure.

In certain embodiments, the subject is anesthetized with a general anesthetic, for example an anesthetic selected from the group consisting of: intravenous anesthetics (e.g., etomidate, propofol, fospropofol, barbiturates (e.g., ipratropium, methoprene, thiobarbital, or thiobarbital), benzodiazepinesClass of drugs (e.g. diazepam, lorazepam or midazolam), triazolobenzodiazepineClass of drugs (e.g. alprazolam), thienotriazolodiazepine>A drug-like substance (e.g., brotizolam), dexmedetomidine, ketamine, and an opioid (e.g., fentanyl, alfentanil, remifentanil, or sufentanil); and inhalation anesthetics (e.g., nitrous oxide, xenon, cyclopropane, or volatile anesthetics (e.g., halogenated anesthetics (e.g., halothane, enflurane, isoflurane, sevoflurane, or desflurane)).

In certain embodiments, the POCD is anesthesia induced POCD. For example, POCD induced by or associated with a general anesthetic (e.g., one or more of the general anesthetics described above). In certain embodiments, the POCD is an inflammation-induced POCD, such as inflammation induced by or associated with a major surgical procedure (e.g., one or more of the surgical procedures described above).

The compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered to a subject before, after, or during surgery. In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered to a subject prior to surgery. In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered to a subject during surgery. In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered to a subject after surgery.

In certain embodiments, the subject is at least 60 years old. In certain embodiments, the subject is less than 60 years old, e.g., 18 to 59 years old.

The extent of cognitive dysfunction associated with surgery and the role of the compounds of the invention in therapeutic POCD can be assessed using a suitable clinical scoring system. For example, subjects may be evaluated and scored before and after surgery. For example, subjects may be scored 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days prior to surgery. Patients may be scored 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, 1 month, 2 months, 3 months, 6 months, or 12 months after surgery. The severity of POCD in a subject can be determined by comparing clinical scores before and after surgery. Similarly, the effect of a compound of the invention on treatment or prevention of POCD can be determined by comparing clinical scores before and after treatment with a compound of the invention. Suitable scoring systems for assessing cognitive function are well known and include, for example, cogState Brief Battery (CBB) (Maruff et al, 2013,BMC psychology[BMC psychology ] volume 1, 1 30). The field of immediate memory, visual space and delayed memory can be assessed by a repeatable set of neuropsychological state assessments (Repeatable Battery for the Assessment of Neuropsychological Status, RBANS) (Karantzoulis et al, 2013, arch. Clin. Neuropresychol. [ clinical neuropsychological archives ];28 (8): 837-44). The speech fluency and executive function may be assessed using a controlled spoken language association test (Controlled Oral Word Association Test, COWAT) (Malek-Ahmadi et al, 2011, segment Geriatr. Cognition. Disord. [ dementia and senile cognitive impairment ];32 (4): 235-40). Visual space and executive function may be assessed using trajectory planning tests (Trail Making Tests) A and B (TMT) (Terada et al 2013,Psychiatry Res [ psychiatric Studies ];213 (3): 249-55).

Selectivity of

Nonselective GABA inhibition _A R may cause undesirable side effects such as convulsions and/or anxiety-causing effects. Selective alpha 5-GABA _A R inhibition is expected to provide beneficial therapeutic effects, such as improving cognition while avoiding or minimizing non-selective GABA _A R inhibits the risk of associated undesirable side effects (e.g., convulsions and/or anxiogenic effects).

Thus, preferred compounds of the invention are directed against GABA that does not contain the alpha 5 subunit _A R pair contains GABA _A The α5 subunit of R has selective affinity and/or reduces its function. For example, GABA containing the α1, α2, α3, α4 or α6 subunit _A R vs. the compounds of the invention are directed to alpha 5-GABA _A R has selective affinity and/or selectively inhibits its function. In certain embodiments, the compounds of the invention are useful for the treatment of alpha 5-GABA when measured using the in vitro radioligand binding assays described herein _A Affinity (Ki) alignment of R to GABA containing alpha 1-, alpha 2-or alpha 3-subunits _A The Ki of the receptor is 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).

In some embodiments, the compounds of the invention exhibit α5gaba when measured in the in vitro electrophysiology recording assays described herein _A R NAM activity. Preferred compounds of the invention are relative to GABA containing the alpha 1, alpha 2 or alpha 3 subunit when measured in the in vitro electrophysiological recording assay described herein _A R selective inhibition of alpha 5-GABA _A Function of R.

Relative to GABA containing an alpha 1-, alpha 2-or alpha 3-subunit _A R, preferred compounds of the invention are directed to alpha 5-GABA _A R has selective affinity and selectively inhibits alpha 5-GABA _A Function of R.

In certain embodiments, such selective compounds may be used to treat or prevent any of the diseases or medical conditions described herein.

Combination therapy

The compounds of the present invention may be used alone to provide therapeutic effects. The compounds of the present invention may also be used in combination with one or more additional therapeutic agents.

In some 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, norsertraline or fluoxetine;

typical or atypical antipsychotics;

acetylcholinesterase inhibitors (e.g., galantamine or donepezil);

anti-inflammatory agents;

GABA other than the Compound of the present invention _A R modulators, e.g. via GABA _A GABA acting as a surrogate binding site on the R receptor _A R modulators, or acting on GABA through alternative subunits _A GABA of R _A An R regulator;

antiepileptic drugs (e.g., acetazolamide, buvaracetam, cannabidiol, carbamazepine, clobazam, clonazepam, eslicarbazepine, ethosuximide, everolimus, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pamphlet Fu Ni, pirenzenene, phenobarbital, phenytoin, piracetam, pregabalin, paminone, prafenoamide (pufinamide), sodium valproate, settop, tiagabine, topiramate, valproic acid, vigabatrinor, or zonisamide); or alternatively

Agents that inhibit the metabolic rate of the compounds of the invention.

Such combination therapy may be achieved by simultaneous, sequential or separate administration of the individual components of the therapy. Such combination products employ the compounds of the invention in the therapeutically effective dosage ranges described above and other pharmaceutically active agents in approved dosage ranges.

Herein, when the term "combination" is used, it is understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to administration alone. In another aspect of the invention, "combination" refers to sequential administration. In the case of sequential or separate administration, the delay in the administration of the second component should not be such that the beneficial effects of the combination are lost.

In some embodiments using combination therapy, the amount of the compound of the invention and the amount of one or more other pharmaceutically active agents, when combined, are therapeutically effective for treating a targeted disorder in a patient. Herein, a combined amount is a "therapeutically effective amount" if the combination is sufficient to achieve: alleviating or completely alleviating symptoms of the disorder or other deleterious effects; curing the disorder; reversing, stopping altogether, or slowing the progression of the disorder; or reduce the risk of deterioration of the disorder. Typically, such amounts may be determined by one of skill in the art, for example, starting from the dosage ranges of the compounds of the invention described in this specification and one or more dosage ranges approved or otherwise published for one or more other pharmaceutically active compounds.

Biological assays

The biological effects of the compounds can be assessed using one or more of the assays described herein.

Cell lines

Stable expression of human α1β3γ2, α2β3γ2, α3β3γ2, α5β3γ2gaba _A R mouse L (tk) ^- ) Cells (by growth in mouse L (tk) ^- ) Transfection of dexamethasone with the various subunits of the expression vector pMSGneo (Hadingham et al, 1993, mol. Pharmacol. [ molecular pharmacology ] ]43:970-975 and 1993 mol. Pharmacol. [ molecular pharmacology ]]44:1211-1218) for binding and functional assays. For certain compounds, stable expression of human α1β3γ2l, α2β3γ2l, α3β3γ2l, and α5β3γ2l GABA was used _A HEK293 cells of the receptor to evaluate their functional effects in a SyncroPatch electrophysiology assay.

Cell culture

Will stabilizeExpression of human α1β3γ2, α2β3γ2, α3β3γ2, α5β3γ2gaba _A L (tk) of R ^- ) Cells were incubated in an incubator at 37℃with 5% CO ₂ Is maintained in DMEM F12 medium supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and 1mg/mL geneticin G418.

For the QPatch electrophysiology test, 1 μm dexamethasone was added to L (tk) 24 hours before recording ^- ) In the medium of the cells. Cells are typically used for electrophysiology experiments 72-96 hours after resolution.

In vitro radioligand binding assay (alpha 5-GABA) _A R Ki)

Compound recombinant GABA for human _A Benzodiazepines of RAffinity (Ki) of the drug-like site inhibits selective benzodiazepine by means of it>Class of pharmaceutical antagonists ³ H]Ro15-1788([ ³ H]Flumazenil) binding capacity.

Harvesting human recombinant GABA expressing alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 5 beta 3 gamma 2 subunit _A L (tk) of R ^- ) Cells and in phosphate buffer (K ₂ PO ₄ Preparation of membranes for each receptor combination in 10mM, pH 7.0 (Hadingham et al (1992) Proc. Natl. Acad. Sci. USA [ Proc. Natl. Acad. Sci. USA, USA. Natl. Sci. USA. Natl. Sci. USA)]The method comprises the steps of carrying out a first treatment on the surface of the 89 (14):6378-82). Prior to evaluating the Ki value of a compound, determination is made ³ H]Protein concentration, receptor expression and Kd of Ro 15-1788. For Kd evaluation, by associating membranes with different concentrations [ ³ H]Ro15-1788 (82.5 Ci/mM) was incubated together to obtain a saturated binding curve and non-specific binding was measured in the presence of 1. Mu.M TP 003.

[ ³ H]Ro15-1788([ ³ H]Flumazenil) tritiated on N-methyl as follows:

TP003 non-selective GABA _A R benzodiazepinesA drug-like site agonist having the formula:

for Ki evaluation, cell membranes were incubated with 4nM [ ³ H]Ro15-1788 and a range of concentrations of test compound. Nonspecific binding was determined using 1 μm TP 003. All incubations were performed in assay buffer at 4℃for 1 hour. The total assay volume was 0.5mL containing 100 μg membrane protein/well α1β3γ2, α2β3γ2, α3β3γ2, and 50 μg membrane protein/well α5β3γ2. Incubation was terminated by filtration over Whatman GF/B filters and washing with ice-cold Tris-HCl buffer (50 mm, ph=7.4) and radioactivity of the filters was measured using liquid scintillation counting.

Will [ ³ H]The% inhibition of Ro15-1788 binding is plotted as a function of compound concentration and IC is calculated ₅₀ . According to IC ₅₀ Methods using Cheng and Prusoff, use [ [ ³ H]The Kd value obtained from Ro15-1788 is used to calculate the affinity (Ki).

The compounds of the present invention tested in the above assay were found to be useful for the detection of alpha 5-GABA _A R has affinity. Relative to alpha 1-, alpha 2-, and alpha 3-GABA _A R, preferred compounds are directed to alpha 5-GABA _A R has Ki<30nM and selectivity (20-1000 fold).

In vitro electrophysiological recording assay (alpha 5-GABA) _A R relative efficacy

The efficacy of the modulators was assessed using an automated patch clamp platform QPatch16 (Sophion corporation, copenhagen, denmark) or SyncroPatch384i (naine technologies corporation (Nanion Technologies), germany). Cells were harvested from flasks by enzymatic hydrolysis and resuspended in serum-free medium.

For QPatch recordings, all experiments were performed at room temperature (20 ℃ -22 ℃) using standard whole cell procedures and physiological solutions. The gigaseal is formed after performing the combined pumping/voltage scheme, with subsequent increased pumping resulting in whole cell configuration. The recorded current was collected at 1KHz and filtered at 0.3KHz using a Bessel (Bessel) filter. Whole cell current was measured at a holding potential of-65 mV.

For the syncopatch recordings, a stack addition protocol was used, in which GABA was applied rapidly and then washed out of the cells. All experiments were performed using standard whole cell procedures at room temperature (20-22 ℃). The recorded current was collected at 2kHz and filtered using a bessel filter. Whole cell current was measured at a holding potential of-80 mV.

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

For syncopatch recordings, the extracellular recording solution contains: 140mM NaCl, 4mM KCl, 2mM CaCl ₂ 、1mM MgCl ₂ 10mM HEPES, 5mM glucose (pH 7.4, osmolality about 300-310 mOsm/L). The intracellular recording solution comprises: 90mM KCl, 50mM KF, 1.5mM MgCl ₂ 11.1mM EGTA and 10mM HEPES (pH 7.2, osmolality about 300 mOsm/L). On the day of the test, 2mM NaATP was added to the intracellular solution.

In the presence of sub-maximum GABA concentrations (which typically give 10-20% activation of the response caused by saturated GABA concentrations (GABA EC _10-20 ) The effect of the regulator is evaluated in the case of a). For QPatch recordings, GABA EC was continuously applied alone prior to compound addition in order to check and ensure baseline current stability prior to compound addition _10-20 Five times (each application lasts 2 seconds, with a rinse time of at least 1 minute interval). At and GABA EC _10-20 At least 1 minute prior to co-application, the test compound is applied using a pipetting system of the QPatch system. For the SyncroPatch record, GABA EC was applied alone prior to compound addition ₂₀ Three times (1 second long application with a wash step in between). Followed by pre-incubation with test compound for 1-2 minutes, followed by re-application of GABA EC in the presence of compound _10-20 . Finally, after a further washing step, a saturated concentration of GABA is applied, so that the baseline activation percentage per cell caused by the applied sub-maximum GABA can be accurately assessed.

The compounds were first dissolved in DMSO to make a 10mM stock solution, and then further diluted to the test concentration so that the final DMSO concentration in the extracellular recording solution remained constant at 0.1% for QPatch recordings and 0.2% for SyncroPatch recordings.

The% efficacy of the modulator is determined based on the GABA-induced current recorded in the presence and absence of the test compound using the formula:

[ (compound peak current-leakage) - (GABA peak current-leakage))/(GABA peak current-leakage) ]. 100,

where "leakage" is the leakage baseline current at-65 mV, and "compound peak current" is the current caused by the co-application of the compound and GABA, and "GABA peak current" is the current caused by GABA alone during the 5 th GABA application. The results are presented as "relative efficacy" at concentrations of each compound that are generally equal to or higher than 100 times their defined Ki. The relative efficacy of a compound was calculated by normalizing its efficacy against: the efficacy of methyl-6, 7-dimethoxy-4-ethyl- β -carboline-3-carboxylate (DMCM), which efficacy alone is measured, yields a GABA-induced current decay of-57±4%, n=5.

The compounds of the present invention tested in the above assay were found to have a 5-GABA _A R NAM activity and selectivity for the α5 subtype over α1, α2 and α3.

Electrophysiology-long-term potentiation assay of hippocampal slices

Hippocampal long-term potentiation (LTP) is a synaptic plasticity associated with learning and memory formation. When etomidate, an intravenous general anesthetic, is applied acutely to in vitro mouse hippocampal slice preparations, LTP of CA1 pyramidal neurons is compromised. This effect of etomidate Can be coated with alpha 5-GABA _A R NAM reverses, and at α5 ^-/- No occurrence in the equivalent recordings of mice suggests that alpha 5-GABA _A R plays a key role in this form of synaptic plasticity (Martin et al 2009, anesthesiology [ anesthesia ]]The method comprises the steps of carrying out a first treatment on the surface of the 111:1025-1035; zurek et al 2014,J Clin Invest [ journal of clinical research]The method comprises the steps of carrying out a first treatment on the surface of the 124 (12):5437-5441). By determining alpha 5-GABA _A R NAM rescues the ability of LTP to be inhibited by the presence of etomidate to assess its efficacy.

Wild male mice (C57 Bl 6J) 2-5 months old were decapitated after cervical dislocation, and brains were rapidly removed and placed in ice-cold, oxygenated (95% O) ₂ 、5％ CO ₂ ) Artificial cerebrospinal fluid (aCSF) (composition in mM: 124NaCl, 3KCl, 1.75MgCl ₂ 、1CaCl ₂ 、1.25NaH ₂ PO ₄ 、26NaHCO ₃ And 10D-glucose), wherein the osmolality of aCSF is adjusted to 300-310mOsm. Brain sections (400 μm) containing sagittal slices of hippocampus were prepared using VT1000E tissue microtomes (Leica). After a recovery period of 1 hour in oxygenated aCSF, the sections were transferred to a submerged recording chamber where they were incubated with a solution containing 1mM MgCl ₂ And 2.5mM CaCl ₂ Is continuously perfused with oxygenated aCSF.

For electrophysiological recording, single slices were transferred to an immersion recording room (scientific systems design company (Scientific Systems Design), mississauga) (Mississauga), ontario, canada. The oxygenated aCSF solution was maintained at 32 ℃ by a temperature controller (digital timer) proportional temperature controller PTC 03). The slices were oxygenated in a perfusion system with aCSF (flow rate about 2 ml/min).

To monitor basal synaptic transmission, bipolar stimulating electrodes (made by hand from twisted polytetrafluoroethylene coated tungsten wires (An Hong research materials (Advent research materials, ltd), enkem, oxford, uk) or commercial electrodes (world precision instruments (World Precision Instruments), florida, usa)) are used to stimulate Schaffer-side commissure pathways from the CA3 region to the CA1 region of the hippocampus. Stimulation was delivered to the slice every 30 seconds to record the dynamic changes in the neuroevoked field excitatory postsynaptic potential (fEPSP). Stimulation was provided by a constant current isolation electronic stimulator (Digitimer Ltd, model DS2, herfordshire, uk). The stimulus current was adjusted to produce a response of fEPSP slope that was 40% of the maximum population spike-free response. fEPSP was recorded using an aCSF-filled glass borosilicate microelectrode (gold precision glass Co., kind precision glass, inc., claremont, U.S.A.) and placed in the apical dendrite layer of CA1 pyramidal cells.

For the control LTP experiments, the fEPSP generated by the 1/30 second delivered stimulation was monitored for 15-20 minutes to ensure stability (fEPSP slope and amplitude) recorded prior to LTP induction. For subsequent induction of control maximum LTP, a Theta Burst Stimulation (TBS) protocol (4 pulses at 100Hz, repeated 10 times, with a 200ms interval between 4 pulses of each group; 4-TBS) was provided, followed by a return to 1/30 second single stimulation.

After 4-TBS delivery, the fEPSP measurement (1/30 seconds) was monitored for another 60 minutes. fEPSP analysis was performed using WinLTP software (Anderson, https:// www.winltp.com /). LTP was statistically analyzed using GraphPad Prism statistical software and the effect of drug on the extent of LTP was measured by one-way ANOVA 50-60 minutes after 4-TBS and compared to control baseline fEPSP.

By application of vehicle, etomidate or etomidate+α5-GABA prior to delivery of 4-TBS _A R NAM for at least 30 minutes to study etomidate alone or in alpha 5-GABA _A Effect of etomidate on LTP in the presence of R NAM.

Dissolving etomidate in H ₂ 0 as a 10mM stock solution. Alpha 5-GABA _A Stock solutions of R NAM (10 mM; in 100% DMSO) were diluted as necessary with vehicle at a maximum final concentration of 0.01%.

Certain compounds of the invention were tested in the above assays and found to partially or fully restore LTP inhibition by etomidate.

In vivo brain receptor occupancy assay

Inhibition by Compounds [ ³ H]L-655,708 in vivo binding capacity to measure Compound to rat brain benzodiazepinesOccupancy of drug-like binding sites. The radioligand pair contains GABA of alpha 5 subunit _A Recipient benzodiazepine>Site-selective class of drugs (Quirk et al 2001,Journal of Neurochemistry journal of neurochemistry ]77445-51) and has been previously used to measure α5-GABAAR occupancy in vivo (Atack et al 2005, neuropharmacology [ neuropharmacology ]],49 220-229)。/>

Male Sprague-Dawley rats (250-310 g, 4-6 per group) were dosed orally (5 mL/kg) with vehicle (0.5% methylcellulose) or test compounds suspended in vehicle (1, 3 and 10 mg/kg) 30 minutes to 4 hours before death. To block all benzodiazepinesClass drug binding sites and therefore are defined [ ³ H]L-655,708, another group of animals received an oral dose of TPA023 (5 ml/kg) of 10mg/kg made of 0.5% methylcellulose (Atack et al 2008CNS Neuroscience Therapeutics[CNS neuroscience and therapeutics)]14 25-35). Animals pretreated with compound received tail vein injection one minute prior to sacrifice ³ H]L-655,708 (0.5. Mu.L/g, 30Ci/mM,1:60 diluted in 0.9% NaCl solution).

Animals were then sacrificed by stunning and decapitation, the whole brain was removed quickly, cerebellum and brainstem were discarded, forebrain was left, weighed and homogenized in 10 volumes of ice-cold homogenization buffer (10 mM potassium phosphate buffer, pH7.4, containing 100mM KCl). Aliquots (500. Mu.L) were then added directly to scintillation vials (total radioactivity) or filtered through Whatman glass microfiber GF/B filters and washed with 5ml Tris-HCl buffer (50 mM, pH 7.4). The washed filters were then placed in scintillation vials (three filters per vial) and scintillation fluid was added to all vials, which were then counted on a Perkin-Elmer Tricarb 2900TR scintillation counter (membrane bound radioactivity).

The percentage occupancy is defined as the percentage of specific binding in the vehicle-treated group that is inhibited by the drug treatment. Thus, in vivo binding of the modulator in the drug-treated animals is expressed as: % binding = [ (cpm vehicle-cpm sample)/(cpm vehicle-cpm NSB) ]. 100, where "cpm vehicle", "cpm sample" and "cpm NSB" are the average counts of vehicle, modulator and TPA023 treated animals, respectively.

Certain compounds of the present invention were tested in the above assays and showed that brain alpha 5-GABA in vivo when orally administered _A R is jointed.

Other in vivo assays

The in vivo biological effects of the compounds can be assessed using other assays, some of which can be T-maze spontaneous alternation tasks (a behavioral test widely used to assess cognitive abilities of rodents) and in vivo EEG recordings made (which give a measure of the brain network involved).

Spontaneous alternation task in T maze is a hippocampal-dependent task, is sensitive to various pharmacological manipulations affecting memory process, and alpha 5-GABA _A R NAM may be tested in this assay to reverse induced cognitive deficits (Gerlai, 1998Behav.Brain Res. [ behavioral and brain studies]The method comprises the steps of carrying out a first treatment on the surface of the 95 91-101 parts; andribameloson et al 2014, pharmacol. Res. Perspect [ Pharmacology Studies prospect ] ]；2(4):e00048)。

Performing in vivo rodent EEG recordings may be another suitable assay for assessing alpha 5-GABA _A Influence of R NAM on EEG Power Spectrum reflecting in vivo changes in brain activity in awake rodents (Zanos et al 2017, eNeuro;4 (1): ENEURO. [ neurology)]0285-16.2017)

Synthesis

In the description of the synthetic methods described below and in the reference synthetic methods for preparing the starting materials, it should be understood that all the reaction conditions presented, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and post-treatment procedures, can be selected by a person skilled in the art.

Those skilled in the art of organic synthesis will appreciate that the functional groups present on each part of the molecule must be compatible with the reagents and reaction conditions used.

The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in connection with the following representative process variants and in the examples that follow. Alternatively, the necessary starting materials may be obtained by similar procedures as shown within the ordinary skill of the organic chemist.

It will be appreciated that during the synthesis of the compounds of the invention in the methods defined below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents from their undesired reactions. The skilled chemist will understand when such protection is required and how to put such protecting groups in place and subsequently remove them.

For examples of protecting groups, see one of many general texts on this subject, for example 'Protective Groups in Organic Synthesis [ protecting group in organic Synthesis ]' (publisher: john Wiley & Sons [ John Wili parent-child publishing company ]). The protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as being suitable for removing the protecting groups in question, such a method being chosen so as to effect removal of the protecting groups with minimal interference from groups elsewhere in the molecule.

Thus, if a reactant includes a group such as an amino, carboxyl, or hydroxyl group, it may be desirable to protect the group in some of the reactions mentioned herein.

Suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example alkanoyl groups, such as acetyl or trifluoroacetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl, or aroyl groups, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups may be prepared, for example, by reacting with a suitable compound such as an alkali metal hydroxide (e.g., lithium hydroxide or sodium hydroxide) The base is hydrolyzed for removal. Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon or by treatment with a Lewis acid (e.g., BF ₃ .OEt ₂ ) Processing to remove. Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g. dimethylaminopropylamine) or with hydrazine.

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

Suitable protecting groups for the carboxyl groups are, for example, esterifying groups, e.g. methyl or ethyl groups which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups which can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid, or benzyl groups which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Resins may also be used as protecting groups.

General synthetic routes

The compounds of the present invention may be prepared by a variety of synthetic routes including, but not limited to, the following routes.

Compounds of formula (I) wherein ring B is linked to the remainder of the compound of formula (I) through a ring nitrogen in ring B may be prepared by reacting: a compound of formula (a):

wherein Lg1 is a suitable leaving group; and is also provided with

Ring A, R ³ X ¹ 、X ² And X ³ A compound having any of the meanings defined herein, with the exception of any functional group which is protected if necessary, and of formula (B):

wherein ring B has any of the meanings defined herein, except for any functional groups that are protected if necessary, provided that ring B has an-NH-group;

and optionally thereafter performing one or more of the following procedures:

● Converting a compound of formula (I) to another compound of formula (I); and/or

● Removing any protecting groups; and/or

● Forming a pharmaceutically acceptable salt.

Lg1 is a suitable leaving group, such as halo, particularly Br or I. Suitably, the reaction is carried out in a suitable solvent (e.g. DMSO, DMF or NMP) 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).

The compounds of formula (a) may be prepared using, for example, reaction scheme 1:

reaction scheme 1:

wherein ring A, R ³ X ¹ 、X ² And X ³ Having any of the meanings defined herein, except any functional groups that are protected when necessary; and Lg ₁ Is a suitable leaving group.

Reaction scheme 1 notice

(1): the carboxylic acid (B) is coupled with the aniline (C). The reaction is suitably carried out in the presence of a suitable activator (e.g. EDC, HATU, HBTU, pyBroP or T3P). The coupling reaction is suitably 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-diisopropylethylamine or DMAP).

(2): the carboxylic acid (B) can be converted to the corresponding acid chloride (D) using known methods. For example 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 (e.g., DMF).

(3): the acid chloride (D) is reacted with aniline (C). The reaction is suitably 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).

(4): reacting carboxylic acid (B) with a suitable activator, such as 1,1' -Carbonyldiimidazole (CDI), in a suitable solvent, such as THF, 1, 4-dioxane or DCM, gives CDI adduct (E).

(5) The adduct (E) is reacted with aniline in the presence of a suitable base, such as lithium bis (trimethylsilyl) amide, in a suitable solvent, such as THF or dioxane, to give compound (a).

The carboxylic acid (B), aniline (C) and ring B are commercially available or can be prepared using well 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 h.m. et al 2012Journal of Medicinal Chemistry [ journal of pharmaceutical chemistry ] 552144-2153).

Compounds of formula (I) wherein ring B is attached to the remainder of the compound of formula (I) through a ring carbon atom in ring B may be prepared by coupling: a compound of formula (A1):

Wherein Lg ₂ Is a halo or triflate; and is also provided with

Ring A, R ³ X ¹ 、X ² And X ³ With any meaning defined herein, except that any functional group, if necessary, is protected, with a compound of formula (F):

wherein ring B has any of the meanings defined herein, except for any functional groups that are protected if necessary, and

bx is boric acid or an ester thereof, or a trifluoroborate;

and optionally thereafter performing one or more of the following procedures:

● Converting a compound of formula (I) to another compound of formula (I); and/or

● Removing any protecting groups; and/or

● Forming a pharmaceutically acceptable salt.

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

The group Bx may be boric acid (-B (OH) ₂ ). Alternatively, bx may be a borate ester, such as catechol borate, pinacol borate, alkyl glycol esters (e.g., 1, 3-propanediol or neopentyl glycol esters). In certain embodiments, bx is a trifluoroborate (e.g., a potassium trifluoroborate salt).

The compounds of formula (F) are commercially available or can be prepared using well known methods.

Compounds of formula (I) wherein ring B is attached to the remainder of the compound of formula (I) through a ring carbon atom in ring B may be prepared by coupling: a compound of formula (G):

wherein Bx is boric acid or an ester thereof, or a trifluoroborate; and is also provided with

Ring A, R ³ X ¹ 、X ² And X ³ A compound having any of the meanings defined herein, except any functional groups that are protected if necessary, with formula (H):

wherein ring B has any of the meanings defined herein, except for any functional groups that are protected if necessary, and

Lg ₂ is a halo or triflate;

and optionally thereafter performing one or more of the following procedures:

converting a compound of formula (I) into another compound of formula (I); and/or

Removing any protecting groups; and/or

Form a pharmaceutically acceptable salt.

The coupling reaction may be carried out using a method similar to the coupling of (A) and (F) described above.

The compounds of formula (G) may be prepared by converting the compounds of formula (a) to their corresponding boronic acid or boronic ester using a suitable boron reagent, for example 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1,3, 2-dioxapentaborane, in the presence of a suitable catalyst, for example [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, and a suitable base, for example potassium acetate. The reaction is suitably carried out in the presence of a suitable solvent, such as dioxane or DMSO. The compounds of formula (H) are commercially available or can be prepared using well known methods.

The compounds of formula (I) may also be prepared according to scheme 2, among others:

reaction scheme 2:

wherein ring A, ring B, R ³ X ¹ 、X ² And X ³ Having any of the meanings defined herein, except any functional groups that are protected when necessary;

and optionally thereafter performing one or more of the following procedures:

● Converting a compound of formula (I) to another compound of formula (I); and/or

● Removing any protecting groups; and/or

● Forming a pharmaceutically acceptable salt.

The reaction conditions of steps (1), (2), (3), (4) and (5) are similar to those described in reaction scheme 1 above.

The compounds of formula (J) are commercially available or may be prepared using well known methods, such as those described in the examples herein.

Examples

Abbreviations (abbreviations)

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Naming the name

Exemplary compounds were named using the Dotmatics ELN or Perkin-Elmer ChemDraw software. Other compounds, particularly commercial agents, use either the names generated by the Dotmatics ELN or Perkin-Elmer ChemDraw software or the names commonly found in online databases and directories.

NMR

All NMR spectra were obtained using the following: varian VNMRS 600; varian VNMRS 500; bruker Avance III 500 or Bruker Avance 400 spectrometer. Chemical shifts are expressed in parts per million (ppm, delta) relative to residual isotopic solvent, for example as described in Gottlieb et al J.org Chem [ journal of organic chemistry ] (1997) 62 7512. The observed multiplicity of certain signals is abbreviated as: s (single peak); br (broad peak); d (doublet); t (triplet); q (quartet); m (multiple peaks); or a combination thereof. The number of protons (n) for a given resonance signal is denoted nH. The coupling constant (J) is accurate to 1 bit after the decimal point in Hz.

Mass spectrometry

Mass spectral data were obtained as part of LCMS analysis using the following recordings: waters 2695HPLC was used in conjunction with Thermo LCQ ESI-MS or APCI-MS mass spectrometers; shimadzu Prominence series was used with LCMS-2020ESI and APCI mass spectrometers, or Waters acquisition H grade plus UPLC with Waters Acquity QDa API-ES mass detector. Only molecular ions, fractions of molecular ions, and other major peaks are reported in mass/charge (m/z) ratios.

Example 1N- (6-imidazol-1-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1 Synthesis of intermediate 1-N- (6-bromo-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

5-methyl-3-phenyl-1, 2-oxazole-4-carboxylic acid (10 g,49.25 mmol) was suspended in SOCl ₂ (39.5 mL,541.77 mmol). The mixture was aliquoted into 4x 20ml Biotage microwave vials and heated to 65 ℃ overnight using aluminum heat blocks. After cooling to room temperature, the vials were combined and excess SOCl was removed under reduced pressure in a fume hood ₂ . The residue was dissolved in DCM (10 mL) and added dropwise to 6-bromo-2-methoxy-3-pyridinamine (10 g,49.25 mmol) and Et ₃ N (8.2 mL,59.1 mmol) in DCM (50 mL) pre-cooled in an ice bathA solution. After the addition was complete (about 10 minutes), the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (60 mL) and washed successively with water (2X 50 mL), 2M NaOH solution (2X 40 mL), 1M HCl solution (3X 40 mL) and brine (40 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give N- (6-bromo-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (intermediate 1) as a brown solid (18.14 g,90% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.54 (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[ M+H ]] ⁺ For the following ⁸¹ Br。

Step 2

Intermediate 1 (1.00 g,2.58 mmol), imidazole (220 mg,3.23 mmol), L-proline (120 mg,1.04 mmol) and K ₂ CO ₃ (720 mg,5.21 mmol) in DMSO (10 mL) was bubbled with nitrogen for 10 min. Copper iodide (200 mg,1.05 mmol) was added to the mixture and heated to 80 ℃ in a sealed 20mL microwave vial with conventional heating overnight. The mixture was partitioned between 200mL EtOAc, 200mL water and 100mL brine. The mixture was filtered through celite, separated and the aqueous phase extracted with EtOAc (2×150 mL). The combined organic layers were washed with 100mL of 1:1 water, brine, over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Purification by flash silica column chromatography on an ISCO system (24 g silica, eluting with a 0-5% MeOH/DCM gradient) gave about 800mg of an orange solid. It was redissolved in refluxing isopropanol (10 mL). About 10mL of water was added to initiate precipitation. After returning to reflux, the solution was first filtered hot and cooled to room temperature, and then left in a-20 ℃ refrigerator for 30 minutes. The solid was isolated by filtration and washed with 20mL of cold (-20 ℃) isopropanol to give N- (6-imidazol-1-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (550 mg, 56% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.62(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] ⁺ 。

Example 2N- (4-imidazol-1-yl-2-methoxy-phenyl) -5-methyl-3-phenyl-isoxazole-4-carboxylic acid amide

Step 1

To a solution of 4-fluoro-2-methoxy-1-nitro-benzene (1.00 g,5.8 mmol) in DMF (20 mL) was added K ₂ CO ₃ (178 mg,5.8 mmol) and imidazole (480 mg,7.0 mmol). The reaction mixture 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). ¹ H NMR (500 MHz, chloroform-d) δ8.03 (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)] ⁺ 。

Step 2

A solution of 1- (3-methoxy-4-nitro-phenyl) imidazole (350 mg,1.6 mmol) in MeOH was degassed by bubbling nitrogen for 3 min. Palladium on carbon (34 mg,0.03 mmol) was added, the atmosphere was replaced with hydrogen, and the reaction was carried out under H ₂ (balloon) stirring for 2 hours. TLC indicated 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 as a pale pink solid (230 mg,72% yield). ¹ H NMR (500 MHz, chloroform-d) delta 7.72 (s, 1H), 7.16 (dt, J=10.0, 1.2Hz, 2H), 6.81-6.76 (m, 2H), 6.73 (d, J=8.1 Hz, 1H), 3.91 (s, 2H), 3.88 (s, 3H) m/z 190.1[ M+H ] ] ⁺ 。

Step 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 minutes, then 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 (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated under reduced pressure. Through ISCO systemPurification by flash silica column chromatography (elution with a 2% meoh/DCM gradient) afforded N- (4-imidazol-1-yl-2-methoxy-phenyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a yellow solid (95 mg,46% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.56 (d, J=8.7 Hz, 1H), 7.82 (s, 2H), 7.67-7.52 (m, 5H), 7.29-7.13 (m, 2H), 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 ]] ⁺ 。

Example 3N- (2-imidazol-1-yl-4-methoxy-pyrimidin-5-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

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) with saturated NaHCO ₃ (30 mL), water (30 mL), and brine (30 mL), over MgSO ₄ Dried, 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. ¹ H NMR (500 MHz, chloroform-d): delta 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, 0.8Hz, 1H), 2.63 (s, 3H). m/z 254.0[ M+H ]] ⁺ 。

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 slowly added a 1M solution of lithium bis (trimethylsilyl) amide in THF (9.4 mL,9.4 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 40 minutes and then warmed to room temperature for 10 minutes. The reaction mixture was then cooled back to 0 ℃ and intermediate 2 (1.90 g) was then added 7.52 mmol) in THF (50 mL). The reaction mixture was stirred at 0 ℃ for 10 minutes and then at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (100 mL) and the organics were washed with water (2×15 mL) followed by saturated brine solution (1×25 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) δ9.38 (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 ]] ⁺ 。

Step 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 K ₂ CO ₃ (601 mg,4.35 mmol). The reaction mixture was then heated to 100 ℃ overnight. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (25 mL) and the organics were washed with water (2×5 mL) and then with saturated brine solution (1×20 mL). The organics were dried (MgSO ₄ ) And concentrated under reduced pressure. The crude material was purified by flash silica column chromatography on 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) δ9.43 (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 ]] ⁺ 。

Example 4N- [ 2-methoxy-6- (1-methylpyrazol-4-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (60 mg,0.15 mmol) and tripotassium phosphate (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 bubbled with nitrogen for 10 min. Then mix into the reactionPd (dppf) Cl was added to the mixture ₂ (complexing with DCM, 13mg,0.02 mmol), sealing in a microwave tube and heating at 110℃for 3 hours. The reaction mixture was concentrated under reduced pressure and taken up in DCM. Water was added and 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 (0-80% EtOAc/PE gradient) over ISCO system to give N- [ 2-methoxy-6- (1-methylpyrazol-4-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (36 mg, 57% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.60 (d, j=8.1 hz, 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=8.1 hz, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 2.82 (s, 3H) m/z 390.0[ m+h ] ] ⁺ 。

Example 5N- (4- (1H-imidazol-1-yl) -2-methoxyphenyl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Step 1100mL RBF was charged with 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 tan solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ8.48(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] ⁺ 。

Step 2

100mL of RBF were charged under nitrogen 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). Then use H ₂ (balloon) purge the reaction flask and at H ₂ Stirred overnight at room temperature. The reaction flask was purged with nitrogen, then the reaction mixture was filtered through celite,wash with MeOH and then 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(500MHz,DMSO-d ₆ ):δ8.01(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] ⁺ 。

Step 310mL 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), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude residue was dissolved in DMSO (1 mL) and purified on Shimadzu MDAP preparation system running 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 as an off-white solid (60 mg,29% yield). ¹ H NMR (600 MHz, methanol-d) ₄ ):δ8.27(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] ⁺ 。

Example 6N- [6- (3, 5-dimethylisoxazol-4-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 1 (50 mg,0.13 mmol), tripotassium phosphate (55 mg,0.26 mmol) and (3, 5-dimethylisoxazol-4-yl) boronic acid (28 mg,0.15 mmol) were added to a microwave vial, nitrogen backfilled and 1, 4-dioxane (2 mL) was added. The mixture was purged with nitrogen (10 minutes) and then Pd (dppf) Cl was added ₂ (complexing with DCM, 11mg,0.01 mmol) and sealing the vial. The mixture was swept for another 10 minutes and then in a microwave reactorIs reacted at 110℃for 2 hours. The solvent was removed via Genevac and DCM and water were added to the resulting solid. The biphasic solution was vigorously stirred 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-pyridinyl ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (11 mg,20% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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[ M-H ]] ^- 。

Example 7N- (2-methoxy-6-pyrimidin-5-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

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℃for 3 hours, 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), the phases were shaken and separated. The organic phase was washed with brine (50 mL), dried (MgSO ₄ ) Filtered and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash silica column chromatography on ISCO system (40 g silica, gradient elution with 0-20% EtOAc/PE) using collection of all functions to give N- (2-methoxy-6-pyrimidin-5-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (382 mg,73% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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, 6.5,2.1hz, 2H), 7.37 (d, j=8.1 hz, 1H), 3.70 (s, 3H), 2.83 (s, 3H) m/z 388.0[ m+h)] ⁺

Example 8N- [ 2-methoxy-6- (3-nitrophenyl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 1 (50 mg,0.13 mmol), tripotassium phosphate (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). The mixture was purged with nitrogen (10 minutes) and then Pd (dppf) Cl was added ₂ (complexing with DCM, 11mg,0.01 mmol) and sealing the vial. The reaction mixture was purged for another 10 minutes and then reacted in a microwave reactor at 110℃for 2 hours. The solvent was removed via Genevac and DCM and water were added to the resulting solid. The biphasic solution was vigorously stirred 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-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (45 mg,77% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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, 2.3,1.0Hz, 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 ] ] ⁺ 。

Example 9N- (3-methoxy-5-pyrimidin-5-yl-2-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1-Synthesis of intermediate 4-N- (5-bromo-3-methoxy-2-pyridinyl) -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 (627 mg,2.46 mmol). The reaction mixture was heated at 80 ℃ overnight. Then heated to 120℃for a further 48 hours. The reaction mixture was concentrated to dryness and the residue was purified by flash silica column chromatography (gradient 25-40% EtOAc/PE) to give a white solid(5-bromo-3-methoxy-2-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (intermediate 4) (345 mg, 35% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.06 (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 ]] ⁺ 。

Step 2

A solution of tripotassium phosphate (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 rapidly, the solution was again degassed for 10 minutes and the mixture was stirred overnight at 100 ℃. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO system (elution with a 3% MeOH/DCM gradient) afforded N- (3-methoxy-5-pyrimidin-5-yl-2-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a white solid (32 mg,61% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.23 (s, 1H), 8.88 (s, 2H), 8.24 (d, j=2.0 hz, 1H), 8.00 (s, 1H), 7.65 (d, j=7.4 hz, 2H), 7.58 (t, j=7.3 hz, 1H), 7.54 (t, j=7.4 hz, 2H), 7.10 (d, j=2.1 hz, 1H), 3.60 (s, 3H), 2.84 (s, 3H) m/z 388.0[ m+h ]] ⁺ 。

Example 10N- [ 2-methoxy-6- (2-methoxythiazol-5-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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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 tripotassium phosphate (98 mg,0.46 mmol) and the mixture was bubbled with nitrogen for 10 min. Pd (dppf) Cl was then added to the reaction mixture ₂ (complexing with DCM, 13mg,0.02 mmol), sealing and heating overnight at 110 ℃. The reaction mixture was concentrated under reduced pressure and dissolved in DCM (10 mL).Water (10 mL) was added and 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, eluting with a 0-40% EtOAc/PE gradient) to give N- [ 2-methoxy-6- (2-methoxythiazol-5-yl) -3-pyridinyl ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (15 mg,21% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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 ]] ⁺ 。

Example 11N- [6- (5-amino-3-pyridinyl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and 5- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. The reaction mixture was concentrated under reduced pressure and dissolved in DCM (10 mL). Water (10 mL) was added and organics were separated using a phase separator. The organics were concentrated under reduced pressure to give a dark oil which was purified by flash column chromatography on ISCO system (12 g silica, gradient elution with 0-50% EtOAc/PE) to give N- [6- (5-amino-3-pyridinyl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (43 mg,79% yield). ¹ HNMR (600 MHz, chloroform-d) δ8.71 (d, j=8.2 hz, 1H), 8.59 (d, j=1.8 hz, 1H), 8.06 (d, j=2.7 hz, 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=8.2 hz, 1H), 3.75 (s, 2H), 3.70 (s, 3H), 2.84 (s, 3H) m/z 402.0[ m+h ]] ⁺ 。

Example 12N- [ 2-methoxy-4- (1-methylpyrazol-4-yl) phenyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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-anisole (1.00 g,4.95 mmol), DIPEA (1.72 mL,9.9 mmol) in DCM (40 mL) was added dropwise a 0.4M solution of 5-methyl-3-phenyl-isoxazole-4-carbonyl chloride (12.37 mL,4.95 mmol) in DCM solution (synthesized according to step 1 of example 1). The reaction mixture was stirred at room temperature overnight. Water (20 mL) was added and the reaction mixture was extracted with DCM (3X 20 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography (elution with a 20% EtOAc/PE gradient) on ISCO system afforded N- (4-bromo-2-methoxy-phenyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (intermediate 5) (1.50 g,74% yield). ¹ H NMR (400 MHz, chloroform-d) δ8.34 (d, j=8.7 hz, 1H), 7.74 (s, 1H), 7.67-7.49 (m, 5H), 7.06 (dd, j=8.7, 2.1hz, 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 ]] ⁺ 。

Step 2

A5 mL microwave vial was charged with 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 and degassed, and then heated in a microwave for 45 minutes at 100 ℃. 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 dried over MgSO ₄ Dried, filtered through celite and concentrated under reduced pressure. The residue was purified on Shimadzu MDAP (gradient elution with 30% -95% MeCN/water+0.1% formic acid) to give N- [ 2-methoxy-4- (1-methylpyrazol-4-yl) phenyl as an off-white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (16 mg,31% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.42 (d, j=8.4 hz, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.65 (d, j=7.6 hz, 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] ⁺ 。

Example 13N- (2-methoxy-4-pyrimidin-5-yl-phenyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

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Into a 5mL microwave vial was charged 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 and degassed, and then heated in a microwave at 90 ℃ for 4 hours. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the phases separated. The organic phase was washed with brine (20 mL), over MgSO ₄ Dried, filtered through celite and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-80% etoac/PE) 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 (600 MHz, chloroform-d) delta 9.17 (s, 1H), 8.89 (s, 2H), 8.62 (d, j=8.4 hz, 1H), 7.90 (s, 1H), 7.67-7.63 (m, 2H), 7.61 (t, j=7.3 hz, 1H), 7.56 (t, j=7.4 hz, 2H), 7.19-7.15 (m, 1H), 6.89 (d, j=1.9 hz, 1H), 3.53 (s, 3H), 2.84 (s, 3H) m/z 387.0[ m+h)] ⁺ 。

Example 14N- [5- (3, 5-dimethylisoxazol-4-yl) -3-methoxy-2-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 rapidly and the solution was again degassed 1 0 minutes, and the mixture was stirred at 80 ℃ overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography gave N- [5- (3, 5-dimethylisoxazol-4-yl) -3-methoxy-2-pyridinyl ] as a pale yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (26 mg,47% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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=1.9 Hz, 1H), 3.55 (s, 3H), 2.84 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H) m/z 405.0[ M+H ]] ⁺ 。

Example 15N- [ 3-methoxy-5- (1-methylpyrazol-4-yl) -2-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 rapidly, the solution was again degassed for 10 minutes and the mixture stirred overnight at 80 ℃. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography gave N- [ 3-methoxy-5- (1-methylpyrazol-4-yl) -2-pyridinyl ] as a white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (22 mg,42% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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 ]] ⁺ 。

Example 16N- [6- [3- (dimethylamino) phenyl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 1 (50 mg,0.13 mmol) and [3- (dimethylamino) phenyl ]]A solution of boric 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction, sealed and heated overnight at 80 ℃. The reaction mixture was concentrated via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash column chromatography on ISCO (elution with a 0-50% PE/EtOAc gradient) to give N- [6- [3- (dimethylamino) phenyl ]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (42 mg,72% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.68 (d, J=8.2 Hz, 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 ]] ⁺ 。

Example 17N- [6- (2-cyclopropylpyrimidin-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. The reaction mixture was concentrated via Genevac, then DCM and water were added. The reaction mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on ISCO system and further purified by mass directed prep HPLC to give N- [6- (2-cyclopropylpyrimidin-5-yl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (8 mg,16% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.07 (s, 2H), 8.74 (d, J=8.2 Hz, 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] ⁺ 。

Example 18N- [ 3-methoxy-5- (1H-pyrazol-4-yl) -2-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 rapidly, the solution was again degassed for 10 minutes and the mixture stirred overnight at 80 ℃. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO4 and filtered, then concentrated to dryness. Purification by flash silica column chromatography gave N- [ 3-methoxy-5- (1H-pyrazol-4-yl) -2-pyridinyl ] as a white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (23 mg,45% yield). ¹ H NMR (600 MHz, chloroform-d) δ10.65 (br s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.82 (s, 2H), 7.65 (d, J=7.3 Hz, 2H), 7.53 (dt, J=15.0, 7.4Hz, 3H), 7.06 (s, 1H), 3.59 (s, 3H), 2.82 (s, 3H) m/z 375.9[ M+H ]] ⁺ 。

Example 19N- [ 3-methoxy-5- (1-methylpyrazol-4-yl) pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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) was added lithium bis (trimethylsilyl) amide solution (99.25 mL,99.25 mmol) at-78deg.C. The reaction mixture was brought to-78Stirred for 10 minutes at C, warmed to room temperature for 20 minutes, and then cooled back to-78 ℃. A solution of intermediate 2 (20.11 g,79.4 mmol) in THF (30 mL) was slowly added and the reaction mixture was allowed to gradually warm to room temperature and stirred 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) by 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) and washed with water (100 mL) via heat/sonication over MgSO ₄ Dried, 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, 13.2g, 49%) as a tan solid. ¹ H NMR (600 MHz, chloroform-d) delta 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[ M+H ] ] ⁺ for ⁸¹ Br。

Step 2

5mL microwave vials were filled with 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 and degassed, and then heated in a microwave at 120 ℃ for 1 hour. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the phases separated. The organic phase was washed with brine (20 mL), over MgSO ₄ Dried, filtered through celite and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-80% EtOAc/PE) to give N- [ 3-methoxy-5- (1-methylpyrazol-4-yl) pyrazin-2-yl as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (50 mg,48% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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)] ⁺ 。

Example 20N- [6- (1, 3-dimethylpyrazol-4-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and 1, 3-dimethyl-4- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. The reaction mixture was reduced via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on ISCO system (0-10% MeOH/DCM gradient) and further purified by flash silica column chromatography on ISCO system (0-100% EtOAc/PE gradient) to give N- [6- (1, 3-dimethylpyrazol-4-yl) -2-methoxy-3-pyridinyl ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (37 mg,69% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.60 (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 ]] ⁺ 。

Example 21N- [6- (1-isopropylpyrazol-4-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and 1-isopropyl-4- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. The reaction mixture was reduced via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and purified by flash silica column chromatography on ISCO system (0-60% EtOAc/PE gradient) to give N- [6- (1-isopropylpyrazol-4-yl) -2-methoxy-3-pyridinyl)]-5-methyl-3-phenyl-isoxazole-4-carboxamide (33 mg, 58% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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 (hepet, 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 ] ] ⁺ 。

Example 22N- [ 2-methoxy-6- (1, 3, 5-trimethylpyrazol-4-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and 1,3, 5-trimethyl-4- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction, sealed and heated overnight at 80 ℃. The reaction mixture was reduced via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography (0-90% EtOAc/PE gradient) on ISCO system to give N- [ 2-methoxy-6- (1, 3, 5-trimethylpyrazol-4-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 32%). ¹ H NMR (600 MHz, chloroform-d) delta 8.64 (d, j=8.1 hz, 1H), 7.70 (s, 1H), 7.66-7.59 (m, 3H), 7.59-7.55 (m, 2H), 6.86 (d, j=8.1 hz, 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 ]] ⁺ 。

Example 23N- [ 2-methoxy-6- (2-methylpyrazol-3-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 1 (50 mg,0.13 mmol) and 1-methyl-5-A solution of (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. The reaction mixture was reduced via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography (0-90% EtOAc/PE gradient) on ISCO system to give N- [ 2-methoxy-6- (2-methylpyrazol-3-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (38 mg,72% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.71 (d, j=8.1 hz, 1H), 7.75 (s, 1H), 7.66-7.61 (m, 3H), 7.60-7.57 (m, 2H), 7.45 (d, j=1.9 hz, 1H), 7.18 (d, j=8.1 hz, 1H), 6.52 (d, j=1.9 hz, 1H), 4.17 (s, 3H), 3.65 (s, 3H), 2.83 (s, 3H) m/z 390.0[ m+h)] ⁺ 。

Example 24N- [ 2-methoxy-6- (3-methyl-4-pyridinyl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and (3-methyl-4-pyridinyl) 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. The reaction mixture was reduced via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on ISCO system and further purified by mass directed prep HPLC to give N- [ 2-methoxy-6- (3-methyl-4-pyridinyl) -3-pyridinyl ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (5 mg,9% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.75 (d, j=8.0 hz, 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=5.0 hz, 1H), 7.09 (d, j=8.1 hz, 1H), 3.64 (s, 3H), 2.84 (s, 3H), 2.42(s,3H)。m/z 401.0[M+H] ⁺ 。

Example 25N- [6- (3, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 mL microwave vial was charged with intermediate 1 (50 mg,0.13 mmol), 1, 3-dimethyl-4- (4, 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, then Pd-118 (8.4 mg,0.01 mmol) was added and the vial was sealed and heated at 80℃for 16 h. The reaction mixture was concentrated under reduced pressure and 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-pyridinyl) as a colorless solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg,33% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.64 (d, j=8.1 hz, 1H), 7.70 (s, 1H), 7.66-7.63 (m, 2H), 7.63-7.59 (m, 1H), 7.57 (dd, j=8.1, 6.6hz, 2H), 6.91 (d, j=8.1 hz, 1H), 3.65 (d, j=1.3 hz, 3H), 2.83 (s, 3H), 2.44 (d, j=1.2 hz, 6H) m/z 404.0[ m+h] ⁺ 。

Example 26N- [ 2-methoxy-6- (1H-pyrazol-4-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and 4- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture, sealed and heated overnight at 80 ℃. Will be reversedThe mixture should be reduced via Genevac, then DCM and water are added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography (0-10% MeOH/DCM gradient) on ISCO system and the resulting solid triturated with ether to give N- [ 2-methoxy-6- (1H-pyrazol-4-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (35 mg,69% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.63 (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[ M-H ] ] ^- 。

Example 27N- [6- [6- (hydroxymethyl) -3-pyridinyl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1 Synthesis of intermediate 7-N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl ] -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, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1,3, 2-dioxapentaborane (1.28 g,5.02 mmol) and anhydrous 1, 4-dioxane (44 mL). The solution was degassed with nitrogen for 15 min and then Pd (dppf) Cl was added rapidly ₂ (Complex with DCM, 315mg,0.380 mmol) and KOAc (1.14 g,11.59 mmol). The mixture was again degassed with nitrogen for 15 minutes and then heated to 80 ℃ for 1 hour using an aluminum heating block. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The solution was washed with water (20 mL), and MgSO was used ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by trituration with PE (60 mL). The suspension was allowed to settle, the supernatant removed and the milling process repeated with additional PE (20 mL). The resulting solid was dried under reduced pressure to give N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl as a brown powder ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (intermediate 7,1.69g, 95%))。 ¹ H NMR (500 MHz, chloroform-d) δ8.60 (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, 1.3Hz, 1H), 3.66 (s, 3H), 2.81 (s, 3H), 1.34 (s, 12H) M/z 354.0[ M+H for boric acid ]] ⁺ 。

Step 2

A solution of KF (76.1 mg,1.31 mmol), (5-bromopyridin-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 rapidly, the solution was again degassed for 10 min and the mixture was stirred at room temperature overnight. LCMS analysis in the morning the next day indicated that the reaction was near completion, so the reaction mixture was heated to 45 ℃ for 4 hours to promote reaction completion. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous phase was back extracted with DCM (3X 20 mL) and the combined organic extracts were dried over MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product which was purified by automatic column chromatography (12 g silica, gradient 0-10% MeOH/DCM) to give N- [6- [6- (hydroxymethyl) -3-pyridinyl ] as a grey solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (102 mg,56% yield); ¹ H NMR (500 MHz, chloroform-d) δ9.13 (s, 1H), 8.73 (d, j=8.1 hz, 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=8.1 hz, 1H), 7.29 (d, j=8.2 hz, 1H), 4.79 (s, 2H), 3.71 (s, 3H), 2.84 (s, 3H). M/z 417.1[ m+h ]] ⁺ 。

Example 28N- [ 2-methoxy-6- (1-methyl-6-oxo-3-pyridinyl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (50 mg,0.13 mmol) and 1-methyl-5- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction mixture and sealedAnd heated at 80 ℃ overnight. The reaction mixture was reduced via Genevac, then DCM and water were added. The mixture was vigorously stirred and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography (0-10% MeOH/DCM gradient) on ISCO system and the resulting solid was triturated with ether to give N- [ 2-methoxy-6- (1-methyl-6-oxo-3-pyridinyl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (38 mg, 67%). ¹ H NMR (600 MHz, chloroform-d) delta 8.67 (d, j=8.1 hz, 1H), 7.98 (d, j=2.5 hz, 1H), 7.90 (dd, j=9.5, 2.6hz, 1H), 7.72 (s, 1H), 7.67-7.60 (m, 3H), 7.59-7.56m, 2H), 7.06 (d, j=8.2 hz, 1H), 6.63 (d, j=9.5 hz, 1H), 3.67 (s, 3H), 3.63 (s, 3H), 2.83 (s, 3H) m/z 417.0[ m+h)] ⁺

Example 29N- (5-imidazo [1,2-a ] pyridin-5-yl-3-methoxy-2-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

To a solution of intermediate 4 (100 mg,0.24 mmol) in 1, 4-dioxane (3 mL) was added B ₂ Pin ₂ (80.8 mg,0.32 mmol) and KOAc (72 mg,0.73 mmol). The reaction mixture was degassed by bubbling nitrogen for 3 min and then Pd (dppf) Cl was added ₂ (Complex with DCM, 10mg,0.01 mmol). The reaction mixture was heated at 90 ℃ for one hour. 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 over MgSO ₄ Dried and filtered, and then 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 ] are added]Pyridine (35 mg,0.18 mmol) and the solution was degassed with nitrogen for 15 min. Rapid addition of Pd (dppf) Cl ₂ (6.1 mg,0.01 mmol), the solution was again degassed for 10 minutes and the mixture was left at 80℃overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. By flash silica column chromatography on ISCO system (with 3% MeOHGradient elution with DCM) to give N- (5-imidazo [1, 2-a) as a white solid]Pyridin-5-yl-3-methoxy-2-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (17 mg,25% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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=6.9 Hz, 1H), 3.56 (s, 3H), 2.86 (s, 3H) m/z 426.11[ M+H ]] ⁺ 。

Example 30N- (6-imidazo [1,2-a ] pyridin-5-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

KOAc (31.5 mg,0.32 mmol), 5-bromoimidazo [1,2-a]A solution of 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 added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 90℃for 40min. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO system (elution with a 3% MeOH/DCM gradient) afforded N- (6-imidazo [1, 2-a) as a pale yellow solid ]Pyridin-5-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (28 mg,24% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.83 (d, j=8.1 hz, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.66 (d, j=6.6 hz, 5H), 7.61 (d, j=7.3 hz, 2H), 7.36 (d, j=8.1 hz, 1H), 7.23 (d, j=8.3 hz, 1H), 7.04 (d, j=7.0 hz, 1H), 3.69 (s, 3H), 2.86 (s, 3H) m/z 426.0[ m+h] ⁺ 。

Example 31N- [5- (3, 5-dimethyl-1H-pyrazol-4-yl) -3-methoxy-2-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Adding to a microwave vialIntermediate 4 (50 mg,0.13 mmol), 1, 4-dioxane (2.0 mL), water (0.2 mL), 3, 5-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (34.3 mg,0.15 mmol) and KOAc (25.3 mg,0.26 mmol) were added. The reaction mixture was degassed with nitrogen for 3 min, then Pd-118 (4.2 mg, 0.010mmol) was added. The vial was sealed and heated at 80 ℃ overnight. Once cooled, the mixture was concentrated under reduced pressure and the crude product was purified directly by automatic 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-pyridinyl) as a pale yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (12.0 mg,20% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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 ]] ⁺ 。

Example 32N- [ 2-methoxy-6- (4-methoxy-1H-indazol-6-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 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, then Pd-118 (13 mg,0.02 mmol) was added and the vial was sealed and heated at 80℃for 16 hours. 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-pyridinyl ] as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg,23% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ13.14(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] ⁺ 。

Example 33N- [6- (3-amino-1H-indazol-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 80℃for 3h. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography gave N- [6- (3-amino-1H-indazol-5-yl) -2-methoxy-3-pyridinyl ] as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10.8 mg,14% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ11.47(s,1H),9.44(s,1H),8.55-8.13(m,1H),7.90(s,1H),7.72(t,J＝8.4Hz,3H),7.61(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] ⁺ 。

Example 34N- [6- (1H-indazol-6-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 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, then Pd-118 (13 mg,0.02 mmol) was added and the vial was sealed and heated at 80℃for 16 hours. 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-pyridinyl ] as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (13.3 mg,18% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ13.15(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,J＝7.1Hz,2H),7.67(d,J＝8.2Hz,1H),7.59-7.52(m,3H),3.93(s,3H),2.66(s,3H).m/z 426.0[M+H] ⁺ 。

Example 35N- [6- (3-amino-1H-indazol-6-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 80℃for 3h. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography gave N- [6- (3-amino-1H-indazol-6-yl) -2-methoxy-3-pyridinyl ] as a pale yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10.8 mg,14% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ11.47(s,1H),9.44(s,1H),8.55-8.13(m,1H),7.90(s,1H),7.72(t,J＝8.4Hz,3H),7.61(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] ⁺ 。

Example 36N- [6- (2-chloropyrimidin-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 1 (2.00 g,5.15 mmol) in 1, 4-dioxane (5 mL) was bubbled 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 another 10 minutes and then heated at 80 ℃. 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 hours using a syringe pump. After the addition is completedThe reaction was kept at 80 ℃ overnight. The reaction mixture was concentrated under reduced pressure and dissolved in DCM (30 mL). Water (30 mL) was added and 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, eluting with a 0-50% PE/EtOAc gradient, then rinsed with a 0-10% MeOH/DCM gradient) to give N- [6- (2-chloropyrimidin-5-yl) -2-methoxy-3-pyridinyl as a yellow solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (1599 mg,7% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.12 (d, j=1.1 hz, 2H), 8.79 (d, j=8.1 hz, 1H), 7.80 (s, 1H), 7.67-7.61 (m, 3H), 7.61-7.56 (m, 2H), 7.35 (d, j=8.2 hz, 1H), 3.69 (s, 3H), 2.84 (s, 3H) m/z 421.0[ m+h ]] ⁺ 。

Example 37N- (6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

A10 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, 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 minutes. Pd-118 (8.4 mg,0.01 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 80 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-90% EtOAc/PE, 25 CV). The CV containing products were combined and evaporated under reduced pressure. The precipitate was then dried in vacuo at 40℃to give N- (6-methoxy- [2,3' -bipyridine) as a pale yellow solid ]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (40.0 mg, 76%). ¹ H NMR (600 MHz, chloroform-d) δ9.28-9.14 (m, 1H), 8.74 (d, j=8.1 hz, 1H), 8.57 (dt, j=4.8, 1.3hz, 1H), 8.21 (dq, j=8.1,1.6Hz,1H),7.78(s,1H),7.63(ddd,J＝8.9,7.1,1.3Hz,3H),7.58(t,J＝7.6Hz,2H),7.40-7.31(m,2H),3.71(s,3H),2.84(s,3H).m/z 387.0[M+H] ⁺ 。

Example 38N- (6-imidazo [1,2-a ] pyrazin-8-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

8-chloroimidazo [1,2-a ] was added to a 5mL microwave vial]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, then Pd-118 (11.3 mg,0.02 mmol) was added. The vial was sealed and heated at 80 ℃ overnight. The mixture was concentrated under reduced pressure, and the residue was purified by automatic column chromatography to give N- (6-imidazo [1, 2-a)]Pyrazin-8-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (8.8 mg, 15%). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.46(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] ⁺ 。

Example 39N- [6- (5-amino-6-methoxy-pyrazin-2-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 80℃for 3h. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Drying and filtering, and concentratingAnd (5) drying. Purification by flash silica column chromatography gave N- [6- (5-amino-6-methoxy-pyrazin-2-yl) -2-methoxy-3-pyridinyl ] as a white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10 mg,16% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.37(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] ⁺ 。

Example 40N- [6- (6-Aminopyrazin-2-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 80℃for 3h. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine, dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography gives N- [6- (6-aminopyrazin-2-yl) -2-methoxy-3-pyridinyl ]]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 32% yield) as a white solid. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.42(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] ⁺ 。

Example 41N- (2-methoxy-6- (2-methoxypyrimidin-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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 are added successively ₂ CO ₃ (130 mg,1.22 mmol) and Pd (dppf) Cl ₂ (complexing with DCM, 20mg,0.03 mmol). The resulting mixture was stirred at 90 ℃ overnight. After the reaction was completed, 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 over Na ₂ SO ₄ Dried and concentrated under reduced pressure to give the crude product, which was further purified on C18 HPLC (gradient 0-100% MeOH/water) to give N- (2-methoxy-6- (2-methoxypyrimidin-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (92 mg, 45% yield). 1HNMR (600 MHz, chloroform-d) delta 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 ]] ⁺ 。

Example 42N- (6-methoxy- [2,4' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

A10 mL microwave vial was charged with intermediate 1 (50.0 mg,0.13 mmol), 4- (4, 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 minutes. Pd-118 (8.4 mg,0.01 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 80 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica eluting with 0-90% EtOAc/PE) to give N- (6-methoxy- [2,4' -bipyridine) as a tan solid]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (26.0 mg, 50%). ¹ H NMR (600 MHz, chloroform-d) δ8.76 (d, J=8.1 Hz, 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=8.1 Hz, 1H), 3.71 (s, 3H), 2.84 #s,3H).m/z 387.0[M+H] ⁺ 。

Example 43N- [6- (2-aminopyrimidin-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 rapidly, the solution was again degassed for 10 minutes and the mixture was stirred at room temperature overnight. LCMS analysis in the next morning indicated that the reaction was near completion, but two starting materials were still observed-thus the mixture was heated at 45 ℃ and monitored by LCMS analysis. LCMS analysis after 4 hours 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 (3X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product which is purified by automatic column chromatography (12 g silica, eluted with a 0-10% MeOH/DCM gradient) to give N- [6- (2-aminopyrimidin-5-yl) -2-methoxy-3-pyridinyl as an off-white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (114 mg,64% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.45(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/z403.0[M+H] ⁺ 。

Example 44N- (5-imidazol-1-yl-3-methoxy-pyrazin-2-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

To a solution of L-proline (4.5 mg,0.04 mmol) in DMSO (1.5 mL) was added 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). The reaction mixture was degassed with nitrogen and then imidazole (17 mg,0.26 mmol) was added. The reaction mixture was heated at 80 ℃ for 16 hours, then diluted with EtOAc (30 mL) and filtered through celite. The filtrate was washed with water (30 mL), brine (30 mL), and over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified on Shimadzu MDAP (eluted with a 10-95% MeCN/water+0.1% formic acid gradient) to give N- (5-imidazol-1-yl-3-methoxy-pyrazin-2-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a cream solid (38 mg, 37% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.17 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.64-7.59 (m, 3H), 7.57 (t, J=7.5 Hz, 2H), 7.26 (d, J=1.3 Hz, 2H), 3.76 (s, 3H), 2.85 (s, 3H) m/z 377.0[ M+H ]] ⁺ 。

Example 45N- (6- (2- (dimethylamino) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

A10 mL microwave vial was charged with example 36 (30.0 mg,0.07 mmol), dimethylamine (71.1. Mu.L, 0.14 mmol), DIPEA (24.8. Mu.L, 0.14 mmol), and THF (1.5 mL). The reaction mixture was heated to 70 ℃ and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (4 g, silica, elution with a gradient of 0-100% EtOAc/PE). The CV-containing products 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 as a colorless solid (14.0 mg,41% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.89 (s, 2H), 8.65 (d, j=8.1 hz, 1H), 7.70 (s, 1H), 7.66-7.59 (m, 3H), 7.57 (dd, j=7.9, 6.5hz, 2H), 7.15 (d, j=8.2 hz, 1H), 3.66 (s, 3H), 3.24 (s, 6H), 2.83 (s, 3H) m/z 431.0[ m+h ]] ⁺ 。

Example 46N- [ 2-methoxy-6- (1, 2, 4-triazol-1-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

To a solution of intermediate 1 (100 mg,0.25 mmol) in DMSO (2 mL) was added 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). The reaction mixture was evacuated and backfilled three times with nitrogen and then heated overnight at 120 ℃. The reaction mixture was diluted with EtOAc (10 mL) and filtered through celite. The clear filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was then dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO system (elution with a 35% EtOAc/PE gradient) afforded N- [ 2-methoxy-6- (1, 2, 4-triazol-1-yl) -3-pyridinyl as a white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (27 mg,26% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.93 (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 ]] ⁺ 。

Example 47N- [ 2-methoxy-6- [2- (methylamino) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

To a solution of example 36 (50 mg,0.12 mmol) in THF (2 mL) was added a 2M methylamine solution in THF (0.18 mL,0.36 mmol) and DIPEA (0.06 mL,0.36 mmol). The reaction mixture was stirred at 70 ℃ overnight. Another portion of methylamine (0.18 mL,0.36 mmol) and DIPEA (0.06 mL,0.36 mmol) was added and the reaction continued for an additional 7 hours. 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 evaporated under reduced pressure. The residue was then purified by flash silica column chromatography on 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, yield54％)。 ¹ H NMR (600 MHz, chloroform-d) delta 8.86 (s, 2H), 8.68 (d, j=8.4 hz, 1H), 7.72 (s, 1H), 7.66-7.60 (m, 3H), 7.57 (t, j=7.4 hz, 2H), 7.16 (d, j=8.2 hz, 1H), 5.22 (s, 1H), 3.67 (s, 3H), 3.05 (d, j=5.0 hz, 3H), 2.83 (s, 3H), m/z 417.0[ m+h ]] ⁺ 。

Example 48N- [6- (2-ethoxypyrimidin-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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 rapidly, the solution was again degassed for 10 min and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by automatic column chromatography (12 g, silica, gradient from 0-10% MeOH: DCM) to give the partially purified product. Trituration was performed in MeOH (5 mL) allowing the solids to settle and the supernatant removed by pipette. The solid was further dried in a vacuum oven at 40 ℃ for 3 hours to give N- [6- (2-ethoxypyrimidin-5-yl) -2-methoxy-3-pyridinyl as an off-white solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (95 mg, 48%). ¹ H NMR (500 MHz, chloroform-d) δ9.04 (s, 2H), 8.74 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.69-7.63 (m, 3H), 7.63-7.57 (m, 2H), 7.30-7.24 (m, 2H), 4.48 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 2.85 (s, 3H), 1.47 (t, J=7.1 Hz, 3H) m/z 432.1[ M+H ]] ⁺ 。

Example 49N- [6- (1H-benzotriazol-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 1 (60 mg)0.15 mmol), 5- (4, 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) were filled into microwave vials. The reaction mixture was evacuated and backfilled three times with nitrogen. 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, followed by microwave irradiation at 120 ℃ for 30 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on ISCO system (elution with a 3% MeOH/DCM gradient) gave N- [6- (1H-benzotriazol-5-yl) -2-methoxy-3-pyridinyl as a white solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10 mg,14% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.47(s,1H),8.55(s,1H),8.39(s,1H),8.18(d,J＝8.6Hz,1H),7.96(s,1H),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] ⁺ 。

Example 50N- [6- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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) were charged into a microwave vial. The reaction mixture was evacuated and backfilled three times with nitrogen. Adding Na ₂ CO ₃ (146 mg,1.37 mmol) and Pd (dppf) Cl ₂ (10 mg,0.014 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 30 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried and concentrated to dryness under reduced pressure. By flash silica column chromatography on ISCO system (with a solution containing 1% NH ₃ Aqueous solutionGradient elution with 25% MeOH/DCM) to give N- [6- (2-amino- [1,2, 4) as a white solid]Triazolo [1,5-a ]]Pyridin-5-yl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (21 mg, 33% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.51(s,1H),8.70(d,J＝8.0Hz,1H),8.48(s,1H),7.77-7.65(m,3H),7.60-7.49m,4H),7.41(d,J＝8.6Hz,1H),6.13(s,2H),3.89(s,3H),2.67(s,3H).m/z442.1[M+H] ⁺ 。

Example 51N- [ 2-methoxy-6- (1-methyl-1, 2, 4-triazol-3-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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) were charged to a microwave vial. The reaction mixture was evacuated and backfilled three times with nitrogen. Adding Na ₂ CO ₃ (146 mg,1.37 mmol) and Pd (dppf) Cl ₂ (10 mg,0.014 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 30 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on ISCO system (elution with a 3% MeOH/DCM gradient) gave N- [ 2-methoxy-6- (1-methyl-1, 2, 4-triazol-3-yl) -3-pyridinyl as a white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (17 mg,32% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.41(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] ⁺ 。

Example 52N- [ 2-methoxy-6- (2-methyl-1, 2, 4-triazol-3-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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) were charged to a microwave vial. The reaction mixture was evacuated and backfilled three times with nitrogen. Adding Na ₂ CO ₃ (146 mg,1.37 mmol) and Pd (dppf) Cl ₂ (10 mg,0.014 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 30 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on ISCO system (elution with a 3% MeOH/DCM gradient) gave N- [ 2-methoxy-6- (2-methyl-1, 2, 4-triazol-3-yl) -3-pyridinyl as a white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (8 mg,14% yield). ¹ H NMR (600 MHz, chloroform-d) delta 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), 7.62-7.56m, 2H), 4.30 (s, 3H), 3.67 (s, 3H), 2.84 (s, 3H) m/z 391.2[ m+h ]] ⁺ 。

Example 53N- [ 2-methoxy-6- [2- (trifluoromethyl) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a solution of 5-bromo-2- (trifluoromethyl) pyrimidine (100 mg,0.44 mmol) in 1, 4-dioxane (5 mL) was added B ₂ Pin ₂ (145 mg,0.57 mmol). The reaction mixture was degassed with nitrogen for 10 min, then Pd (dppf) Cl was added ₂ (complexing with DCM, 18mg,0.02 mmol) and KOAc (130 mg,1.32 mmol). The reaction mixture was degassed for an additional 10 minutes and then heated to 90 ℃ for 1.5 hours. 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 over MgSO ₄ Drying, then evaporating to dryness and triturating the residue with diethyl etherA solid was obtained which was used directly in the next step without further purification.

Step 2

A solution of intermediate 1 (50 mg,0.13 mmol) and crude 5- (4, 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 bubbled with nitrogen for 10 min. Pd-118 (8 mg,0.01 mmol) was then added to the reaction, sealed and heated overnight at 80 ℃. The reaction mixture was concentrated under reduced pressure and dissolved in DCM (10 mL). Water (10 mL) was added and organics were separated using a phase separator. The organics were then concentrated under reduced pressure and the residue purified by flash column chromatography on an ISCO system (12 g silica, eluting 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). ¹ HNMR (600 MHz, chloroform-d) δ9.38 (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 ]] ⁺ 。

Example 54N- [6- (3-Aminopyrazin-2-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Na is mixed with ₂ CO ₃ A solution of (36 mg,0.33 mmol), 3-bromopyrazin-2-amine (22 mg,0.13 mmol) and intermediate 7 (50 mg,0.12 mmol) in 1, 4-dioxane (2 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (8.4 mg,0.013 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 120℃for 1 hour. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine (10 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO system (elution with a 2% MeOH/DCM gradient) afforded N- [6- (3-aminopyrazin-2-yl) -2-methyl as a yellow solidOxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg,37% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.83 (d, j=8.4 hz, 1H), 8.11 (d, j=8.5 hz, 1H), 7.97 (d, j=2.4 hz, 1H), 7.94 (d, j=2.4 hz, 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) ] ⁺ 。

Example 55N- [6- (5-Aminopyrazin-2-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Na is mixed with ₂ CO ₃ A solution of (146 mg,1.37 mmol), 5-bromopyrazin-2-amine (88 mg,0.50 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (8 mL) and water (4 mL) was degassed with nitrogen for 15 min. Pd-118 (33.6 mg,0.046 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at 100℃for 1 hour. Water (10 mL) was added and the reaction mixture was extracted with DCM (3X 10 mL). The combined organics were washed with brine (10 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO (elution with a 2% MeOH/DCM gradient) afforded the free base followed by treatment with HCl (1.2 eq.) afforded N- [6- (5-aminopyrazin-2-yl) -2-methoxy-3-pyridinyl) as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (23 mg,11% yield). ¹ H NMR(600MHz,DMSO-d ₆ ) Delta 9.40 (s, 1H), 8.77 (s, 1H), 8.30 (d, j=8.0 hz, 1H), 7.91 (d, j=1.4 hz, 1H), 7.77-7.68 (M, 2H), 7.66 (d, j=8.0 hz, 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 ]] ⁺ 。

Example 56N- (3-methoxy-5- (pyrimidin-5-yl) pyrazin-2-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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Into a 5mL microwave vialIntermediate 6 (30 mg,0.08 mmol), pyrimidin-5-ylboronic acid (19 mg,0.15 mmol), tripotassium phosphate (55 mg,0.26 mmol) and Pd (dppf) Cl ₂ (complexing with DCM, 10.6mg,0.01 mmol). The vial was sealed, purged with nitrogen, then treated with 1, 4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was heated at 120℃for 16 hours. 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 dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was then purified by reverse phase column chromatography (12 g, C18 column, eluting with a 10-100% MeOH/water gradient) and the relevant fractions concentrated to give an aqueous solution. The solution was extracted with EtOAc (20 mL) and the organic extract was washed with brine (10 mL) over MgSO ₄ Dried, filtered and 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. ¹ H NMR (600 MHz, chloroform-d) δ9.23 (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 ] ] ⁺ 。

Example 57N- [6- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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) were charged into a microwave vial. The reaction mixture was evacuated and backfilled three times with nitrogen. Adding Na ₂ CO ₃ (146 mg,1.37 mmol) and Pd (dppf) Cl ₂ (10 mg,0.014 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 30 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography (elution with a 3% MeOH/DCM gradient) on an ISCO system afforded N- [6- (2-amino- [1,2, 4) as a white solid]Triazolo [1,5-a ]]Pyridin-6-yl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (20 mg, 31% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.97 (s, 1H), 8.73 (d, j=8.2 hz, 1H), 7.93 (d, j=9.2 hz, 1H), 7.76 (s, 1H), 7.68-7.62 (m, 3H), 7.59 (t, j=7.6 hz, 2H), 7.41 (d, j=9.2 hz, 1H), 7.27 (s, 1H), 4.50 (s, 2H), 3.70 (s, 3H), 2.84 (s, 3H) m/z 442.2[ m+h ] ] ⁺ 。

Example 58N- [ 2-methoxy-6- (1, 3, 4-oxadiazol-2-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

A5 mL microwave vial was charged with palladium (II) acetate (3.5 mg,0.02 mmol) and tri-tert-butyltetrafluorophosphonium borate (18 mg,0.06 mmol). The vial was flushed with nitrogen and then with phenyl formate (126 mg,1.03 mmol), intermediate 1 (200 mg,0.52 mmol), and Et ₃ A solution of N (0.14 mL,1.03 mmol) in MeCN (2 mL) was treated. The vial was sealed, purged with nitrogen and heated to 80 ℃ for 16 hours. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL) and the layers separated. The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, gradient elution with 0-90% EtOAc/PE) to give phenyl 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino as a colorless solid]Pyridine-2-carboxylic acid ester (118 mg, 51%). ¹ H NMR (600 MHz, chloroform-d) delta 8.82 (d, j=8.1 hz, 1H), 7.93 (s, 1H), 7.91 (d, j=8.1 hz, 1H), 7.67-7.61 (m, 3H), 7.61-7.55 (m, 2H), 7.44-7.39 (m, 2H), 7.30-7.24 (m, 1H), 7.21 (d, j=8.1 hz, 2H), 3.71 (s, 3H), 2.85 (s, 3H) m/z 430.0[ m+h ]] ⁺ 。

Step 2

Into a 5mL microwave vial was charged phenyl 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonylRadical) amino group]Pyridine-2-carboxylic acid ester (80 mg,0.19 mmol), hydrazine hydrate (0.01 mL,0.22 mmol) and EtOH (2 mL). The vials were sealed and heated in a microwave at 100 ℃ for 30 minutes. Volatiles were removed under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, gradient elution with 0-90% EtOAc/PE) to give N- [6- (hydrazinocarbonyl) -2-methoxy-3-pyridinyl ] as a colorless solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (55 mg, 76%). ¹ H NMR (600 MHz, chloroform-d) delta 8.80 (d, j=8.1 hz, 1H), 8.51 (s, 1H), 7.81 (s, 1H), 7.78 (d, j=8.1 hz, 1H), 7.66-7.60 (m, 3H), 7.58 (t, j=7.5 hz, 2H), 4.02 (s, 2H), 3.61 (s, 3H), 2.83 (s, 3H) m/z 368.0[ m+h ]] ⁺ 。

Step 3

A5 mL microwave vial was charged with N- [6- (hydrazinocarbonyl) -2-methoxy-3-pyridinyl]-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 ℃ for 10 minutes. 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, gradient elution with 0-90% EtOAc/PE) to give N- [ 2-methoxy-6- (1, 3, 4-oxadiazol-2-yl) -3-pyridinyl as a colorless solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (42 mg, 77%). ¹ H NMR (600 MHz, chloroform-d) δ8.84 (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 ]] ⁺ 。

Example 59N- [ 2-methoxy-6- [2- (2, 2-trifluoroethoxy) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

To example 36 (30 mg,0.07 mmol) in 2, 2-trifluoroethanol (2 mL,27.45 mmol) was added KOH (40 mg,0.71 mmol) and the reaction was stirred at 50℃for 2 hours. Will beThe reaction mixture was poured into water, the solid was isolated by filtration, washed with cold diethyl ether and dried in a vacuum oven to give N- [ 2-methoxy-6- [2- (2, 2-trifluoroethoxy) pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (16 mg, 44% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.06 (s, 2H), 8.75 (d, j=8.1 hz, 1H), 7.77 (s, 1H), 7.66-7.61 (m, 3H), 7.59 (t, j=7.6 hz, 2H), 7.28 (d, j=8.2 hz, 1H), 4.86 (q, j=8.3 hz, 2H), 3.69 (s, 3H), 2.84 (s, 3H) m/z 486.0[ m+h ]] ⁺ 。

Example 60 5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] -2-pyridinyl ] pyrimidine-2-carboxylic acid

In a 25mL 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 2.5h. 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 1M HCl. The solid was filtered under vacuum and washed with water (10 mL), then MeOH (10 mL). The sample was further dried in a vacuum oven at 40 ℃ overnight to give 5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ]-2-pyridyl group]Pyrimidine-2-carboxylic acid (143.7 mg,75% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.44 (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 ]] ⁺ 。

Example 61N- [6- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

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) was filled into microwave vials. The reaction mixture was evacuated and backfilled three times with nitrogen. Adding Na ₂ CO ₃ (146 mg,1.37 mmol) and Pd (dppf) Cl ₂ (10 mg,0.014 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 1 hour. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried, filtered and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography (elution with a 40% EtOAc/PE gradient) on an ISCO system afforded the free base as an off-white solid. The solid was dissolved in DCM (1 mL) and then 1M HCl in ether (0.1 mL) was added. Instantaneous formation of solids was noted. The reaction was stirred for 1 hour. 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-cooled ether (2 mL) and dried under reduced pressure to give N- [6- (2-amino- [1,2, 4) as a white solid ]Triazolo [1,5-a ]]Pyridin-7-yl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (27 mg, 33% yield). ¹ H NMR(600MHz,DMSO-d ₆ ) Delta 9.52 (s, 1H), 8.79 (d, j=7.0 hz, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.94-7.81 (M, 2H), 7.69 (d, j=7.2 hz, 2H), 7.60-7.50 (M, 3H), 3.92 (s, 3H), 2.66 (s, 3H) M/z 442.2[ m+h for free base ]] ⁺ 。

Example 62N- [ 2-methoxy-6- (1, 2, 4-triazol-4-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 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, followed by the addition of copper (I) iodide (24.5 mg,0.13 mmol). The reaction mixture was then heated at 80 ℃ overnight. Subsequently, the reaction mixture was diluted with EtOAc (20 mL) and then washed with water (3×20 mL). However, the method is thatThe organic layer was then washed with brine, over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Purification by flash silica column chromatography on ISCO system (elution with a 35% EtOAc/PE gradient) afforded N- (6-amino-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a white solid (100 mg,45% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.36 (d, J=8.3 Hz, 1H), 7.66-7.60 (m, 2H), 7.58-7.51 (m, 3H), 7.39 (s, 1H), 6.04 (d, J=8.4 Hz, 1H), 4.13 (br s, 2H), 3.56 (s, 3H), 2.79 (s, 3H) m/z 325.2[ M+H ]] ⁺ 。

Step 2

N- (6-amino-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (100 mg,0.29 mmol) and 1, 2-dicarboxylic acid hydrazide (25.7 mg,0.29 mmol) are mixed in a microwave vial and heated at 150℃for 1 hour. To the reaction mixture was added water (10 mL) and extracted with EtOAc (3X 10 mL). The collected organics were washed with brine (10 mL), dried over MgSO ₄ Dried, filtered and evaporated under reduced pressure. Purification by flash silica column chromatography on ISCO system (elution with a 3% MeOH/DCM gradient) gave N- [ 2-methoxy-6- (1, 2, 4-triazol-4-yl) -3-pyridinyl as a pale yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (26 mg,22% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.86 (d, J=8.3 Hz, 1H), 8.72 (s, 2H), 7.72 (s, 1H), 7.68-7.54 (m, 5H), 6.95 (d, J=8.3 Hz, 1H), 3.67 (s, 3H), 2.84 (s, 3H) m/z 377.0[ M+H ]] ⁺ 。

Example 63N- (2-methoxy-6-pyrimidin-2-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 7 (75 mg,0.170 mmol), 2-bromopyrimidine (27 mg,0.170 mmol) and KF (123 mg,2.12 mol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (45.8 mg,0.070 mmol) was added and the solution was degassed for an additional 10 minutes, and the mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3×20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash silica column chromatography (eluting with a 50-100% EtOAc/N-hexane gradient) to give N- (2-methoxy-6-pyrimidin-2-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as an off-white solid (41 mg,58% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.85 (d, j=4.8 hz, 2H), 8.82 (d, j=8.2 hz, 1H), 8.12 (d, j=8.2 hz, 1H), 7.89 (s, 1H), 7.66-7.60 (m, 3H), 7.57 (dd, j=8.0, 6.5hz, 2H), 7.23 (t, j=4.8 hz, 1H), 3.78 (s, 3H), 2.84 (s, 3H) m/z 388.1[ m+h ]] ⁺ 。

Example 64N- (2-methoxy-6-pyridazin-3-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 7 (75 mg,0.170 mmol), 3-bromopyridazine (27.4 mg,0.170 mmol) and KF (123 mg,2.12 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (46 mg,0.07 mmol) was added and the solution was degassed for an additional 10 minutes and then stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash silica column chromatography (elution with a gradient of 50-100% EtOAc/N-hexane) to give N- (2-methoxy-6-pyridazin-3-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as an off-white solid (17 mg,24% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.12 (dd, J=4.9, 1.8Hz, 1H), 8.84 (d, J=8.3 Hz, 1H), 8.36-8.28 (m, 2H), 7.82 (s, 1H), 7.67-7.61 (m, 3H), 7.61-7.56 (m, 2H), 7.51 (dd, J=8.5, 4.9Hz, 1H), 3.70 (s, 3H), 2.84 (s, 3H) m/z 388.1[ M+H ]] ⁺ 。

Example 65N- (2-methoxy-6-pyrimidin-4-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 7 (75 mg,0.170 mmol), 4-chloropyrimidine (20 mg,0.170 mmol) and KF (123 mg,2.12 mmol) in 1, 4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (45.8 mg,0.070 mmol) was added and the solution was degassed for an additional 10 minutes and then heated to 50℃overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash silica column chromatography (elution with a gradient of 50% -100% EtOAc/N-hexane) to give N- (2-methoxy-6-pyrimidin-4-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a light brown solid (17 mg,24% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.20 (d, j=1.3 hz, 1H), 8.82 (d, j=8.2 hz, 1H), 8.77 (d, j=5.3 hz, 1H), 8.14 (dd, j=5.3, 1.4hz, 1H), 8.12 (d, j=8.2 hz, 1H), 7.86 (s, 1H), 7.67-7.62 (m, 3H), 7.62-7.54 (m, 2H), 3.71 (s, 3H), 2.84 (s, 3H) m/z 388.1[ m+h) ] ⁺ 。

Example 66N- (2-methoxy-6-thiazol-2-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of 2-bromo-1, 3-thiazole (37.7 mg,0.230 mmol), intermediate 7 (100 mg,0.230 mmol) and KF (40.1 mg,0.690 mmol) in 1, 4-dioxane (2.8 mL) and water (0.28 mL) was degassed with nitrogen for 15 min. Pd-118 (15.0 mg, 0.020mmol) was added and the solution was degassed for an additional 10 minutes and then stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product which was purified by flash silica column chromatography (gradient from 0-25% PE/EtOAc over 20CV followed by a 5CV flash gradient to 100% EtOAc). The material was triturated in PE (5 mL) and stirred for 10 min. Once settled, the supernatant was removed and the process repeated. The resulting solid was dried under reduced pressure to give N- (2-methoxy-6-thiazol-2-yl-3-pyridinyl) in the form of a beige solid5-methyl-3-phenyl-isoxazole-4-carboxamide (43 mg,45% yield). ¹ HNMR (500 MHz, chloroform-d) δ8.76 (d, j=8.1 hz, 1H), 7.84 (d, j=3.2 hz, 1H), 7.78 (s, 1H), 7.76 (d, j=8.2 hz, 1H), 7.67-7.61 (m, 3H), 7.60-7.54 (m, 2H), 7.34 (d, j=3.2 hz, 1H), 3.68 (s, 3H), 2.83 (s, 3H) m/z 393.1[ m+h ] ] ⁺ 。

Example 67N- [5- (2-aminopyrimidin-5-yl) -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 6 (300 mg,0.77 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (213 mg,0.96 mmol) and KF (134 mg,2.31 mmol) were mixed in a 10mL vial in 1, 4-dioxane (2 mL) and water (1.5 mL). The mixture was degassed for 10 minutes. Pd-118 (50 mg,0.08 mmol) in 1, 4-dioxane (2 mL) was added in a separate vial and the mixture was degassed for 10 minutes. This was transferred to the main reaction vessel using a syringe and stirred at room temperature overnight. The suspension was filtered and washed with water (10 mL) and diethyl ether (20 mL). The solid was dried in vacuo at 40℃for 3 hours to give N- [5- (2-aminopyrimidin-5-yl) -3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (181 mg, 55% yield). ¹ HNMR(500MHz,DMSO-d ₆ ):δ10.54(s,1H),8.92(s,2H),8.47(s,1H),7.64(d,J＝6.8Hz,2H),7.42-7.53(m,3H),7.10(s,2H),3.96(s,3H),2.61(s,3H).m/z 404.1[M+H] ⁺ 。

Example 68N- (6-isoxazol-4-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 mL microwave vial was charged with intermediate 1 (100 mg,0.26 mmol), isoxazole-4-boronic acid (35 mg,0.31 mmol), KOAc (101 mg,1.03 mmol), pd-118 (16.8 mg,0.03 mmol), 1, 4-dioxane (2 mL) and water (0.2 mL). The vial was sealed, purged with nitrogen and degassed, then at 80 degrees celsius Heat down for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (25 mL) and washed with water (25 mL). The organic layer was concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-90% EtOAc/PE) to give N- (6-isoxazol-4-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (21 mg,20% yield) as a brown solid. ¹ H NMR (600 MHz, chloroform-d) delta 8.80 (s, 1H), 8.69 (d, j=8.0 hz, 1H), 8.65 (s, 1H), 7.74 (s, 1H), 7.63 (d, j=7.5 hz, 3H), 7.58 (t, j=7.5 hz, 2H), 7.05 (d, j=8.1 hz, 1H), 3.65 (s, 3H), 2.83 (s, 3H). M/z 377.0[ m+h ]] ⁺ 。

Example 69N- (6-Isothiazol-3-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of 3-bromoisothiazole (37.7 mg,0.230 mmol), intermediate 7 (100 mg,0.230 mmol) and KF (40.1 mg,0.690 mmol) in 1, 4-dioxane (2.8 mL) and water (0.28 mL) was degassed with nitrogen for 15 min. Pd-118 (15.0 mg,0.023 mmol) was added rapidly and the solution was degassed for an additional 10 minutes and then stirred overnight at room temperature. TLC analysis (3:1 pe: etoac) showed complete consumption of starting material and the presence of two new species (rf=0.45 and 0.05). The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash silica column chromatography (gradient 15cv 0-20% EtOAc/N-hexane, then rapid gradient to 100% EtOAc) to give the desired product, which was further purified by trituration with PE (5 mL) and dried to give N- (6-isothiazol-3-yl-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a light brown solid (11 mg,12% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.76 (d, j=8.2 hz, 1H), 8.65 (d, j=4.7 hz, 1H), 7.89 (d, j=4.7 hz, 1H), 7.81 (d, j=8.2 hz, 1H), 7.79 (s, 1H), 7.63 (td, j=7.5, 1.4hz, 3H), 7.58 (dd, j=8.3, 6.3hz, 2H), 3.69 (s, 3H), 2.84 (s,3H).m/z 393.1[M+H] ⁺ 。

Example 70 methyl 5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] -2-pyridinyl ] pyrimidine-2-carboxylic acid ester

In a 25mL microwave vial, intermediate 7 (100 mg,0.23 mmol), methyl 5-bromopyrimidine-2-carboxylate (60 mg,0.28 mmol) and KF (40 mg,0.69 mmol) were dissolved in 1, 4-dioxane (4 mL) and water (1 mL), and the mixture was degassed for 10 min. Pd-118 (15 mg,0.02 mmol) was added to the mixture and the reaction mixture was stirred at room temperature overnight. Water (5 mL) was added to the reaction mixture and the solid was collected by vacuum filtration, washed with water (10 mL) and MeOH (10 mL), then dried in a vacuum oven (40 ℃ C.) for 3 hours to give methyl 5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ]-2-pyridyl group]Pyrimidine-2-carboxylic acid ester (58 mg, 54% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.41 (s, 2H), 8.82 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 7.68-7.56 (m, 5H), 7.46 (d, J=8.1 Hz, 1H), 4.09 (s, 3H), 3.70 (s, 3H), 2.85 (s, 3H) m/z 446.0[ M+H ]] ⁺ 。

Example 71N- [ 3-methoxy-5- (6-methoxy-3-pyridinyl) pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 mL microwave vial was charged with intermediate 6 (100 mg,0.26 mmol), KOAc (101 mg,1.03 mmol), pd-118 (16.8 mg,0.03 mmol), (6-methoxypyridin-3-yl) boronic acid (47 mg,0.31 mmol), 1, 4-dioxane (2 mL) and water (0.2 mL). The vial was sealed, purged with nitrogen and degassed, then heated at 80 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (15 mL) and washed with water (15 mL), brine (15 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g diSilica, gradient elution with 0-90% EtOAc/PE) to give N- [ 3-methoxy-5- (6-methoxy-3-pyridinyl) pyrazin-2-yl as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (98 mg,87% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.73 (s, 1H), 8.31 (s, 1H), 8.07 (d, j=8.9 hz, 1H), 7.90 (s, 1H), 7.65-7.58 (m, 3H), 7.56 (t, j=7.5 hz, 2H), 6.82 (d, j=8.7 hz, 1H), 3.98 (s, 3H), 3.75 (s, 3H), 2.85 (s, 3H) m/z 418.0[ m+h ] ] ⁺ 。

Example 72N- [ 3-methoxy-5- (2-methoxypyrimidin-5-yl) pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 mL microwave vial was charged with intermediate 6 (100 mg,0.26 mmol), KOAc (101 mg,1.03 mmol), pd-118 (16.8 mg,0.03 mmol), (2-methoxy-5-pyrimidinyl) boronic acid (47 mg,0.31 mmol), 1, 4-dioxane (2 mL) and water (0.2 mL). The vial was sealed, purged with nitrogen and degassed, then heated at 80 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (15 mL) and washed with water (15 mL), brine (15 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-90% EtOAc/PE) to give N- [ 3-methoxy-5- (2-methoxypyrimidin-5-yl) pyrazin-2-yl as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (107 mg,94% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.01 (s, 2H), 8.32 (s, 1H), 7.95 (s, 1H), 7.66-7.59 (m, 3H), 7.57 (t, J=7.4 Hz, 2H), 4.07 (s, 3H), 3.75 (s, 3H), 2.85 (s, 3H) m/z 419.0[ M+H ]] ⁺ 。

Example 73N- [ 2-methoxy-6- (2-pyridinyl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 7 (100 mg,0.26 mmol) and 2-bromopyridine (49 m)g,0.31 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was bubbled with nitrogen for 10 min. The reaction was then charged with Pd-118 (17 mg,0.03 mmol) and KF (45 mg,0.77 mmol), the vessel was sealed and heated to 40℃overnight. The temperature was raised to 80 ℃ for 4 hours, then further raised to 120 ℃ overnight. The reaction mixture was concentrated under reduced pressure and dissolved in chloroform. Water was added and organics were separated using a phase separator. The organics were removed under reduced pressure and the residue was purified by flash column chromatography on an ISCO system (20 g silica, eluting with a 0-50% EtOAc/PE gradient) to give N- [ 2-methoxy-6- (2-pyridinyl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (32 mg,31% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.78 (d, j=8.2 hz, 1H), 8.62 (t, j=3.1 hz, 1H), 8.23 (d, j=8.0 hz, 1H), 8.02 (d, j=8.2 hz, 1H), 7.80 (s, 1H), 7.74 (t, j=7.8 hz, 1H), 7.67-7.61 (m, 3H), 7.58 (t, j=7.5 hz, 2H), 7.23 (dd, j=7.1, 5.2hz, 1H), 3.72 (s, 3H), 2.84 (s, 3H) m/z 387.0[ m+h ]] ⁺ 。

Example 74N- [6- [2- [ (dimethylamino) methyl ] pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1-Synthesis of intermediate 8-5-bromo-2- (bromomethyl) pyrimidine

To a suspension of 5-bromo-2-methylpyrimidine (4.00 g,23.12 mmol) and N-bromosuccinimide (5.20 g,29.22 mmol) in benzotrifluoride (50 mL) was added 2,2' - [ E-1, 2-diazenediyl)]Bis (2-methylpropionitrile) (115 mg,0.70 mmol). The mixture was heated to 80 ℃ and held for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by flash silica column chromatography (80 g silica, eluted with a 0-15% EtOAc/PE gradient) over ISCO system to give 5-bromo-2- (bromomethyl) pyrimidine (1.40 g, 24% yield). ¹ H NMR (500 MHz, chloroform-d): delta 8.80 (s, 2H), 4.57 (s, 2H). m/z 252.8[ M+H ]] ⁺ For the following ⁸¹ Br。

Step 2 Synthesis of intermediate 9-1- (5-bromopyrimidin-2-yl) -N, N-dimethyl-methylamine

To a solution of intermediate 8 (500 mg,1.98 mmol) in THF (7 mL) was added 2M dimethylamine in THF (3.97 mL,7.94 mmol) and the reaction mixture was stirred at RT. The reaction formed a thick white precipitate almost immediately. After 2 hours, the suspension was evaporated to dryness and partitioned between EtOAc (30 mL) and 2M NaOH (10 mL). The organics were separated and the aqueous phase was further extracted with EtOAc (2×30 mL). The organics were dried over MgSO ₄ Dried, filtered and concentrated to give 1- (5-bromopyrimidin-2-yl) -N, N-dimethyl-methylamine (450 mg,100% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.71 (s, 2H), 3.65 (s, 2H), 2.29 (s, 6H). M/z216.0[ M+H ]] ⁺ 。

Step 3

A mixture of intermediate 7 (900 mg,2.07 mmol), intermediate 9 (450 mg,2.08 mmol) and triturated KF (360 mg,6.2 mmol) in 1, 4-dioxane (10 mL) and water (5 mL) was bubbled with nitrogen for 10 min. Pd-118 (135 mg,0.21 mmol) was added and the mixture was heated to 45℃overnight. 1, 4-dioxane was removed under reduced pressure and the mixture was partitioned between DCM (20 mL) and brine (10 mL). The mixture was passed through a phase separator and the aqueous phase was further extracted with DCM (2X 20 mL). The organics were combined and concentrated to dryness and the residue was purified by flash silica column chromatography (24 g silica, eluting with a 0-20% meoh/EtOAc gradient) on an ISCO system. The resulting crude solid was recrystallized from a minimum amount of isopropanol (about 30 mL). The solid was cooled in a refrigerator for 2 hours and then filtered to give N- [6- [2- [ (dimethylamino) methyl ]]Pyrimidin-5-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (280 mg,0.60mmol, 29% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.23 (s, 2H), 8.78 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.68-7.56 (m, 5H), 7.37 (d, J=8.1 Hz, 1H), 3.79 (s, 2H), 3.70 (s, 3H), 2.85 (s, 3H), 2.39 (s, 6H) m/z 445.1[ M+H ] ] ⁺ 。

Example 75N- [ 2-methoxy-6- [2- (methylcarbamoyl) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

5-bromo-2-pyrimidinecarboxylic acid (300 mg,1.48 mmol) and SOCl ₂ (2 mL,27.42 mmol) was heated in a sealed 20mL microwave vial at 65℃overnight. The mixture was cooled to room temperature and chloroform (2 mL) was then added, followed by DMF (3 drops). The mixture was then reheated to 80 ℃ and maintained for 2 hours. Volatiles were removed under reduced pressure and the solid was redissolved in DCM (5 mL). The solution was cooled using an ice bath and a 2M methylamine solution (2 mL,4.0 mmol) in THF was added dropwise. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 3.5 hours. Water (10 mL) and additional DCM (20 mL) were added. The layers were separated and the aqueous layer was extracted twice with DCM (2X 15 mL). The combined organics were washed with 2M NaOH solution (2X 20 mL) over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give 5-bromo-N-methyl-pyrimidine-2-carboxamide as a white crystalline solid (277 mg,86% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.87 (s, 2H), 7.89 (s, 1H), 3.03 (d, J=5.1 Hz, 3H), m/z 217.9[ M+H ]] ⁺ For the following ⁸¹ Br。

Step 2

A solution of KF (76.1 mg,1.31 mmol), 5-bromo-N-methyl-pyrimidine-2-carboxamide (99.3 mg,0.459 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (3.4 mL) and water (0.8 mL) was degassed with nitrogen for 15 min. Pd-118 (28.5 mg,0.044 mmol) was added, the solution was again degassed for 10 min, and the mixture was stirred at room temperature overnight. The reaction was heated to 45 ℃ for 5 hours to drive the reaction to completion. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), the aqueous phase was back-extracted with DCM (3×20 mL), and the combined organic extracts were taken over MgSO ₄ Drying, filtration and concentration under reduced pressure afforded the crude product, which was purified by ISCO column chromatography (12 g silica, 0-10% MeOH/DCM gradient) to afford a partially pure product, which was further purified by trituration in MeOH (20 mL), removal of the supernatant by pipette, concentration of the solid under reduced pressure afforded N- [ 2-methoxy-6- [2- (methylcarbamoyl) pyrimidin-5-yl as a beige solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (111 mg,54% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.34 (s, 2H), 8.81 #d,J＝8.1Hz,1H),8.02(d,J＝5.6Hz,1H),7.82(s,1H),7.69-7.62(m,3H),7.63-7.56(m,2H),7.44(d,J＝8.1Hz,1H),3.71(s,3H),3.10(d,J＝5.1Hz,3H),2.85(s,3H).m/z 445.1[M+H] ⁺ 。

Example 76N- (6-methoxy-6 '- ((trifluoromethyl) thio) - [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (33 mg,16% yield) was replaced with (6- ((trifluoromethyl) thio) pyridin-3-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.52(s,1H),9.33(d,J＝2.4Hz,1H),8.53(dd,J＝8.2,2.4Hz,1H),8.44(s,1H),7.84(d,J＝8.2Hz,1H),7.78(d,J＝8.1Hz,1H),7.73-7.68(m,2H),7.61-7.51(m,3H),3.92(s,3H),2.67(s,3H).m/z 487.0[M+H] ⁺ 。

Example 77N- (2-methoxy-6- (3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using (3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ]]Imidazol-5-yl) boronic acid instead of (2-methoxypyrimidin-5-yl) boronic acid (192 mg,76% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ10.97(s,1H),9.44(s,1H),8.30(d,J＝8.2Hz,1H),7.81-7.75(m,2H),7.75-7.70(m,2H),7.60-7.55(m,4H),7.05(d,J＝8.1Hz,1H),3.93(s,3H),3.35(s,3H),2.67(s,3H).m/z 456.1[M+H] ⁺ 。

Example 78N- (4 '-amino-6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (4-aminopyridin-3-yl) boronic acid was used instead of (2-methoxypyrimidin-5-yl) boronic acid (40 mg,19% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.55(s,1H),8.46(s,1H),8.35(d,J＝8.2Hz,1H),7.99(d,J＝5.6Hz,1H),7.75-7.70(m,2H),7.60-7.51(m,3H),7.43(d,J＝8.2Hz,1H),6.90(s,2H),6.67(d,J＝5.6Hz,1H),3.86(s,3H),2.66(s,3H).m/z402.2[M+H] ⁺ 。

Example 79N- [6- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-3-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

In a 5mL microwave vial, 5H,6H, 8H-imidazo [2,1-c][1,4]A solution of oxazine (500 mg,4.03 mmol) in MeCN (2 mL) was treated with a suspension of N-bromosuccinimide (7197 mg,4.03 mmol) in MeCN (1 mL) at 0deg.C and the reaction was stirred at 0deg.C for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in EtOAc (10 mL), washed with water (3×10 mL), brine (10 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The quality recovery rate is low; thus, all aqueous solutions were combined and extracted with EtOAc (2X 25 mL). The combined organic extracts were dried over MgSO ₄ Drying, filtration and concentration under reduced pressure with the previously extracted compound gives 3-bromo-6, 8-dihydro-5H-imidazo [2,1-c ] as an off-white solid][1,4]Oxazine (599 mg). The crude solid (90% pure) was used directly in the next step. ¹ H NMR (500 MHz, chloroform-d) delta 6.98 (s, 1H), 4.79 (s, 2H), 4.11-4.05 (m, 2H), 3.94-3.83 (m, 2H) m/z 202.9[ M+H, ⁷⁹ Br] ⁺ ,204.9[M+H, ⁸¹ Br] ⁺ 。

step 2

A25 mL microwave vial was charged with intermediate 7 (687 mg,1.50 mmol), crude 3-bromo-5, 6-dihydro-8H-imidazo [2,1-c][1,4]Oxazine (406 mg,1.80 mmol), KF (261 mg,4.50 mmol), 1, 4-dioxane (15 mL) and water (5 mL). The mixture was degassed for 10 minutes and then addedPd-118 (196 mg,0.30 mmol) was added. The vials were sealed and heated at 50 ℃ for 16 hours. Another portion of Pd-118 (98 mg,0.15 mmol) was added and the reaction mixture was heated at 50℃for 1 hour. Water (10 mL) was added and the solution extracted with EtOAc (3X 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, elution with a 0-10% MeOH/EtOAc gradient) to give a yellow solid which was triturated in EtOAc then PE to give N- [6- (6, 8-dihydro-5H-imidazo [2, 1-c) as a brown solid][1,4]Oxazin-3-yl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (83 mg,12% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.66 (d, j=8.2 hz, 1H), 7.68 (s, 1H), 7.66-7.53 (m, 5H), 7.36 (s, 1H), 7.15 (d, j=8.2 hz, 1H), 4.90 (s, 2H), 4.42 (t, j=5.3 hz, 2H), 4.04 (t, j=5.2 hz, 2H), 3.61 (s, 3H), 2.83 (s, 3H) m/z 432.0[ m+h ] ] ⁺ 。

Example 80N- (6- (1-ethyl-3- (thiazol-2-yl) -1H-pyrazol-5-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (28 mg,14% yield) was replaced with (1-ethyl-3- (thiazol-2-yl) -1H-pyrazol-5-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.48(s,1H),8.40(s,1H),8.37-8.32(m,1H),7.90(d,J＝2.3Hz,1H),7.74-7.66(m,2H),7.61(d,J＝8.1Hz,1H),7.59-7.49(m,3H),6.76(d,J＝2.3Hz,1H),4.22(q,J＝7.3Hz,2H),3.87(s,3H),2.65(s,3H),1.42(t,J＝7.3Hz,3H).m/z 487.1[M+H] ⁺ 。

Example 81N- (2 ' -amino-6-methoxy-6 ' -methyl- [2,4' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described with respect to example 41,(2-amino-6-methylpyridin-4-yl) boronic acid was used instead of (2-methoxypyrimidin-5-yl) boronic acid (44 mg,22% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.47(s,1H),8.39(d,J＝7.7Hz,1H),7.73-7.68(m,2H),7.60-7.47(m,4H),6.97(d,J＝1.4Hz,1H),6.91(s,1H),5.91(s,2H),3.90(s,3H),2.66(s,3H),2.30(s,3H).m/z 416.2[M+H] ⁺ 。

Example 82N- (2 '- (dimethylamino) -6-methoxy- [2,4' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2- (dimethylamino) pyridin-4-yl) boronic acid was used instead of (2-methoxypyrimidin-5-yl) boronic acid (58 mg,27% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.47(s,1H),8.40(s,1H),8.16(d,J＝5.2Hz,1H),7.74-7.68(m,3H),7.61-7.52(m,3H),7.23(s,1H),7.20(dd,J＝5.2,1.4Hz,1H),3.90(s,3H),3.09(s,6H),2.67(s,3H).m/z 430.2[M+H] ⁺ 。

Example 83N- (2-methoxy-6- (pyrazolo [1,5-b ] pyridazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Pyrazolo [1,5-b ] is used by the method described for example 41]Pyridazin-3-ylboronic acid was used instead of (2-methoxypyrimidin-5-yl) boronic acid (58 mg,34% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.49(s,1H),8.94(dd,J＝9.0,1.9Hz,1H),8.73(s,1H),8.55-8.48(m,1H),8.29(d,J＝8.1Hz,1H),7.76-7.71(m,2H),7.60-7.51(m,4H),7.39-7.30(m,1H),3.97(s,3H),2.67(s,3H).m/z 427.2[M+H] ⁺ 。

Example 84N- (2-methoxy-6- (2- (tetrahydro-2H-pyran-2-yl) -2H-1,2, 3-triazol-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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By the method described for example 41, instead of 2- (oxiran-2-yl) -4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-1,2, 3-triazole (42 mg,21% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.47(s,1H),8.40(d,J＝7.9Hz,1H),8.27(s,1H),7.74-7.68(m,2H),7.61-7.46(m,4H),5.79(dd,J＝9.4,2.5Hz,1H),3.94-3.82(m,4H),3.73-3.68(m,1H),2.66(s,3H),2.35-2.24(m,1H),2.07-1.98(m,2H),1.75-1.71(m,1H),1.63-1.55(m,2H).m/z 461.1[M+H] ⁺ 。

Example 85N- (6- (2- (4-hydroxypiperidin-1-yl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, 1- [5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl]Piperidin-4-ol replaced (2-methoxypyrimidin-5-yl) boronic acid (218 mg,87% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.45(s,1H),9.00(s,2H),8.27(s,1H),7.74-7.69(m,2H),7.57-7.52(m,3H),7.52-7.47(m,1H),4.77-4.71(m,1H),4.36-4.28(m,2H),3.88(s,3H),3.80-3.73(m,1H),2.66(s,3H),1.83-1.77(m,2H),1.40-1.30(m,2H)。CH ₂ Under residual solvent. M/z487.2[ M+H ]] ⁺ 。

Example 86N- (3 '-amino-6-methoxy- [2,4' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (80 mg,39% yield) was replaced with (3-aminopyridin-4-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.56(s,1H),8.41(s,1H),8.14(s,1H),7.80(d,J＝5.2Hz,1H),7.74-7.69(m,2H),7.60-7.51(m,4H),7.44(d,J＝5.2Hz,1H),6.36(s,2H),3.86(s,3H),2.66(s,3H).m/z 402.2[M+H] ⁺ 。

Example 87N- (5 '- (difluoromethoxy) -6-methoxy- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (221 mg,88% yield) was replaced with 3- (difluoromethoxy) -5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.51(s,1H),9.19-9.15(m,1H),8.51(d,J＝2.7Hz,1H),8.43(s,1H),8.23(s,1H),7.78(d,J＝8.1Hz,1H),7.71(d,J＝7.0Hz,2H),7.62-7.52(m,3H),7.44(t,J＝73.8Hz,1H)3.92(s,3H),2.67(s,3H).m/z 453.1[M+H] ⁺ 。

Example 88N- (6 '- (difluoromethoxy) -6-methoxy- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (13 mg,6% yield) was replaced with 2- (difluoromethoxy) -5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.50(s,1H),8.94(d,J＝2.5Hz,1H),8.54(dd,J＝8.6,2.5Hz,1H),8.39(d,J＝10.9Hz,1H),7.76(t,J＝74.5Hz,1H),7.74-7.69(m,2H),7.69-7.64(m,1H),7.59-7.50(m,3H),7.20(d,J＝8.6Hz,1H),3.91(s,3H),2.66(s,3H).m/z 453.1[M+H] ⁺ 。

Example 89N- (6 '-amino-6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41The method replaced (2-methoxypyrimidin-5-yl) boronic acid (15 mg,8% yield) with (6-aminopyridin-3-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.42(s,1H),8.64(d,J＝2.4Hz,1H),8.23(d,J＝7.9Hz,1H),8.03(dd,J＝8.7,2.5Hz,1H),7.74-7.69(m,2H),7.60-7.51(m,3H),7.41(d,J＝8.1Hz,1H),6.51(d,J＝8.7Hz,1H),6.25-6.20(m,2H),3.88(s,3H),2.66(s,3H).m/z 402.2[M+H] ⁺ 。

Example 90N- (6-methoxy-5 '- (1H-pyrazol-1-yl) - [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (55 mg,27% yield) was replaced with (5- (1H-pyrazol-1-yl) pyridin-3. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.53(s,1H),9.21(d,J＝2.0Hz,1H),9.13(d,J＝2.4Hz,1H),8.79-8.75(m,1H),8.73(d,J＝2.6Hz,1H),8.46(s,1H),7.87(d,J＝1.7Hz,1H),7.84(d,J＝8.1Hz,1H),7.72(d,J＝6.9Hz,2H),7.62-7.52(m,3H),6.67-6.63(m,1H),3.95(s,3H),2.68(s,3H).m/z 453.2[M+H] ⁺ 。

Example 91N- (2-methoxy-6- (1-methyl-1H-benzo [ d ] [1,2,3] triazol-6-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (57 mg,29% yield) was replaced with 1-methyl-6- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1,2, 3-benzotriazole. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.50(s,1H),8.50(s,1H),8.44(s,1H),8.17(dd,J＝8.7,1.5Hz,1H),8.09(d,J＝8.8Hz,1H),7.79(d,J＝8.1Hz,1H),7.72(dd,J＝6.8,1.4Hz,2H),7.62-7.52(m,3H),4.38(s,3H),3.97(s,3H),2.68(s,3H).m/z 441.2[M+H] ⁺ 。

Example 92N- (6- (2- (3- (hydroxymethyl) piperidin-1-yl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, {1- [5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl } -]Piperidin-3-yl } methanol was substituted for (2-methoxypyrimidin-5-yl) boronic acid (32 mg,16% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.46(s,1H),8.99(s,2H),8.26(d,J＝7.8Hz,1H),7.74-7.69(m,2H),7.60-7.51(m,3H),7.49(d,J＝8.1Hz,1H),4.75(dd,J＝13.0,3.9Hz,1H),4.61(d,J＝13.0Hz,1H),4.57(t,J＝5.3Hz,1H),3.89(s,3H),3.40-3.24(m,2H),2.95(dt,J＝10.1,2.7Hz,1H),2.72(dd,J＝13.0,10.6Hz,1H),2.66(s,3H),1.79-1.68(m,2H),1.62-1.54(m,1H),1.41(tdd,J＝12.1,8.3,3.8Hz,1H),1.24(tdd,J＝11.9,11.5,3.5Hz,1H).m/z501.2[M+H] ⁺ 。

Example 93N- (2-methoxy-6- (4-methoxypyrimidin-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (63 mg,32% yield) was replaced with 4-methoxy-5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.50(s,1H),9.15(s,1H),8.81(s,1H),8.38(s,1H),7.73-7.67(m,3H),7.61-7.51(m,3H),4.07(s,3H),3.89(s,3H),2.67(s,3H).m/z 418.2[M+H] ⁺ 。

Example 94N- (2-methoxy-6- (thiazol-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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By the method described for example 41, using (2-methoxyThe (2-methoxypyrimidin-5-yl) boronic acid was replaced with the (6- (thiazol-5-yl) pyridin-3-yl) boronic acid (33 mg,21% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.60-9.45(m,1H),9.10(s,1H),8.50(s,1H),8.35(s,1H),7.70(d,J＝7.5Hz,2H),7.63-7.45(m,4H),3.85(s,3H),2.66(s,3H).m/z 393.1[M+H] ⁺ 。

Example 95N- (5 '- (dimethylcarbamoyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (106 mg,49% yield) was replaced with N, N-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinecarboxamide. ¹ H NMR (600 MHz, chloroform-d) δ9.21 (d, j=2.1 hz, 1H), 8.76 (d, j=8.1 hz, 1H), 8.61 (d, j=1.9 hz, 1H), 8.30 (d, j=2.2 hz, 1H), 7.79 (s, 1H), 7.68-7.60 (m, 3H), 7.60-7.55 (m, 2H), 7.39 (d, j=8.2 hz, 1H), 3.70 (s, 3H), 3.16 (s, 3H), 3.04 (s, 3H), 2.84 (s, 3H) m/z 458.0 m+h [ s,3H ] ] ⁺ 。

Example 96N- (6- ([ 1,2,4] triazolo [4,3-a ] pyridin-6-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using [1,2,4]]Triazolo [4,3-a ]]Pyridin-6-ylboronic acid replaces (2-methoxypyrimidin-5-yl) boronic acid (81 mg,32% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.87 (s, 1H), 8.77 (d, J=8.2 Hz, 1H), 8.75 (s, 1H), 7.87-7.76 (m, 3H), 7.69-7.61 (m, 3H), 7.60-7.55 (m, 2H), 7.31 (d, J=8.2 Hz, 1H), 3.72 (s, 3H), 2.84 (s, 3H) m/z 427.0[ M+H ]] ⁺ 。

Example 97N- (2-methoxy-6- (1-oxoisoindolin-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (55 mg,28% yield) was replaced with 4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-isoindol-1-one. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.53(s,1H),8.69(s,1H),8.43(br s,1H),8.16(d,J＝7.8Hz,1H),7.75-7.64(m,4H),7.62-7.48(m,4H),4.84(s,2H),3.92(s,3H),2.67(s,3H).m/z 441.1[M+H] ⁺ 。

Example 98N- (5 ' -chloro-6 ' - (dimethylamino) -6-methoxy- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (186 mg,76% yield) was replaced with (5-chloro-6- (dimethylamino) pyridin-3-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.47(s,1H),8.87-8.83(m,1H),8.35-8.29(m,2H),7.71(d,J＝6.9Hz,2H),7.60(d,J＝8.4Hz,1H),7.58-7.51(m,3H),3.90(s,3H),3.01(s,6H),2.66(s,3H).m/z 464.1[M+H] ⁺ 。

Example 99 (R) -N- (6 '- (3-hydroxypyrrolidin-1-yl) -6-methoxy- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid was used instead of (3R) -1- [5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]Pyrrolidin-3-ol (91 mg,46% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.42(s,1H),8.81(d,J＝2.5Hz,1H),8.22(d,J＝8.1Hz,1H),8.14(dd,J＝8.9,2.5Hz,1H),7.72(d,J＝6.5Hz,2H),7.64-7.49(m,3H),7.45(d,J＝8.1Hz,1H),6.51(d,J＝8.9Hz,1H),5.07-4.91(m,1H),4.40(s,1H),3.89(s,3H),3.62-3.42(m,3H),3.42-3.33(m,1H),2.67(s,3H),2.11-1.97(m,1H),1.97-1.84(m,1H).m/z 472.2[M+H] ⁺ 。

Example 100N- (2-methoxy-6- (1-methyl-1H-pyrazolo [4,3-b ] pyridin-6-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using (1-methyl-1H-pyrazolo [4, 3-b)]Pyridin-6-yl) boronic acid replaces (2-methoxypyrimidin-5-yl) boronic acid (41 mg,20% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.51(s,1H),9.27(s,1H),8.72(d,J＝1.8Hz,1H),8.45(s,1H),8.30(s,1H),7.83(d,J＝8.1Hz,1H),7.73(d,J＝7.1Hz,2H),7.62-7.52(m,3H),4.16(s,3H),3.97(s,3H),2.68(s,3H).m/z441.2[M+H] ⁺ 。

Example 101N- (6- (1, 5-dimethyl-1H-1, 2, 3-triazol-4-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (38 mg,18% yield) was replaced with 1, 5-dimethyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1,2, 3-triazole. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.49(s,1H),8.32(d,J＝8.1Hz,1H),7.75-7.64(m,3H),7.60-7.51(m,3H),3.98(s,3H),3.88(s,3H),2.68(s,3H),2.67(s,3H).m/z 405.1[M+H] ⁺ 。

Example 102N- (2-methoxy-6- (1-methyl-1H-1, 2, 3-triazol-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using 1-methyl-5- (tetramethyl)-1,3, 2-dioxaborolan-2-yl) -1H-1,2, 3-triazole substituted for (2-methoxypyrimidin-5-yl) boronic acid (33 mg,16% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.56(s,1H),8.42(br s,1H),8.24(s,1H),7.70(d,J＝7.0Hz,2H),7.61-7.50(m,4H),4.35(s,3H),3.89(s,3H),2.66(s,3H).m/z 391.2[M+H] ⁺ 。

Example 103N- (6-methoxy-2 '- (methylamino) - [2,4' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, N-methyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (34 mg,17% yield) was replaced with (2-methoxypyrimidin-5-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.48(s,1H),8.41(s,1H),8.05(d,J＝5.4Hz,1H),7.71(d,J＝7.5Hz,2H),7.63-7.51(m,4H),7.15-7.09(m,2H),6.70(s,1H),3.90(s,3H),2.83(s,3H),2.66(s,3H).m/z 416.2[M+H] ⁺ 。

Example 104N- (2-methoxy-6- (pyridazin-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (59 mg,29% yield) was replaced with 4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridazine. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.89(s,1H),9.54(s,1H),9.32(d,J＝5.6Hz,1H),8.51(s,1H),8.24(dd,J＝5.5,2.4Hz,1H),7.93(d,J＝8.1Hz,1H),7.70(dd,J＝7.2,1.4Hz,2H),7.62-7.51(m,3H),3.94(s,3H),2.67(s,3H).m/z 388.2[M+H] ⁺ 。

Example 105N- (2-methoxy-6- (1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using 3- (tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrrolo [2,3-b]Pyridine replaces (2-methoxypyrimidin-5-yl) boronic acid (50 mg,25% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ12.02(s,1H),9.46(s,1H),8.76(d,J＝7.9Hz,1H),8.27(d,J＝4.6Hz,1H),8.24-8.17(m,2H),7.77-7.71(m,2H),7.58-7.49(m,4H),7.19(dd,J＝8.0,4.7Hz,1H),3.98(s,3H),2.67(s,3H).m/z 426.2[M+H] ⁺ 。

Example 106N- (6- ([ 1,3] dioxolo [4,5-b ] pyridin-6-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, the [1,3] boronic acid was replaced with (2-methoxypyrimidin-5-yl) boronic acid ]Dioxolo [4,5-b ]]Pyridin-6-ylboronic acid (84 mg,43% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.47(s,1H),8.36-8.30(m,2H),7.86(s,1H),7.71(d,J＝7.0Hz,2H),7.60-7.51(m,4H),6.21(s,2H),3.90(s,3H),2.66(s,3H).m/z 431.1[M+H] ⁺ 。

Example 107N- (6 ' -hydroxy-6-methoxy-5 ' - (trifluoromethyl) - [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (215 mg,86% yield) was replaced with (6-hydroxy-5- (trifluoromethyl) pyridin-3-yl) boronic acid. ¹ H NMR(500MHz,DMSO-d ₆ )δ12.71(s,1H),9.47(s,1H),8.55(s,1H),8.39(s,1H),8.31-8.26(m,1H),7.73-7.68(m,2H),7.58-7.52(m,4H),3.87(s,3H),2.65(s,3H).m/z 471.1[M+H] ⁺ 。

Example 108N- (6 '-acetamido-6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (178 mg,72% yield) was substituted with (6-acetamidopyridin-3-yl) boronic acid. ¹ H NMR (600 MHz, chloroform-d) delta 8.84 (s, 1H), 8.71 (d, j=8.3 hz, 1H), 8.26-8.22 (m, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7-70-7.60 (m, 3H), 7.58 (d, j=7.5 hz, 2H), 7.30 (d, j=8.3 hz, 1H), 3.70 (s, 3H), 2.83 (s, 3H), 2.23 (s, 3H) m/z 444.0[ m+h)] ⁺ 。

Example 109N- (2-methoxy-6- (5-methoxy-1-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, 5-methoxy-1-methyl-3- (tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrrolo [2,3-c ] is replaced with (2-methoxypyrimidin-5-yl) boronic acid ]Pyridine (65 mg,32% yield). ¹ HNMR(500MHz,DMSO-d ₆ )δ9.46(s,1H),8.49(s,1H),8.25(s,1H),8.19(d,J＝8.2Hz,1H),7.76-7.71(m,2H),7.66(s,1H),7.58-7.53(m,3H),7.39(d,J＝8.1Hz,1H),3.97(s,3H),3.90(s,3H),3.87(s,3H),2.66(s,3H).m/z 470.2[M+H] ⁺ 。

Example 110N- (2-methoxy-6- (1- (pyridin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using 4- [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl]Pyridine replaces (2-methoxypyrimidin-5-yl) boronic acid (47 mg,23% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.45(s,1H),9.23(s,1H),8.71-8.66(m,2H),8.40(s,1H),8.30(d,J＝8.1Hz,1H),7.97-7.92(m,2H),7.72(d,J＝6.8Hz,2H),7.56(d,J＝7.1Hz,3H),7.44(d,J＝8.0Hz,1H),3.93(s,3H),2.67(s,3H).m/z 453.1[M+H] ⁺ 。

Example 111N- (6- (1, 2-dimethyl-1H-benzo [ d ] imidazol-5-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (32 mg,16% yield) was replaced with 1, 2-dimethyl-5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-1, 3-benzodiazole. ¹ H NMR(500MHz,DMSO-d ₆ )δ9.45(s,1H),8.30(d,J＝8.2Hz,1H),8.23(s,1H),7.95(d,J＝8.4Hz,1H),7.75-7.70(m,2H),7.62(d,J＝8.1Hz,1H),7.60-7.51(m,4H),3.94(s,3H),3.76(s,3H),2.67(s,3H),2.54(s,3H).m/z 454.1[M+H] ⁺ 。

Example 112N- (2-methoxy-6- (pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, 3- (tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyrazolo [1,5-a]Pyrimidine replaces (2-methoxypyrimidin-5-yl) boronic acid (190 mg,76% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.43(s,1H),9.22(d,J＝7.0Hz,1H),8.80(s,1H),8.78-8.72(m,1H),8.33-8.28(m,1H),8.02(d,J＝8.1Hz,1H),7.73(d,J＝6.7Hz,2H),7.58-7.53(m,3H),7.20-7.14(m,1H),3.93(s,3H),2.67(s,3H).m/z 427.1[M+H] ⁺ 。

Example 113N- (2-methoxy-6- (pyrazin-2-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid was replaced with pyrazin-2-yl boronic acid (70 mg,28% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.51(s,1H),9.51-9.48(m,1H),8.85-8.79(m,1H),8.73-8.69(m,1H),8.67(d,J＝2.6Hz,1H),7.99(d,J＝8.1Hz,1H),7.74-7.69(m,2H),7.62-7.52(m,3H),3.95(s,3H),2.68(s,3H).m/z 388.2[M+H] ⁺ 。

Example 114N- (2-methoxy-6- (2-oxo-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridin-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using (2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) boronic acid replaces (2-methoxypyrimidin-5-yl) boronic acid (210 mg,86% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.75-8.67 (m, 2H), 8.12-8.01 (m, 2H), 7.75 (s, 1H), 7.70-7.50 (m, 5H), 3.70 (s, 3H), 3.63 (s, 2H), 2.84 (s, 3H) m/z 483.0[ M+CH ] ₃ CN+H] ⁺ 。

Example 115N- (2-methoxy-6- (3-methyl-1- (thiazol-2-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using 2- [ 3-methyl-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl]-1, 3-thiazole instead of (2-methoxypyrimidin-5-yl) boronic acid (200 mg,79% yield). ¹ HNMR(500MHz,DMSO-d ₆ )δ9.48(s,1H),8.96(s,1H),8.27(d,J＝8.0Hz,1H),7.75-7.70(m,2H),7.65(d,J＝3.4Hz,1H),7.59-7.43(m,5H),3.89(s,3H),2.66(s,3H),2.61(s,3H).m/z 473.2[M+H] ⁺ 。

Example 116N- (5 ' -fluoro-6-methoxy-6 ' -oxo-1 ',6' -dihydro- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (186 mg,74% yield) was replaced with (5-fluoro-6-oxo-1, 6-dihydropyridin-3-yl) boronic acid. ¹ H NMR (600 MHz, chloroform-d) delta 8.70 (s, 1H), 7.90-7.77 (m, 2H), 7.73 (s, 1H), 7.70-7.50 (m, 6H), 7.05 (d, J=8.4 Hz, 1H), 3.66 (s, 3H), 2.83 (s, 3H) m/z 462.0[ M+CH ] ₃ CN+H] ⁺ 。

Example 117N- (2-methoxy-6- (1-oxo-1, 2-dihydro-phthalazin-6-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (160 mg,65% yield) was replaced with (1-oxo-1, 2-dihydropyrazin-6-yl) boronic acid. ¹ H NMR (600 MHz, chloroform-d) δ9.77 (s, 1H), 8.80 (d, j=8.3 hz, 1H), 8.44 (d, j=8.5 hz, 1H), 8.37 (d, j=8.4 hz, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.69-7.61 (m, 3H), 7.61-7.55 (m, 2H), 7.51 (d, j=8.1 hz, 1H), 3.76 (s, 3H), 2.85 (s, 3H) m/z 495.0[ m+ch ] ₃ CN+H] ⁺ 。

Example 118N- (2-methoxy-6- (1H-pyrrolo [2,3-b ] pyridin-5-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, using 5- (tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrrolo [2,3-b]Pyridine replaces (2-methoxypyrimidin-5-yl) boronic acid (190 mg,75% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.77(s,1H),9.48(s,1H),8.95(s,1H),8.59(s,1H),8.35-8.31(m,1H),7.75-7.71(m,2H),7.65(d,J＝8.1Hz,1H),7.58-7.53(m,3H),7.53-7.49(m,1H),6.53(s,1H),3.95(s,3H),2.67(s,3H).m/z 426.2[M+H] ⁺ 。

Example 119N- (2-methoxy-6- (2-oxo-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazin-6-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

By the method described for example 41, (2-methoxypyrimidin-5-yl) boronic acid (193 mg,78% yield) was replaced with 6- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 4-dihydro-1H-3, 1-benzoxazin-2-one. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.30(s,1H),9.45(s,1H),8.31(s,1H),7.97(d,J＝8.4Hz,1H),7.93(s,1H),7.74-7.69(m,2H),7.59-7.48(m,4H),6.96(d,J＝8.3Hz,1H),5.37(s,2H),3.90(s,3H),2.66(s,3H).m/z 457.1[M+H] ⁺ 。

Example 120N- (5-isoxazol-4-yl-3-methoxy-pyrazin-2-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 mL microwave vial was charged with intermediate 6 (100 mg,0.26 mmol), isoxazole-4-boronic acid (35 mg,0.31 mmol), KOAc (101 mg,1.03 mmol), pd-118 (17 mg,0.03 mmol), 1, 4-dioxane (2 mL) and water (0.2 mL). The vial was sealed, purged with nitrogen and degassed, then heated at 80 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in DCM (25 mL) and washed with water (25 mL). The organic phase was concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-90% EtOAc/PE) to give N- (5-isoxazol-4-yl-3-methoxy-pyrazin-2-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (23 mg,22% yield) as a tan solid. ¹ H NMR (600 MHz, chloroform-d) δ8.84 (s, 1H), 8.66 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.66-7.59(m,3H),7.57(t,J＝7.6Hz,2H),3.72(s,3H),2.84(s,3H).m/z 378.0[M+H] ⁺ 。

Example 121N- [6- (1H-imidazol-2-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 7 (50 mg,0.13 mmol), 2-bromo-1H-imidazole (19 mg,0.13 mmol), 1, 4-dioxane (1 mL) and water (0.5 mL) were charged to a microwave vial. The reaction mixture was evacuated and backfilled three times with nitrogen. Then, na is added ₂ CO ₃ (68 mg,0.64 mmol) and tetrakis (triphenylphosphine) palladium (0) (29 mg,0.03 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 1 hour. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on ISCO system (elution with a 4% MeOH/DCM gradient) gave N- [6- (1H-imidazol-2-yl) -2-methoxy-3-pyridinyl as a colorless solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10.5 mg,21% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.89 (s, 1H), 8.76 (d, J=8.1 Hz, 1H), 7.78-7.69 (m, 2H), 7.68-7.53 (m, 5H), 7.13 (s, 2H), 3.66 (s, 3H), 2.83 (s, 3H) m/z 375.9[ M+H ]] ⁺ 。

Example 122N- [ 2-methoxy-6- (2H-tetrazol-5-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

In a microwave vial was placed intermediate 1 (500 mg,1.29 mmol) and DMSO (10 mL). Copper (I) cyanide (90 mg,1.29 mmol) was added thereto, and the vial was sealed and heated at 100℃overnight. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (3×3 mL). Separating organic matters by MgSO ₄ Dried and evaporated. The crude N- (6-cyano-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (about 50 mg) was thus obtained as an off-white solid directly used in the next step. ¹ H NMR (600 MHz, chloroform-d) δ8.75 (d, j=8.0 hz, 1H), 7.85 (s, 1H), 7.68-7.55 (m, 5H), 7.31 (d, j=8.1 hz, 1H), 3.62 (s, 3H), 2.83 (s, 3H).

Step 2

To a solution of N- (6-cyano-2-methoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (50 mg,0.15 mmol) in DMF (1 mL) was added sodium azide (29 mg,0.45 mmol) and NH ₄ Cl (80 mg,1.49 mmol). The reaction mixture was heated at 120℃for 3 days. The reaction mixture was then reacted with saturated NaHCO ₃ (10 mL) and then extracted with EtOAc (3X 5 mL). The aqueous phase was carefully acidified by dropwise addition of concentrated HCl to ph=2, then extracted with DCM (3×5 mL). The combined organics were washed with water (3 mL), and dried over MgSO ₄ Dried and evaporated. The crude product obtained was triturated with MeCN to give N- [ 2-methoxy-6- (2H-tetrazol-5-yl) -3-pyridinyl ] as a colorless solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg,30% yield). ¹ H NMR(600MHz,DMSO-d ₆ )δ9.52(s,1H),8.54(s,1H),7.82(d,J＝8.0Hz,1H),7.68(d,J＝7.2Hz,2H),7.60-7.49(m,3H),3.93(s,3H),2.65(s,3H).m/z 378.0[M+H] ⁺ 。

Example 123N- (2-methoxy-6-oxazol-2-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

In a 5mL microwave vial, a solution of intermediate 1 (100 mg,0.26 mmol) and tetrakis (triphenylphosphine) palladium (0) (30 mg,0.03 mmol) in 1, 4-dioxane (2.5 mL) was treated with 2- (tributylstannyl) -1, 3-oxazole (0.12 mL,0.36 mmol). The vial was sealed, purged with nitrogen and degassed, then heated at 120 ℃ for 24 hours, then at room temperature for 2 days. The reaction mixture was partitioned between EtOAc (25 mL) and water (25 mL) and the layers separated. The organic layer was washed with brine, over MgSO ₄ Drying, filtering and reducingConcentrating under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-90% EtOAc/PE) to give an insufficiently pure solid. The material was purified again by flash column chromatography (4 g silica, eluting with a 0-5% meoh/DCM gradient) to give N- (2-methoxy-6-oxazol-2-yl-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (24 mg,23% yield) as a colorless solid. ¹ H NMR (600 MHz, chloroform-d) δ8.78 (d, j=8.2 hz, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.70 (d, j=8.2 hz, 1H), 7.63 (d, j=7.3 hz, 3H), 7.58 (t, j=7.6 hz, 2H), 5.30 (s, 1H), 3.73 (s, 3H), 2.84 (s, 3H). M/z376.9[ m+h ]] ⁺ 。

Example 124N- (6- (isoxazol-4-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Step 1 Synthesis of intermediate 10-N- (6-bromo-2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxylic acid (0.95 g,4.68 mmol) was dissolved in SOCl ₂ (3.75 mL,51.4 mmol) and the reaction mixture was heated to 65℃overnight. After cooling to room temperature, excess SOCl was removed under reduced pressure in a fume hood ₂ . The residue was dissolved in DCM (10 mL) and then added dropwise to 6-bromo-2-methoxy-3-pyridinamine (0.95 g,4.68 mmol) and Et at 0deg.C ₃ A solution of N (0.78 mL,5.61 mmol) in DCM (10 mL). The reaction mixture was stirred at 0 ℃ for 2 hours and allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with water (20 mL), 1M NaOH (2X 20 mL), 1M HCl (3X 20 mL) and brine (20 mL). The organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give N- (6-bromo-2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a brown solid (1.20 g,59% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.48 (d, J=8.2 Hz, 1H), 7.72 (br s, 1H), 7.56-7.63 (m, 3H), 7.51-7.56 (m, 2H), 7.06 (d, J=8.2 Hz, 1H), 3.85 (s, 3H), 2.69 (s, 3H) m/z 388.0[ M+H, ⁷⁹ Br] ⁺ ,390.0[M+H, ⁸¹ Br] ⁺ 。

step 2

A20 mL microwave vial was charged with intermediate 10 (200 mg,0.52 mmol), isoxazole-4-boronic acid (64 mg,0.57 mmol), KF (90 mg,1.55 mmol), 1, 4-dioxane (9 mL), and water (3 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (34 mg,0.05 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 35 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-100% EtOAc/PE, 25 CV). The CV containing products were combined and evaporated under reduced pressure. The precipitate was then dried in vacuo at 40 ℃ to give N- (6- (isoxazol-4-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a yellow solid (94 mg,46% yield). ¹ H NMR (400 MHz, chloroform-d) δ8.83 (s, 1H), 8.68 (s, 1H), 8.63 (d, J=8.1 Hz, 1H), 7.88 (br s, 1H), 7.49-7.69 (m, 5H), 7.07 (d, J=8.2 Hz, 1H), 3.90 (s, 3H), 2.71 (s, 3H) m/z 377.1[ M+H ]] ⁺ 。

Example 125N- [ 2-methoxy-6- [2- (methoxymethyl) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 7 (80 mg,0.18 mmol) and KF (32 mg,0.55 mmol) in 1, 4-dioxane (3.2 mL) and water (0.8 mL) was treated with 5-bromo-2- (methoxymethyl) pyrimidine (45 mg,0.22 mmol) and the mixture was bubbled with nitrogen for 10 min. Pd-118 (12 mg,0.02 mmol) was then added to the reaction, sealed and heated overnight at 40 ℃. The reaction mixture was concentrated under reduced pressure and dissolved in chloroform. Water was added and organics were separated using a phase separator. The organics were concentrated under reduced pressure and the residue purified by flash silica column chromatography on an ISCO system to give N- [ 2-methoxy-6- [2- (methoxymethyl)Base) pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (58 mg,69% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.24 (s, 2H), 8.77 (d, J=8.1 Hz, 1H), 7.79 (s, 1H), 7.66-7.61 (m, 3H), 7.62-7.55 (m, 2H), 7.36 (d, J=8.1 Hz, 1H), 4.74 (s, 2H), 3.70 (s, 3H), 3.57 (s, 3H), 2.84 (s, 3H) m/z 432.0[ M+H ] ] ⁺ 。

Example 126N- [6- [2- (aminomethyl) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1-Synthesis of intermediate 11-tert-butyl N- [ (5-bromopyrimidin-2-yl) methyl ] carbamate

7M NH in MeOH ₃ The solution (10 mL,70 mmol) was added to intermediate 8 (800 mg,3.18 mmol) and the solution was stirred at room temperature. After about 1 hour a suspension was formed. After 4 hours, the mixture was concentrated to give an off-white solid. DCM (15 mL) was added followed by Et ₃ N (0.89 mL,6.35 mmol). The open flask was stirred for about 20 minutes. Di-tert-butyl dicarbonate (830 mg,3.81 mmol) was then added, a precipitate formed briefly, and then a yellow solution was formed, which was stirred at room temperature overnight. The reaction was concentrated to MgSO ₄ On top of this, followed by flash column chromatography on ISCO system (24 g silica, gradient elution with 0-20% EtOAc/PE) afforded tert-butyl N- [ (5-bromopyrimidin-2-yl) methyl]Carbamate (450 mg,44% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.77 (s, 2H), 5.75 (br s, 1H), 4.57 (d, J=5.3 Hz, 2H), 1.48 (s, 9H) m/z 231.9/233.9[ M-C (CH) ₃ ) ₃ +H] ⁺ 。

Step 2

A mixture of intermediate 7 (450 mg,1.03 mmol), intermediate 11 (300 mg,1.04 mmol) and triturated KF (180 mg,3.1 mmol) in 1, 4-dioxane (5 mL) and water (2.5 mL) was bubbled with nitrogen for 10 min. Pd-118 (67 mg,0.10 mmol) was added and the mixture was heated to 45℃overnight. The reaction mixture was partitioned between DCM (70 mL) and water (25 mL). The organic layer was separated and washed with DCM (25 mL) The aqueous layer was further extracted. The organics were combined, passed over MgSO ₄ Dried, filtered and concentrated to a brown solid. The solid was suspended in isopropanol (20 mL) and cooled in a refrigerator (-20 ℃ C.) for 1.5 hours. The precipitate was isolated by filtration and washed with additional cold isopropanol (-20 ℃,20 mL) to give tert-butyl N- [ [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ]]-2-pyridyl group]Pyrimidin-2-yl]Methyl group]Carbamate (520 mg,88% yield). ¹ H NMR (500 MHz, chloroform-d) delta 9.20 (s, 2H), 8.77 (d, j=8.1 hz, 1H), 7.81-7.77 (m, 1H), 7.68-7.62 (m, 3H), 7.62-7.55 (m, 2H), 7.35 (d, j=8.1 hz, 1H), 5.70 (br s, 1H), 4.63 (d, j=5.1 hz, 2H), 3.69 (s, 3H), 2.84 (s, 3H), 1.48 (s, 9H) m/z 517.2[ m+h)] ⁺ 。

Step 3

To tert-butyl N- [ [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ]]-2-pyridyl group]Pyrimidin-2-yl]Methyl group]To a suspension of carbamate (120 mg,0.21 mmol) in 1, 4-dioxane (1 mL) was added a solution of 2M HCl in ether (5 mL,10 mmol) and the resulting fine suspension was stirred at room temperature overnight. LCMS of the suspension indicated completion of the reaction. The solid was isolated by filtration to give a hygroscopic solid, which was suspended in isopropanol (20 mL) by sonication and then evaporated using Biotage V10. The resulting solid was dried in a vacuum oven at 40℃for 3 hours to give N- [6- [2- (aminomethyl) pyrimidin-5-yl ] ]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (96 mg,99% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.56(s,1H),9.50(s,2H),8.54-8.36(m,4H),7.84(d,J＝8.2Hz,1H),7.72(d,J＝7.1Hz,2H),7.61-7.53(m,3H),4.39(s,2H),3.94(s,3H),2.68(s,3H).m/z 417.1[M+H] ⁺ 。

Example 127N- [6- (6-Aminopyridazin-3-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

6-bromopyridazin-3-amine (40 mg,0.23 mmol), intermediate 7 (100 mg,0.23 mmol) and KF (40 mg,0.71 mmol) in 1, 4-dioxane (4 mL) andthe solution in water (1 mL) was degassed with nitrogen for 15 minutes. Pd-118 (15 mg,0.023 mmol) was added rapidly and the solution was degassed for an additional 10 minutes and then stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by automatic column chromatography (20 CV from 0-50% EtOAc/n-hexane gradient followed by a rapid gradient to 100% EtOAc) to give a partially purified product which was triturated with ether (5 mL) and stirred rapidly for 15 minutes. The suspension was allowed to settle and the supernatant removed by pipetting. The procedure was repeated twice and the resulting solid was dried under reduced pressure to give N- [6- (6-aminopyridazin-3-yl) -2-methoxy-3-pyridinyl as a beige solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (11 mg,12% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.77 (d, j=8.2 hz, 1H), 8.16-8.07 (m, 2H), 7.76 (s, 1H), 7.68-7.60 (m, 3H), 7.57 (t, j=7.4 hz, 2H), 6.79 (d, j=9.1 hz, 1H), 4.82 (s, 2H), 3.68 (s, 3H), 2.83 (s, 3H). M/z 403.1[ m+h ]] ⁺ 。

Example 128N- [ 2-methoxy-6- (6-methoxypyridazin-3-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of 3-bromo-6-methoxypyridazine (43 mg,0.23 mmol), intermediate 7 (100 mg,0.23 mmol) and KF (40 mg,0.69 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (15 mg,0.023 mmol) was added rapidly and the solution was degassed for an additional 10 minutes and then stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by automatic column chromatography (gradient from 0-50% EtOAc/n-hexane over 15CV followed by a rapid gradient to 100% EtOAc) to give the partially purified product, which was dissolved in minimal DCM (about 0.5 mL) and PE (about 3 mL) was added. The solution was left for several hours, allowing the product to precipitate as the DCM evaporated. By movingExcess PE was removed by the liquid tube and the resulting solid was washed three times with PE (supernatant removed each time). The solid was dried under reduced pressure to give N- [ 2-methoxy-6- (6-methoxypyridazin-3-yl) -3-pyridinyl ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (29 mg,30% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.80 (d, j=8.3 hz, 1H), 8.25 (d, j=9.2 hz, 1H), 8.17 (d, j=8.3 hz, 1H), 7.78 (s, 1H), 7.69-7.61 (m, 3H), 7.58 (t, j=7.3 hz, 2H), 7.01 (d, j=9.2 hz, 1H), 4.17 (s, 3H), 3.69 (s, 3H), 2.83 (s, 3H) m/z 418.2[ m+h] ⁺ 。

Example 129N- [6- (2-carbamoyl-pyrimidin-5-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Example 60 (50 mg,0.12 mmol) and 7M NH in MeOH ₃ A solution (33. Mu.L, 0.23 mmol) in DMF (1 mL) was treated with HATU (66 mg,0.17 mmol) followed by the addition of the schnik base (0.04 mL,0.23 mmol) and the reaction mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was redissolved in chloroform. Addition of NaHCO ₃ The reaction was stirred vigorously and then passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a solid which was purified by flash column chromatography using an ISCO system (24 g silica column; 0-10% MeOH/DCM gradient) to give N- [6- (2-carbamoyl-pyrimidin-5-yl) -2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (34 mg,65% yield). ¹ H NMR(600MHz,DMSO-d ₆ ) δ9.51 (s, 2H), 8.46 (s, 1H), 8.21 (s, 1H), 7.92-7.79 (m, 2H), 7.69 (d, j=7.1 hz, 2H), 7.61-7.43 (m, 3H), 3.92 (s, 3H), 2.66 (s, 3H). An amide NH exchange. m/z 431.0[ M+H ] ] ⁺ 。

Example 130N- [6- [2- (dimethylcarbamoyl) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of example 60 (50 mg,0.12 mmol) and 2M dimethylamine (0.12 mL,0.23 mmol) in DMF (1 mL) was treated with HATU (66.1 mg, 0.1700mmol), then added with the addition of the schnik base (0.04 mL,0.23 mmol) and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was redissolved in chloroform. Addition of NaHCO ₃ The reaction was stirred vigorously and then passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a solid which was purified by flash column chromatography using an ISCO system (24 g silica column; 0-10% MeOH/DCM gradient) followed by second column chromatography (12 g silica column; 0-100% EtOAc/PE gradient) to give N- [6- [2- (dimethylcarbamoyl) pyrimidin-5-yl)]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-4-isoxazole-carboxamide (28 mg, 50% yield). ¹ H NMR (600 MHz, chloroform-d) δ9.29 (s, 2H), 8.79 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.67-7.61 (M, 3H), 7.61-7.55 (M, 2H), 7.40 (d, J=8.1 Hz, 1H), 3.70 (s, 3H), 3.16 (s, 3H), 2.98 (s, 3H), 2.83 (s, 3H) M/z459.0[ M+H ]] ⁺ 。

Example 131N- [6- [2- (dimethylamino) - [1,2,4] triazolo [1,5-a ] pyridin-7-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Intermediate 7 (60 mg,0.14 mmol), 7-bromo-N, N-dimethyl- [1,2,4]Triazolo [1,5-a ]]Pyridin-2-amine (42 mg,0.14 mmol), 1, 4-dioxane (1.2 mL) and water (0.3 mL) were charged into a microwave vial. The reaction mixture was evacuated and backfilled three times with nitrogen. KOAc (40.5 mg,0.42 mmol) and Pd (dppf) Cl were then added ₂ (10 mg,0.014 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 1 hour. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were subjected to MgSO ₄ Dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash silica column chromatography on ISCO system (with 3%MeOH/DCM gradient elution). The desired fractions were concentrated to dryness under reduced pressure. The off-white solid product thus obtained was dissolved in DCM (1 mL) and HCl in ether (1M solution in ether, 1 mL) was then added. Instantaneous formation of solids was noted. The reaction mixture was stirred for 1 hour. The reaction mixture was then evaporated under reduced pressure and the solid was further triturated with ether (3 mL). The solid was filtered and washed with ice-cooled ether (2 mL) and dried under reduced pressure to give N- [6- [2- (dimethylamino) - [1,2,4 ] as a colorless solid ]Triazolo [1,5-a ]]Pyridin-7-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (25 mg,34% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.80 (d, j=7.7 hz, 1H), 8.53-8.45 (M, 1H), 8.35 (d, j=6.7 hz, 1H), 7.88 (d, j=6.7 hz, 1H), 7.85 (s, 1H), 7.67-7.62 (M, 3H), 7.60 (d, j=7.4 hz, 2H), 7.55 (d, j=8.2 hz, 1H), 3.73 (s, 3H), 3.31 (s, 6H), 2.84 (s, 3H) M/z 470.0[ m+h for free base ]] ⁺ 。

Example 132N- [ 2-methoxy-6- (3-methylimidazol-4-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A5 mL microwave vial was charged with intermediate 1 (250 mg,0.64 mmol), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-imidazole (161 mg,0.77 mmol), pd-118 (42 mg,0.06 mmol), KOAc (255 mg,2.58 mmol), 1, 4-dioxane (2 mL) and water (0.2 mL). The vial was sealed, purged with nitrogen and heated at 80 ℃ for 16 hours, then at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in EtOAc (20 mL), washed with water (10 mL), brine (10 mL), and dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-5% MeOH/DCM) to give N- [ 2-methoxy-6- (3-methylimidazol-4-yl) -3-pyridinyl as an off-white solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (108 mg,41% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.67 (d, J=8.2 Hz, 1H), 7.70 (s, 1H),7.66-7.60(m,3H),7.60-7.54(m,2H),7.45(s,1H),7.37(s,1H),7.16(d,J＝8.2Hz,1H),3.93(s,3H),3.63(s,3H),2.83(s,3H).m/z 390.0[M+H] ⁺ 。

Example 133N- [5- (5-fluoro-6-oxo-1H-pyridin-3-yl) -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Into a microwave vial was charged intermediate 13 (300 mg,0.77 mmol), 5-bromo-3-fluoro-1H-pyridin-2-one (156 mg,0.77 mmol), na ₂ CO ₃ (408 mg,3.85 mmol) and Pd (dppf) Cl ₂ (56 mg,0.077 mmol). The reaction mixture was then evacuated and backfilled with nitrogen three times, followed by microwave irradiation at 120 ℃ for 40 minutes. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (20 mL) and the organics were washed with water (20 mL) then brine (20 mL). The collected organics were subjected to MgSO ₄ Dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash silica column chromatography on ISCO system (eluting with a 4% MeOH/DCM gradient) to give N- [5- (5-fluoro-6-oxo-1H-pyridin-3-yl) -3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg,5% yield). ¹ H NMR (500 MHz, chloroform-d) δ13.27 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=10.6 Hz, 1H), 7.68-7.61 (m, 3H), 7.58 (d, J=7.2 Hz, 1H), 3.71 (s, 3H), 2.85 (s, 3H) m/z 422.1[ M+H ] ] ⁺ 。

Example 134 ethyl 2- [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] -2-pyridinyl ] -2-methyl-imidazol-1-yl ] acetate

Step 1

A stirred solution of 4-bromo-2-methyl-1H-imidazole (2.00 g,12.4 mmol) in acetone (20 mL) was treated with K ₂ CO ₃ (2.58 g,18.6 mmol) and ethyl chloroacetate (1.33 mL,12.4 mmol). The reaction mixture was stirred at 60 ℃ for 15 hours, then at room temperature for 5 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, gradient elution with 0-100% etoac/PE) to give ethyl 2- (5-bromo-2-methyl-imidazol-1-yl) acetate (890 mg,28% yield) as an off-white solid. ¹ H NMR (500 MHz, chloroform-d) delta 6.80 (s, 1H), 4.54 (s, 2H), 4.25 (q, j=7.1 hz, 2H), 2.33 (s, 3H), 1.29 (t, j=7.1 hz, 3H), m/z 246.8[ m+h, ⁷⁹ Br] ⁺ ,248.8[M+H, ⁸¹ Br] ⁺ 。

step 2

A5 mL microwave vial was charged with intermediate 7 (100 mg,0.26 mmol), ethyl 2- (5-bromo-2-methyl-imidazol-1-yl) acetate (76 mg,0.31 mmol), pd-118 (17 mg,0.03 mmol), KOAc (101 mg,1.03 mmol), 1, 4-dioxane (1.6 mL) and water (0.16 mL). The vessel was sealed, purged with nitrogen and heated at 80 ℃ for 16 hours. The solvent was removed under reduced pressure, and the residue was redissolved in EtOAc (20 mL), washed with water (10 mL), brine (10 mL), and dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, elution with a 0-5% MeOH/DCM gradient) to give ethyl 2- [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] as a brown solid]-2-pyridyl group]-2-methyl-imidazol-1-yl]Acetate (15 mg,12% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.65 (d, j=8.2 hz, 1H), 7.71 (s, 1H), 7.65-7.62 (m, 2H), 7.62-7.58 (m, 1H), 7.58-7.53 (m, 2H), 7.48 (d, j=8.2 hz, 1H), 7.34 (s, 1H), 4.61 (s, 2H), 4.24 (q, j=7.2 hz, 2H), 3.62 (s, 3H), 2.82 (s, 3H), 2.40 (s, 3H), 1.29 (t, j=7.1 hz, 3H) m/z 476.0[ m+h)] ⁺ 。

Example 135N- (6- (imidazo [1,2-a ] pyrazin-3-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Into a 20mL microwave vial was charged intermediate 7 (150 mg,0.34 mmol), 3-bromoimidazoleAzolo [1,2-a ]]Pyrazine (75 mg,0.38 mmol), KF (60 mg,1.03 mmol), 1, 4-dioxane (4.5 mL), and water (1.5 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (23 mg,0.03 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-100% EtOAc/PE, 40 CV). The CV containing products were combined and evaporated under reduced pressure. The precipitate was then dried in vacuo at 40℃to give N- (6- (imidazo [1, 2-a) as a tan solid]Pyrazin-3-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (48.4 mg,30% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.44 (dd, j=4.9)&1.5Hz,1H),9.14(d,J＝1.5Hz,1H),8.80(d,J＝8.3Hz,1H),8.19(s,1H),7.94(d,J＝4.7Hz,1H),7.78(br s,1H),7.70-7.58(m,5H),7.39(d,J＝8.2Hz,1H),3.75(s,3H),2.85(s,3H).m/z 427.1[M+H] ⁺ 。

Example 136N- (6- (imidazo [1,2-a ] pyrimidin-3-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

A10 mL microwave vial was charged with intermediate 7 (80 mg,0.19 mmol), 3-bromoimidazo [1,2-a]Pyrimidine (41 mg,0.21 mmol), KF (33 mg,0.57 mmol), 1, 4-dioxane (3 mL), and water (1 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (12 mg,0.02 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-100% EtOAc/PE, 40 CV). The CV containing products were combined and evaporated under reduced pressure. The residue was taken up in hot EtOAc (3 mL) Grinding, and vacuum drying the precipitate at 40deg.C to obtain N- (6- (imidazo [1, 2-a) as cream solid]Pyrimidin-3-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (25.9 mg,29% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.90 (dd, j=6.9)&2.1Hz,1H),8.78(d,J＝8.3Hz,1H),8.58(dd,J＝4.1&2.0Hz,1H),8.23(s,1H),7.74(br s,1H),7.68-7.58(m,5H),7.37(d,J＝8.3Hz,1H),6.94(dd,J＝7.0&4.1Hz,1H),3.73(s,3H),2.85(s,3H).m/z 427.1[M+H] ⁺ 。

Example 137N- (2-methoxy-6- (7-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Step 1

A20 mL microwave vial was charged with intermediate 7 (0.40 g,0.92 mmol), tert-butyl 3-bromo-5, 6-dihydroimidazo [1,2-a]Pyrazine-7 (8H) -carboxylate (0.31 g,1.01 mmol), KF (160 mg,2.76 mmol), 1, 4-dioxane (9 mL), and water (3 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (60 mg,0.09 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 50 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-100% EtOAc/PE+1% Et ₃ N, 40 CV). The CV containing products were combined and evaporated under reduced pressure. The precipitate was then dried under vacuum at 40 ℃ to give tert-butyl 3- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydroimidazo [1,2-a as a yellow solid ]Pyrazine-7 (8H) -carboxylic acid ester (0.21 g,42% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.66 (d, j=8.2 hz, 1H), 7.69 (br s, 1H), 7.66-7.60 (m, 3H), 7.60-7.55 (m, 2H), 7.36 (s, 1H), 7.13 (d, j=8.2 hz, 1H), 4.74 (s, 2H), 4.39 (t, j=5.4 hz, 2H), 3.82 (t, j=5.5 hz, 2H), 3.61 (s, 3H), 2.83 (s, 3H), 1.49 (s, 9H), m/z 531.2[ m+m ]H] ⁺ 。

Step 2

Into a 10mL microwave vial was charged tert-butyl 3- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydroimidazo [1,2-a]Pyrazine-7 (8H) -carboxylic acid ester (50 mg,0.09 mmol), paraformaldehyde (11 mg,0.38 mmol) and formic acid (2 mL). The reaction mixture was heated to 95 ℃ and stirred for 2 hours. The reaction mixture was cooled, diluted with DCM (15 mL) and washed successively with 2M NaOH (2X 15 mL), water (2X 15 mL) and brine (1X 15 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc/PE (1:3 ratio) and the precipitate dried under vacuum at 40℃to give N- (2-methoxy-6- (7-methyl-5, 6,7, 8-tetrahydroimidazo [1, 2-a) as a brown solid]Pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (28 mg, 64% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.67 (d, j=8.2 hz, 1H), 7.70 (br s, 1H), 7.60-7.69 (m, 3H), 7.62-7.57 (m, 2H), 7.35 (s, 1H), 7.15 (d, j=8.2 hz, 1H), 4.43 (t, j=5.6 hz, 2H), 3.74 (s, 2H), 3.63 (s, 3H), 2.83-2.87 (s, 3H) &t,J＝5.2Hz,2H),2.52(s,3H).m/z 445.2[M+H] ⁺ 。

Example 138N- (2-methoxy-6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide hydrochloride

Into a 10mL microwave vial was charged tert-butyl 3- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydroimidazo [1,2-a]Pyrazine-7 (8H) -carboxylate (synthesized according to example 137) (75 mg,0.14 mmol), HCl (2M in ether, 0.71mL,1.41 mmol) and DCM (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the precipitate was dried in vacuo at 40 ℃ to give N- (2-methoxy-6- (5, 6,7, 8-tetrahydroimidazo [1, 2-a) as a pale yellow solid]Pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide hydrochloride (58 mg,86% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.91 (br s, 2H), 9.60 (s, 1H), 8.35 (br s, 1H), 7.90 (br s, 1H), 7.72 (d, j=6.8 hz, 2H), 7.61-7.52 (M, 3H), 7.49 (d, j=8.1 hz, 1H), 4.74 (t, j=5.8 hz, 2H), 4.57 (s, 2H), 3.88 (s, 3H), 3.66 (t, j=5.8 hz, 2H), 2.66 (s, 3H) M/z 431.2[ m+h for free base ]] ⁺ 。

Example 139N- [6- (4-cyanoimidazol-1-yl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

5mL microwave vials were filled with intermediate 1 (100 mg,0.26 mmol), K ₂ CO ₃ (356 mg,2.58 mmol), L-proline (15 mg,0.13 mmol), copper (I) iodide (25 mg,0.13 mmol), 1H-imidazole-4-carbonitrile (29 mg,0.31 mmol) and DMSO (2 mL). The vials were sealed and degassed and then heated at 80 ℃ for 16 hours. The reaction was partitioned between water (20 mL) and EtOAc (30 mL). The phases were separated and the organic layer was washed with brine (20 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica, gradient elution with 0-90% EtOAc/PE) to give N- [6- (4-cyanoimidazol-1-yl) -2-methoxy-3-pyridinyl as a pale yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (14 mg,12% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.85 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 7.66-7.56 (m, 5H), 6.94 (d, J=8.3 Hz, 1H), 3.67 (s, 3H), 2.83 (s, 3H) m/z 401.0[ M+H ]] ⁺ 。

Example 140N- [ 2-methoxy-6- [4- (trifluoromethyl) imidazol-1-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

5mL microwave vials were filled with intermediate 1 (100 mg,0.26 mmol), K ₂ CO ₃ (356 mg,2.58 mmol), L-proline (15 mg,0.13 mmol), copper (I) iodide (25 mg,0.13 mmol), 4- (trifluoromethyl) -1H-imidazole (42 mg,0.31 mmol) and DMSO (2 mL). The vials were sealed and degassed and then heated at 80 ℃ for 16 hours. The reaction was partitioned between water (20 mL) and EtOAc (30 mL). The phases were separated and the organic layer was washed with brine (20 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica, gradient elution with 0-90% EtOAc/PE) to give N- [ 2-methoxy-6- [4- (trifluoromethyl) imidazol-1-yl as a brown solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (49 mg,41% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.83 (d, j=8.3 hz, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.66-7.60 (m, 3H), 7.58 (t, j=7.5 hz, 2H), 6.93 (d, j=8.3 hz, 1H), 3.67 (s, 3H), 2.83 (s, 3H) m/z 443.9[ m+h ]] ⁺ 。

Example 141 3- (4-fluorophenyl) -N- (6-imidazol-1-yl-2-methoxy-3-pyridyl) -5-methyl-isoxazole-4-carboxamide

Step 1-Synthesis of intermediate 12-N- (6-bromo-2-methoxy-3-pyridinyl) -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide

To a solution of 6-bromo-2-methoxy-3-pyridinamine (2.00 g,9.85 mmol) in DMF (40 mL) was added HATU (4.49, 11.8 mmol) and schnikose base (5.15 mL,29.55 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then 3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxylic acid (2.18 g,9.86 mmol) was added. The reaction mixture was then heated at 80 ℃ overnight. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (25 mL). The organic layer was washed with water (2X 5 mL) and then with saturated brine solution (10 mL). The organics were dried over MgSO ₄ Dried, filtered and concentrated to dryness under reduced pressure. The crude product was then purified by flash column chromatography (eluting with 70-80% PE/EtOAc). The desired fractions were concentrated to dryness under reduced pressure. The resulting product was triturated with MeOH (3 mL) and then filtered to give N- (6-bromo-2-methoxy-3-pyridinyl) -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (1.3 g,33% yield) as a colorless solid. ¹ H NMR (600 MHz, chloroform-d)δ8.53(d,J＝8.2Hz,1H),7.68-7.55(m,2H),7.52(s,1H),7.31-7.20(m,2H),7.03(d,J＝8.2Hz,1H),3.68(s,3H),2.79(s,3H).m/z 405.9[M+H] ⁺ 。

Step 2

To a solution of intermediate 12 (150 mg,0.37 mmol) in DMSO (3 mL) was added L-proline (21.2 mg,0.18 mmol), copper (I) iodide (35 mg,0.18 mmol), imidazole (30 mg,0.44 mmol) and K ₂ CO ₃ (153 mg,1.10 mmol). The reaction mixture was evacuated and backfilled 3 times with nitrogen and then heated overnight at 60 ℃. The reaction mixture was diluted with EtOAc (20 mL) and filtered through celite. The organic layer was then washed with water (20 mL) and brine (20 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude product was then purified by flash silica column chromatography on ISCO system (eluting with a 3% MeOH/DCM gradient) to give 3- (4-fluorophenyl) -N- (6-imidazol-1-yl-2-methoxy-3-pyridinyl) -5-methyl-isoxazole-4-carboxamide (38 mg,25% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.78 (d, j=8.4 hz, 1H), 8.21 (d, j=1.2 hz, 1H), 7.68-7.57 (m, 3H), 7.50 (d, j=1.4 hz, 1H), 7.28 (t, j=8.5 hz, 2H), 7.15 (d, j=1.3 hz, 1H), 6.90 (d, j=8.3 hz, 1H), 3.74 (s, 3H), 2.82 (s, 3H) m/z 394.1[ m+h] ⁺ 。

Example 142N- [5- (2-ethoxypyrimidin-5-yl) -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

Sodium (390 mg,17.1 mmol) was added portionwise to ice-cold EtOH (10 mL). After the addition was complete, the cooling bath was removed and sodium consumption was monitored by naked eyes. Once the sodium was consumed (45 minutes), 5-bromo-2-chloropyrimidine (2.00 g,10.34 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give 5-bromo-2-ethoxy-pyrimidine (2.04 g,97% yield) as a colourless solid. ¹ HNMR (500 MHz, chlorine)Imitation-d) delta 8.49 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H), m/z 204.9[ M+H, ⁸¹ Br] ⁺ 。

step 2-Synthesis of intermediate 13-N- [ 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Intermediate 6 (0.50 g,1.28 mmol), B were added to a microwave vial under an inert atmosphere ₂ Pin ₂ (1.31 g,5.14 mmol) and 1, 4-dioxane (12 mL). The solution was degassed with nitrogen for 15 min, then Pd (dppf) ₂ Cl ₂ DCM complex (105 mg,0.13 mmol) and KOAc (378 mg,3.85 mmol) were added rapidly. The mixture was again degassed with nitrogen for 15 minutes and then heated to 80 ℃ for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The solution was washed with water (20 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product. PE (80 mL) was added and the suspension was triturated overnight. After allowing the suspension to settle, the supernatant was removed with a pipette and the process repeated (this time stirring for only 10 minutes). The solid obtained was dried under reduced pressure and made into smaller particles using a spatula. Diethyl ether (80 mL) was added and the mixture was heated to boiling point using a heat gun under rotation. The suspension was filtered while hot (gravity, filter paper) and the filtrate was concentrated under reduced pressure to give N- [ 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (483 mg, 82% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.32 (s, 1H), 8.01 (s, 1H), 7.64-7.56 (M, 3H), 7.55-7.50 (M, 2H), 3.69 (s, 3H), 2.82 (s, 3H), 1.33 (s, 12H) M/z 354.9[ M+H for boric acid ] ] ⁺ 。

Step 3

A solution of 5-bromo-2-ethoxy-pyrimidine (90 mg,0.44 mmol), intermediate 13 (200 mg,0.43 mmol) and KF (64 mg,1.10 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen for 15 min. Pd-118 (24 mg,0.037 mmol) was added rapidly and the solution was degassed for an additional 10 minutes and then stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Drying, filtering and decompressingConcentration gave the crude product which was purified by automatic column chromatography (gradient from 0-50% EtOAc/N-hexane over 25CV, then rapid gradient to 100% EtOAc) to give N- [5- (2-ethoxypyrimidin-5-yl) -3-methoxy-pyrazin-2-yl as a pale yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (111 mg,59% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.99 (s, 2H), 8.31 (s, 1H), 7.95 (s, 1H), 7.66-7.60 (m, 3H), 7.59-7.54 (m, 2H), 4.48 (q, J=7.1 Hz, 2H), 3.75 (s, 3H), 2.85 (s, 3H), 1.46 (t, J=7.1 Hz, 3H) m/z 433.1[ M+H ]] ⁺ 。

Example 143N- (6- (7-acetyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Dried 10mL microwave vials were charged with example 138 (30 mg,0.06 mmol), et under nitrogen ₃ N (20. Mu.L, 0.18 mmol) and anhydrous DCM (2 mL). Acetyl chloride (1M, 70. Mu.L, 0.07mmol in DCM) was then added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (10 mL) and sequentially saturated NaHCO ₃ The solution (2X 10 mL), water (2X 10 mL) and brine (10 mL) were washed. The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g, silica, 0-10% MeOH/DCM+1% Et ₃ N, 30 CV). The CV containing products were combined and evaporated under reduced pressure. The precipitate was then dried in vacuo at 40℃to give N- (6- (7-acetyl-5, 6,7, 8-tetrahydroimidazo [1, 2-a) as a colourless solid]Pyrazin-3-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (8.7 mg,29% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.68 (d, j=8.1 hz, 1H), 7.70 (br s, 1H), 7.66-7.61 (m, 3H), 7.61-7.55 (m, 2H), 7.37 (br s, 1H), 7.14 (d, j=8.2 hz, 1H), 4.81 (s, 2H), 4.40 (t, j=5.6 hz, 2H), 4.04-3.97 (m, 2H), 3.60 (s, 3H), 2.83 (s, 3H), 2.20 (s, 3H). The compounds were present as a mixture of rotamers (in chloroform-d in a ratio of about 3:1 in DMSO-d ₆ In a ratio of about 1:1), in DMSO-d ₆ Is confirmed in the temperature change experiment. M/z473.1[ M+H ]] ⁺ 。

Example 144N- [5- [2- [ (dimethylamino) methyl ] pyrimidin-5-yl ] -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 9 (119 mg,0.55 mmol), intermediate 13 (0.300 g,0.687 mmol) and KF (96 mg,1.65 mmol) in 1, 4-dioxane (12 mL) and water (3 mL) was degassed with nitrogen for 15 min. Pd-118 (36 mg,0.055 mmol) was added rapidly and the solution was degassed for an additional 10 minutes and then stirred overnight at room temperature. After degassing, additional KF (96 mg,1.65 mmol) and Pd-118 (36 mg,0.055 mmol) were added and the mixture was heated at 35℃overnight. Another portion of KF (96 mg,1.65 mmol) and Pd-118 (36 mg,0.055 mmol) were added and the mixture was stirred for 2 days. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product which is purified by automatic column chromatography (gradient from 0-10% MeOH/DCM over 35 CV) to give N- [5- [2- [ (dimethylamino) methyl ] as a pale brown solid]Pyrimidin-5-yl]-3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (82 mg, 33% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.20 (s, 2H), 8.41 (s, 1H), 8.02 (s, 1H), 7.66 (m, 3H), 7.60 (d, J=7.4 Hz, 2H), 3.82 (s, 2H), 3.78 (s, 3H), 2.87 (s, 3H), 2.40 (s, 6H) m/z 446.1[ M+H ]] ⁺ 。

Example 145N- [ 3-methoxy-5- [2- (methylamino) pyrimidin-5-yl ] pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 13 (356 mg,0.77 mmol), 5-bromo-N-methyl-pyrimidin-2-amine (145 mg,0.73 mmol) and KF (127 mg,2.19 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen for 15 minAnd (3) a clock. Pd-118 (48 mg,0.073 mmol) was added rapidly and the solution was degassed for an additional 10 minutes and then stirred for 2 days at 35 ℃. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (30 mL). The organic phase was concentrated directly under reduced pressure without MgSO ₄ And (5) drying. The resulting solid was washed with diethyl ether (3×30 mL) and then MeOH (40 mL) to give a very fine suspension which was gravity filtered through filter paper. After drying, the solid was collected and further dried in a vacuum oven at 40℃for 1 hour to give N- [ 3-methoxy-5- [2- (methylamino) pyrimidin-5-yl]Pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (135 mg,44% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ10.55(s,1H),9.08-8.87(m,2H),8.47(s,1H),7.63(d,J＝7.4Hz,2H),7.61-7.54(m,1H),7.52-7.41(m,3H),3.95(s,3H),2.87(d,J＝4.8Hz,3H),2.61(s,3H).m/z 418.1[M+H] ⁺ 。

Example 146N- (6-imidazol-1-yl-2-methoxy-3-pyridinyl) -5-methyl-3- (2-pyridinyl) isoxazole-4-carboxamide

Step 1

To a solution of 5-methyl-3- (2-pyridinyl) -1, 2-oxazole-4-carboxylic acid (500 mg,2.45 mmol) in DMF (5 mL) was added HATU (1.12 g,2.94 mmol) and a schnik base (1.28 mL,7.35 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then 6-bromo-2-methoxy-3-pyridineamine (497 mg,2.45 mmol) was added. The reaction mixture was then heated at 70 ℃ overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (50 mL). The organic layer was washed with water (2X 5 mL), brine solution (1X 20 mL), and over MgSO ₄ Dried and concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluting with 80% PE/EtOAc) to give N- (6-bromo-2-methoxy-3-pyridinyl) -5-methyl-3- (2-pyridinyl) isoxazole-4-carboxamide (0.56 g,56% yield) as a colorless solid. ¹ H NMR (500 MHz, chloroform-d) delta 13.37 (s, 1H), 8.69 (ddd, j=5.0, 1.8,0.9hz, 1H), 8.63 (d, j=8.2 hz, 1H), 8.23 (dt, j=8.1, 1.1hz, 1H), 7.93 (td, j=7.8, 1.8hz, 1H)H),7.51(ddd,J＝7.6,5.0,1.2Hz,1H),7.09(d,J＝8.2Hz,1H),4.13(s,3H),2.86(s,3H).m/z 390.9[M+H, ⁸¹ Br] ⁺ 。

Step 2

To a solution of N- (6-bromo-2-methoxy-3-pyridinyl) -5-methyl-3- (2-pyridinyl) isoxazole-4-carboxamide (150 mg,0.39 mmol) in DMSO (3 mL) was added K ₂ CO ₃ (160 mg,1.16 mmol), L-proline (22 mg,0.19 mmol) and imidazole (32 mg,0.46 mmol). The mixture was degassed by bubbling with nitrogen for 3 minutes, then copper (I) iodide (37 mg,0.19 mmol) was added and the mixture was heated at 80 ℃ overnight. TLC analysis showed new product formation, LCMS showed the desired quality of the desired product. The reaction mixture was diluted with EtOAc (20 mL) and filtered through a celite pad. The clear filtrate was washed with water (2X 3 mL) and the organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified using automatic column chromatography (2-4% MeOH in DCM) to give N- (6-imidazol-1-yl-2-methoxy-3-pyridinyl) -5-methyl-3- (2-pyridinyl) isoxazole-4-carboxamide as an off-white solid (63 mg,41% yield). ¹ H NMR (500 MHz, chloroform-d) delta 13.47 (s, 1H), 8.87 (d, j=8.3 hz, 1H), 8.73 (ddd, j=5.0, 1.8,0.9hz, 1H), 8.35 (s, 1H), 8.25 (dt, j=8.0, 1.1hz, 1H), 7.95 (td, j=7.8, 1.8hz, 1H), 7.64 (s, 1H), 7.53 (ddd, j=7.6, 5.0,1.2hz, 1H), 7.23 (s, 1H), 6.96 (d, j=8.4 hz, 1H), 4.18 (s, 3H), 2.89 (s, 3H) M/z377.2[ m+h ]] ⁺ 。

Example 147N- [5- (6-acetamido-3-pyridinyl) -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of 2-acetamido-5-bromopyridine (224 mg,1.04 mmol), intermediate 13 (178 mg,1.10 mmol), and KF (181 mg,3.12 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen for 15 min. Pd-118 (68 mg,0.12 mmol) was added rapidly and the solution was degassed for an additional 10 minutes, then stirred at room temperature over the weekend. The reaction mixture was diluted with EtOAc (20 mL). It appears that the product is present in suspensionIn the organic layer, the organic phase is thus filtered under the action of gravity (filter paper). Purification by silica automatic column chromatography (12 g, gradient 0-10% MeOH/DCM, 25 CV) gave N- [5- (6-acetamido-3-pyridinyl) -3-methoxy-pyrazin-2-yl as a colorless solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (225 mg,49% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.79 (d, J=2.3 Hz, 1H), 8.34 (s, 1H), 8.30-8.25 (m, 1H), 8.22-8.16 (m, 2H), 7.97 (s, 1H), 7.66-7.59 (m, 3H), 7.56 (dd, J=8.0, 6.5Hz, 2H), 3.75 (s, 3H), 2.84 (s, 3H), 2.24 (s, 3H), m/z 445.1[ M+H ]] ⁺ 。

Example 148N- [5- [6- (hydroxymethyl) -3-pyridinyl ] -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of (5-bromopyridin-2-yl) methanol (202 mg,1.08 mmol), intermediate 13 (490 mg,1.12 mmol) and KF (188 mg,3.23 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen for 15 min. Pd-118 (70 mg,0.11 mmol) was added rapidly and the solution was degassed for an additional 10 minutes, then stirred at room temperature over the weekend. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (4×30 mL). The organic fraction was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by automatic column chromatography (12 g silica, 0-10% MeOH/DCM gradient, 25 CV). The fractions containing the product were collected and concentrated under reduced pressure to give N- [5- [6- (hydroxymethyl) -3-pyridinyl ] as a pale brown powder]-3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (239 mg, 53% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.09 (s, 1H), 8.39 (s, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.97 (s, 1H), 7.67-7.59 (m, 3H), 7.56 (t, J=7.6 Hz, 2H), 7.34 (d, J=8.2 Hz, 1H), 4.81 (s, 2H), 3.76 (s, 3H), 3.70 (br s), 2.85 (s, 3H) m/z 418.1[ M+H ]] ⁺ 。

Example 149N- [ 3-methoxy-5- (1-methyl-6-oxo-3-pyridinyl) pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 13 (450 mg,1.03 mmol) 5-bromo-1-methyl-2 (1H) -pyridone (184 mg,0.98 mmol) and KF (171 mg,2.94 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen for 15 min. Pd-118 (64 mg,0.98 mmol) was added rapidly and the solution was degassed for an additional 10 minutes, then stirred at room temperature over the weekend. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (30 mL), which resulted in an intractable emulsion. For this, the aqueous phase was extracted three times with DCM (3X 20 mL) and the combined organics were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by automated purification of silica column chromatography (12 g, gradient from 0-10% MeOH/DCM, 25 CV) to give N- [ 3-methoxy-5- (1-methyl-6-oxo-3-pyridinyl) pyrazin-2-yl as an orange solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (336 mg,82% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.14 (s, 1H), 7.95-7.88 (m, 2H), 7.86 (dd, J=9.5, 2.6Hz, 1H), 7.68-7.60 (m, 3H), 7.56 (t, J=7.4 Hz, 2H), 6.65 (d, J=9.5 Hz, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 2.84 (s, 3H) m/z 418.1[ M+H ]] ⁺ 。

Example 150N- [5- (5-aminopyrazin-2-yl) -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A solution of intermediate 13 (530 mg,1.21 mmol), 5-bromopyrazin-2-amine (200 mg,1.15 mmol) and KF (201 mg,3.46 mmol) in 1, 4-dioxane (8 mL) and (2 mL) was degassed with nitrogen. Pd-118 (75 mg,0.12 mmol) was added and the solution was degassed for an additional 10 minutes and then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was washed with DCM (80 mL), hot-boiling EtOAc (80 mL), hot-boiling MeCN (80 mL) and hot-boiling chloroform (80 mL). The combined organic washes were concentrated under reduced pressure to give the crude product, which was partially dissolved in DCM and dried onto silica. By silica automatic column chromatography (12g silica, eluting with 0-10% MeOH/DCM) to give N- [5- (5-aminopyrazin-2-yl) -3-methoxy-pyrazin-2-yl as a beige solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (132 mg,27% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ10.57(s,1H),8.75(s,1H),8.56(s,1H),7.97(s,1H),7.72-7.62(m,2H),7.55-7.39(m,3H),6.94(s,2H),3.98(s,3H),2.61(s,3H).m/z 404.1[M+H] ⁺ 。

Example 151N- (6- (1H-imidazol-1-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Intermediate 10 (96 mg,0.22 mmol) was added to imidazole (36 mg,0.54 mmol), K ₂ CO ₃ (123 mg), 0.90 mmol) and L-proline (5 mg,0.04 mmol) in DMSO (4 mL) and degassing the reaction mixture with nitrogen. Copper (I) iodide (9 mg,0.04 mmol) was added rapidly and the reaction mixture was further degassed and then heated at 80℃for 16 hours. The reaction mixture was diluted with EtOAc (15 mL) and filtered through celite. The filtrate was washed with water (2×15 mL), and the organic layer was washed with MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica, eluting with 0-100% EtOAc/PE) to give N- (6- (1H-imidazol-1-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a pink solid (18 mg, 21% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.73 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 7.81 (br s, 1H), 7.55-7.63 (m, 5H), 7.51-7.54 (m, 1H), 7.17 (s, 1H), 6.92 (d, J=8.3 Hz, 1H), 3.91 (s, 3H), 2.72 (s, 3H) m/z 376.1[ M+H ]] ⁺ 。

Example 152N- [6- [4- [ (dimethylamino) methyl ] imidazol-1-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Example 153N- [6- [5- [ (dimethylamino) methyl ] imidazol-1-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

A solution of 4-imidazole carboxaldehyde (266 mg,2.77 mmol) in THF (10 mL) was treated with dimethylamine (2M in THF, 2.08mL,4.15 mmol) and acetic acid (0.02 mL,0.3 mmol). The yellow reaction mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (880 mg,4.15 mmol) was added. The yellow mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the organic layer was washed with brine (10 mL), over MgSO ₄ Dried, filtered and concentrated to give 1- (1H-imidazol-4-yl) -N, N-dimethyl-methylamine (64 mg, 18%) as a yellow oil, which was used in the next step without further purification. ¹ H NMR(600MHz,DMSO-d ₆ )δ7.49(s,1H),6.80(s,1H),3.29(s,2H),2.08(s,6H).m/z 126.0[M+H] ⁺ 。

Step 2

5mL microwave vials were filled with intermediate 1 (200 mg,0.52 mmol), K ₂ CO ₃ (710 mg,5.15 mmol), L-proline (30 mg,0.26 mmol), copper (I) iodide (49 mg,0.26 mmol), 1- (1H-imidazol-4-yl) -N, N-dimethylmethylamine (64 mg,0.52 mmol) and DMSO (4 mL). The vials were sealed and degassed and then heated at 80 ℃ for 16 hours. The reaction was partitioned between water (20 mL) and EtOAc (50 mL) and separated. The organic layer was washed with brine (20 mL), and dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified on Shimadzu MDAP (eluted with a 10-95% MeCN/water +0.1% formic acid gradient) to give the two regioisomers. Regiochemistry is not precisely specified, so the isomer is arbitrarily designated as N- [6- [4- [ (dimethylamino) methyl ] as a tan solid]Imidazol-1-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10 mg, 4% yield) N- [6- [5- [ (dimethylamino) methyl ] as an off-white solid]Imidazol-1-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (15 mg,6% yield). Isomers are distinguished by differences in NMR spectra.

N- [6- [4- [ (dimethylamino) methyl ] methyl]Imidazol-1-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide: ¹ h NMR (600 MHz, chloroform-d) delta 8.79 (d, j=8.3 hz, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.65-7.60 (m, 3H), 7.60-7.55 (m, 2H), 6.90 (d, j=8.3 hz, 1H), 4.00 (s, 2H), 3.66 (s, 3H), 2.83 (s, 3H), 2.65 (s, 6H), m/z 433.1[ m+h ]] ⁺ 。

N- [6- [5- [ (dimethylamino) methyl ] methyl]Imidazol-1-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide: ¹ h NMR (600 MHz, chloroform-d) delta 8.84 (d, j=8.2 hz, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.66-7.61 (m, 3H), 7.59 (dd, j=8.2, 6.9hz, 2H), 7.19 (s, 1H), 7.14 (d, j=8.2 hz, 1H), 4.03 (s, 2H), 3.63 (s, 3H), 2.83 (s, 3H), 2.30 (s, 6H) m/z 433.1[ m+h) ] ⁺ 。

Example 154N- (6- (1H-imidazol-1-yl) -2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Step 1

1-methyl-4-phenyl-triazole (0.45 g,2.8mmol, synthesized according to WO 2012/062687) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen in a microwave vial and the reaction mixture was cooled to-78 ℃. 1.6M butyllithium (5.2 mL,8.4 mmol) in hexane was then added dropwise and the resulting yellow solution stirred for 40 min. CO is then removed using a cannula ₂ (generated from dry ice) was bubbled into the-78 ℃ solution for 1 hour during which time the mixture was warmed to room temperature. The reaction mixture was quenched with water (about 3 mL) and the reaction mixture was evaporated under reduced pressure. To the residue was added 2M NaOH (about 20 mL). The aqueous layer was washed with EtOAc (3X 20 mL) and then neutralized with 1M HCl (about 30 mL). The neutralized extract was then concentrated in vacuo. The precipitate was filtered, washed with additional water (about 10 mL) and petroleum ether (about 10 mL) and then dried in vacuo to give 1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxylic acid (0.2 g,34% yield) as a colorless solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ7.68-7.75(m,2H),7.39-7.49(m,3H),4.25(s,3H).m/z 204.1[M+H] ⁺ 。

Step 2

1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxylic acid (197.0 mg,0.97 mmol) was dissolved in SOCl ₂ (0.78 mL,11 mmol) and the reaction mixture was heated to 65℃for 16 h. After cooling to room temperature, excess SOCl was removed under reduced pressure ₂ . The residue was dissolved in DCM (5 mL) at 0deg.C and then added dropwise to 6-bromo-2-methoxy-3-pyridinamine (197mg, 0.97 mmol) and Et ₃ N (0.16 mL,1.2 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (10 mL) and washed successively with water (10 mL), 1M NaOH (2X 10 mL), 1M HCl (3X 10 mL) and brine (10 mL). The organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a brown solid (164 mg,41% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.53 (d, J=8.2 Hz, 1H), 8.03 (br s, 1H), 7.60-7.66 (m, 2H), 7.52-7.58 (m, 3H), 7.07 (d, J=8.2 Hz, 1H), 4.42 (s, 3H), 3.63 (s, 3H) m/z 388.0[ M+H, ⁷⁹ Br] ⁺ ,390.0[M+H, ⁸¹ Br] ⁺ 。

step 3

N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide (64 mg,0.33 mmol) was added to imidazole (27 mg,0.40 mmol), K ₂ CO ₃ (91 mg, 0.66 mmol) and L-proline (4 mg,0.04 mmol) in DMSO (3 mL) and degassing the reaction mixture with nitrogen. Copper (I) iodide (6 mg,0.04 mmol) was added rapidly and the reaction mixture was further degassed and then stirred at 80 ℃ for 16 hours. The reaction mixture was diluted with EtOAc (10 mL) and filtered through celite. The filtrate was washed with water (2×10 mL), and the organic layer was washed with MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was then triturated with hot EtOAc (3 mL), the precipitate collected and dried in vacuo at 40 ℃ to give N- (6- (1H-imidazol-1-yl) -2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a colorless solid (21 mg, 31% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.80 (d, j=8.3 hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.68 (dd, j=)6.4&2.5Hz,2H),7.57-7.62(m,3H),7.55(br s,1H),7.19(s,1H),6.95(d,J＝8.3Hz,1H),4.46(s,3H),3.72(s,3H).m/z 376.1[M+H] ⁺ 。

Example 155N- [5- (6, 8-dihydro-5H-imidazo [2,1-c ] [1,4] oxazin-3-yl) -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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KF (108 mg,1.86 mmol), 3-bromo-5, 6-dihydro-8H-imidazo [2,1-c ]][1,4]A solution of oxazine (168 mg,0.62 mmol) and intermediate 13 (284 mg,0.65 mmol) in 1, 4-dioxane (6 mL) and water (1.5 mL) was degassed with nitrogen. Pd-118 (61 mg,0.093 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture stirred at room temperature for 16 hours. The solution was degassed and additional Pd-118 (61 mg,0.093 mmol) was added, followed by degassing for an additional 10 minutes. The mixture was heated at 45 ℃ for 16 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) followed by flash reversed phase automatic chromatography (30 g hpc18 Aq, gradient from water to MeOH). The sample was stirred in ether (5 mL) for 15 minutes, the solids were allowed to settle and the supernatant removed with a pipette. The resulting solid was further dried in a vacuum oven at 40℃for 2 hours to give N- [5- (6, 8-dihydro-5H-imidazo [2,1-c ] as a colorless solid ][1,4]Oxazin-3-yl) -3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (27 mg, 10%). ¹ H NMR (500 MHz, chloroform-d) delta 8.20 (s, 1H), 7.85 (s, 1H), 7.63 (d, j=7.4 hz, 2H), 7.59 (d, j=6.9 hz, 1H), 7.55 (t, j=7.3 hz, 2H), 7.41 (s, 1H), 4.90 (s, 2H), 4.33 (t, j=5.2 hz, 2H), 4.05 (t, j=5.2 hz, 2H), 3.69 (s, 3H), 2.83 (s, 3H) m/z 433.1[ m+h)] ⁺ 。

Example 156N- [5- [2- (aminomethyl) pyrimidin-5-yl ] -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1

A mixture of intermediate 13 (220 mg,0.50 mmol), intermediate 11 (150 mg,0.52 mmol) and triturated KF (88 mg,1.5 mmol) in 1, 4-dioxane (2.5 mL) and water (1.5 mL) was bubbled with nitrogen. Pd-118 (33 mg,0.050 mmol) was added and the mixture was heated at 45℃for 16 hours. The solvent was removed in vacuo and the mixture partitioned between DCM (20 mL) and brine (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2X 20 mL). The organic extract was concentrated to dryness and purified by flash silica column chromatography (12 g silica, eluting with 50-100% EtOAc/PE). The isolated crude material was recrystallized from isopropanol to give tert-butyl N- [ [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] ]Pyrazin-2-yl]Pyrimidin-2-yl]Methyl group]Carbamate (170 mg,62% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.18 (s, 2H), 8.39 (s, 1H), 8.01 (s, 1H), 7.67-7.61 (m, 3H), 7.58 (t, J=7.4 Hz, 2H), 5.89-5.37 (m, 1H), 4.65 (d, J=5.2 Hz, 2H), 3.77 (s, 3H), 2.86 (s, 3H), 1.49 (s, 9H) m/z 518.1[ M+H ]] ⁺ 。

Step 2

To tert-butyl N- [ [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ]]Pyrazin-2-yl]Pyrimidin-2-yl]Methyl group]To a suspension of carbamate (180 mg,0.35 mmol) in 1, 4-dioxane (1 mL) was added 2M HCl (in ether, 5mL,10 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The solid was collected by filtration, washed with ether and dried in a vacuum oven at 40 ℃ for 6 hours to give N- [5- [2- (aminomethyl) pyrimidin-5-yl]-3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (160 mg, 99% yield). ¹ H NMR(500MHz,DMSO-d6)δ10.73(s,1H),9.50(s,2H),8.74(s,1H),8.56(s,3H),7.60(d,J＝7.6Hz,2H),7.48(t,J＝7.3Hz,1H),7.42(t,J＝7.5Hz,2H),4.00(s,3H),2.63(s,3H)。CH ₂ Under the NMR solvent peak. M/z 418.1[ M+H for free base ]] ⁺ 。

Example 157N- (2-methoxy-6- (pyrimidin-5-yl) pyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Intermediate 10 (100 mg,0.26 mmol) was added to a solution of 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (58 mg,0.28 mmol) and KF (45 mg,0.77 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen. Pd-118 (17 mg,0.030 mmol) was added rapidly and the mixture was further degassed and then stirred at 50℃for 16 hours. The reaction mixture was concentrated under reduced pressure. The dark residue was dissolved in DCM (10 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica, 0-100% EtOAc/PE+1% Et ₃ N elution) to give N- (2-methoxy-6- (pyrimidin-5-yl) pyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a yellow solid (28 mg,27% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.28 (s, 2H), 9.20 (s, 1H), 8.73 (d, J=8.2 Hz, 1H), 7.93 (br s, 1H), 7.54-7.65 (m, 5H), 7.40 (d, J=8.1 Hz, 1H), 3.95 (s, 3H), 2.73 (s, 3H) m/z 388.1[ M+H ]] ⁺ 。

Example 158N- [5- [5- (difluoromethoxy) -3-pyridinyl ] -3-methoxy-pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

5-bromopyridin-3-ol (868 mg,4.99 mmol) and KOH (5.88 g,105 mmol) were dissolved in water (20 mL) and MeCN (20 mL). The solution was cooled to-78 ℃ and the mixture was then solidified. 2-chloro-2, 2-difluoroacetophenone (0.88 mL,6.0 mmol) was added dropwise, and after the addition was complete, the mixture was first warmed to room temperature and then heated at 80℃for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ether (80 mL), washed with water (6X 40 mL), and concentrated over MgSO ₄ Drying, filtering and concentrating under reduced pressure (using unheated water bath) to give colorlessLiquid 3-bromo-5- (difluoromethoxy) pyridine (269 mg,22% yield), which was used without further purification. Samples were stored cryogenically in tin foil protected flasks. ¹ H NMR (500 MHz, chloroform-d) δ8.57 (d, j=2.0 hz, 1H), 8.44 (d, j=2.4 hz, 1H), 7.69 (d, j=2.3 hz, 1H), 6.58 (t, j=72.0 hz, 1H). ¹⁹ FNMR (376 MHz, chloroform-d) delta-81.9 (d, J=72 Hz, 2F). M/z 225.9[ M+H, ⁸¹ Br] ⁺ 。

step 2

A solution of KF (153 mg,2.63 mmol), intermediate 13 (380 mg,0.88 mmol) and 3-bromo-5- (difluoromethoxy) pyridine (267 mg,1.20 mmol) in 1, 4-dioxane (6.5 mL) and water (1.5 mL) was degassed with nitrogen. Pd-118 (57 mg,0.088 mmol) was added, the solution was again degassed and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give N- [5- [5- (difluoromethoxy) -3-pyridinyl ] as a pale brown solid]-3-methoxy-pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (221 mg,55% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.99 (s, 1H), 8.48 (d, j=2.5 hz, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.62 (m, 3H), 7.56 (t, j=7.7 hz, 2H), 6.61 (t, j=72.0 hz, 1H), 3.76 (s, 3H), 2.84 (s, 3H). ¹⁹ F NMR (376 MHz, chloroform-d) delta-81.3 (d, J=72.0 Hz, 2F). M/z 454.0[ M+H ] ] ⁺ 。

Example 159N- (6- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Step 1 Synthesis of intermediate 14-N- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Intermediate 10 (936 mg,2.15 mmol), B ₂ pin ₂ (708mg，2.79mmol)、Pd(dppf)Cl ₂ (177 mg,0.21 mmol) and KOAc (292 mg,6.44 mmol) were dissolved in 1, 4-dioxane (15 mL). The reaction mixture was degassed with nitrogen and then heated at 90 ℃ for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL), washed with water (2×50 mL), and the organic layer was washed with MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by trituration with PE (50 mL) to give N- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a brown solid (1.03 g,99% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.54 (d, J=7.8 Hz, 1H), 7.97 (br s, 1H), 7.51-7.62 (M, 5H), 7.46 (d, J=7.8 Hz, 1H), 3.91 (s, 3H), 2.70 (s, 3H), 1.35 (s, 12H) M/z 354.0[ M+H for boric acid ]] ⁺ 。

Step 2

Intermediate 14 (100 mg,0.23 mmol) was added to 7-bromo- [1,2,4 ]Triazolo [1,5-a ]]In a solution of pyridin-2-amine (53 mg,0.25 mmol) and KF (40 mg,0.69 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen. Pd-118 (15 mg,0.02 mmol) was added and the mixture was further degassed and then stirred at 80℃for 16 hours. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (10 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, eluting with 0-10% MeOH/DCM) to give N- (6- (2-amino- [1,2, 4) as a cream solid]Triazolo [1,5-a ]]Pyridin-7-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide (33 mg, 31% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.71 (d, j=8.1 hz, 1H), 8.31 (d, j=7.1 hz, 1H), 8.03 (s, 1H), 7.93 (br s, 1H), 7.54-7.66 (m, 5H), 7.46 (d, j=7.0 hz, 1H), 7.43 (d, j=8.1 hz, 1H), 4.47 (br s, 2H), 3.96 (s, 3H), 2.73 (s, 3H) m/z 442.0[ m+h)] ⁺ 。

Example 160N- (6 '- (hydroxymethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Intermediate 14 (100 mg,0.23 mmol) was added to a solution of (5-bromopyridin-2-yl) methanol (47 mg,0.25 mmol) and KF (40 mg,0.69 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen. Pd-118 (15 mg,0.02 mmol) was added and the mixture was further degassed and then stirred at 50℃for 16 hours. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (10 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica eluting with 0-10% MeOH/DCM) to give N- (6 '- (hydroxymethyl) -6-methoxy- [2,3' -bipyridine as a cream solid]-5-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide (43 mg,43% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.16 (s, 1H), 8.68 (d, j=8.1 hz, 1H), 8.24 (d, j=8.1 hz, 1H), 7.91 (br s, 1H), 7.54-7.65 (m, 5H), 7.37 (d, j=8.2 hz, 1H), 7.31 (d, j=8.2 hz, 1H), 4.81 (d, j=4.6 hz, 2H), 3.95 (s, 3H), 3.64 (br t, j=5.1 hz, 1H), 2.72 (s, 3H) m/z 417.1 m+h] ⁺ 。

Example 161N- (6- (2- ((dimethylamino) methyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Synthesized according to example 160, intermediate 9 was used instead of (5-bromopyridin-2-yl) methanol to give N- (6- (2- ((dimethylamino) methyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a brown solid (62 mg,57% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.25 (s, 2H), 8.71 (d, J=8.1 Hz, 1H), 7.91 (br s, 1H), 7.53-7.67 (m, 5H), 7.38 (d, J=7.6 Hz, 1H), 3.94 (s, 3H), 3.80 (s, 2H), 2.72 (s, 3H), 2.39 (s, 6H) m/z 445.1[ M+H ] ] ⁺ 。

Example 162N- (6- (2-ethoxypyrimidin-5-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Synthesized according to example 160, 5-bromo-2-ethoxypyrimidin instead of (5-bromopyridin-2-yl) methanol gave N- (6- (2-ethoxypyrimidin-5-yl) -2-methoxypyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a yellow solid (39 mg,38% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.05 (s, 2H), 8.67 (d, J=8.2 Hz, 1H), 7.89 (br s, 1H), 7.54-7.65 (m, 5H), 7.27-7.30 (m, 1H), 4.44-4.53 (m, 2H), 3.93 (s, 3H), 2.72 (s, 3H), 1.46 (t, J=7.2 Hz, 3H). M/z 432.1[ M+H ]] ⁺ 。

Example 163N- [6- [2- [2- (dimethylamino) ethoxy ] pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

Metallic sodium (190 mg,8.26 mmol) was added portionwise to ice-cold 2-dimethylaminoethanol (5.00 mL,49.7 mmol). The reaction mixture was stirred until all sodium was completely dissolved (45 minutes). 5-bromo-2-chloropyrimidine (1.00 g,5.17 mmol) was added (slightly exothermic) and the reaction mixture was stirred at room temperature for 15 min, then diluted with EtOAc (20 mL), washed with water (7X 30 mL) and brine (30 mL). The organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give 2- (5-bromopyrimidin-2-yl) oxy-N, N-dimethyl-ethylamine (780 mg,61% yield) as a colorless liquid, which was used without further purification. ¹ H NMR (500 MHz, chloroform-d) δ8.50 (s, 2H), 4.43 (t, J=5.9 Hz, 2H), 2.73 (t, J=5.9 Hz, 2H), 2.31 (s, 6H) m/z 247.9[ M+H, ⁸¹ Br] ⁺ 。

step 2

A solution of KF (76 mg,1.31 mmol), 2- (5-bromopyrimidin-2-yl) oxy-N, N-dimethyl-ethylamine (110 mg,0.45 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen.Pd-118 (29 mg,0.044 mmol) was added and the reaction mixture was further degassed, then stirred at room temperature for 16 hours, then at 45℃for 5 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (20 mL) and the aqueous phase extracted with DCM (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give N- [6- [2- [2- (dimethylamino) ethoxy ] as a beige solid]Pyrimidin-5-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (127 mg,58% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.03 (s, 2H), 8.73 (d, j=8.1 hz, 1H), 7.75 (s, 1H), 7.67-7.62 (m, 3H), 7.62-7.54 (m, 2H), 7.26 (s, 1H), 4.52 (t, j=6.0 hz, 2H), 3.68 (s, 3H), 2.84 (s, 3H), 2.79 (t, j=6.0 hz, 2H), 2.35 (s, 6H) m/z 475.1[ m+h) ] ⁺ 。

Example 164N- (5 ' -fluoro-6-methoxy-6 ' -oxo-1 ',6' -dihydro- [2,3' -bipyridin ] -5-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Intermediate 14 (100 mg,0.23 mmol) was added to a solution of 5-bromo-3-fluoropyridin-2 (1H) -one (48 mg,0.25 mmol) and KF (40 mg,0.69 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen. Pd-118 (15 mg,0.02 mmol) was added and the mixture was further degassed and then stirred at 35℃for 16 hours. The reaction mixture was concentrated under reduced pressure and the dark residue was dissolved in DCM (10 mL) and washed with water (2×10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica eluting with 0-10% MeOH/DCM) to give N- (5 ' -fluoro-6-methoxy-6 ' -oxo-1 ',6' -dihydro- [2,3' -bipyridine) as a bronze solid]-5-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide (28 mg,28% yield). ¹ H NMR (500 MHz, chloroform-d) δ12.99 (br s, 1H), 8.64 (d, J=8.1 Hz, 1H), 7.99 (br s, 1H), 7.83-7.92 (m, 2H), 7.53-7.65 (m, 5H), 7.08 (d, J=8.1 Hz, 1H), 3.90 (s, 3H), 2.71 (s, 3H) m/z 421.1[M+H] ⁺ 。

Example 165 5- (6-methoxy-5- (4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidine-2-carboxamide

Step 1

Intermediate 14 (200 mg,0.46 mmol) was added to a solution of methyl 5-bromopyrimidine-2-carboxylate (110 mg,0.51 mmol) and KF (80 mg,1.4 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen. Pd-118 (30 mg,0.05 mmol) was added and the mixture was further degassed and then stirred at 50℃for 16 hours. The reaction mixture was concentrated under reduced pressure and the dark residue was dissolved in DCM (10 mL) and washed with water (2×10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, eluting with 0-10% MeOH/DCM) to give methyl 5- (6-methoxy-5- (4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidine-2-carboxylate (155 mg,72% yield) as an orange solid. ¹ H NMR (500 MHz, chloroform-d) δ9.43 (s, 2H), 8.77 (d, J=8.1 Hz, 1H), 7.95 (br s, 1H), 7.54-7.67 (m, 5H), 7.48 (d, J=8.1 Hz 1H), 4.10 (s, 3H), 3.95 (s, 3H), 2.73 (s, 3H) m/z 446.0[ M+H ]] ⁺ 。

Step 2

LiOH (38 mg,0.51 mmol) was added to a solution of methyl 5- (6-methoxy-5- (4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidine-2-carboxylate (150 mg,0.34 mmol) in THF (3 mL) and water (1 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. 0.1M HCl (10 mL) was added and the resulting precipitate was filtered, washed with water (10 mL) and EtOAc (10 mL), then dried under vacuum at 40℃to give 5- (6-methoxy-5- (4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidine-2-carboxylic acid (145 mg,95% yield) as a cream-like solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ13.62(br s,1H),10.28(s,1H),9.56(s,2H),8.38(br s,1H),7.87(d,J＝8.1Hz,1H),7.50-7.69(m,5H),4.02(s,3H)。CH ₃ Under the NMR solvent peak. m/z 432.0[ M+H ]] ⁺ 。

Step 3

NH is added to ₃ (7M in MeOH, 0.10mL,0.70 mmol) was added to a solution of 5- (6-methoxy-5- (4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidine-2-carboxylic acid (75 mg,0.17 mmol), HATU (198mg, 0.52 mmol) and DIPEA (0.12 mL,0.70 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 24 hours. The resulting precipitate was collected by vacuum filtration, washed with water (10 mL) and diethyl ether (3×10 mL), and then dried in vacuo at 40 ℃ to give 5- (6-methoxy-5- (4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidine-2-carboxamide (62 mg,79% yield) as a colorless solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ10.28(s,1H),9.55(s,2H),8.38(br s,1H),8.23(s,1H),7.78-7.98(m,2H),7.50-7.75(m,5H),4.03(s,3H)。CH ₃ Under the NMR solvent peak. m/z 431.1[ M+H ]] ⁺ 。

Example 166N- (2-methoxy-6- (2- (methylamino) pyrimidin-5-yl) pyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide

Synthesized according to example 160, substituting 5-bromo-N-methyl-pyrimidin-2-amine for (5-bromopyridin-2-yl) methanol gave N- (2-methoxy-6- (2- (methylamino) pyrimidin-5-yl) pyridin-3-yl) -4-methyl-1-phenyl-1H-1, 2, 3-triazole-5-carboxamide as a cream solid (30 mg,30% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.89 (s, 2H), 8.61 (d, j=8.1 hz, 1H), 7.85 (br s, 1H), 7.52-7.65 (m, 5H), 7.18 (d, j=8.1 hz, 1H), 5.21-5.28 (m, 1H), 3.90 (s, 3H), 3.07 (d, j=4.6 hz, 3H), 2.71 (s, 3H) m/z 417.1[ m+h ] ] ⁺ 。

Example 167N- [6- [2- [2- (dimethylamino) ethylamino ] pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a dry 20mL Biotage microwave vial was added 5-bromo-2-chloropyrimidine (500 mg,2.6 mmol). The vial was purged with nitrogen for 10 minutes, then EtOH (2.5 mL) and DIPEA (0.28 mL,2.6 mmol) were added. The vial was sealed and the mixture was heated at 80 ℃ for 16 hours. The reaction mixture was diluted with DCM (40 mL) and saturated NaHCO ₃ (20 mL) washing. The aqueous phase was extracted with DCM (4X 20 mL) and the combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give N- (5-bromopyrimidin-2-yl) -N ', N' -dimethyl-ethane-1, 2-diamine (292 mg,46% yield) as a pale yellow oil, which solidified upon standing. ¹ H NMR (500 MHz, chloroform-d) δ8.26 (s, 2H), 5.74 (s, 1H), 3.45-3.38 (m, 2H), 2.51 (t, J=6.1 Hz, 2H), 2.25 (s, 6H) m/z 246.9[ M+H, ⁸¹ Br] ⁺ 。

step 2

A solution of KF (76 mg,1.3 mmol), N- (5-bromopyrimidin-2-yl) -N ', N' -dimethyl-ethane-1, 2-diamine (113 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. Pd-118 (29 mg,0.044 mmol) was added and the reaction mixture was further degassed and stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3×20 mL). The first aqueous phase was back extracted with DCM (2X 20 mL) and the combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give the crude product, which was triturated with MeCN (25 mL) and filtered through filter paper (gravity filtration). The solid was washed with additional MeCN (30 mL), then redissolved in DCM (40 mL), and the DCM filtrate concentrated under reduced pressure to give N- [6- [2- [2- (dimethylamino) ethylamino ] as a colorless solid]Pyrimidin-5-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (47 mg,22% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.84 (s, 2H), 8.65 (d, J=8.0 Hz, 1H), 7.70 (s, 1H),7.65-7.55(m,5H),7.14(d,J＝8.1Hz,1H),5.90-5.74(m,1H),3.66(s,3H),3.57-3.45(m,2H),2.82(s,3H),2.53(t,J＝6.1Hz,2H),2.26(s,6H).m/z 474.1[M+H] ⁺ 。

Example 168N- [ 2-methoxy-6- [2- (methylaminomethyl) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1-Synthesis of intermediate 15-tert-butyl N- [ (5-bromopyrimidin-2-yl) methyl ] -N-methyl-carbamate

To a solution of intermediate 8 (450 mg,1.79 mmol) in THF (2.5 mL) was added a 2M methylamine solution in THF (2.7 mL,5.4 mmol). A white precipitate formed immediately. After 2 hours, the suspension was concentrated to dryness and resuspended in DCM (7.5 mL). Addition of Et ₃ N (0.50 mL,3.57 mmol) and stirring for 10 min, then di-tert-butyl dicarbonate (4638 mg,2.14 mmol) was added immediately and a yellow solution appeared immediately. After 1 hour, the solution was diluted with water (5 mL) and brine (5 mL). The layers were separated and the organic layer was concentrated to a yellow oil/suspension. Purification of the material by flash silica column chromatography (12 g silica, eluting with 0-20% EtOAc/PE) afforded tert-butyl N- [ (5-bromopyrimidin-2-yl) methyl as a yellow oil ]-N-methyl-carbamate (300 mg,53% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.74 (s, 2H), 4.78-4.41 (m, 2H), 3.06-2.94 (m, 3H), 1.54-1.29 (m, 9H) m/z 201.9[ M-Boc+H, ⁷⁹ Br] ⁺ ,203.9[M-Boc+H, ⁸¹ Br] ⁺ 。

step 2

A mixture of intermediate 7 (200 mg,0.46 mmol), intermediate 15 (150 mg,0.50 mmol) and triturated KF (80 mg,1.4 mmol) in 1, 4-dioxane (2 mL) and water (1 mL) was bubbled with nitrogen. Pd-118 (30 mg,0.05 mmol) was added and the reaction mixture was heated at 50℃for 16 hours. The reaction mixture was partitioned between DCM (10 mL) and brine (5 mL) and separated. The aqueous layer was extracted with DCM (2×10 mL) and the combined organic extracts were concentrated to dryness. The crude material was purified by flash silica column chromatography (12g silica, eluting with 60-100% EtOAc/PE) to give the Boc-protected product as a yellow solid. The solid was suspended in 4M HCl (4 ml,16 mmol) in 1, 4-dioxane and stirred for 1 hour. The suspension was diluted with TBME (40 mL) and the solid collected by vacuum filtration, washed with TBME (2X 40 mL) and dried in a vacuum oven to give N- [ 2-methoxy-6- [2- (methylaminomethyl) pyrimidin-5-yl as a pale yellow solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (160 mg,69% yield). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 9.56 (s, 1H), 9.49 (s, 2H), 9.32 (s, 2H), 8.45 (s, 1H), 7.84 (d, j=8.1 hz, 1H), 7.71 (d, j=7.0 hz, 2H), 7.61-7.51 (m, 3H), 4.50 (t, j=6.2 hz, 2H), 2.72 (d, j=5.7 hz, 3H), 2.67 (s, 3H). Note CH ₃ Under the water peak. M/z 431.1[ M+H for free base ]] ⁺ 。

Example 169N- [ 3-methoxy-5- [2- (methylaminomethyl) pyrimidin-5-yl ] pyrazin-2-yl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

A mixture of intermediate 13 (160 mg,0.37 mmol), intermediate 15 (150 mg,0.50 mmol) and triturated KF (80 mg,1.4 mmol) in 1, 4-dioxane (1.5 mL) and water (0.8 mL) was bubbled with nitrogen. Pd-118 (30 mg,0.05 mmol) was added and the reaction mixture was heated at 50℃for 16 hours. The reaction mixture was partitioned between DCM (10 mL) and brine (5 mL) and separated. The aqueous layer was extracted with DCM (2X 10 mL). The combined organic extracts were concentrated to dryness and purified by flash silica column chromatography (12 g silica eluting with 40-100% EtOAc/PE) to give the Boc-protected product as a yellow foam. The material was stirred in 4M HCl in 1, 4-dioxane (4.0 mL,16 mmol) at room temperature for 1 hour and diluted with TBME (40 mL) and the solid was collected by vacuum filtration, washed with TBME (2X 40 mL) and dried overnight in a vacuum oven at 40℃to give N- [ 3-methoxy-5- [2- (methylaminomethyl) pyrimidin-5-yl as an off-white solid ]Pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (120 mg,66% yield). ¹ H NMR (500 MHz, DMSO-d 6) delta 10.73 (s, 1H), 9.51 (s, 2H), 9.28 (s, 2H), 8.74 (s, 1H), 7.61-7.57 (M, 2H), 7.52-7.45 (M, 1H), 7.45-7.40 (M, 2H), 4.57-4.51 (M, 2H), 4.00 (s, 3H), 2.73 (s, 3H), 2.63 (s, 3H) M/z 432.1[ M+H for free base ]] ⁺ 。

Example 170N- [ 2-methoxy-6- [2- [2- (methylamino) ethylamino ] pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1

To a dry 20mL Biotage microwave vial was added 5-bromo-2-chloropyrimidine (0.25 g,1.3 mmol), DIPEA (0.27 mL,1.6 mmol), tert-butyl (2-aminoethyl) methylcarbamate (225 mg,1.29 mmol) and EtOH (1.25 mL). The vials were capped and the mixture was heated at 70 ℃ for 16 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by automatic column chromatography (12 g silica, eluting with 0-100% EtOAc/PE) to give tert-butyl N- [2- [ (5-bromopyrimidin-2-yl) amino as a colorless oil]Ethyl group]-N-methyl-carbamate (401 mg,94% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.26 (s, 2H), 5.64 (s, 0.5H), 5.35 (s, 0.5H), 3.57-3.48 (m, 2H), 3.49-3.38 (m, 2H), 2.88 (s, 3H), 1.43 (s, 9H) m/z 333.0[ M+H, ⁸¹ Br] ⁺ 。

step 2

KF (76 mg,1.3 mmol), tert-butyl N- [2- [ (5-bromopyrimidin-2-yl) amino]Ethyl group]A solution of N-methyl-carbamate (152 mg,0.46 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed. Pd-118 (29 mg,0.044 mmol) was added and the reaction mixture was again degassed and stirred at room temperature for 16 hours, then heated at 45℃for 5 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (20 mL), and the aqueous phase was back-extracted with additional DCM (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. By passing throughThe crude material was purified by flash column chromatography (12 g silica, eluting with 10% MeOH/DCM) and then the crude product was again purified by flash column chromatography (12 g silica, eluting with 0-100% EtOAc/PE). The separated residue was triturated with MeOH (70 mL), the suspension filtered and the filtrate concentrated under reduced pressure to give the Boc-protected product (20 mg). The material was dissolved in DCM (1 mL) and treated with 4M HCl in 1, 4-dioxane (1 mL,4 mmol). The mixture was stirred at room temperature for 2 hours. The sample was concentrated under reduced pressure to give N- [ 2-methoxy-6- [2- [2- (methylamino) ethylamino ] as a beige solid ]Pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (20 mg,9% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.48(s,1H),9.00(s,2H),8.66(s,2H),8.28(d,J＝8.1Hz,1H),7.77-7.69(m,2H),7.65(t,J＝5.7Hz,1H),7.61-7.50(m,4H),3.89(s,3H),3.67-3.59(m,2H),3.17-3.07(m,2H),2.66(s,3H),2.59(t,J＝5.4Hz,3H).m/z 460.1[M+H] ⁺ 。

Example 171N- [6- [2- (2-Aminoethylamino) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1

To a dry 20mL Biotage microwave vial was added 5-bromo-2-chloropyrimidine (1.00 g,5.17 mmol), etOH (5 mL) and ethylenediamine (0.39 mL,5.2 mmol). The vial was sealed and the mixture was heated at 80 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure, then partitioned between EtOAc (30 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with DCM (3X 30 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give N' - (5-bromopyrimidin-2-yl) ethane-1, 2-diamine (600 mg,51% yield) as a colorless solid, which was used without further purification. ¹ H NMR (500 MHz, chloroform-d) δ8.27 (s, 2H), 5.59 (s, 1H), 3.44 (q, J=6.0 Hz, 2H), 2.91 (t, J=6.1 Hz, 2H) m/z 219.0[ M+H, ⁸¹ Br] ⁺ 。

step 2

To a suspension of N' - (5-bromopyrimidin-2-yl) ethane-1, 2-diamine (250 mg,1.15 mmol) and DIPEA (0.23 mL,1.3 mmol) in DCM (10 mL) was added a solution of di-tert-butyl dicarbonate (287 mg,1.31 mmol) in DCM (5 mL) and DMAP (14 mg,0.11 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc (20 mL), washed with water (3X 20 mL) and brine (20 mL). The organic extract was subjected to MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which is purified by automatic column chromatography (12 g silica, eluting with 0-50% EtOAc/PE) to give tert-butyl N- [2- [ (5-bromopyrimidin-2-yl) amino as a colorless solid]Ethyl group]Carbamate (178 mg,49% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.26 (s, 2H), 5.69-5.56 (m, 1H), 5.00-4.81 (m, 1H), 3.54-3.46 (m, 2H), 3.39-3.29 (m, 2H), 1.43 (s, 9H) m/z 319.0[ M+H, ⁸¹ Br] ⁺ 。

step 3

KF (76 mg,1.3 mmol), tert-butyl N- [2- [ (5-bromopyrimidin-2-yl) amino]Ethyl group]A solution of carbamate (146 mg,0.46 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed. Pd-118 (29 mg,0.044 mmol) was added and the reaction mixture was again degassed and stirred at room temperature for 16 hours, then at 45℃for 5 hours. The solution was diluted with DCM (50 mL), washed with water (20 mL) and the aqueous phase was back-extracted with DCM (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give the Boc-protected product as a colourless solid. It was suspended in DCM (10 mL) and then treated with 4M HCl in 1, 4-dioxane (2.5 mL,10 mmol). The mixture was stirred at room temperature for 2 hours and volatiles were removed under reduced pressure to give N- [6- [2- (2-aminoethylamino) pyrimidin-5-yl ] as a pale yellow solid ]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (110 mg,50% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.48(s,1H),9.05(s,2H),8.29(d,J＝7.9Hz,1H),8.25-8.15(m,3H),7.96(s,1H),7.75-7.68(m,2H),7.59-7.1(m,4H),3.89(s,3H),3.65(t,J＝6.2Hz,2H),3.03(q,J＝6.0Hz, 2H), 2.66 (s, 3H) M/z 446.1[ M+H for the free base ]] ⁺ 。

Example 172N- [6- [2- [2- (dimethylamino) ethylcarbamoyl ] pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

5-bromo-2-pyrimidinecarboxylic acid (300 mg,1.48 mmol) and SOCl ₂ (2.00 mL,27.4 mmol) was heated in a sealed microwave vial at 65℃for 16 hours. The mixture was cooled to room temperature and chloroform (2 mL) was then added, followed by DMF (3 drops). The mixture was then heated at 80 ℃ for a further 16 hours, after which all material was dissolved. Once cooled to room temperature, volatiles were removed under reduced pressure. The acid chloride was dissolved in DCM (2.5 mL) and added dropwise to a stirred solution of N ', N' -dimethylethane-1, 2-diamine (130 mg,1.48 mmol) and DIPEA (0.31 mL,1.8 mmol) in DCM (2.5 mL), and the reaction mixture was stirred for 15 min. The reaction mixture was diluted with DCM (10 mL) and washed with 2M NaOH (30 mL). The aqueous phase was back extracted twice with DCM (2X 15 mL) and the combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product which is purified by automatic silica column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give 5-bromo-N- [2- (dimethylamino) ethyl ] as an orange-brown solid ]Pyrimidine-2-carboxamide (186 mg,44% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.84 (s, 2H), 8.27-8.12 (m, 1H), 3.54-3.46 (m, 2H), 2.46 (t, J=6.0 Hz, 2H), 2.20 (s, 6H) m/z 275.0[ M+H, ⁸¹ Br] ⁺ 。

step 2

KF (76 mg,1.3 mmol), 5-bromo-N- [2- (dimethylamino) ethyl]A solution of pyrimidine-2-carboxamide (126 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. Pd-118 (29 mg,0.044 mmol) was added and the reaction mixture was again degassed and then stirred at room temperature for 48 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (20 mL), and further washed withThe aqueous phase was back extracted with DCM (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product which is purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give N- [6- [2- [2- (dimethylamino) ethylcarbamoyl ] as a beige solid]Pyrimidin-5-yl]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (82 mg, 36% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.54(s,2H),9.52(s,1H),8.76(t,J＝5.7Hz,1H),8.48(d,J＝7.7Hz,1H),7.87(d,J＝8.1Hz,1H),7.74-7.68(m,2H),7.60-7.52(m,3H),3.94(s,3H),3.46-3.39(m,2H),2.67(s,3H),2.46(t,J＝6.5Hz,2H),2.21(s,6H).m/z502.1[M+H] ⁺ 。

Example 173N- [ 2-methoxy-6- [2- [2- (methylamino) ethylcarbamoyl ] pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1

5-bromo-2-pyrimidinecarboxylic acid (300 mg,1.48 mmol), SOCl ₂ (2.0 mL,27 mmol), chloroform (2 mL) and DMF (3 drops) were heated at 80℃for 16 h. After cooling to room temperature, the volatiles were removed under reduced pressure to give the crude acid chloride. The acid chloride was redissolved in DCM (2.5 mL) and added dropwise to a stirred solution of DIPEA (0.31 mL,1.77 mmol) and tert-butyl N- (2-aminoethyl) -N-methyl-carbamate (258 mg,1.48 mmol) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for 20 minutes. Water (10 mL) was added followed by DCM (20 mL). The layers were separated and the aqueous layer was extracted twice with DCM (2X 15 mL). The combined organic extracts were washed with 2M NaOH solution (2X 20 mL) over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product which is purified by silica autopolumn (12 g silica, eluting with 0-10% MeOH/DCM) to give tert-butyl N- [2- [ (5-bromopyrimidine-2-carbonyl) amino as a pale yellow oil]Ethyl group]-N-methyl-carbamate (382 mg,68% yield), which cures after standing. ¹ H NMR (500 MHz, chloroform-d) delta8.80(s,2H),8.34(s,0.5H),8.03(s,0.5H),3.62-3.49(m,2H),3.43(t,J＝5.9Hz,2H),2.80(s,3H),1.40-1.26(m,9H).m/z 261.0[M-Boc+H, ⁸¹ Br] ⁺ 。

Step 2

KF (76 mg,1.3 mmol), tert-butyl N- [2- [ (5-bromopyrimidine-2-carbonyl) amino group]Ethyl group]A solution of N-methyl-carbamate (165 mg,0.46 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed. Pd-118 (28 mg,0.044 mmol) was added and the reaction mixture was further degassed and stirred at room temperature for 16 hours, then heated at 45℃for 5 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (20 mL), and the aqueous phase was back-extracted with additional DCM (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by automatic column chromatography (12 g silica, eluting with 0-10% MeOH/DCM) to give the Boc-protected product. The material was dissolved in DCM (6.8 mL) and treated with 4M HCl in 1, 4-dioxane (2.5 mL) and the reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure to give N- [ 2-methoxy-6- [2- [2- (methylamino) ethylcarbamoyl) as a yellow solid]Pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (145 mg,96% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.60-9.51(m,3H),9.22(t,J＝6.0Hz,1H),8.87-8.76(m,2H),8.48(s,1H),7.91(d,J＝8.1Hz,1H),7.76-7.65(m,2H),7.61-7.51(m,3H),3.94(s,3H),3.64(q,J＝6.0Hz,2H),3.16-3.09(m,2H),2.68(s,3H),2.58(t,J＝5.4Hz,3H).m/z 488.1[M+H] ⁺ 。

Example 174N- (6- (2-amino- [1,2,4] triazolo [1,5-a ] pyridin-7-yl) -2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-5-carboxamide

N- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide synthesized according to example 154 (45 mg, 0.10)mmol) added to 7-bromo [1,2,4]Triazolo [1,5-a ]]A solution of pyridin-2-amine (24 mg,0.11 mmol) and KF (18 mg,0.31 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen. Pd-118 (6.7 mg, 0.010mmol) was added and the reaction mixture was further degassed and then stirred at 80℃for 16 hours. The reaction mixture was then concentrated under reduced pressure, the dark residue was dissolved in DCM (10 mL) and washed with water (2×10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g silica, eluting with 0-10% MeOH/DCM) to give a residue, which was then triturated with MeOH and the precipitate dried in vacuo at 40 ℃ to give N- (6- (2-amino- [1,2, 4) as a cream solid]Triazolo [1,5-a ]]Pyridin-7-yl) -2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide (12 mg, 26% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.75 (d, J=8.1 Hz, 1H), 8.31 (d, J=7.1 Hz, 1H), 8.23 (br s, 1H), 8.03 (s, 1H), 7.64-7.69 (m, 2H), 7.54-7.61 (m, 3H), 7.41-7.49 (m, 2H), 4.47 (br s, 2H), 4.45 (s, 3H), 3.73 (s, 3H) m/z 442.0[ M+H ]] ⁺ 。

Example 175N- [6- [2- (2-hydroxyethylamino) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a 20mL microwave vial was added 5-bromo-2-chloropyrimidine (500 mg,2.58 mmol), DIPEA (0.54 mL,3.1 mmol), ethanolamine (0.17 mL,2.8 mmol), and EtOH (2.5 mL). The vial was capped and the mixture was heated at 80 ℃ for 2 hours. The reaction mixture was partitioned between DCM (30 mL) and water (20 mL). 2M NaOH (20 mL) was added and the layers separated. The aqueous phase was back extracted with DCM (2X 20 mL) and the combined organics were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give 2- [ (5-bromopyrimidin-2-yl) amino as a colorless solid]Ethanol (295 mg,50% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ8.35(s,2H),7.32(t,J＝5.8Hz,1H),4.66(t,J＝5.6Hz,1H),3.48(q,J＝6.1Hz,2H),3.32-3.27(m,2H).m/z219.9[M+H, ⁸¹ Br] ⁺ 。

Step 2

KF (76 mg,1.3 mmol), 2- [ (5-bromopyrimidin-2-yl) amino group]A solution of ethanol (100 mg,0.44 mmol) and intermediate 7 (200 mg,0.46 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen. Pd-118 (28 mg,0.044 mmol) was added and the reaction mixture was again degassed and stirred at room temperature for 16 hours. The reaction mixture was partitioned between DCM (30 mL) and water (30 mL) and separated. The suspension in the aqueous layer was washed with DCM (20 mL), the solid was collected and dried in a vacuum oven set at 40℃for 1 hour to give N- [6- [2- (2-hydroxyethylamino) pyrimidin-5-yl as a beige solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (89 mg,43% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.44(s,1H),8.93(s,2H),8.26(d,J＝8.0Hz,1H),7.77-7.66(m,2H),7.59-7.50(m,3H),7.48(d,J＝8.0Hz,1H),7.38(t,J＝5.8Hz,1H),4.70(s,1H),3.88(s,3H),3.54(t,J＝6.3Hz,2H),3.44-3.37(m,2H),2.66(s,3H).m/z 447.1[M+H] ⁺ 。

Example 176N- [2- (dimethylamino) -6-imidazol-1-yl-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

At 0℃with K ₂ CO ₃ (1.72 g,12.4 mmol) A stirred suspension of 2, 6-dichloro-3-nitropyridine (2.00 g,10.4 mmol) in THF (30 mL) was treated and then a solution of dimethylamine (2M in THF, 5.18mL,10.4 mmol) in THF (15 mL) was added dropwise over 40 minutes. The yellow suspension was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (80 g silica, eluting with 0-60% EtOAc/PE) to give 6-chloro-N, N-dimethyl-3-nitropyridin-2-amine as a yellow solid (816 mg, 37% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.06 (d, J=8.4, 0.7Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 3.05 (s, 6H). M/z 201.9[ M+M ]H] ⁺ 。

Step 2

To a stirred solution of imidazole (276 mg,4.05 mmol) in dry DMF (5 mL) at 0deg.C was added sodium hydride (60% in mineral oil, 194mg,4.86 mmol) in portions over 10 minutes. The reaction mixture was stirred at 0deg.C for 30 min, then a solution of 6-chloro-N, N-dimethyl-3-nitro-pyridin-2-amine (816 mg,4.05 mmol) in DMF (3 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled in an ice bath and treated with water (30 mL). The yellow precipitate formed was collected by vacuum filtration and the solid cake was washed with water and air dried to give 6-imidazol-1-yl-N, N-dimethyl-3-nitro-pyridin-2-amine (809 mg,81% yield) as a yellow solid which was used in the next step without further purification. ¹ H NMR(600MHz,DMSO-d ₆ )δ8.59(d,J＝1.1Hz,1H),8.40(d,J＝8.6Hz,1H),7.97(t,J＝1.4Hz,1H),7.15-7.10(m,2H),3.01(s,6H).m/z 233.7[M+H] ⁺ 。

Step 3

To a stirred solution of 6-imidazol-1-yl-N, N-dimethyl-3-nitro-pyridin-2-amine (810 mg,3.47 mmol) in EtOH (20 mL) was added 10% Pd/carbon (37 mg,0.35 mmol). The flask was sealed with a rubber septum, purged with nitrogen, then with H ₂ (balloon) purging. The reaction mixture was stirred under hydrogen at room temperature for 16 hours. The reaction mixture was filtered through celite and washed with EtOH. Concentrating the filtrate under reduced pressure to give 6-imidazol-1-yl-N as tan solid ² ,N ² -dimethyl-pyridine-2, 3-diamine (626 mg,84% yield), which was used in the next step without further purification. ¹ H NMR (600 MHz, chloroform-d) δ8.18 (s, 1H), 7.50 (s, 1H), 7.13 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 3.74 (s, 2H), 2.81 (s, 6H) m/z 204.0[ M+H ]] ⁺ 。

Step 4

To 6-imidazol-1-yl-N ² ,N ² -dimethyl-pyridine-2, 3-diamine (65 mg,0.32 mmol) and (5-methyl-3-phenyl-isoxazol-4-yl) - (triazolo [4, 5-b)]To a suspension of pyridin-3-yl) methanone (98 mg,0.32 mmol) in DMF (0.32 mL) was added DIPEA (0.17 mL,0.96 mmol). The reaction mixture was heated at 60 ℃ for 16 hours. Will beThe reaction mixture was partitioned between EtOAc (150 mL) and 1M NaOH (50 mL) and the phases separated. The organic phase was washed with water (100 mL), brine (50 mL), and over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified on Shimadzu MDAP (eluted with a 30-95% MeCN/water +0.1% formic acid gradient) to give an off-white solid. The material was adsorbed onto silica and purified again by flash column chromatography (4 g silica, eluting with 0-80% EtOAc/PE) to give N- [2- (dimethylamino) -6-imidazol-1-yl-3-pyridinyl) as a tan solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (45 mg, 34% yield). ¹ H NMR (600 MHz, chloroform-d) delta 8.74 (d, j=8.5 hz, 1H), 8.23 (s, 1H), 7.89 (s, 1H), 7.64-7.56 (m, 3H), 7.56-7.50 (m, 3H), 7.14 (s, 1H), 6.99 (d, j=8.5 hz, 1H), 2.83 (s, 3H), 2.31 (s, 6H) m/z 389.0[ m+h ]] ⁺ 。

Example 177N- (6- (1H-imidazol-1-yl) -2- (methylamino) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

To 6-imidazol-1-yl-N ² Methyl-pyridine-2, 3-diamine (according to the procedure described in example 176 as 6-imidazol-1-yl-N ² ,N ² Synthesis of-dimethyl-pyridine-2, 3-diamine in a similar manner) (61 mg,0.32 mmol) and 1H-benzo [ d ]][1,2,3]To a stirred suspension of triazol-1-yl 5-methyl-3-phenylisoxazole-4-carboxylate (98 mg,0.31 mmol) in DMF (2 mL) was added DIPEA (0.17 mL,0.96 mmol). The reaction mixture was heated at 60 ℃ for 16 hours. The reaction mixture was cooled to room temperature, then partitioned between EtOAc (150 mL) and 1M NaOH (50 mL) and separated. The organic phase was washed with water (100 mL), brine (50 mL), and over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by ISCO Prep system (40 g silica, eluting with 0-90% EtOAc/PE) in 3 batches to give N- [ 6-imidazol-1-yl-2- (methylamino) -3-pyridinyl as a tan solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (5.8 mg,4% yield). ¹ H NMR (600 MHz, chloroform-d) δ8.25 (s, 1H), 7.69-7.59(m,5H),7.57(d,J＝8.1Hz,1H),7.52(s,1H),7.12(s,1H),6.57(d,J＝8.1Hz,1H),6.50(s,1H),3.99(s,1H),2.85(d,J＝4.8Hz,3H),2.81(s,3H).m/z 375.0[M+H] ⁺ 。

Example 178N- [ 2-methoxy-6- (4, 5,6, 7-tetrahydroimidazo [4,5-c ] pyridin-1-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1

To intermediate 1 (750 mg,1.93 mmol), tert-butyl 3,4,6, 7-tetrahydroimidazo [4,5-c]Pyridine-5-carboxylic acid ester (500 mg,2.24 mmol) and L-proline (22 mg,0.19 mmol) in DMSO (15 mL) was added K ₂ CO ₃ (354 mg,3.86 mmol) and the resulting suspension was bubbled with nitrogen. Copper (I) iodide (37 mg,0.19 mmol) was added and the mixture was again bubbled with nitrogen, followed by heating at 80℃for 16 hours. The reaction mixture was cooled to room temperature and additional copper (I) iodide (150 mg,0.79 mmol) and L-proline (90 mg,0.78 mmol) were added. The reaction mixture was bubbled with nitrogen and then heated at 80 ℃ for another 48 hours. The reaction mixture was poured onto ice-cold water (500 mL) and the brown solid was collected by vacuum filtration. The solid was dissolved in DCM, passed through a phase separator and concentrated to dryness. Purification by flash silica column chromatography (40 g silica eluting with 50-100% EtOAc/PE) afforded the two regioisomers. Regiochemistry is not precisely specified, so isomers are arbitrarily designated as tert-butyl 1- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ]-2-pyridyl group]-6, 7-dihydro-4H-imidazo [4,5-c]Pyridine-5-carboxylic acid ester (140 mg, 13% yield) and tert-butyl 3- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino group]-2-pyridyl group]-6, 7-dihydro-4H-imidazo [4,5-c]Pyridine-5-carboxylic acid ester (90 mg,7% yield). The isomers can be clearly distinguished by NMR spectroscopy and TLC.

Tert-butyl 1- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino group]-2-pyridyl group]-6, 7-dihydro-4H-imidazo [4,5-c]Pyridine-5-carboxylic acid ester: r is R _f (EtOAc)＝0.2。 ¹ H NMR (500 MHz, chloroform-d) delta 8.79 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 7.69 (s, 1H), 7.68-7.62 (m, 3H), 7.62-7.55 (m, 2H), 6.86 (d, J=8.3 Hz, 1H), 4.54 (s, 2H), 3.74-3.68 (m, 2H), 3.63 (s, 3H), 3.00-2.86 (m, 2H), 2.83 (s, 3H), 1.48 (s, 9H) m/z 531.1[ M+H ]] ⁺ 。

Tert-butyl 3- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino group]-2-pyridyl group]-6, 7-dihydro-4H-imidazo [4,5-c]Pyridine-5-carboxylic acid ester: r is R _f (EtOAc)＝0.13。 ¹ H NMR (500 MHz, chloroform-d) δ8.80 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.70-7.58 (m, 6H), 6.92 (d, J=8.2 Hz, 1H), 4.79 (s, 2H), 3.82-3.72 (m, 2H), 3.68 (s, 3H), 2.86 (s, 3H), 2.77-2.66 (m, 2H), 1.49 (s, 9H), m/z 531.1[ M+H ]] ⁺ 。

Step 2

Tert-butyl 1- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino group ]-2-pyridyl group]-6, 7-dihydro-4H-imidazo [4,5-c]A suspension of pyridine-5-carboxylate (140 mg,0.26 mmol) in 1, 4-dioxane (1 mL) was treated with 4M HCl in 1, 4-dioxane (0.56 mL,16 mmol). An orange solution was briefly produced, and then a precipitate formed. The mixture was stirred at room temperature for 1 hour, then diluted with TBME (30 mL), and the solid was collected by filtration and washed with TBME (2X 30 mL). The solid was dried in a vacuum oven at 40 ℃ overnight to give N- [ 2-methoxy-6- (4, 5,6, 7-tetrahydroimidazo [4, 5-c) as a pale yellow solid]Pyridin-1-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (110 mg,87% yield). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 9.72 (s, 1H), 9.48 (s, 2H), 8.42 (s, 1H), 7.81-7.64 (m, 2H), 7.62-7.47 (m, 4H), 7.37 (d, j=7.3 hz, 1H), 3.88 (s, 3H), 3.49-3.27 (m, 4H), 2.66 (s, 3H). CH (CH) ₂ Under NMR solvent. M/z 431.1[ M+H for free base ]] ⁺ 。

Example 179N- [ 2-methoxy-6- (4, 5,6, 7-tetrahydroimidazo [4,5-c ] pyridin-3-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide dihydrochloride

To the exampleTert-butyl 3- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] synthesized as described in 178]-2-pyridyl group]-6, 7-dihydro-4H-imidazo [4,5-c ]To a suspension of pyridine-5-carboxylate (90 mg,0.17 mmol) (as indicated, regiochemistry was not determinable) in 1, 4-dioxane (1.5 mL) was added 4M HCl in 1, 4-dioxane (0.83 mL,24 mmol). A pale yellow solution was produced, and a white suspension was gradually formed. After stirring for 1 hour at room temperature, the reaction mixture was diluted with TBME (30 mL) and the solid was collected by filtration and washed with TBME (2X 30 mL). The solid was dried in a vacuum oven at 40 ℃ overnight to give N- [ 2-methoxy-6- (4, 5,6, 7-tetrahydroimidazo [4, 5-c) as a colorless solid]Pyridin-3-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide dihydrochloride (85 mg,93% yield). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 9.74 (s, 1H), 9.46 (s, 2H), 8.80 (s, 1H), 8.42 (s, 1H), 7.84-7.62 (M, 2H), 7.62-7.49 (M, 4H), 7.47 (d, J=8.5 Hz, 1H), 4.66 (s, 2H), 3.90 (s, 3H), 3.47-3.42 (M, 2H), 2.97-2.83 (M, 2H), 2.65 (s, 3H), M/z 431.1[ M+H for free base ]] ⁺ 。

Example 180N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide hydrochloride

Step 1

N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide (0.16 g,0.42 mmol), B synthesized according to example 154 ₂ Pin ₂ (0.14g，0.55mmol)、Pd(dppf)Cl ₂ (35 mg,0.040 mmol) and KOAc (124 mg,1.26 mmol) were dissolved in 1, 4-dioxane (5 mL). The reaction mixture was degassed with nitrogen for 5 minutes and then heated to 90 ℃ for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with water (2×20 mL), and the organic layer was washed with MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was purified by trituration with PE (20 mL) to give N- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide (98 mg,51% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.58 (d, J=7.8 Hz, 1H), 8.24 (br s, 1H), 7.62-7.65 (m, 2H), 7.49-7.57 (m, 3H), 7.47 (d, J=7.8 Hz, 1H), 4.42 (s, 3H), 3.68 (s, 3H), 1.35 (s, 12H) m/z 354.0[ M+H ]] ⁺ For boric acid.

Step 2

N- (2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide (81 mg,0.19 mmol) was added to a solution of intermediate 11 (59 mg,0.20 mmol) and KF (32 mg,0.56 mmol) in 1, 4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (12 mg,0.018 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 35 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (10 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g, silica, 0-10% MeOH/DCM). The CV-containing products were combined and evaporated under reduced pressure to give tert-butyl ((5- (6-methoxy-5- (1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidin-2-yl) methyl) carbamate (30.2 mg,30% yield) as a brown solid. ¹ H NMR (500 MHz, chloroform-d) δ9.22 (s, 2H), 8.76 (d, J=8.2 Hz, 1H), 8.21 (br s, 1H), 7.63-7.69 (m, 2H), 7.54-7.61 (m, 3H), 7.38 (d, J=8.1 Hz, 1H), 5.69 (br s, 1H), 4.64 (d, J=5.1 Hz, 2H), 4.44 (s, 3H), 3.71 (s, 3H), 1.49 (s, 9H) m/z 517.1[ M+H ]] ⁺ 。

Step 3

Tert-butyl ((5- (6-methoxy-5- (1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide) pyridin-2-yl) pyrimidin-2-yl) methyl) carbamate (30 mg,0.06 mmol) was dissolved in DCM (5 mL) and HCl (2 m in ether, 0.29mL,0.58 mmol) was then added. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide hydrochloride (23.7 mg, 8) as a bronze solid 4% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ10.45(s,1H),9.52(s,2H),8.38-8.49(m,4H),7.89(d,J＝8.1Hz,1H),7.80(d,J＝7.6Hz,2H),7.46-7.53(m,2H),7.38-7.46(m,1H),4.39(s,2H),4.18(s,3H),3.99(s,3H).m/z 417.0[M+H] ⁺ 。

Example 181N- [ 2-methoxy-6- [2- (morpholinomethyl) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a solution of the schnikose base (0.21 mL,1.2 mmol) and intermediate 8 (0.15 g,0.60 mmol) in THF (6 mL) was added morpholine (60. Mu.L, 0.65 mmol) dropwise. The solution gradually became a suspension and was stirred at room temperature overnight. The reaction mixture was diluted with additional THF (5 mL) and gravity filtered through filter paper. The filtrate was concentrated under reduced pressure and the solid was further dried in a vacuum oven (40 ℃) for 2 hours to give 4- [ (5-bromopyrimidin-2-yl) methyl as an off-white solid]Morpholine (0.17 g,100% yield), which was used without further purification. ¹ H NMR (500 MHz, chloroform-d) delta 8.76 (s, 2H), 3.77-3.73 (m, 6H), 2.60-2.52 (m, 4H).

Step 2

KF (103 mg,1.78 mmol), 4- [ (5-bromopyrimidin-2-yl) methyl]A solution of morpholine (170 mg, 0.560 mmol) and intermediate 7 (271mg, 0.560 mmol) in 1, 4-dioxane (5.7 mL) and water (1.4 mL) was degassed with nitrogen for 15 min. Pd-118 (38 mg,0.060 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture was stirred at room temperature overnight. The mixture was heated at 40℃for 4 hours. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL). The organic phase was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which is purified by silica automatic column chromatography (12 g, gradient 0-10% MeOH/DCM, 30 CV) to give N- [ 2-methoxy-6- [2- (morpholinomethyl) pyrimidin-5-yl as an off-white solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (145 mg,48% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.21 (s, 2)H),8.75(d,J＝8.1Hz,1H),7.78(s,1H),7.67-7.60(m,3H),7.60-7.54(m,2H),7.34(d,J＝8.1Hz,1H),3.84(s,2H),3.77(t,J＝4.6Hz,4H),3.68(s,3H),2.82(s,3H),2.60(t,J＝4.6Hz,4H).m/z 487.1[M+H] ⁺ 。

Example 182N- [6- [4- (aminomethyl) phenyl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

A suspension of KF (95 mg,1.6 mmol), 4-bromobenzylamine (70. Mu.L, 0.55 mmol) and intermediate 7 (0.25 g,0.55 mmol) in 1, 4-dioxane (5 mL) and water (1.25 mL) was degassed with nitrogen for 15 min. Pd-118 (35 mg,0.054 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture was stirred at room temperature overnight. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine (10 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a 10% MeOH/DCM gradient) afforded the free base which was then treated with 1.2 equivalents of HCl (4N in 1, 4-dioxane) in DCM to afford N- [6- [4- (aminomethyl) phenyl ] as a brown solid after evaporation of the volatile residue ]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (74 mg,29% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.53(s,1H),8.51(s,3H),8.11(d,J＝7.9Hz,2H),7.72(d,J＝6.7Hz,2H),7.66-7.53(m,6H),7.47(d,J＝8.1Hz,1H),4.07(q,J＝5.6Hz,2H),3.92(s,3H),2.67(s,3H).m/z 398.0[M-NH ₃ ] ⁺ ,416.0[M-NH ₂ +OH+H] ⁺ 。

Example 183N- [ 2-methoxy-6- [4- (methylaminomethyl) phenyl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

As synthesized for example 182The 4-bromobenzylamine was replaced by 1- (4-bromophenyl) -N-methyl-methylamine to give N- [ 2-methoxy-6- [4- (methylaminomethyl) phenyl ] as a brown solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (100 mg, 35% yield) ¹ H NMR(400MHz,DMSO-d ₆ ) δ9.53 (s, 1H), 8.96 (s, 2H), 8.38 (s, 1H), 8.14 (d, J=8.0 Hz, 2H), 7.72 (d, J=6.8 Hz, 2H), 7.69-7.46 (M, 6H), 4.17 (s, 2H), 3.93 (s, 3H), 3.57 (s, 3H), 2.67 (s, 3H) M/z 429.2[ M+H for free base ]] ⁺ 。

Example 184N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -4- (4-fluorophenyl) -1-methyl-1H-1, 2, 3-triazole-5-carboxamide hydrochloride

As described for the synthesis of example 180, N- (6-bromo-2-methoxypyridin-3-yl) -4- (4-fluorophenyl) -1-methyl-1H-1, 2, 3-triazole-5-carboxamide (synthesized by the method described in step 1 of example 154 using the appropriate starting material) was used instead of N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide to give N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -4- (4-fluorophenyl) -1-methyl-1H-1, 2, 3-triazole-5-carboxamide hydrochloride as a yellow solid (35 mg,47% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ10.46(s,1H),9.52(s,2H),8.35-8.54(m,4H),7.89(d,J＝8.0Hz,1H),7.80-7.87(m,2H),7.35(t,J＝8.6Hz,2H),4.40(s,2H),4.19(s,3H),4.01(s,3H).m/z 435.1[M+H] ⁺ 。

Example 185N- [6- [2- (aminomethyl) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide hydrochloride

Step 1

Intermediate 12 (0.49 g,1.2 mmol), B were added to a microwave vial under an inert atmosphere ₂ Pin ₂ (0.46g，1.8mmol) and 1, 4-dioxane (9 mL). The solution was degassed with nitrogen for 15 min and then Pd (dppf) Cl was added rapidly ₂ (Complex with DCM, 0.10g,0.12 mmol) and KOAc (355 mg,3.62 mmol). The mixture was again degassed with nitrogen for 15 minutes and then heated to 80 ℃ for 1 hour. The reaction mixture was cooled and diluted with EtOAc (20 mL). The solution was washed with water (20 mL), over MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by trituration with PE. The suspension was allowed to settle, the supernatant PE was removed and the milling repeated with more PE. The brown powder obtained was dried under reduced pressure to give 3- (4-fluorophenyl) -N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridyl group as a brown powder]-5-methyl-isoxazole-4-carboxamide (0.50 g,76% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.59 (d, j=7.8 hz, 1H), 7.76 (s, 1H), 7.64-7.60 (m, 2H), 7.46 (d, j=7.8 hz, 1H), 7.25-7.21 (m, 2H), 3.74 (s, 3H), 2.81 (s, 3H), 1.35 (s, 12H). m/z 372.1[ M+H ] ] ⁺ For boric acid.

Step 2

KF (77 mg,1.3 mmol), intermediate 11 (0.13 mL,0.44 mmol) and 3- (4-fluorophenyl) -N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl]A solution of 5-methyl-isoxazole-4-carboxamide (0.20 g,0.44 mmol) in 1, 4-dioxane (3.8 mL) and water (0.9 mL) was degassed with nitrogen for 15 min. Pd-118 (29 mg,0.044 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture was stirred at room temperature overnight. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine (10 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. The crude product was then treated with HCl (4N, in 1, 4-dioxane, 0.22ml,0.88 mmol), and once the starting material was completely deprotected, the reaction mixture was basified and extracted with DCM. Purification by flash silica column chromatography on an ISCO system (elution with an 8% MeOH/DCM gradient) afforded the free base which was then treated with 1.2 equivalents of HCl (4N in 1, 4-dioxane) in DCM to afford N- [6- [2- (aminomethyl) pyrimidin-5-yl as a brown solid after evaporation of the solvent]-2-methoxy-3-pyridinyl]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide hydrochloride 80mg,37% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.65(s,1H),9.50(s,2H),8.57(s,3H),8.44(s,1H),7.85(d,J＝8.1Hz,1H),7.78(dd,J＝8.5,5.4Hz,2H),7.41(t,J＝8.7Hz,2H),4.38(q,J＝5.9Hz,2H),3.97(s,3H),2.67(s,3H).m/z 435.1[M+H] ⁺ 。

Example 186N- (2-methoxy-6- (7-methyl-5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Step 1

A20 mL microwave vial was charged with intermediate 7 (0.40 g,0.92 mmol), tert-butyl 1-bromo-6, 8-dihydro-5H-imidazo [1,5-a ]]Pyrazine-7-carboxylic acid ester (417 mg,1.38 mmol), KF (160 mg,2.76 mmol), 1, 4-dioxane (9 mL), and water (3 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (60 mg,0.091 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 35 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-100% EtOAc/PE+1% Et ₃ N, 40 CV). The CV containing products were combined and evaporated under reduced pressure. The residue was then triturated with hot MeOH (3 mL) and the precipitate dried in vacuo at 40 ℃ to give tert-butyl 1- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydroimidazo [1,5-a ] as a cream solid ]Pyrazine-7 (8H) -carboxylic acid ester (0.19 g,38% yield). ¹ HNMR (500 MHz, chloroform-d) delta 8.68 (d, j=8.2 hz, 1H), 7.61-7.70 (m, 3H), 7.53-7.61 (m, 4H), 7.46 (s, 1H), 5.06 (s, 2H), 4.06 (t, j=5.4 hz, 2H), 3.83 (m, 2H), 3.68 (s, 3H), 2.82 (s, 3H), 1.48 (s, 9H) m/z 531.2[ m+h ]] ⁺ 。

Step 2

Into a 10mL microwave vial was charged tert-butyl 1- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl)-5, 6-dihydroimidazo [1,5-a ]]Pyrazine-7 (8H) -carboxylic acid ester (95 mg,0.18 mmol), paraformaldehyde (22 mg,0.72 mmol) and formic acid (3 mL). The reaction mixture was heated to 95 ℃ and stirred for 2 hours. The reaction mixture was cooled, diluted with DCM (15 mL) and washed successively with 2M NaOH (2X 15 mL), water (2X 15 mL) and brine (1X 15 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g, silica, 0-10% MeOH/DCM, 25 CV). The CV containing products were combined and evaporated under reduced pressure. The precipitate was then dried in vacuo at 40 ℃ to give N- (2-methoxy-6- (7-methyl-5, 6,7, 8-tetrahydroimidazo [1, 5-a) as an orange solid]Pyrazin-1-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (49 mg,58% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.66 (d, J=8.2 Hz, 1H), 7.62-7.68 (m, 3H), 7.54-7.62 (m, 4H), 7.43 (s, 1H), 4.10 (t, J=5.4 Hz, 2H), 4.07 (s, 2H), 3.64 (s, 3H), 2.79-2.86 (m, 5H) 2.50 (s, 3H) m/z 445.2[ M+H ]] ⁺ 。

Example 187N- (2-methoxy-6- (5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide dihydrochloride

Into a 10mL microwave vial was charged tert-butyl 1- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydroimidazo [1,5-a]Pyrazine-7 (8H) -carboxylate (synthesized according to example 186) (81 mg,0.15 mmol), HCl (2M in ether, 0.76mL,1.5 mmol) and DCM (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the precipitate was dried in vacuo at 40 ℃ to give N- (2-methoxy-6- (5, 6,7, 8-tetrahydroimidazo [1, 5-a) as a pale yellow solid]Pyrazin-1-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide hydrochloride (77 mg, 95%). ¹ H NMR(500MHz,DMSO-d ₆ ) δ9.87 (br s, 2H), 9.54 (s, 1H), 8.41 (br s, 1H), 8.32 (br s, 1H), 7.72 (d, j=6.8 hz, 2H), 7.50-7.63 (m, 4H), 4.81 (s, 2H), 4.43 (t, j=5.7 hz, 2H), 3.90 (s, 3H), 2.66 (s, 3H). CH (CH) ₂ The signal overlaps with the NMR solvent. M/z 431.1[ M+H for free base ] ] ⁺ 。

Example 188N- [6- [2- (azetidin-3-ylamino) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a 25mL microwave vial was added 5-bromo-2-chloropyrimidine (0.50 g,2.6 mmol), DIPEA (0.54 mL,3.1 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (0.17 mL,2.9 mmol), and MeCN (2.5 mL). The vials were sealed and heated at 80 ℃ for 16 hours. The volatiles were removed under reduced pressure and the residue was redissolved in DCM (20 mL) and partitioned with 1M NaOH (20 mL). The aqueous layer was further extracted with DCM (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give tert-butyl 3- [ (5-bromopyrimidin-2-yl) amino as an orange solid]Azetidine-1-carboxylic acid ester (1.00 g,100% yield) was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) delta 8.29 (s, 2H), 5.51 (d, j=6.8 hz, 1H), 4.60 (dtd, j=12.4, 7.3,5.2hz, 1H), 4.29 (dd, j=9.2, 7.5hz, 2H), 3.78 (dd, j=9.2, 5.1hz, 2H), 1.44 (s, 9H) m/z 272.9/274.9[ m-C (CH) ₃ ) ₃ +H] ⁺ 。

Step 2

A25 mL microwave vial was charged with intermediate 7 (0.40 g,0.92 mmol), tert-butyl 3- [ (5-bromopyrimidin-2-yl) amino]Azetidine-1-carboxylic acid ester (0.36 g,1.1 mmol), KF (0.16 g,2.8 mmol), 1, 4-dioxane (8 mL), and water (2 mL). The mixture was degassed for 10 min, then Pd-118 (0.06 g,0.09 mmol) was added and the vial was sealed and stirred at room temperature for 14 h. Water (20 mL) was added and the mixture extracted with DCM (3X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The solid was triturated in EtOAc and the solid collected by vacuum filtration to give tert-butyl 3- ((5- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) pyrimidine) as an off-white solid2-yl) amino) azetidine-1-carboxylic acid ester (0.22 g,40% yield) which was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) delta 8.86 (s, 2H), 8.69 (d, j=8.1 hz, 1H), 7.73 (s, 1H), 7.63 (t, j=7.2 hz, 3H), 7.60-7.52 (M, 2H), 7.17 (d, j=8.1 hz, 1H), 5.53 (d, j=6.7 hz, 1H), 4.76-4.64 (M, 1H), 4.33 (t, j=8.3 hz, 2H), 3.82 (dd, j=9.1, 5.2hz, 2H), 3.67 (s, 3H), 2.83 (s, 3H), 1.45 (s, 9H). M/z558.2[ m+h ]] ⁺ 。

Step 3

To a suspension of tert-butyl 3- ((5- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) pyrimidin-2-yl) amino) azetidine-1-carboxylate (0.15 g,0.26 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.0 mL,13 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled in an ice bath and treated with 2M NaOH (10 mL) and the mixture was stirred in an ice bath for 30 minutes. The mixture was further diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous phase was further extracted with DCM (2X 20 mL). The combined organic extracts were washed with brine (20 mL), over MgSO ₄ Drying, filtration and concentration under reduced pressure afforded a solid which was triturated in MeOH to give N- [6- [2- (azetidin-3-ylamino) pyrimidin-5-yl as a yellow solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (0.09 g, 71% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.45(s,1H),8.95(s,2H),8.26(d,J＝8.1Hz,1H),8.00(d,J＝6.9Hz,1H),7.71(d,J＝6.9Hz,2H),7.55(q,J＝6.5Hz,3H),7.49(d,J＝8.1Hz,1H),4.75-4.62(m,1H),3.89(s,3H),3.59(t,J＝7.4Hz,2H),3.50(t,J＝7.3Hz,2H),2.66(s,3H).m/z 458.1[M+H] ⁺ 。

Example 189N- [6- [2- (azetidin-3-yloxy) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

Tert-butyl 3-hydroxyazetidine-1-carboxylic acid ester (0.68 g,3.9 mmol) at TThe solution in HF (15 mL) was cooled in an ice bath. Sodium hydride (60%, in mineral oil, 0.17g,4.1 mmol) was added and the suspension stirred at 0℃for 30 min. 5-bromo-2-chloropyrimidine (0.76 g,3.9 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with water (1 mL), and the mixture was diluted with 1M NaOH (20 mL), brine (20 mL), and DCM (50 mL). The aqueous layer was further extracted with DCM (2X 50 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated to give tert-butyl 3- (5-bromopyrimidin-2-yl) oxyazetidine-1-carboxylate (1.3 g,90% yield) as an off-white solid, which was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) δ8.53 (s, 2H), 5.27 (td, J=6.7, 3.3Hz, 1H), 4.31 (dd, J=10.1, 6.6Hz, 2H), 4.03 (dd, J=10.1, 4.3Hz, 2H), 1.44 (s, 9H) m/z 273.9/275.9[ M-C (CH) ₃ ) ₃ +H] ⁺ 。

Step 2

A25 mL microwave vial was charged with intermediate 7 (0.40 g,0.92 mmol), tert-butyl 3- (5-bromopyrimidin-2-yl) oxyazetidine-1-carboxylate (0.36 g,1.1 mmol), KF (0.16 g,2.8 mmol), 1, 4-dioxane (8 mL), and water (2 mL). The mixture was degassed for 10 min, then Pd-118 (0.06 g,0.09 mmol) was added and the vial was sealed and stirred at room temperature for 14 h. Water (20 mL) was added and the mixture extracted with DCM (3X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The material was triturated in EtOAc and the solid collected by vacuum filtration to give tert-butyl 3- [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] as an off-white solid]-2-pyridyl group]Pyrimidin-2-yl]Oxetazetidine-1-carboxylic acid ester (0.22 g,40% yield) was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) δ9.03 (s, 2H), 8.74 (d, j=8.1 hz, 1H), 7.77 (s, 1H), 7.63 (d, j=6.9 hz, 3H), 7.61-7.53 (m, 2H), 7.29-7.26 (m, 1H), 5.35 (ddt, j=10.1, 5.4,2.7hz, 1H), 4.35 (dd, j=9.8, 6.8hz, 2H), 4.07 (dd, j=10.0, 4.2hz, 2H), 3.69 (s, 3H), 2.84 (s, 3H), 1.45 (s, 9H). M/z 559.2[ m+h ] ] ⁺

Step 3

To tert-butyl 3- [5- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl ]) Amino group]-2-pyridyl group]Pyrimidin-2-yl]To a suspension of oxetane-1-carboxylate (0.22 g,0.39 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.0 mL,13 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled in an ice bath and treated with 2M NaOH (10 mL) and the mixture was stirred in an ice bath for 30 minutes. The mixture was further diluted with DCM (20 mL) and water (20 mL). The layers were separated and the aqueous phase was further extracted with DCM (2X 20 mL). The combined organic extracts were washed with brine (20 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, 5-10% MeOH/DCM+1% Et ₃ N gradient elution) to give N- [6- [2- (azetidin-3-yloxy) pyrimidin-5-yl ] as a yellow solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (0.11 g, 58% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.52(s,1H),9.25(s,2H),8.37(d,J＝8.1Hz,1H),7.68-7.61(m,3H),7.61-7.55(m,3H),5.55 -5.46(m,1H),4.21(dd,J＝10.9,6.8Hz,2H),3.95(dd,J＝11.1,5.4Hz,2H),3.91(s,3H),2.66(s,3H).m/z 459.1[M+H] ⁺ 。

Example 190N- [ 2-methoxy-6- [6- (methylaminomethyl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a solution of 5-bromopyridine-2-carbaldehyde (463mg, 2.45 mmol) in MeOH (10 mL) was added 2M methylamine (1.38 mL,2.75 mmol) in DCM. The reaction mixture was stirred at room temperature for 2 hours. Additional 2M methylamine (0.14 mL,0.28 mmol) in DCM was added and the mixture was stirred at room temperature overnight. Sodium borohydride (151 mg,3.99 mmol) was added in portions and the mixture was stirred at room temperature for 30 minutes. 2M NaOH (aqueous, 10 mL) was added and the crude mixture was concentrated under reduced pressure (MeOH removed). The resulting aqueous phase was extracted with DCM (3X 20 mL) and EtOAc (2X 40 mL) and the combined organic extracts were dried over MgSO ₄ Drying and concentrating under reduced pressure to give the final product1- (5-bromo-2-pyridinyl) -N-methyl-methylamine (487 mg,91% yield) as a pale yellow oil, which was used without further purification. ¹ H NMR (500 MHz, chloroform-d) delta 8.59 (s, 1H), 7.75 (d, j=8.3 hz, 1H), 7.21 (d, j=8.3 hz, 1H), 3.81 (s, 2H), 2.45 (s, 3H) m/z 203.0 m+h, ⁸¹ Br] ⁺ 。

step 2

A solution of KF (95 mg,1.6 mmol), 1- (5-bromo-2-pyridinyl) -N-methyl-methylamine (115 mg,0.550 mmol) and intermediate 7 (250 mg,0.550 mmol) in 1, 4-dioxane (5 mL) and water (1.25 mL) was degassed with nitrogen for 15 min. Pd-118 (35 mg,0.050 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture was stirred at room temperature overnight. The mixture was heated to 40 ℃ and held for 3 hours. Additional Pd-118 (35 mg,0.050 mmol) and KF (95 mg,1.6 mmol) were added and the mixture stirred for 4 hours. Finally, the mixture was heated to 70 ℃ and stirred overnight. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL), and concentrated over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by automatic silica column chromatography (12 g, gradient 0-10% MeOH/DCM). The resulting crude product was further purified by trituration in EtOAc (2X 4 mL) to give N- [ 2-methoxy-6- [6- (methylaminomethyl) -3-pyridinyl ] as a beige solid ]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (71 mg,29% yield). ¹ HNMR (500 MHz, chloroform-d) δ9.13 (s, 1H), 8.73 (d, j=8.2 hz, 1H), 8.21 (d, j=8.2 hz, 1H), 7.77 (s, 1H), 7.68-7.61 (m, 3H), 7.61-7.54 (m, 2H), 7.42 (d, j=8.1 hz, 1H), 7.34 (d, j=8.1 hz, 1H), 4.08 (s, 2H), 3.69 (s, 3H), 2.84 (s, 3H), 2.61 (s, 3H) m/z 430.1[ m+h ]] ⁺ 。

Example 191N- [ 2-methoxy-6- (2-methoxy-4-methyl-pyrimidin-5-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To an ice-cooled MeOH solution (10 mL) was added sodium (92 mg,4.0 mmol) in portions. The mixture was stirred until all sodium metalCompletely dissolved. 5-bromo-2-chloro-4-methyl-pyrimidine (0.42 g,2.0 mmol) was added to the solution and the reaction mixture was stirred for 16 hours. The solvent was removed under reduced pressure and water (20 mL) was added to the residue. The solution was extracted with EtOAc (3×20 mL), and the organic extract was washed with MgSO ₄ Drying, filtration and concentration under reduced pressure gave 5-bromo-2-methoxy-4-methyl-pyrimidine (0.34 g,79% yield) as a yellow oil, which was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) delta 8.43 (s, 1H), 3.98 (s, 3H), 2.55 (s, 3H) m/z 203.0/204.8[ M+H ]] ⁺ 。

Step 2

A10 mL microwave vial was charged with intermediate 7 (0.20 g,0.46 mmol), 5-bromo-2-methoxy-4-methyl-pyrimidine (0.11 g,0.55 mmol), KF (80 mg,1.4 mmol), 1, 4-dioxane (4 mL), and water (1 mL). The mixture was degassed for 10 min, then Pd-118 (0.03 g,0.05 mmol) was added and the vial was sealed and stirred at room temperature for 2 hours. Water (10 mL) was added and the mixture extracted with DCM (3X 10 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, gradient elution with 0-50% EtOAc/PE) to give a solid which was further triturated with EtOAc/PE to give N- [ 2-methoxy-6- (2-methoxy-4-methyl-pyrimidin-5-yl) -3-pyridinyl as a yellow solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (0.11 g, 51% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.73 (d, J=8.0 Hz, 1H), 8.51 (s, 1H), 7.76 (s, 1H), 7.69-7.54 (M, 5H), 7.00 (d, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.63 (s, 3H), 2.84 (s, 3H), 2.58 (s, 3H) M/z432.1[ M+H)] ⁺ 。

Example 192N- [ 2-methoxy-6- [ 4-methyl-2- (methylamino) pyrimidin-5-yl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

A10 mL microwave vial was charged with 5-bromo-2-chloro-4-methyl-pyrimidine (0.42 g,2.0 mmol), THF (2 mL),Et ₃ N (0.84 mL,6.0 mmol), methylamine hydrochloride (0.27 g,4.0 mmol), and water (0.2 mL). The vials were sealed and heated at 85 ℃ for 17 hours. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, eluting with a 0-20% EtOAc/PE gradient) to give 5-bromo-N, 4-dimethyl-pyrimidin-2-amine (0.33 g,78% yield) as a colorless solid. ¹ H NMR (500 MHz, chloroform-d) δ8.21 (s, 1H), 5.06 (s, 1H), 2.97 (d, J=5.1 Hz, 3H), 2.43 (s, 3H) m/z 202.0/204.0[ M+H ]] ⁺ 。

Step 2

A10 mL microwave vial was charged with intermediate 7 (0.20 g,0.46 mmol), 5-bromo-N, 4-dimethyl-pyrimidin-2-amine (0.11 g,0.55 mmol), KF (80 mg,1.4 mmol), 1, 4-dioxane (4 mL), and water (1 mL). The mixture was degassed for 10 min, then Pd-118 (0.03 g,0.05 mmol) was added and the vial was sealed and stirred at room temperature for 2 hours. Water (10 mL) was added and the mixture extracted with DCM (3X 10 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, gradient elution with 0-100% EtOAc/PE) to give a solid which was further triturated in EtOAc/PE to give N- [ 2-methoxy-6- [ 4-methyl-2- (methylamino) pyrimidin-5-yl as a tan solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (109 mg,52% yield). ¹ HNMR (500 MHz, chloroform-d) delta 8.68 (d, j=8.0 hz, 1H), 8.36 (s, 1H), 7.73 (s, 1H), 7.67-7.51 (m, 5H), 6.95 (d, j=8.0 hz, 1H), 5.08 (q, j=4.7 hz, 1H), 3.63 (s, 3H), 3.03 (d, j=5.0 hz, 3H), 2.83 (s, 3H), 2.48 (s, 3H) m/z 431.1[ m+h ] ] ⁺ 。

Example 193N- [ 2-methoxy-6- (2-methoxy-4, 6-dimethyl-pyrimidin-5-yl) -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To an ice-cooled MeOH solution (7.5 mL) was added sodium (69 mg,3.0 mmol) in portions. Stirring the mixtureUntil all sodium metal is completely dissolved. 5-bromo-2-chloro-4, 6-dimethyl-pyrimidine (0.33 g,1.5 mmol) was added to the solution and the reaction mixture was stirred for 30 min. The solvent was removed under reduced pressure and water (20 mL) was added to the residue. The solution was extracted with EtOAc (3×20 mL), and the organic extract was washed with MgSO ₄ Dried, filtered and concentrated under reduced pressure to give 5-bromo-2-methoxy-4, 6-dimethyl-pyrimidine (0.30 g,88% yield) as an orange solid, which was used in the next step without further purification. ¹ H NMR (500 MHz, chloroform-d) delta 3.96 (s, 3H), 2.56 (s, 6H) m/z 216.9/219.0[ M+H ]] ⁺ 。

Step 2

A10 mL microwave vial was charged with intermediate 7 (0.20 g,0.46 mmol), 5-bromo-2-methoxy-4, 6-dimethyl-pyrimidine (0.11 g,0.51 mmol), KF (80 mg,1.4 mmol), 1, 4-dioxane (4 mL), and water (1 mL). The mixture was degassed for 10 min, then Pd-118 (0.03 g,0.05 mmol) was added and the vial was sealed and stirred at room temperature for 14 h. Water (20 mL) was added and the mixture extracted with DCM (3X 10 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, gradient elution with 0-50% EtOAc/PE) to give a solid which was recrystallized from EtOAc/PE and left in the refrigerator overnight. The supernatant was removed and the solid was dried to give N- [ 2-methoxy-6- (2-methoxy-4, 6-dimethyl-pyrimidin-5-yl) -3-pyridinyl as an orange solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (0.12 g,57% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.72 (d, J=7.8 Hz, 1H), 7.79 (s, 1H), 7.72-7.51 (m, 5H), 6.81 (d, J=7.9 Hz, 1H), 4.00 (s, 3H), 3.59 (s, 3H), 2.85 (s, 3H), 2.24 (s, 6H) m/z 446.1[ M+H ]] ⁺ 。

Example 194N- (6- (4, 6-dimethyl-2- (methylamino) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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Step 1

To 10mA L microwave vial was filled with 5-bromo-2-chloro-4, 6-dimethyl-pyrimidine (0.33 g,1.5 mmol), THF (1.5 mL), et ₃ N (0.63 mL,4.5 mmol), methylamine hydrochloride (0.20 g,3.0 mmol), and water (0.15 mL). The vials were sealed and heated at 85 ℃ for 16 hours. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, eluting with a 0-50% EtOAc/PE gradient) to give 5-bromo-N, 4, 6-trimethyl-pyrimidin-2-amine (0.20 g,59% yield) as a yellow solid. ¹ H NMR (500 MHz, chloroform-d) δ4.91 (s, 1H), 2.96 (d, J=5.1 Hz, 3H), 2.45 (s, 6H). M/z 216.0/218.0[ M+H ]] ⁺ 。

Step 2

A10 mL microwave vial was charged with intermediate 7 (0.20 g,0.46 mmol), 5-bromo-N, 4, 6-trimethyl-pyrimidin-2-amine (0.11 g,0.51 mmol), KF (80 mg,1.4 mmol), 1, 4-dioxane (4 mL), and water (1 mL). The mixture was degassed for 10 min, then Pd-118 (0.03 g,0.05 mmol) was added and the vial was sealed and stirred at room temperature for 14 h. Water (20 mL) was added and the mixture extracted with DCM (3X 10 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, gradient elution with 0-100% EtOAc/PE) to give a solid which was triturated with EtOAc/PE to give N- [6- [4, 6-dimethyl-2- (methylamino) pyrimidin-5-yl as an orange solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (0.11 g,53% yield). ¹ HNMR (500 MHz, chloroform-d) delta 8.67 (d, j=8.0 hz, 1H), 7.77 (s, 1H), 7.68-7.54 (m, 5H), 6.79 (d, j=7.9 hz, 1H), 4.93 (q, j=4.9 hz, 1H), 3.59 (s, 3H), 3.01 (d, j=5.0 hz, 3H), 2.84 (s, 3H), 2.14 (s, 6H) m/z 445.1[ m+h ]] ⁺ 。

Example 195N- (2-methoxy-6- (7-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Step 1

Direction 2A0 mL microwave vial was charged with intermediate 7 (500 mg,1.15 mmol), tert-butyl 3-bromo-6, 8-dihydro-5H- [1,2,4]Triazolo [4,3-a ]]Pyrazine-7-carboxylic acid ester (457 mg,1.49 mmol), tripotassium phosphate (732 mg,3.45 mmol), 1, 4-dioxane (10 mL), and water (2.5 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Rapid addition of Pd (dppf) Cl ₂ (complexing with DCM, 0.11g,0.14 mmol) and further degassing the mixture with nitrogen and stirring at 80℃for 4 hours. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-100% EtOAc/PE+1% Et ₃ N, 40 CV). The CV containing products were combined and evaporated under reduced pressure. The residue was then triturated with hot EtOAc (3 mL) and the precipitate dried in vacuo at 40 ℃ to give tert-butyl 3- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydro [1,2,4 ] as an off-white solid]Triazole [4,3-a ]]Pyrazine-7 (8H) -carboxylic acid ester (280.5 mg, 44%). ¹ H NMR (500 MHz, chloroform-d) delta 8.81 (d, j=8.2 hz, 1H), 7.91 (d, j=8.2 hz, 1H), 7.76 (br s, 1H), 7.62-7.67 (m, 3H), 7.57-7.61 (m, 2H), 4.89 (s, 2H), 4.49 (t, j=5.6 hz, 2H), 3.84 (t, j=5.6 hz, 2H), 3.63 (s, 3H), 2.84 (s, 3H), 1.50 (s, 9H) m/z 532.1[ m+h ] ] ⁺ 。

Step 2

Into a 10mL microwave vial was charged tert-butyl 3- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydro [1,2,4]Triazolo [4,3-a ]]Pyrazine-7 (8H) -carboxylic acid ester (0.14 g,0.25 mmol), paraformaldehyde (30 mg,1.0 mmol) and formic acid (3 mL). The reaction mixture was heated to 95 ℃ and stirred for 2 hours. The reaction mixture was cooled, diluted with DCM (15 mL) and washed successively with 2M NaOH (2X 15 mL), water (2X 15 mL) and brine (1X 15 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (4 g, silica, 0-10% MeOH/DCM, 25 CV). The CV containing products were combined and evaporated under reduced pressure. The residue was then triturated with hot EtOAc (3 mL) and the precipitate dried in vacuo at 40℃to give a solid as a creamN- (2-methoxy-6- (7-methyl-5, 6,7, 8-tetrahydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (38 mg, 32% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.79 (d, j=8.3 hz, 1H), 7.91 (d, j=8.3 hz, 1H), 7.75 (br s, 1H), 7.55-7.67 (m, 5H), 4.48 (t, j=5.6 hz, 2H), 3.83 (s, 2H), 3.62 (s, 3H), 2.79-2.87 (m, 5H) 2.52 (s, 3H) m/z 446.1[ m+h ] ] ⁺ 。

Example 196N- (2-methoxy-6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide dihydrochloride

Into a 10mL microwave vial was charged tert-butyl 3- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -5, 6-dihydro [1,2,4]Triazolo [4,3-a ]]Pyrazine-7 (8H) -carboxylate (0.13 g,0.25 mmol) (synthesized according to example 195), HCl (2M in ether, 1.25mL,2.50 mmol) and DCM (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the precipitate was dried under vacuum at 40℃to give N- (2-methoxy-6- (5, 6,7, 8-tetrahydro- [1,2, 4) as a pale yellow solid]Triazolo [4,3-a ]]Pyrazin-3-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide dihydrochloride (0.13 g,98% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.95(br s,2H),9.61(s,1H),8.48(br s,1H),7.84(d,J＝8.1Hz,2H),7.71(d,J＝7.0Hz,2H),7.51-7.60(m,3H),4.75(t,J＝5.8Hz,2H),4.61(s,2H),3.89(s,3H),3.63(t,J＝6.4Hz,2H),2.67(s,3H).m/z 432.1[M+H] ⁺ 。

Example 197N- [4- (2-aminopyrimidin-5-yl) -2-methoxy-phenyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

Step 1

To a microwave vial was added intermediate 5 (1.50 g,3.87 mmol), B ₂ Pin ₂ (1.47 g,5.81 mmol) and 1, 4-dioxane (30 mL). The solution was degassed with nitrogen for 15 min and then Pd (dppf) Cl was added rapidly ₂ (complexing with DCM, 0.32g,0.39 mmol) and KOAc (11.4 g,11.6 mmol). The mixture was again degassed with nitrogen for 15 minutes and then heated to 80 ℃ for 1 hour using an aluminum heating block. The reaction mixture was cooled and diluted with EtOAc (30 mL). The solution was washed with water (30 mL), and dried over MgSO ₄ Drying, filtration and concentration under reduced pressure gave the crude product, which was purified by trituration with PE. The suspension was allowed to settle, the supernatant PE was removed and the milling repeated with more PE. The brown powder obtained was dried under reduced pressure to give N- [ 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl group as a brown powder]-5-methyl-3-phenyl-isoxazole-4-carboxamide (1.6 g,78% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.46 (d, j=8.0 hz, 1H), 7.94 (s, 1H), 7.63 (d, j=7.3 hz, 2H), 7.59-7.49 (m, 3H), 7.42 (d, j=8.0 hz, 1H), 7.12 (s, 1H), 3.47 (s, 3H), 2.81 (s, 3H), 1.32 (s, 12H) m/z 435.1[ m+h] ⁺ 。

Step 2

KF (77 mg,1.3 mmol), 2-amino-5-bromopyrimidine (80. Mu.L, 0.44 mmol) and N- [ 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl group]A solution of 5-methyl-3-phenyl-isoxazole-4-carboxamide (0.20 g,0.44 mmol) in 1, 4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (28 mg,0.040 mmol) was added rapidly, the solution was again degassed for 10 min, and the mixture was stirred at room temperature overnight. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine (10 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO system (elution with 8% MeOH/DCM gradient) afforded the free base, which was then treated with 1.2 equivalents of HCl to afford N- [4- (2-aminopyrimidin-5-yl) -2-methoxy-phenyl ] as a brown solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (0.10 g,49% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.28(s,1H),8.74(s,2H),7.99(d,J＝8.4Hz,1H),7.78-7.69(m,2H),7.60-7.51(m,3H),7.30(s,1H),7.24(d,J＝8.2Hz,1H),3.78(s,3H),2.67(s,3H).M/z402.1[ M+H for free base ]] ⁺ 。

Example 198N- [4- (5-Aminopyrazin-2-yl) -2-methoxy-phenyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

KF (100 mg,1.73 mmol), 5-bromopyrazin-2-amine (0.12 mL,0.69 mmol) and N- [ 2-methoxy-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]A solution of 5-methyl-3-phenyl-isoxazole-4-carboxamide (0.25 g,0.58 mmol) (synthesized as described in example 197) in 1, 4-dioxane (5 mL) and water (1.25 mL) was degassed with nitrogen for 15 min. Pd-118 (37 mg,0.060 mmol) was added rapidly, the solution was again degassed for 10 minutes and the mixture was stirred at room temperature overnight. Water (10 mL) was then added and the reaction mixture extracted with DCM (3X 10 mL). The combined organics were washed with brine (10 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography on ISCO system (elution with 8% MeOH/DCM gradient) afforded the free base, which was then treated with 1.2 equivalents of HCl to afford N- [4- (5-aminopyrazin-2-yl) -2-methoxy-phenyl ] as a brown solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (51 mg,19% yield). ¹ H NMR(400MHz,DMSO-d ₆ ) Delta 9.25 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.77-7.68 (M, 2H), 7.55 (M, 5H), 3.76 (s, 3H), 2.67 (s, 3H) M/z 402.1[ M+H for free base ]] ⁺ 。

Example 199N- [6- [6- (aminomethyl) -3-pyridinyl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride

A solution of KF (95.1 mg,1.64 mmol), intermediate 7 (250 mg,0.550 mmol) and tert-butyl (5-bromopyridin-2-ylmethyl) carbamate (156 mg,0.550 mmol) in 1, 4-dioxane (5.0 mL) and water (1.25 mL) was degassed for 10 min.Pd-118 (35 mg,0.050 mmol) was added rapidly, the microwave vial was capped and the mixture was degassed for an additional 10 minutes. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 mL) and washed with water (20 mL). The aqueous phase was back extracted twice with DCM (2X 15 mL) and the combined organic extracts were dried over MgSO ₄ Drying and filtering. Silica was added directly and the mixture was concentrated under reduced pressure to give a crude product adsorbed on silica, which was purified by silica auto-column chromatography (12 g, gradient from 0-10% MeOH/DCM, 25 CV) to give the Boc-protected product as a white solid (217 mg, m/z 516.1[ M+H ] ] ⁺ ). The Boc-protected product was dissolved in a minimal amount of DCM (5.0 mL) and 4M HCl in 1, 4-dioxane (0.2 mL) was added dropwise. The mixture was stirred at room temperature and after 5 hours, additional 4M HCl in 1, 4-dioxane (0.2 mL) was added. After 1 hour, another portion of 4M HCl in 1, 4-dioxane (0.4 mL) was added, along with additional DCM (2.0 mL) to aid in stirring, and the mixture was stirred at room temperature overnight. The sample was concentrated under reduced pressure to give N- [6- [6- (aminomethyl) -3-pyridinyl ] as a pale yellow solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (200 mg,77% yield). ¹ HNMR(500MHz,DMSO-d ₆ ) Delta 9.54 (s, 1H), 9.29 (s, 1H), 8.64 (s, 3H), 8.54 (d, j=8.2 hz, 1H), 8.41 (d, j=7.7 hz, 1H), 7.76 (d, j=8.1 hz, 1H), 7.74-7.68 (M, 3H), 7.61-7.51 (M, 3H), 4.26 (q, j=7.5 hz, 2H), 3.93 (s, 3H), 2.68 (s, 3H) M/z 416.1[ m+h for free base ]] ⁺ 。

Example 200N- (6- (1- (2-aminoethyl) -1H-imidazol-4-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide dihydrochloride

Step 1

A20 mL microwave vial was charged with 5-bromo-1H-imidazole (515 mg,3.50 mmol), 2- (Boc-amino) ethyl bromide (864 mg,3.85 mmol), K ₂ CO ₃ (1.21 g,8.76 mmol) and MeCN (8 mL). The reaction mixture was stirred at 80℃for 24 hours. Filtering the solids And the filtrate was concentrated under reduced pressure. The crude mixture was then dissolved in a minimum amount of MeOH and subjected to reverse phase column chromatography (0-100% MeOH/water over 30 minutes). The CV-containing products were combined to give tert-butyl (2- (4-bromo-1H-imidazol-1-yl) ethyl) carbamate (170 mg,10% yield) as an orange oil. ¹ H NMR (500 MHz, chloroform-d) delta 7.51 (s, 1H), 7.03 (s, 1H), 4.64 (br s, 1H), 4.11 (t, j=5.9 hz, 2H), 3.41 (q, j=5.8 hz, 2H), 1.44 (s, 9H). ¹³ C (125 MHz, chloroform-d) delta 28.5,40.1,45.6,80.3,102.9,130.2,138.6,155.9.M/z 291.9/293.9[ M+H ]] ⁺ . The compound and another regioisomer isolated during purification were subjected to regiochemistry confirmation by HMBC experiments.

Step 2

A20 mL microwave vial was charged with intermediate 7 (0.35 g,0.80 mmol), tert-butyl (3- (4-bromo-1H-imidazol-1-yl) propyl) carbamate (0.27 g,0.92 mmol), KF (140 mg,2.41 mmol), 1, 4-dioxane (9 mL), and water (3 mL). The reaction mixture was degassed with nitrogen for 5 minutes. Pd-118 (52 mg,0.080 mmol) was added rapidly and the mixture was further degassed with nitrogen and then stirred overnight at 50 ℃. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2X 10 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-10% MeOH/DCM+1% Et ₃ N, 25 CV). The CV containing products were combined and evaporated under reduced pressure. The residue was then triturated with hot EtOAc (3 mL) and the precipitate dried under vacuum at 40 ℃ to give tert-butyl (2- (4- (6-methoxy-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -1H-imidazol-1-yl) ethyl) carbamate (50 mg,11% yield) as a cream solid. ¹ H NMR (500 MHz, chloroform-d) δ8.68 (d, J=8.2 Hz, 1H), 7.71 (br s, 1H), 7.59-7.66 (m, 3H), 7.54-7.59 (m, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 4.64 (br s, 1H), 4.05-4.16 (m, 2H), 3.65 (s, 3H), 3.46 (q, J=6.0 Hz, 2H), 2.83 (s, 3H), 1.43 (s, 9H) m/z 519.2[ M+H ]] ⁺ 。

Step 3

A10 mL microwave vial was charged with tert-butyl (2- (4- (6-methoxy) butyl)-5- (5-methyl-3-phenylisoxazole-4-carboxamido) pyridin-2-yl) -1H-imidazol-1-yl) ethyl) carbamate (50 mg,0.10 mmol), HCl (2 m in ether, 0.71mL,1.4 mmol) and DCM (3 mL). The reaction mixture was stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the precipitate was dissolved in EtOAc (20 mL) and treated with saturated NaHCO ₃ (3X 10 mL) washing. The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The precipitate was redissolved in DCM (1 mL) and HCl (2M in ether, 74. Mu.L, 0.15 mmol) was then added. The reaction mixture was stirred at room temperature for 5 minutes. The mixture was then concentrated under reduced pressure to give N- (6- (1- (2-aminoethyl) -1H-imidazol-4-yl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide dihydrochloride (8 mg,16% yield) as a pale yellow solid. ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 9.49 (br s, 1H), 8.35 (br s, 1H), 7.98-8.13 (m, 4H), 7.71 (d, j=7.2 hz, 2H), 7.49-7.60 (m, 5H), 4.39 (br s, 2H), 3.91 (s, 3H), 2.66 (s, 3H). CH (CH) ₂ The signal overlaps with the NMR solvent. M/z 419.1[ M+H for free base ]] ⁺ 。

Example 201N- [6- [2- (1-hydroxy-1-methyl-ethyl) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

To a dry 100mL RBF equipped with a magnetic stir bar was added 5-bromo-2-iodopyrimidine (0.50 g,1.76 mmol) and anhydrous THF (10.0 mL). The solution was cooled to-78 ℃ using a dry ice-acetone bath. After allowing the reaction mixture to cool, n-BuLi (1.2M, 1.46mL,1.76 mmol) was slowly added dropwise while stirring the reaction mixture rapidly. Immediately after the addition of n-BuLi, acetone (0.300 mL) was added dropwise. After the addition was complete, the cooling bath was removed and the mixture was allowed to gradually warm to room temperature over 1 hour. The mixture was quenched with water (10 mL) and poured into a separatory funnel. The resulting aqueous phase was extracted with DCM (4X 50 mL). The combined organic extracts were dried over MgSO ₄ Drying, filtering and concentrating under reduced pressure to give the crude product, which is passed through twoSilica was purified by autopilot column chromatography (12 g, gradient 0-10% MeOH/DCM, 25 CV) to give 2- (5-bromopyrimidin-2-yl) propan-2-ol as a pale orange crystalline solid (84.0 mg,21% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.66 (s, 2H), 1.62 (s, 6H) m/z 219.0[ for ⁸¹ M+H of Br] ⁺ 。

Step 2

A solution of KF (26 mg,0.45 mmol), intermediate 7 (68 mg,0.15 mmol), 2- (5-bromopyrimidin-2-yl) propan-2-ol (34 mg,0.15 mmol), 1, 4-dioxane (2 mL) and water (0.5 mL) in a 20mL Biotage microwave vial was degassed for 10 min. Pd-118 (10 mg, 0.010mmol) was added quickly, the microwave vial was capped and the mixture was degassed for an additional 10 minutes. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 mL) and washed with water (20 mL). The aqueous phase was back extracted twice with DCM (2X 15 mL) and the combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by automatic silica column chromatography (12 g,0-10% MeOH/DCM gradient, 25 CV). After evaporation, the resulting solid was triturated with PE (3×5 mL) and the supernatant removed after each settling of the solid. The resulting solid was further dried using Biotage V10 to give N- [6- [2- (1-hydroxy-1-methyl-ethyl) pyrimidin-5-yl as a beige solid ]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (28 mg,40% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.95 (s, 2H), 8.81 (d, J=8.2 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.88 (s, 1H), 7.67-7.60 (m, 3H), 7.59-7.54 (m, 2H), 3.77 (s, 3H), 2.84 (s, 3H), 1.90 (s, 1H), 1.64 (s, 6H) m/z 446.1[ M+H ]] ⁺ 。

Example 202N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -1-methyl-4- (pyridin-2-yl) -1H-1,2, 3-triazole-5-carboxamide hydrochloride

As described for the synthesis of example 180, N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4- (pyridin-2-yl) -1H-1,2, 3-triazole-5-carboxamide (using the appropriate starting material through the step of example 154Synthesized as described in step 1) instead of N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide. In the last step, after concentrating the reaction mixture under reduced pressure, 1:1MeOH: naHCO ₃ (10 mL) was added to the precipitate, which was then filtered and treated with additional MeOH (5 mL) and H ₂ O (5 mL) was washed. The filtered solid was then redissolved in DCM (5 mL) and then 2M HCl in ether (30. Mu.L, 0.18 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes. The mixture was then concentrated under reduced pressure to give N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -1-methyl-4- (pyridin-2-yl) -1H-1,2, 3-triazole-5-carboxamide hydrochloride (10 mg,12% yield) as a yellow solid. ¹ H NMR(500MHz,DMSO-d ₆ )δ14.45(s,1H),9.54(s,2H),8.85(d,J＝8.1Hz,1H),8.78(d,J＝4.9Hz,1H),8.49(br s,3H),8.41(d,J＝8.1Hz,1H),8.16(t,J＝7.8Hz,1H),7.91(d,J＝8.1Hz,1H),7.66(t,J＝6.4Hz,1H),4.34-4.47(m,5H),4.25(s,3H).m/z 418.1[M+H] ⁺ 。

Example 203N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -4- (5-chloropyridin-2-yl) -1-methyl-1H-1, 2, 3-triazole-5-carboxamide hydrochloride

As described for the synthesis of example 180, N- (6-bromo-2-methoxypyridin-3-yl) -4- (5-chloropyridin-2-yl) -1-methyl-1H-1, 2, 3-triazole-5-carboxamide (synthesized by the method described in step 1 of example 154 using the appropriate starting material) was substituted for N- (6-bromo-2-methoxypyridin-3-yl) -1-methyl-4-phenyl-1H-1, 2, 3-triazole-5-carboxamide to give N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-methoxypyridin-3-yl) -4- (5-chloropyridin-2-yl) -1-methyl-1H-1, 2, 3-triazole-5-carboxamide hydrochloride as a pale yellow solid (45 mg,94% yield). ¹ H NMR(500MHz,DMSO-d ₆ )δ13.54(s,1H),9.54(s,2H),8.80(d,J＝8.1Hz,1H),8.69-8.74(m,1H),8.48(br s,3H),8.38(dd,J＝8.8&2.5Hz,1H),8.28(d,J＝8.5Hz,1H),7.91(d,J＝7.7Hz,1H),4.39(br s,5H),4.23(s,3H).m/z 452.0/454.0[M+H] ⁺ 。

Example 204 3- (4-fluorophenyl) -N- (6-imidazol-1-yl-2-isopropoxy-3-pyridinyl) -5-methyl-isoxazole-4-carboxamide

Step 1

A suspension of sodium hydride (60% in mineral oil, 700mg,17.5 mmol) in dry THF (3 mL) was filled into a microwave vial. The mixture was cooled to 0deg.C in an ice-water bath and 2-propanol (3.98 mL,51.6 mmol) was added dropwise. After stirring at 0 ℃ for 20 minutes, the mixture was allowed to reach room temperature and stirring was continued for more than 10 minutes. Then, 2, 6-dibromopyridin-3-amine (500 mg,1.98 mmol) in THF (2 mL) was added and the reaction mixture was heated at 80 ℃ for 6 hours and 65 ℃ for 10 hours. The crude mixture was treated with saturated NH ₄ Cl (10 mL) quench. THF was removed under reduced pressure and DCM (10 mL) was added to the resulting aqueous suspension. The organic layer was separated and the aqueous phase extracted with DCM (2X 10 mL). The combined organic extracts were washed with brine (10 mL), over MgSO ₄ Dried, filtered, concentrated under reduced pressure and passed through an SCX-2 column. The collected organics were then concentrated under reduced pressure to give 6-bromo-2-isopropoxy-pyridin-3-amine (390 mg,81% yield) as a brown oil. The crude product was used in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ6.88-6.79(m,2H),5.11(heptet,J＝6.2Hz,1H),5.01(s,2H),1.29(d,J＝6.2Hz,6H).m/z 231.0-233.0[M+H] ⁺ 。

Step 2

To a mixture of 6-bromo-2-isopropoxy-pyridin-3-amine (1.20 g,5.19 mmol) DIPEA (1.81 mL,10.4 mmol) in DCM (40 mL) was added dropwise a 0.4M solution of 3- (4-fluorophenyl) -5-methyl-isoxazole-4-carbonyl chloride (13.0 mL,5.19 mmol) in DCM (synthesized by the method described in step 1 of example 1 using the appropriate starting material). The reaction mixture was stirred at room temperature overnight. Then, water (30 mL) was added and the reaction mixture was extracted with DCM (3×30 mL). The combined organics were washed with brine (30 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. General purpose medicinePurification by flash silica column chromatography on ISCO system (elution with a 20% etoac/PE gradient) afforded N- (6-bromo-2-isopropoxy-3-pyridinyl) -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (2.00 g,85% yield) as a brown solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.47(s,1H),8.20(d,J＝8.1Hz,1H),7.77(dd,J＝8.5,5.6Hz,2H),7.37(t,J＝8.7Hz,2H),7.22(d,J＝8.1Hz,1H),5.15(heptet,J＝6.2Hz,1H),2.66(s,3H),1.22(d,J＝6.2Hz,6H).m/z 434.0/436.0[M+H] ⁺ 。

Step 3

Into a 10mL microwave vial was charged N- (6-bromo-2-isopropoxy-3-pyridinyl) -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (0.40 g,0.92 mmol), imidazole (78 mg,1.2 mmol), L-proline (42 mg,0.37 mmol), K ₂ CO ₃ (255 mg,1.84 mmol) and DMSO (3.5 mL) and degassing the reaction mixture. Copper (I) iodide (70 mg,0.37 mmol) was added to the reaction, and the vial was sealed and heated at 80℃for 16 hours. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the phases separated. The aqueous layer was further extracted with EtOAc (50 mL). The combined organic extracts were quenched with water (3X 25 mL), saturated NH ₄ Cl (25 mL), brine (25 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, elution with a 0-5% MeOH/DCM gradient) to give an orange foam. The crude material was repurified by flash column chromatography (12 g silica, eluting with a 0-10% meoh/EtOAc gradient) to give an off-white foam. Precipitation was induced by a small amount of EtOAc, which was then recrystallized from EtOAc/PE to give 3- (4-fluorophenyl) -N- (6-imidazol-1-yl-2-isopropoxy-3-pyridinyl) -5-methyl-isoxazole-4-carboxamide as an orange solid (0.11 g,27% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.83 (d, j=8.3 hz, 1H), 8.21 (s, 1H), 7.74-7.64 (m, 2H), 7.62 (s, 1H), 7.50 (s, 1H), 7.23 (t, j=8.6 hz, 2H), 7.16 (s, 1H), 6.89 (d, j=8.3 hz, 1H), 5.22 (hepet, j=6.2 hz, 1H), 2.79 (s, 3H), 1.12 (d, j=6.2 hz, 6H). M/z 422.2[ m+h ]] ⁺ 。

Example 205N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-isopropoxypyridin-3-yl) -3- (4-fluorophenyl) -5-methylisoxazole-4-carboxamide hydrochloride

Step 1

N- (6-bromo-2-isopropoxy-3-pyridinyl) -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (988 mg,2.28 mmol) (synthesized according to steps 1 and 2 in example 204), bis (pinacolato) diboron (750 mg,2.96 mmol) and KOAc (640 mg,6.83 mmol) are added to 1, 4-dioxane (15.6 mL) in 100mL three-necked RBF. The mixture was degassed by stirring under vacuum for 25 min, then Pd (dppf) Cl was added ₂ (complexing with DCM, 94mg,0.11 mmol) and heating the reaction mixture at 90℃for 1 h. The reaction mixture was cooled and the solvent was removed under reduced pressure. The crude residue was dissolved in EtOAc (50 mL) and washed with water (50 mL). The layers were separated and the organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was triturated with PE (3X 50 mL). The residual solvent was removed under reduced pressure to give 3- (4-fluorophenyl) -N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl as a brown solid ]-5-methyl-isoxazole-4-carboxamide (787 mg,68% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.63 (d, j=7.8 hz, 1H), 7.80 (s, 1H), 7.70-7.64 (m, 2H), 7.44 (d, j=7.8 hz, 1H), 7.19 (t, j=8.6 hz, 2H), 5.44 (hepet, j=6.2 hz, 1H), 2.77 (s, 3H), 1.34 (s, 12H), 1.03 (d, j=6.2 hz, 6H). m/z 400.1[ M+H for boric acid] ⁺ 。

Step 2

A10 mL microwave vial was charged with the stirring bar, 3- (4-fluorophenyl) -N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridyl group]-5-methyl-isoxazole-4-carboxamide (0.20 g,0.42 mmol), intermediate 11 (0.12 g,0.42 mmol) and KF (72 mg,1.3 mmol) and the solid was dissolved in 1, 4-dioxane (3.5 mL) and water (0.35 mL). The mixture was degassed then treated with Pd-118 (14 mg, 0.020mmol) and the reaction mixture stirred at room temperature for 91 hours. Water (20 mL) was added and the mixture extracted with DCM (3X 20 mL). The combined organic extracts were dried over MgSO ₄ Drying, filtering andconcentrating under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, eluting with 0-50% EtOAc/PE) to give a solid which was triturated in ether to give tert-butyl N- [ [5- [5- [ [3- (4-fluorophenyl) -5-methyl-isoxazole-4-carbonyl ] as an off-white solid ]Amino group]-6-isopropoxy-2-pyridinyl]Pyrimidin-2-yl]Methyl group]Carbamate (0.11 g,46% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.20 (s, 2H), 8.81 (d, j=8.2 hz, 1H), 7.73 (s, 1H), 7.72-7.64 (m, 2H), 7.35 (d, j=8.2 hz, 1H), 7.23 (t, j=8.6 hz, 2H), 5.70 (s, 1H), 5.31 (hepet, j=6.3 hz, 1H), 4.64 (d, j=5.1 hz, 2H), 2.79 (s, 3H), 1.48 (s, 9H), 1.12 (d, j=6.3 hz, 6H) m/z 563.2[ m+h)] ⁺ 。

Step 3

To tert-butyl N- [ [5- [5- [ [3- (4-fluorophenyl) -5-methyl-isoxazole-4-carbonyl ]]Amino group]-6-isopropoxy-2-pyridinyl]Pyrimidin-2-yl]Methyl group]To a stirred solution of carbamate (0.11 g,0.20 mmol) in DCM (2 mL) was added HCl (4M in 1, 4-dioxane, 1mL,4 mmol) and the reaction mixture was stirred at room temperature for 2.5 h. Volatiles were removed under reduced pressure and the solid was dried in a vacuum oven (40 ℃ C., 30 mbar) to give N- [6- [2- (aminomethyl) pyrimidin-5-yl as an off-white solid]-2-isopropoxy-3-pyridinyl]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide hydrochloride (0.10 g,98% yield). ¹ H NMR(500MHz,DMSO-d ₆ ) Delta 9.45 (s, 2H), 9.43 (s, 1H), 8.56 (s, 3H), 8.45 (d, j=8.1 hz, 1H), 7.84-7.73 (m, 3H), 7.38 (t, j=8.8 hz, 2H), 5.40 (hepet, j=6.2 hz, 1H), 4.36 (s, 2H), 2.70 (s, 3H), 1.27 (d, j=6.1 hz, 6H). m/z 463.2[ M+H for free base ] ⁺ 。

Example 206N- (6- (1H-imidazol-1-yl) -2-isopropoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Step 1

To a mixture of 6-bromo-2-isopropoxy-pyridin-3-amine (1.4 g mg,6.1 mmol) (synthesized according to step 1 in example 204), DIPEA (2.11 mL,12.1 mmol) in DCM (45 mL) was added dropwiseA0.4M solution of 5-methyl-3-phenyl-isoxazole-4-carbonyl chloride (15 mL,6.1 mmol) (synthesized according to step 1 in example 1) in DCM. The reaction mixture was stirred at room temperature overnight. Then, water (30 mL) was added and the reaction mixture was extracted with DCM (3×30 mL). The combined organics were washed with brine (30 mL), dried over MgSO ₄ Dried and filtered, and then concentrated to dryness. Purification by flash silica column chromatography (elution with a 20% etoac/PE gradient) on ISCO system afforded N- (6-bromo-2-isopropoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (2.10 g,77% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.49(s,1H),8.17(d,J＝7.7Hz,1H),7.74-7.66(m,2H),7.55-7.51(m,3H),7.21(d,J＝8.1Hz,1H),5.15(heptet,J＝6.2Hz,1H),2.66(s,3H),1.22(d,J＝6.2Hz,6H).m/z 416.0/418.0[M+H] ⁺ 。

Step 2

A10 mL microwave vial was charged with N- (6-bromo-2-isopropoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (0.30 g,0.72 mmol), imidazole (54 mg,0.79 mmol), L-proline (25 mg,0.22 mmol), K ₂ CO ₃ (199mg, 1.44 mmol) and DMSO (4 mL), and the reaction mixture was degassed. Copper (I) iodide (41 mg,0.22 mmol) was added to the reaction, and the vial was sealed and heated at 80℃for 16 hours. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL) and the phases separated. The aqueous layer was further extracted with DCM (25 mL). The combined organic extracts were washed with brine (25 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, eluting with a 0-5% MeOH/DCM gradient) to give N- (6-imidazol-1-yl-2-isopropoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (140 mg,46% yield) as a pale yellow solid. ¹ H NMR (400 MHz, chloroform-d) delta 8.80 (d, j=8.3 hz, 1H), 8.19 (s, 1H), 7.70-7.63 (m, 3H), 7.59-7.47 (m, 4H), 7.14 (s, 1H), 6.87 (d, j=8.3 hz, 1H), 5.14 (hepet, j=6.1 hz, 1H), 2.78 (s, 3H), 1.05 (d, j=6.2 hz, 6H) m/z 404.2[ m+h ]] ⁺ 。

Example 207N- (6- (2- (aminomethyl) pyrimidin-5-yl) -2-isopropoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide hydrochloride

A10 mL microwave vial was filled with the stir bar and N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (0.30 g,0.65 mmol) (synthesized using the procedure described in steps 1 and 2 in example 204) intermediate 11 (0.18 mL,0.71 mmol) and KF (113 mg,1.94 mmol) were dissolved in 1, 4-dioxane (5 mL) and water (1 mL) using the appropriate starting materials. The mixture was degassed and then treated with Pd-118 (0.02 g,0.03 mmol), the vial sealed and stirred at room temperature for 16 hours. Water (20 mL) was added and the mixture extracted with DCM (3X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was then treated with HCl (4 m in 1, 4-dioxane, 0.97ml,3.9 mmol) and once complete deprotection was achieved, the reaction mixture was basified and extracted with DCM. The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Purification by flash column chromatography (12 g, elution with a 10% MeOH/DCM gradient) gave the free base which was then treated with 1.2 equivalents of HCl to give N- [6- [2- (aminomethyl) pyrimidin-5-yl as a yellow solid]-2-isopropoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (73 mg, 22% yield). ¹ H NMR (500 MHz, methanol-d) ₄ ) δ9.40 (s, 2H), 8.67 (d, j=8.1 hz, 1H), 7.74-7.69 (m, 2H), 7.63 (d, j=8.1 hz, 1H), 7.60-7.52 (m, 3H), 5.39 (hept, j=6.2 hz, 1H), 4.42 (s, 2H), 2.74 (s, 3H), 1.23 (d, j=6.2 hz, 6H). m/z 445.2[ M+H for free base] ⁺ 。

Example 208 3- (4-fluorophenyl) -N- (2-isopropoxy-6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyridin-3-yl) -5-methylisoxazole-4-carboxamide hydrochloride

Into a 10mL microwave vial, stirring was performedStick, 3- (4-fluorophenyl) -N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridyl ]-5-methyl-isoxazole-4-carboxamide (0.30 g,0.65 mmol) (synthesized as described in example 205), 7-boc-3-bromo-5, 6-dihydro-8H-imidazo [1,2-a]Pyrazine (0.18 mL,0.71 mmol) and KF (113 mg,1.94 mmol) and the solid was dissolved in 1, 4-dioxane (5 mL) and water (1 mL). The mixture was degassed and then treated with Pd-118 (21 mg,0.03 mmol), the vial sealed and stirred at room temperature for 16 hours. Water (20 mL) was added and the mixture extracted with DCM (3X 20 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The crude material was then treated with HCl (4 m in 1, 4-dioxane, 0.97ml,3.88 mmol) and once complete deprotection was achieved, the reaction mixture was basified and extracted with DCM. The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Purification by flash column chromatography (12 g silica, eluting with an 80% MeOH/EtOAc gradient) afforded the free base. The free base (0.02 g,0.05 mmol) was dissolved in DCM (0.71 mL) and treated with HCl (70. Mu.L, 2M in ether, 0.14 mmol) and the reaction mixture was stirred at room temperature for 1 h. Volatiles were removed under reduced pressure and the material was dried in a vacuum oven (40 ℃) to give 3- (4-fluorophenyl) -N- (2-isopropoxy-6- (5, 6,7, 8-tetrahydroimidazo [1, 2-a) as a white solid ]Pyrazin-3-yl) pyridin-3-yl) -5-methylisoxazole-4-carboxamide hydrochloride (23 mg,92% yield). ¹ H NMR(400MHz,DMSO-d ₆ ) δ10.00 (s, 2H), 9.46 (s, 1H), 8.37 (d, j=7.7 hz, 1H), 7.95 (s, 1H), 7.79 (dd, j=8.4, 5.4hz, 2H), 7.47 (d, j=8.1 hz, 1H), 7.39 (t, j=8.7 hz, 2H), 5.23 (hepet, j=6.1 hz, 1H), 4.71 (d, j=5.9 hz, 2H), 4.59 (s, 2H), 3.68 (t, j=5.8 hz, 2H), 2.69 (s, 3H), 1.26 (d, j=6.1 hz, 6H). m/z 477.1[ M+H for free base] ⁺ 。

Example 209 3- (4-fluorophenyl) -N- (2-isopropoxy-6- (7-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyridin-3-yl) -5-methylisoxazole-4-carboxamide hydrochloride

To a 10mL microwave vial was added tert-butyl 3- [ 6-methoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino in formic acid (2.2 mL)]-2-pyridyl group]-6, 8-dihydro-5H-imidazo [1,2-a ]]Pyrazine-7-formate (50 mg,0.10 mmol) (synthesized as crude intermediate described in example 208) and paraformaldehyde (13 mg,0.42 mmol) and the reaction heated at 95℃for 2 hours. The reaction mixture was cooled to room temperature and diluted with DCM, then washed with 2M NaOH, water and brine in that order. The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (24 g silica, eluting with a 60% MeOH/EtOAc gradient) to give the free base. The product was dissolved in DCM (1 mL) and then treated with HCl (0.16 mL, 2M in ether, 0.31 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure and the material was dried in a vacuum oven (40 ℃) to give 3- (4-fluorophenyl) -N- (2-isopropoxy-6- (7-methyl-5, 6,7, 8-tetrahydroimidazo [1, 2-a) as a yellow solid ]Pyrazin-3-yl) pyridin-3-yl) -5-methylisoxazole-4-carboxamide hydrochloride (40 mg,69% yield). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.46(s,1H),8.38(d,J＝8.0Hz,1H),7.98(s,1H),7.79(dd,J＝8.4,5.4Hz,2H),7.48(d,J＝8.1Hz,1H),7.39(t,J＝8.7Hz,2H),5.23(hept,J＝6.1Hz,1H)),4.76(s,2H),4.58(s,2H),3.67(s,2H),2.93(s,3H),2.69(s,3H),1.25(d,J＝6.1Hz,6H).m/z 491.2[M+H] ⁺ 。

Example 210 5- (azetidin-1-yl) -3- (4-fluorophenyl) -N- (6-isoxazol-4-yl-2-methoxy-3-pyridinyl) isoxazole-4-carboxamide

Step 1

Into 500mL RBF, hydroxylamine hydrochloride (10.0 g,144 mmol) and Na ₂ CO ₃ (15.3 g,144 mmol) and the solid was suspended in water (250 mL)/EtOH (50 mL). The mixture was stirred for 5 minutes and then treated with 4-fluorobenzaldehyde (12.9 mL,120 mmol) for 5 minutes. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with EtOAc (3X 250 mL) and the combined organic extracts were washed with brine (250 mL) over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give 4-fluorobenzaldehyde oxime (15.7 g,89% yield) as a yellow solid. ¹ H NMR (500 MHz, chloroform-d) δ8.14 (s, 1H), 7.64-7.54 (m, 3H), 7.10 (t, J=8.7 Hz, 2H).

Step 2

To a stirred solution of 4-fluorobenzaldehyde oxime (15.68 g,112.7 mmol) in dry DMF (110 mL) was added N-chlorosuccinimide (15.05 g,112.7 mmol) in portions over 5 minutes. The reaction mixture was stirred at room temperature over the weekend. Additional N-chlorosuccinimide (1.50 g,11.3 mmol) was added and the reaction mixture was further stirred at room temperature. The reaction was quenched with water (200 mL) and then extracted with ether (2X 200 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), and over MgSO ₄ Dried and concentrated under reduced pressure to give 4-fluoro-N-hydroxy-benzylimidoyl chloride (19.20 g,93% yield) as an off-white solid. ¹ H NMR (500 MHz, chloroform-d) delta 7.97 (s, 1H), 7.84 (dd, j=8.9, 5.3hz, 2H), 7.10 (t, j=8.6 hz, 2H).

Step 3

A solution of 4-fluoro-N-hydroxy-phenyliminochloride (7.84 g,45.2 mmol) and methyl cyanoacetate (5.18 mL,58.7 mmol) in MeOH (200 mL) was cooled to-10℃in 3-neck 500mL RBF. After reaching this temperature, sodium methoxide (7.32 g,135 mmol) was added in portions over 5 minutes while maintaining the temperature<-5 ℃. The reaction mixture was stirred at-10 ℃ for 5 minutes and then at room temperature for 2 hours during which time a yellow clear solution precipitated. The solvent was removed under reduced pressure and the solid was suspended in water (100 mL) and filtered under vacuum. The solid was washed with additional water (50 mL) and dried overnight in a vacuum oven (40 ℃) to give methyl 5-amino-3- (4-fluorophenyl) isoxazole-4-carboxylate (9.10 g,81% yield) as a yellow solid. ¹ H NMR (500 MHz, chloroform-d) δ7.64 (dd, J=8.6, 5.5Hz, 2H), 7.12 (t, J=8.7 Hz, 2H), 6.13 (s, 2H), 3.74 (s, 3H). M/z 237.1[ M+H ]] ⁺ 。

Step 4

Methyl 5-amino-3- (4-fluorophenyl) isoxazole-4-carboxylic acid ester (5.00 g,21.17 mmol) and cesium carbonate (13.79 g) A stirred suspension of 42.34mmol in DMF (100 mL) was cooled in an ice bath and then treated with 1, 3-dibromopropane (2.2 6mL,22.23mmol) for 5 min. The reaction was stirred at room temperature for 5 hours. Water (100 mL) was added to the reaction, followed by extraction with ether (3X 100 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), and over MgSO ₄ Dried, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (40 g silica, gradient elution with 0-100% EtOAc/PE) to give methyl 5- (azetidin-1-yl) -3- (4-fluorophenyl) isoxazole-4-carboxylate (2.02 g, 33% yield) as a yellow oil. ¹ H NMR (500 MHz, chloroform-d) delta 7.56 (dd, j=8.6, 5.6hz, 2H), 7.10 (t, j=8.8 hz, 2H), 4.43 (t, j=7.8 hz, 4H), 3.62 (s, 3H), 2.47 (quintuple peak, j=7.8 hz, 2H) m/z 277.0[ m+h)] ⁺ 。

Step 5

To a solution of methyl 5- (azetidin-1-yl) -3- (4-fluorophenyl) isoxazole-4-carboxylate (2.02 g,7.31 mmol) in THF (8 mL) and MeOH (8 mL) was added 2M NaOH (8.01 mL,16.01 mmol) and the reaction mixture was stirred at room temperature 60 ℃ overnight. After completion, volatiles were removed under reduced pressure and the aqueous solution was acidified to pH 2-3 with 2M HCl. The solid was collected under vacuum filtration, washed with water (50 mL) and dried in a vacuum oven (40 ℃) for 3 hours to give 5- (azetidin-1-yl) -3- (4-fluorophenyl) isoxazole-4-carboxylic acid (1.70 g,84% yield) as a white solid. ¹ H NMR(500MHz,DMSO-d ₆ ) δ12.09 (s, 1H), 7.56 (dd, j=8.6, 5.7hz, 2H), 7.26 (t, j=8.9 hz, 2H), 4.31 (t, j=7.7 hz, 4H), 2.37 (quintuple peak, j=7.7 hz, 2H). M/z 263.0[ m+h)] ⁺ 。

Step 6

To a stirred solution of 5- (azetidin-1-yl) -3- (4-fluorophenyl) isoxazole-4-carboxylic acid (671 mg,2.56 mmol) in DMF (5 ml) was added oxalyl chloride (0.21 ml,2.5 mmol). After 15 min, the latter mixture was added to 6-bromo-2-methoxy-3-pyridinamine (400 mg,1.97 mmol) and Et at 0deg.C ₃ N (0.83 mL,5.9 mmol) in DCM (3 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with DCM (25 mL) and washed with water (25 mL), 1M NaOH (25 mL), brine (25 mL),over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Precipitation was induced by the addition of MeOH and recrystallized from MeOH. The solid was collected by vacuum filtration to give 5- (azetidin-1-yl) -N- (6-bromo-2-methoxy-3-pyridinyl) -3- (4-fluorophenyl) isoxazole-4-carboxamide as a colorless solid (373 mg,40% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.47 (d, j=8.2 hz, 1H), 7.60-7.51 (m, 2H), 7.27-7.19 (m, 3H), 6.98 (d, j=8.1 hz, 1H), 4.46 (t, j=7.7 hz, 4H), 3.66 (s, 3H), 2.49 (quintuple peak, j=7.7 hz, 2H) m/z 446.9/448.9[ m+h ] ] ⁺ 。

Step 7

A25 mL microwave vial was charged with stirring bar, 5- (azetidin-1-yl) -N- (6-bromo-2-methoxy-3-pyridinyl) -3- (4-fluorophenyl) isoxazole-4-carboxamide (0.20 g,0.45 mmol), KF (78 mg,1.3 mmol) and 4-isoxazoleboronic acid pinacol ester (87 mg,0.45 mmol), and the solid was dissolved in 1, 4-dioxane (8 mL) and water (2 mL). The mixture was degassed by bubbling nitrogen into the solution for 10 minutes. Pd-118 (29 mg,0.040 mmol) was added to the mixture and the vial was capped and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (10 mL) and water (10 mL). The layers were separated and the aqueous phase was further extracted with DCM (2X 10 mL). The combined organic extracts were dried over MgSO ₄ Dried and concentrated under reduced pressure. The residue was adsorbed onto silica (12 g silica, 0-100% EtOAc/PE gradient) to give 5- (azetidin-1-yl) -3- (4-fluorophenyl) -N- (6-isoxazol-4-yl-2-methoxy-3-pyridinyl) isoxazole-4-carboxamide (78 mg,38% yield) as a tan solid. ¹ H NMR (500 MHz, chloroform-d) delta 8.78 (s, 1H), 8.64 (s, 1H), 8.60 (d, j=8.1 hz, 1H), 7.58 (dd, j=8.4, 5.5hz, 2H), 7.40 (s, 1H), 7.26-7.21 (m, 2H), 7.01 (d, j=8.1 hz, 1H), 4.48 (t, j=7.7 hz, 4H), 3.70 (s, 3H), 2.50 (quintuples, j=7.7 hz, 2H) m/z 436.2[ m+h ] ⁺ 。

Example 211N- [6- [2- (aminomethyl) pyrimidin-5-yl ] -2-methoxy-3-pyridinyl ] -5- (3-chloropropylamino) -3- (4-fluorophenyl) isoxazole-4-carboxamide hydrochloride

Step 1

5- (azetidin-1-yl) -N- (6-bromo-2-methoxy-3-pyridinyl) -3- (4-fluorophenyl) isoxazole-4-carboxamide (79 mg,0.18 mmol) (synthesized as described in steps 1-6 of example 210), bis (pinacolato) diboron (58 mg,0.23 mmol) and KOAc (52 mg,0.53 mmol) in 1, 4-dioxane (1.5 mL) was added in a microwave vial. The mixture was degassed by stirring under vacuum for 5 min, then Pd-118 (15 mg, 0.020mmol) was added and the reaction mixture was heated at 90℃for 2 h. The reaction mixture was cooled and the solvent was removed under reduced pressure. The crude residue was dissolved in EtOAc (10 mL) and washed with water (10 mL). The layers were separated and the organic layer was dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure to give the crude product, which was triturated three times with PE (2×10 mL). The residual solvent was removed under reduced pressure to give 5- (azetidin-1-yl) -3- (4-fluorophenyl) -N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl as a brown solid]Isoxazole-4-carboxamide (89 mg,91% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.51 (d, j=7.9 hz, 1H), 7.56 (dd, j=8.5, 5.4hz, 2H), 7.50 (s, 1H), 7.40 (d, j=7.8 hz, 1H), 7.20 (t, j=8.6 hz, 2H), 4.46 (t, j=7.7 hz, 4H), 3.72 (s, 3H), 2.48 (quintuple peak, j=7.7 hz, 2H), 1.34 (s, 12H). m/z 413.1[ M+H for boric acid] ⁺ 。

Step 2

A5 mL microwave vial was charged with stirring bar, intermediate 11 (47 mg,0.16 mmol), 5- (azetidin-1-yl) -3- (4-fluorophenyl) -N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl]Isoxazole-4-carboxamide (89 mg,0.16 mmol) and KF (28 mg,0.48 mmol) and the solid was dissolved in 1, 4-dioxane (1.5 mL) and water (0.15 mL). The mixture was degassed by bubbling nitrogen into the solution for 10 minutes. Pd-118 (5 mg,0.01 mmol) was added to the mixture and the vial was capped and the reaction mixture was stirred at room temperature. Water (10 mL) was added and the mixture extracted with DCM (3X 10 mL). The combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Adsorption of the residue onto silica and by rapidPurification by column chromatography (12 g silica, gradient elution with 0-100% EtOAc/PE) afforded tert-butyl N- [ [5- [5- [ [5- (azetidin-1-yl) -3- (4-fluorophenyl) isoxazole-4-carbonyl ] as a white solid ]Amino group]-6-methoxy-2-pyridinyl]Pyrimidin-2-yl]Methyl group]Carbamate (49 mg,50% yield). ¹ H NMR (500 MHz, chloroform-d) δ9.19 (s, 2H), 8.69 (d, j=8.1 hz, 1H), 7.59 (dd, j=8.6, 5.4hz, 2H), 7.45 (s, 1H), 7.30 (d, j=8.1 hz, 1H), 7.28-7.23 (M, 2H), 5.70 (s, 1H), 4.63 (d, j=5.1 hz, 2H), 4.49 (t, j=7.7 hz, 4H), 3.75 (s, 3H), 2.50 (quincunx, j=7.7 hz, 2H), 1.48 (s, 9H) M/z576.2[ m+h)] ⁺ 。

Step 3

To tert-butyl N- [ [5- [5- [ [5- (azetidin-1-yl) -3- (4-fluorophenyl) isoxazole-4-carbonyl ]]Amino group]-6-methoxy-2-pyridinyl]Pyrimidin-2-yl]Methyl group]To a solution of carbamate (49 mg,0.090 mmol) in DCM (1 mL) was added HCl solution (4 n in 1, 4-dioxane, 0.51mL,2.1 mmol) and the reaction mixture was stirred at room temperature until LCMS indicated completion of the reaction. Another portion of HCl was added and the reaction mixture was stirred for a total of 21 hours. The volatiles were removed under reduced pressure, triturated in EtOAc and the solid was dried in a vacuum oven (40 ℃) overnight to give N- [6- [2- (aminomethyl) pyrimidin-5-yl as an orange solid]-2-methoxy-3-pyridinyl]-5- (3-chloropropylamino) -3- (4-fluorophenyl) isoxazole-4-carboxamide hydrochloride (35 mg,70% yield). ¹ HNMR(500MHz,DMSO-d ₆ ) Delta 9.42 (s, 2H), 8.66 (d, j=8.2 hz, 1H), 8.45 (s, 3H), 8.30 (t, j=6.4 hz, 1H), 7.79 (d, j=8.2 hz, 1H), 7.75 (dd, j=8.4, 5.5hz, 2H), 7.54 (t, j=8.8 hz, 2H), 7.49 (s, 1H), 4.39-4.29 (m, 2H), 3.76-3.72 (m, 5H), 3.62-3.52 (m, 2H), 2.15-2.05 (m, 2H). m/z 512.1[ M+H for free base ] ⁺ 。

Example 212N- (6-imidazol-1-yl-2-oxo-1H-pyridin-3-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

To a solution of example 1 (36 mg,0.10 mmol) in DCM (2 mL) in ice bath was slowly added 1M BBr in DCM ₃ (0.48mL，048 mmol) while maintaining the reaction temperature at 5 ℃. After 15 min, meOH (0.5 mL) was added to quench excess BBr ₃ . The mixture was evaporated to dryness and the residue was purified by flash column chromatography (4 g silica, 1-2% MeOH/DCM gradient) to give N- (6-imidazol-1-yl-2-oxo-1H-pyridin-3-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (23 mg,63% yield) as a light brown solid. ¹ H NMR(600MHz,DMSO-d ₆ )δ12.38(s,1H),9.75(s,1H),9.56(s,1H),8.46(d,J＝8.0Hz,1H),8.21(s,1H),7.82(s,1H),7.69(d,J＝6.9Hz,2H),7.52-7.46(m,3H),7.44(d,J＝8.3Hz,1H),2.63(s,3H).m/z 362.1[M+H] ⁺ 。

Example 213N- [6- (2-aminopyrimidin-5-yl) -2-methoxy-3-pyridinyl ] -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide

A mixture of 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (109 mg,0.49 mmol), intermediate 12 (200 mg,0.49 mmol) and potassium fluoride (87 mg,1.48 mmol) in 1, 4-dioxane (4 mL) and water (0.4 mL) was prepared by reacting a mixture of 5- (4, 5-dioxaborolan-2-yl) -2-pyrimidinamine with N ₂ The gas was purged for 5 minutes to degas. Pd-118 (16 mg,0.02 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Another part of 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine and Pd-118 were added and the reaction mixture was stirred at 50℃for 16 hours. The reaction mixture was extracted with EtOAc (3×10 mL) and the combined organic extracts were concentrated under reduced pressure. Purification by flash silica column chromatography (elution with a 0-100% EtOAc/petroleum ether gradient) afforded N- [6- (2-aminopyrimidin-5-yl) -2-methoxy-3-pyridinyl ] as an off-white solid ]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (85 mg, 39%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.57(s,1H),8.91(s,2H),8.25(d,J＝8.0Hz,1H),7.78(t,J＝7.1Hz,2H),7.50(d,J＝8.1Hz,1H),7.40(t,J＝8.8Hz,2H),7.00(s,2H),3.91(s,3H),2.65(s,3H).m/z 421.1[M+H] ⁺ 。

Example 214N- [6- (2-aminopyrimidin-5-yl) -2-isopropoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

N- (6-bromo-2-isopropoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (602 mg,1.45 mmol) (synthesized according to step 1 of example 206), B ₂ pin ₂ A solution of (441 mg,1.74 mmol) and KOAc (430 mg,4.34 mmol) in 1, 4-dioxane (11 mL) was prepared by reacting with N ₂ The gas was purged to degas for 5 minutes. Addition of Pd (dppf) Cl ₂ (106 mg,0.14 mmol) and the reaction mixture was heated at 90℃for 3 hours. The solvent was removed under reduced pressure and the residue partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2X 20 mL). The combined organic extracts were dried over MgSO ₄ Drying, filtering and concentrating under reduced pressure to give brown solid, grinding with petroleum ether to give N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3-pyridinyl as brown solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (669 mg, 95%) which was used in the next step without further purification. ¹ H NMR(500MHz,CDCl ₃ ) Delta 8.63 (d, j=7.8 hz, 1H), 7.84 (s, 1H), 7.68-7.62 (m, 2H), 7.56-7.46 (m, 3H), 7.43 (dd, j=7.8, 0.5hz, 1H), 5.38 (hept, j=6.2 hz, 1H), 2.77 (s, 3H), 1.33 (s, 12H), 0.96 (d, j=6.2 hz, 6H). m/z 382.1[ M+H, boric acid ] ⁺ _。

Step 2

N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3-pyridinyl]A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxamide (300 mg,0.62 mmol), 2-amino-5-bromopyrimidine (112 mg,0.65 mmol) and KF (109 mg,1.85 mmol) in 1, 4-dioxane (5 mL) and water (0.5 mL) was degassed for 5 min. Pd-118 (20 mg,0.03 mmol) was added and the reaction mixture was heated at 80℃for 1 hour. Volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc (20 mL) and water (20 mL) and separated. The aqueous layer was extracted with EtOAc (2X 20 mL) and the combined organic extracts were dried over MgSO ₄ Drying, filtering and concentrating under reduced pressureAnd (5) shrinking. By flash silica column chromatography (with 0-5% MeOH/CH ₂ Cl ₂ Gradient elution) to give a brown solid, followed by flash silica column chromatography (using 0-100% EtOAc/CH) ₂ Cl ₂ Gradient elution) to give N- [6- (2-aminopyrimidin-5-yl) -2-isopropoxy-3-pyridinyl) as an off-white solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (89 mg, 32%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.39(s,1H),8.86(s,2H),8.23(d,J＝8.1Hz,1H),7.73(d,J＝7.0Hz,2H),7.59-7.48(m,3H),7.45(d,J＝8.1Hz,1H),6.98(s,2H),5.34(hept,J＝6.0Hz,1H),2.68(s,3H),1.26(d,J＝6.1Hz,6H).m/z 431.2[M+H] ⁺ 。

Example 215N- [6- (6-amino-3-pyridinyl) -2-isopropoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Step 1

N- [ 2-isopropoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3-pyridinyl ]A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxamide (351 mg,0.72 mmol) (synthesized according to step 1 in example 214), tert-butyl (5-bromopyridin-2-yl) carbamate (196 mg,0.72 mmol) and KF (128 mg,2.16 mmol) in 1, 4-dioxane (6 mL) and water (0.6 mL) was degassed for 5 min. Pd-118 (24 mg,0.04 mmol) was added and the reaction mixture was heated at 90℃for 2 hours. The solvent was removed under reduced pressure and purified by flash silica column chromatography (with 0-100% EtOAc/CH ₂ Cl ₂ Gradient elution) followed by trituration in EtOAc afforded tert-butyl N- [5- [ 6-isopropoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino ] as a cream-like solid]-2-pyridyl group]-2-pyridyl group]Urethane (240 mg, 60%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.98(s,1H),9.40(s,1H),8.90(d,J＝2.7Hz,1H),8.36-8.27(m,2H),7.88(d,J＝8.9Hz,1H),7.77-7.68(m,2H),7.60-7.47(m,4H),5.37(hept,J＝6.1Hz,1H),2.68(s,3H),1.49(s,9H),1.27(d,J＝6.2Hz,6H).m/z 530.2[M+H] ⁺ 。

Step 2

Tert-butyl N- [5- [ 6-isopropoxy-5- [ (5-methyl-3-phenyl-isoxazole-4-carbonyl) amino group]-2-pyridyl group]-2-pyridyl group]Carbamate (240 mg,0.43 mmol) in CH ₂ Cl ₂ The solution in TFA (5 mL, 1:1) was stirred at room temperature for 3 hours. The solution was treated with CH ₂ Cl ₂ (10 mL) and water (10 mL) were diluted and then the aqueous layer was basified with 2M NaOH. Separating the layers and using CH ₂ Cl ₂ (2X 20 mL) the aqueous layer was extracted. The combined organic extracts were washed with brine (20 mL), over MgSO ₄ Drying, filtering and concentrating under reduced pressure to obtain N- [6- (6-amino-3-pyridyl) -2-isopropoxy-3-pyridyl ] in the form of cream solid ]-5-methyl-3-phenyl-isoxazole-4-carboxamide (194 mg, 100%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.35(s,1H),8.61(d,J＝2.6Hz,1H),8.19(d,J＝8.1Hz,1H),8.00(dd,J＝8.7,2.5Hz,1H),7.78-7.68(m,2H),7.59-7.48(m,3H),7.38(d,J＝8.1Hz,1H),6.50(d,J＝8.7Hz,1H),6.26(s,2H),5.34(hept,J＝5.9Hz,1H),2.68(s,3H),1.26(d,J＝6.2Hz,6H).m/z 430.2[M+H] ⁺ 。

Example 216N- [6- (2-aminopyrimidin-5-yl) -2- (oxetan-3-yloxy) -3-pyridinyl ] -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide

Step 1

To an ice-cold solution of oxetan-3-ol (89 mg,1.2 mmol) in 1, 4-dioxane (4 mL) was added NaH (56 mg,1.4mmol, 60% in mineral oil) in 5 portions. The mixture was stirred at room temperature for 15 minutes, then 2, 6-dibromopyridin-3-amine (252 mg,1.0 mmol) was added in one portion and the reaction mixture was heated at 100 ℃. After 17 hours, the reaction mixture was treated with oxetan-3-ol (222 mg,3.0 mmol) and NaH (120 mg,3.0mmol, 60% in mineral oil) and the reaction mixture was stirred at 100 ℃ for 21 hours. The solvent was removed under reduced pressure and the residue was taken up in CH ₂ Cl ₂ (20 mL) and saturated aqueous NH ₄ Cl (20 mL) was partitioned and then phase separated by hydrophobic slitsAnd (3) a device. The aqueous layer was treated with CH ₂ Cl ₂ (20 mL) was washed and the combined filtrates were concentrated under reduced pressure to give a brown oil. Purification by flash silica column chromatography (elution with a 0-100% EtOAc/petroleum ether gradient) afforded 6-bromo-2- (oxetan-3-yloxy) pyridin-3-amine (77 mg, 31%) as an orange oil. ¹ H NMR(500MHz,CDCl ₃ )δ6.89(d,J＝7.9Hz,1H),6.80(d,J＝7.9Hz,1H),5.64(tt,J＝6.3,5.3Hz,1H),5.03-4.98(m,2H),4.76-4.72(m,2H),3.80(s,2H).m/z244.9,246.9[M+H] ⁺ 。

Step 2

To CH of 6-bromo-2- (oxetan-3-yloxy) pyridin-3-amine (78 mg,0.31 mmol) and DIPEA (0.080 mL,0.47 mmol) ₂ Cl ₂ To the solution in (5 mL) was added 3- (4-fluorophenyl) -5-methyl-isoxazole-4-carbonyl chloride in CH ₂ Cl ₂ (0.78 mL,0.31 mmol) (synthesized by the method described in step 1 of example 1 using the appropriate starting materials). The reaction mixture was stirred at room temperature for 21 hours, then with CH ₂ Cl ₂ (10 mL) and water (20 mL). The mixture was vigorously stirred for 5 minutes and then passed through a hydrophobic slot phase separator. The aqueous phase is treated with CH ₂ Cl ₂ (20 mL) was washed and the filtrate was concentrated under reduced pressure. By flash silica column chromatography (with 0-100% EtOAc/CH ₂ Cl ₂ Gradient elution) to give N- [ 6-bromo-2- (oxetan-3-yloxy) -3-pyridinyl ] as a colorless solid]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (67 mg, 45%). ¹ H NMR(500MHz,CDCl ₃ )δ8.63(d,J＝8.3Hz,1H),7.70-7.63(m,2H),7.54(s,1H),7.26-7.20(m,2H),7.10(dd,J＝8.3,0.5Hz,1H),5.43(tt,J＝6.3,5.3Hz,1H),4.87-4.80(m,2H),4.31-4.24(m,2H),2.79(s,3H).m/z 448.0,450.0[M+H] ⁺ 。

Step 3

N- [ 6-bromo-2- (oxetan-3-yloxy) -3-pyridinyl]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (67 mg,0.14 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (33 mg,0.15 mmol) and KF (25 mg,0.43 mmol) in 1, 4-dioxane (1.5 mL) and water (0.15 mL) by using a mixture of N ₂ The gas was purged for 5 minutes to degas. Pd-118 (4.6 mg, 0.0070 mmol) was added and the reaction mixture was heated at 90℃for 4 hours. Additional 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (15.7 mg,0.07 mmol) was added and the reaction stirred at 90℃for 16 h. Volatiles were removed under reduced pressure and purified by flash silica column chromatography (with 0-100% EtOAc/CH ₂ Cl ₂ Gradient elution) to give an off-white solid, which was then purified by flash silica column chromatography (eluting with a 0-5% MeOH/EtOAc gradient) to give N- [6- (2-aminopyrimidin-5-yl) -2- (oxetan-3-yloxy) -3-pyridinyl ] as an off-white solid]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (12 mg, 17%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.74(s,1H),8.83(s,2H),8.30(d,J＝8.1Hz,1H),7.80(t,J＝7.1Hz,2H),7.53(d,J＝8.1Hz,1H),7.37(t,J＝8.9Hz,2H),6.98(s,2H),5.68(p,J＝5.7Hz,1H),4.91(t,J＝6.8Hz,2H),4.53(dd,J＝7.2,5.6Hz,2H),2.68(s,3H).m/z 463.2[M+H] ⁺ 。

Example 217N- [6- (2-aminopyrimidin-5-yl) -2- (2-methoxyethoxy) -3-pyridinyl ] -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide

Step 1

NaH (640 mg,16.0mmol in mineral oil 60%) was charged to a 25mL microwave vial and washed with petroleum ether to remove the mineral oil. The solid was suspended in THF (3 mL) and then 2-methoxyethanol (3 mL) was added at 0 ℃. After stirring at room temperature for 2 hours, 2, 6-dibromopyridin-3-amine (504 mg,2.0 mmol) was added to the light brown solution and the reaction mixture was heated at 80 ℃. Adding saturated aqueous NH ₄ Cl (20 mL) and the organic solvent was removed under reduced pressure. Will CH ₂ Cl ₂ (20 mL) was added to the aqueous mixture and then passed through a hydrophobic slit phase separator. By CH ₂ Cl ₂ The aqueous layer was extracted (20 mL) and the combined organic extracts were concentrated under reduced pressure. By flash column chromatography on silica (elution with a gradient of 0-100% EtOAc/petroleum ether)) Purification gave 6-bromo-2- (2-methoxyethoxy) pyridin-3-amine (431 mg, 87%) as an orange solid. ¹ H NMR(500MHz,CDCl ₃ )δ6.90(s,2H),4.54-4.49(m,2H),3.78-3.74(m,2H),3.42(s,3H).m/z 247.0,249.0[M+H] ⁺ 。

Step 2

To 6-bromo-2- (2-methoxyethoxy) pyridin-3-amine (431 mg,1.74 mmol) and DIPEA (0.45 mL,2.62 mmol) in CH ₂ Cl ₂ To the ice-cooled solution in (4 mL) was added 3- (4-fluorophenyl) -5-methyl-isoxazole-4-carbonyl chloride (1.74 mmol) in CH ₂ Cl ₂ (4 mL) of the solution (synthesized by the method described in step 1 of example 1 using the appropriate starting materials). The reaction was stirred for 18 hours, then water (10 mL) was added to the reaction and stirred for 5 minutes, then separated. By CH ₂ Cl ₂ The aqueous layer was extracted (2X 10 mL) and the combined organic extracts were dried over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Purification by flash silica column chromatography (elution with a 30-100% EtOAc/petroleum ether gradient) afforded N- [ 6-bromo-2- (2-methoxyethoxy) -3-pyridinyl ] as an off-white solid ]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (660 mg, 84%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.73(s,1H),8.12(d,J＝8.1Hz,1H),7.78(dd,J＝8.6,5.4Hz,2H),7.42-7.31(m,2H),7.26(d,J＝8.1Hz,1H),4.44-4.31(m,2H),3.66-3.57(m,2H),3.26(s,3H),2.65(s,3H).m/z 450.0,452.0[M+H] ⁺ 。

Step 3

N- [ 6-bromo-2- (2-methoxyethoxy) -3-pyridinyl]A mixture of 3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (360 mg,0.80 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (186 mg,0.84 mmol) and KF (142 mg,2.40 mmol) in 1, 4-dioxane (7 mL) and water (0.7 mL) was degassed for 5 min. Pd-118 (26 mg,0.040 mmol) was added and the reaction mixture was heated at 80℃for 16 hours. Pd-118 (26 mg,0.040 mmol) and 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (88 mg,0.40 mmol) were added and the reaction mixture was heated at 80℃for 1 hour. Volatiles were removed under reduced pressure and purified by flash silica column chromatography (with 0-100% EtOAc/CH ₂ Cl ₂ Gradient elution) to give N- [6- (2-aminopyrimidin-5-yl) -2- (2-methoxyethoxy) -3-pyridinyl ] as an off-white solid]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (224 mg, 57%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.63(s,1H),8.89(s,2H),8.19(d,J＝8.0Hz,1H),7.80(t,J＝7.1Hz,2H),7.49(d,J＝8.0Hz,1H),7.43-7.32(m,2H),6.97(s,2H),4.51(t,J＝4.9Hz,2H),3.70-3.61(m,2H),3.27(s,3H),2.67(s,3H).m/z 465.1[M+H] ⁺ 。

Example 218N- [6- (2-aminopyrimidin-5-yl) -2- (2-hydroxyethoxy) -3-pyridinyl ] -3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide

Step 1

To N- [ 6-bromo-2- (2-methoxyethoxy) -3-pyridinyl at-78 ℃C ]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (300 mg,0.67 mmol) (synthesized according to steps 1 and 2 in example 217) in CH ₂ Cl ₂ To the solution in (6 mL) was added boron tribromide over 2 minutes in CH ₂ Cl ₂ (1M) (0.70 mL,0.70 mmol) and the reaction mixture was warmed to room temperature and stirred for 19 hours. Addition of saturated aqueous NaHCO ₃ (20 mL) and using CH ₂ Cl ₂ (3X 10 mL) the mixture was extracted. The combined organic extracts were washed with brine (10 mL), over MgSO ₄ Dried, filtered and concentrated under reduced pressure. Purification by flash silica column chromatography (elution with a 30-100% EtOAc/petroleum ether gradient) afforded N- [ 6-bromo-2- (2-hydroxyethoxy) -3-pyridinyl ] as a colorless solid]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (166 mg, 51%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.68(s,1H),8.26(d,J＝8.1Hz,1H),7.76(dd,J＝8.2,5.7Hz,2H),7.42-7.30(m,2H),7.25(d,J＝8.1Hz,1H),4.76(t,J＝6.0Hz,1H),4.24(t,J＝4.9Hz,2H),3.65(q,J＝5.4Hz,2H),2.65(s,3H).m/z 458.0,459.9[M+Na] ⁺ 。

Step 2

N- [ 6-bromo-2- (2-hydroxyethoxy) -3-pyridinyl]-3- (4-fluorophenyl)A mixture of 5-methyl-isoxazole-4-carboxamide (166 mg,0.34 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (79 mg,0.36 mmol) and KF (61 mg,1.03 mmol) in 1, 4-dioxane (3 mL) and water (0.3 mL) was degassed for 5 min. Pd-118 (11 mg,0.017 mmol) was added and the reaction mixture was heated at 80℃for 16 hours. Pd-118 (11 mg,0.017 mmol) and 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (38 mg,0.17 mmol) were added and the reaction mixture was heated at 80℃for 1 hour. Volatiles were removed under reduced pressure and purified by flash silica column chromatography (with 0-100% EtOAc/CH ₂ Cl ₂ Gradient elution) to yield an off-white color. The material was triturated in water (50 mL) and the solid collected by vacuum filtration, washed with IPA and dried in a vacuum oven to give N- [6- (2-aminopyrimidin-5-yl) -2- (2-hydroxyethoxy) -3-pyridinyl as a colorless solid]-3- (4-fluorophenyl) -5-methyl-isoxazole-4-carboxamide (77 mg, 47%). ¹ H NMR(500MHz,DMSO-d ₆ )δ9.62(s,1H),8.88(s,2H),8.33(d,J＝8.1Hz,1H),7.78(t,J＝7.1Hz,2H),7.48(d,J＝8.1Hz,1H),7.37(t,J＝8.8Hz,2H),6.96(s,2H),4.77(t,J＝6.1Hz,1H),4.37(t,J＝5.0Hz,2H),3.69(q,J＝5.5Hz,2H),2.67(s,3H).m/z 451.1[M+H] ⁺ 。

Example 219N- [6- [4- (hydroxymethyl) phenyl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Synthesized as described in example 27, step 2, substituting 4-bromophenyl methanol for (5-bromopyridin-2-yl) methanol and heated at 45℃for 18 hours. Obtaining N6 4- (hydroxymethyl) phenyl as light brown cotton candy like solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (370.0 mg,75% yield). ¹ H NMR (500 MHz, chloroform-d) δ8.70 (d, j=8.2 hz, 1H), 7.96 (d, j=8.0 hz, 2H), 7.76 (s, 1H), 7.68-7.61 (m, 3H), 7.61-7.55 (m, 2H), 7.42 (d, j=8.2 hz, 2H), 7.35 (d, j=8.2 hz, 1H), 4.74 (d, j=5.4 hz, 2H), 3.72 (d, j=0.9 hz, 3H), 2.84 (d, j=0.9 hz, 3H), 1.74 (t, j=5.8 hz, 1H) m/z416.2[M+H] ⁺ 。

Example 220N- [6- (4-carboxyphenyl) -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

A suspension of example 219 (360.0 mg,0.9 mmol) and manganese (IV) oxide (850.0 mg,9.8 mmol) in DCM (20 mL) was heated in a sealed tube to 60℃for 2 hours. The filter cake was filtered through celite and washed with 80mL DCM. Concentrated to dryness to give N- [6- (4-formylphenyl) -2-methoxy-3-pyridinyl ] as a pale brown solid]-5-methyl-3-phenyl-isoxazole-4-carboxamide (330.0 mg,88% yield). ¹ H NMR (500 MHz, chloroform-d) δ10.05 (s, 1H), 8.77 (d, j=8.2 hz, 1H), 8.14 (d, j=8.1 hz, 2H), 7.93 (d, j=8.3 hz, 2H), 7.82 (s, 1H), 7.69-7.62 (m, 3H), 7.62-7.56 (m, 2H), 7.46 (d, j=8.2 hz, 1H), 3.74 (s, 3H), 2.86 (s, 3H) m/z 414.2[ m+h ]] ⁺ 。

Example 221 3- (4-fluorophenyl) -N- (6- (isoxazol-4-yl) -2-methoxypyridin-3-yl) -5-methylisoxazole-4-carboxamide

To the reaction vial was added 4-isoxazoleboronic acid pinacol ester (96.0 mg,0.49 mmol), potassium fluoride (87.0 mg,1.47 mmol), intermediate 12 (200.0 mg,0.49 mmol), 1, 4-dioxane (4.8 mL) and water (4.8 mL). The mixture was degassed with nitrogen and then bis [2- (di-t-butylphosphanyl) cyclopent-2, 4-dien-1-yl was added]Iron; palladium dichloride (32.0 mg,0.05 mmol) and the mixture was stirred at room temperature overnight. Another portion of pinacol 4-isoxazoleboronic acid ester (96.0 mg,0.49 mmol) and bis [2- (di-tert-butylphosphinoalkyl) cyclopent-2, 4-dien-1-yl were added ]Iron; palladium dichloride (32.0 mg,0.05 mmol) was used to degas the reaction and stirred at room temperature for 72 hours. The reaction was diluted with EtOAc, washed with water and brine in turn, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Passing the crude material through a flash silica column chromatography on an ISCO system0-90% petroleum ether/EtOAc gradient) to give 3- (4-fluorophenyl) -N- (6- (isoxazol-4-yl) -2-methoxypyridin-3-yl) -5-methylisoxazole-4-carboxamide (66 mg, 34% yield). ¹ H NMR (500 MHz, chloroform-d) delta 8.81 (s, 1H), 8.69 (d, J=8.1 Hz, 1H), 8.67 (s, 1H), 7.67 (s, 1H), 7.67-7.60 (m, 2H), 7.32-7.25 (m, 2H), 7.09-7.02 (m, 1H), 3.73 (s, 3H), 2.82 (s, 3H) m/z 393.2[ M-H ]] ^- 。

Example 222N- (6 '-amino-6-methoxy- [2,3' -bipyridin ] -5-yl) -3- (4-fluorophenyl) -5-methylisoxazole-4-carboxamide

Step 1

A solution of 2- (Boc-amino) -5-bromopyridine (200.0 mg,0.73 mmol), bis (pinacolato) diboron (241.7 mg,0.95 mmol) and potassium acetate (217.8 mg,2.20 mmol) in 1, 4-dioxane (2 mL) was degassed by purging with N2 for 5 min. Addition of [1,1' -bis (diphenylphosphine) ferrocene]Palladium (II) dichloride (26.9 mg,0.04 mmol) and the reaction mixture was sealed and heated at 100℃for 2 hours. The solvent was removed under reduced pressure and the resulting residue was purified by flash silica column chromatography (0-100% EtOAc/petroleum ether gradient) over ISCO system followed by trituration with petroleum ether to give tert-butyl (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamate (140 mg,60% yield) as a colorless solid. ¹ H NMR (500 mhz, cdcl 3) δ9.02 (s, 1H), 8.65 (dd, j=1.9, 1.0hz, 1H), 8.06 (dd, j=8.5, 1.8hz, 1H), 8.02 (dd, j=8.5, 1.1hz, 1H), 1.55 (s, 9H), 1.33 (s, 12H). m/z 183.0[ boric acid+H-tert-butyl ]] ⁺ 。

Step 2

Tert-butyl N- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridinyl]A mixture of carbamate (137.0 mg,0.43 mmol), intermediate 12 (173.8 mg,0.43 mmol) and potassium acetate (75.9 mg,1.28 mmol) in water (0.4 mL) and 1, 4-dioxane (4 mL) was treated with N ₂ And (5) degassing. Addition of bis [2- (di-tert-butylphosphino) cyclopent-2, 4-dien-1-yl ]]Iron; palladium dichloride (14.0 mg,0.02 mmol) and the reaction mixture was heated at 80℃for 18 hours.The solvent was removed under reduced pressure and the crude product was purified by flash silica column chromatography on an ISCO system (0-50% EtOAc/CH ₂ Cl ₂ Gradient) purification followed by trituration in EtOAc afforded tert-butyl (5- (3- (4-fluorophenyl) -5-methylisoxazole-4-carboxamide) -6-methoxy- [2,3' -bipyridine) as an off-white solid]-6' -yl) carbamate. (137 mg, 55%). ¹ H NMR(500MHz,DMSO)δ10.00(s,1H),9.57(s,1H),8.94(d,J＝2.7Hz,1H),8.37(dd,J＝8.8,2.5Hz,1H),8.33(d,J＝8.1Hz,1H),7.89(d,J＝8.8Hz,1H),7.78(t,J＝7.0Hz,2H),7.61(d,J＝8.1Hz,1H),7.45-7.35(m,2H),3.93(s,3H),2.66(s,3H),1.49(s,9H).m/z 520.2[M+H] ⁺ 。

Step 3

Tert-butyl N- [5- [5- [ [3- (4-fluorophenyl) -5-methyl-isoxazole-4-carbonyl ]]Amino group]-6-methoxy-2-pyridinyl]-2-pyridyl group]A solution of carbamate (137.0 mg,0.24 mmol) in DCM (2 mL) and trifluoroacetic acid (2 mL,26.1 mmol) was stirred at room temperature for 16 h. The solution was diluted with DCM (10 mL) and water (10 mL) and then 2M NaOH was added until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with DCM (2X 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give N- (6 '-amino-6-methoxy- [2,3' -bipyridine as a yellow solid ]-5-yl) -3- (4-fluorophenyl) -5-methylisoxazole-4-carboxamide (100 mg,95% yield). ¹ H NMR(500MHz,DMSO)δ9.51(s,1H),8.64(d,J＝2.4Hz,1H),8.20(d,J＝8.1Hz,1H),8.04(dd,J＝8.6,2.5Hz,1H),7.84-7.71(m,2H),7.48-7.33(m,3H),6.51(dd,J＝8.7,0.8Hz,1H),6.27(s,2H),3.90(s,3H),2.65(s,3H).m/z 420.1[M+H] ⁺ 。

Example 223N- (2 '-amino-4-methoxy- [2,5' -bipyrimidin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

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Step 1

A25% sodium methoxide solution in methanol (2.1 mL,9.1 mmol) was added dropwise to a solution of 2, 4-dichloropyrimidin-5-ylamine (1.00 g,6.1 mmol) in methanol (12.5 mL) and inThe mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and quenched with water. The organics were separated and the aqueous layer extracted with EtOAc. The combined organics were washed with water and dried (MgSO ₄ ) Concentration in vacuo afforded 2-chloro-4-methoxypyrimidin-5-amine as an orange solid (0.9 g,86% yield). ¹ H NMR (500 MHz, chloroform-d) delta 7.79 (s, 1H), 4.01 (s, 3H), 3.83 (d, J=29.6 Hz, 2H). M/z 160.0[ M+H ]] ⁺ 。

Step 2

To a stirred suspension of 2-chloro-4-methoxy-pyrimidin-5-amine (628.3 mg,3.94 mmol) and 5-methyl-3-phenyl-1, 2-oxazole-4-carboxylic acid (800.0 mg,3.94 mmol) in DCM (16 mL) was added HATU (1.80 g,4.72 mmol) followed by N-ethyldiisopropylamine (2.02 mL,11.81 mmol) and the reaction was aged overnight at room temperature. The solvent was removed under reduced pressure and DCM was added. Addition of NaHCO ₃ And the reaction was vigorously stirred and then passed through a hydrophobic frit. The solvent was removed under reduced pressure to give a solid. The resulting solid was purified by column chromatography (0-100% pe/EtOAc) to give N- (2-chloro-4-methoxypyrimidin-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (268 mg,19% yield) as a white solid. ¹ H NMR (500 MHz, chloroform-d) δ9.42 (s, 1H), 7.72-7.64 (m, 1H), 7.64-7.58 (m, 4H), 7.46 (s, 1H), 3.73 (s, 3H), 2.86 (s, 3H) m/z 345.0[ M+H ]] ⁺ 。

Step 3

To a 5mL microwave vial was added 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyrimidinamine (117.8 mg,0.53 mmol), N- (2-chloro-4-methoxy-pyrimidin-5-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (175.0 mg,0.51 mmol), then water (1 mL) and 1, 4-dioxane (4 mL) and after addition of potassium fluoride (90.0 mg,1.52 mmol) and bis [2- (di-tert-butylphosphinoalkyl) cyclopent-2, 4-dien-1-yl]Iron; the reaction mixture was degassed by bubbling N2 before palladium dichloride (16.6 mg,0.03 mmol). The reaction mixture was degassed for an additional 10 minutes and then stirred at 90 ℃ overnight. The reaction mixture was cooled to room temperature, then water and DCM were added. The organics were separated and the aqueous phase extracted with DCM (×3). The organics were combined, passed through a hydrophobic frit and concentrated in vacuo. The resulting solid was dissolved in DCM and loaded onto celite. By column chromatography (0-10% DCM-MeOH ladderDegree) purification of the crude mixture to give N- (2 '-amino-4-methoxy- [2,5' -bipyrimidine) as a beige solid]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (131 mg, 61%). ¹ H NMR (500 MHz, chloroform-d) δ9.48 (s, 1H), 9.18 (s, 2H), 7.63-7.57 (m, 1H), 7.57-7.51 (m, 4H), 7.48 (s, 1H), 6.31 (s, 2H), 3.68 (s, 3H), 2.79 (s, 3H) m/z 404.1[ M+H ]] ⁺ 。

Example 224N- [6- [4- (chloromethyl) phenyl ] -2-methoxy-3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

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To a stirred solution of example 219 (300.0 mg,0.72 mmol) in DCM (20 mL) was added thionyl chloride (0.11 mL,1.44 mmol) at 0deg.C. The reaction was stirred at 0℃for 3 hours. The mixture was diluted with saturated sodium bicarbonate and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- [6- [4- (chloromethyl) phenyl ] as a pale brown solid]-2-methoxy-3-pyridinyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (290 mg, 88% yield). ¹ H NMR (500 MHz, chloroform-d) 8.64 (d, J=8.2 Hz, 1H), 7.91-7.85 (m, 2H), 7.70 (s, 1H), 7.60-7.49 (m, 5H), 7.37 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 1H), 4.55 (s, 2H), 3.64 (s, 3H), 2.77 (s, 3H). M/z 434.2[ M+H ]] ⁺ 。

Example 225N- [ 2-methoxy-6- [4- (morpholinomethyl) phenyl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Example 224 (70.0 mg,0.16 mmol), potassium carbonate (44.6 mg,0.32 mmol), potassium iodide (53.9 mg,0.32 mmol) and morpholine (0.02 mL,0.19 mmol) were suspended in DMF (5 mL). The reaction mixture was stirred at 45 ℃ overnight. The mixture was diluted with DCM (10 mL) and extracted three times with saturated sodium bicarbonate (3X 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (elution with a gradient of 0-10% methanol in DCM) Purification gave N- [ 2-methoxy-6- [4- (morpholinomethyl) phenyl ] as an orange solid]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (52 mg,63% yield). ¹ H NMR(500MHz,CDCl ₃ )δ8.63(d,J＝8.2Hz,1H),7.89-7.80(m,2H),7.69(s,1H),7.59-7.54(m,3H),7.53-7.48(m,2H),7.33(s,2H),7.26(d,J＝8.2Hz,1H),3.72(d,J＝62.7Hz,4H),3.64-3.63(m,3H),3.47(s,2H),2.80-2.75(m,3H),2.48(s,4H).m/z 485.2[M+H] ⁺ 。

Example 226N- [ 2-methoxy-6- [4- (2-oxa-6-azaspiro [3.3] hept-6-ylmethyl) phenyl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Synthesized using a method similar to example 225 using 2-oxa-6-azaspiro [3.3]]Heptane replaces morpholine. Providing N- [ 2-methoxy-6- [4- (2-oxa-6-azaspiro [3.3] as a pale orange solid]Hept-6-ylmethyl) phenyl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (72 mg, 60% yield). ¹ H NMR(500MHz,CDCl ₃ )δ8.71(d,J＝8.2Hz,1H),7.95-7.90(m,2H),7.78(s,1H),7.69-7.63(m,3H),7.62-7.58(m,2H),7.37-7.30(m,3H),4.77(s,4H),3.72(s,3H),3.60(s,2H),3.43(s,4H),2.86(s,3H).m/z 497.3[M+H] ⁺ 。

Example 227N- (2-isopropoxy-6- (isoxazol-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

A microwave vial was charged with potassium fluoride (64.0 mg,1.08 mmol), bis [2- (di-tert-butylphosphinoalkyl) cyclopent-2, 4-dien-1-yl]Iron; palladium dichloride (25.0 mg,0.04 mmol) and N- (6-bromo-2-isopropoxy-3-pyridinyl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (see example 206, step 1) (150.0 mg,0.36 mmol). The mixture was solvated with 1, 4-dioxane (3 mL) and water (0.3 mL), degassed with nitrogen for 10 min, then 4-isoxazoleboronic acid pinacol was added Alcohol ester (72.0 mg,0.37 mmol). The mixture was again purged with nitrogen for 5 minutes and then heated to 50 ℃ overnight. The solvent was removed by rotary evaporation. The resulting crude brown solid was suspended in water and filtered, and the sinter was washed with additional water. The solid was subjected to silica gel column chromatography (petroleum ether: DCM, 1:0.fwdarw.0:1); removal of the solvent from the selected fractions resulted in isolation of the desired product as a white solid which was triturated in MeOH to N- (2-isopropoxy-6- (isoxazol-4-yl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide prior to final analysis. ¹ H NMR (500 MHz, chloroform-d) δ8.81 (s, 1H), 8.74 (d, j=8.1 hz, 1H), 8.67 (s, 1H), 7.76 (s, 1H), 7.72-7.65 (m, 2H), 7.63-7.52 (m, 2H), 7.07 (d, j=8.1 hz, 1H), 5.23 (hept, j=6.0 hz, 1H), 2.82 (s, 3H), 1.06 (d, j=6.2 hz, 6H). 405.2[ M+H ]] ⁺ 。

Example 228N- [ 2-methoxy-6- [4- (3-oxa-7-azabicyclo [3.3.1] non-7-ylmethyl) phenyl ] -3-pyridinyl ] -5-methyl-3-phenyl-isoxazole-4-carboxamide

Synthesized using a method similar to example 225 using 3-oxa-7-azabicyclo [3.3.1]Nonane substituted morpholines. Providing N- [ 2-methoxy-6- [4- (3-oxa-7-azabicyclo [3.3.1] as a colorless solid]Non-7-ylmethyl) phenyl ]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (70 mg, 55% yield). ¹ H NMR(500MHz,CDCl ₃ )δ8.71(d,J＝8.2Hz,1H),8.00-7.87(m,2H),7.78(s,1H),7.69-7.63(m,3H),7.60(dd,J＝8.0,6.4Hz,2H),7.47(s,2H),7.36(d,J＝8.2Hz,1H),4.08-3.90(m,2H),3.80(d,J＝10.8Hz,2H),3.73(s,3H),3.57(d,J＝11.0Hz,2H),3.00(d,J＝11.4Hz,2H),2.86(s,3H),2.62-2.22(m,2H),1.89-1.58(m,4H).m/z 525.3[M+H] ⁺ 。

Example 229N- (2-isoxazol-4-yl-4-methoxy-pyrimidin-5-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide

4-isoxazoleboronic acid pinacol ester (75 mg,0.38 mmol), N- (2-chloro-4-methoxy-pyrimidin-5-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide (125 mg,0.36 mmol) (intermediate 3 from example 3), 1, 4-dioxane (2.9 mL) and water (0.70 mL) were charged into a microwave vial and sealed. The mixture was purged with nitrogen for 5 minutes, then potassium fluoride (65 mg,1.1 mmol) and bis [2- (di-tert-butylphosphinoalkyl) cyclopent-2, 4-dien-1-yl were added]Iron; palladium dichloride (Pd 118) (12 mg,0.02 mmol). The mixture was resealed and purged with nitrogen for five minutes and then heated to 90 ℃ overnight. The cooled reaction mixture was quenched with water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude material thus separated was subjected to silica gel column chromatography (eluent DCM: meOH,1:0→95:5). The material thus separated was again subjected to silica gel column chromatography (eluent, petroleum ether: etOAc: DCM: meOH, 1:0:0:0.fwdarw.0:1:0:0.fwdarw.0:0:1:0.fwdarw.0:0:95:5). The fractions identified as containing the desired product were concentrated by rotary evaporation and the material thus isolated was triturated in MeOH and filtered to give the desired product N- (2-isoxazol-4-yl-4-methoxy-pyrimidin-5-yl) -5-methyl-3-phenyl-isoxazole-4-carboxamide as a brown solid (18 mg,0.0477mmol,13.156% yield). 1H NMR (500 MHz, DMSO-d 6) δ9.95 (s, 1H), 9.13 (s, 1H), 8.93 (s, 1H), 7.70-7.64 (m, 2H), 7.59-7.50 (m, 4H), 4.01 (s, 3H), 2.63 (s, 3H). m/z 378.2[ M+H ] ] ⁺ 。

Example 230N- (6-methoxy-6 '- (morpholinomethyl) - [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

Step 1-Synthesis of example 27-N- (6 '- (hydroxymethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

N- [ 2-methoxy-6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3-pyridinyl]A suspension of 5-methyl-3-phenyl-isoxazole-4-carboxamide (intermediate 7) (1500 mg,3.45 mmol), (5-bromopyridin-2-yl) methanol (777.51 mg,4.14 mmol) and potassium fluoride (611.03 mg,10.34 mmol) in dioxane/water (24:6 mL) was purged with nitrogen for 5 min. Then bis [2- (di-tert-butylphosphinoalkyl) cyclopent-2, 4-dien-1-yl was added]Iron palladium dichloride (225.29 mg,0.34 mmol) and the mixture was purged with nitrogen for an additional 5 minutes. The vial was sealed and the suspension was stirred overnight at 45 ℃. The solution was diluted with EtOAc (100 mL) and washed with water (2 x 100 mL); the organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography using ISCO system (24 g silica, 0-5% MeOH gradient in DCM). The fractions containing the product were combined and concentrated to give N- (6 '- (hydroxymethyl) -6-methoxy- [2,3' -bipyridine as a light brown solid ]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (example 27) (510 mg,1.1635mmol,33.762% yield). 1H NMR (500 MHz, CDCl) ₃ )δ9.26-9.08(m,1H),8.77(d,J＝8.1Hz,1H),8.34-8.27(m,1H),7.81(s,1H),7.69-7.64(m,3H),7.63-7.59(m,2H),7.38(d,J＝8.1Hz,2H),4.86(s,2H),3.73(s,3H),2.86(s,3H)。ACQUITYBEH C18 1.7μm：Rt＝1.74min；m/z 417.3[M+H] ⁺ 。

Step 2 Synthesis of intermediate 16-N- (6 '- (chloromethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

To a stirred solution of N- (6 '- (hydroxymethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (example 27) (500 mg,1.2 mmol) in DCM (20 mL) at 0 ℃ was added thionyl chloride (0.18 mL,2.4 mmol). The reaction was stirred at 0 ℃ for 2 hours. The mixture was diluted with DCM (20 mL) and washed three times with saturated sodium bicarbonate (3×20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- (6 '- (chloromethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (intermediate 16) as a light brown solid (430 mg,0.9394mmol,78.236% yield). 1H NMR (500 MHz, CDCl 3) δ9.09 (t, J=6.8 Hz, 1H), 8.69 (t, J=7.0 Hz, 1H), 8.20 (t, J=7.0 Hz, 1H), 7.73 (t, J=6.9 Hz, 1H), 7.63-7.41 (m, 6H), 7.36-7.25 (m, 1H), 4.79-4.54 (m, 2H), 3.76-3.52 (m, 3H), 2.91-2.71 (m, 3H).

ACQUITYBEH C18 1.7μm：Rt＝1.96min；m/z 433.2[M+H]+。

Step 3

N- (6 '- (chloromethyl) -6-methoxy- [2,3' -bipyridine ]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (intermediate 16) (100 mg,0.23 mmol), morpholine (0.02 mL,0.28 mmol), potassium carbonate (64.49 mg,0.46 mmol) and potassium iodide (76.81 mg,0.46 mmol) were suspended in DMF (5 mL) and the reaction stirred at 45 ℃ for 3 hours. The mixture was diluted with DCM (20 mL) and washed with saturated sodium bicarbonate (3×20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by ISCO flash column chromatography (4 g silica, 0-5% methanol/DCM gradient). The fractions containing the product were combined and concentrated to N- (6-methoxy-6 '- (morpholinomethyl) - [2,3' -bipyridine) as a pale orange solid]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (95 mg,0.1917mmol,83.386% yield). 1H NMR (500 MHz, DMSO). Delta.9.49 (s, 1H), 9.17 (d, J=2.3 Hz, 1H), 8.38 (dd, J=8.2, 2.4Hz, 2H), 7.70 (dd, J=26.2, 7.5Hz, 3H), 7.60-7.49 (m, 4H), 3.92 (s, 3H), 3.65 (s, 2H), 3.61 (t, J=4.7 Hz, 4H), 2.67 (s, 3H), 2.44 (s, 4H). ACQUITYBEH C18 1.7μm：Rt＝1.75min；m/z 486.3[M+H]+。

Example 231N- (6 '- ((2-oxa-6-azaspiro [3.3] hept-6-yl) methyl) -6-methoxy- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

N- (6 '- (chloromethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (intermediate 16) (100 mg,0.23 mmol), potassium carbonate (64.49 mg,0.46 mmol), potassium iodide (76.81 mg,0.46 mmol) and 2-oxa-6-azaspiro [3.3] heptane (27.35 mg,0.28 mmol) were suspended in DMF (5 mL).

The reaction was stirred at 45℃for 2 hours. The mixture was diluted with DCM (20 mL) and washed with saturated sodium bicarbonate (3×20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ISCO system (4 g silica, 0-5% methanol/DCM gradient). The fractions containing the product were combined and concentrated to give N- (6' - ((2-oxa-6-azaspiro [3.3 ]) as an orange solid]Hept-6-yl) methyl) -6-methoxy- [2,3' -bipyridine]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (88 mg,0.1733mmol,75.376% yield). 1H NMR (500 MHz, DMSO). Delta.9.49 (s, 1H), 9.14 (dd, J=2.3, 0.8Hz, 1H), 8.50-8.26 (m, 2H), 7.69 (dd, J=29.8, 7.5Hz, 3H), 7.61-7.49 (m, 3H), 7.45-7.39 (m, 1H), 4.63 (s, 4H), 3.92 (s, 3H), 3.67 (s, 2H), 3.40 (s, 4H), 2.67 (s, 3H). ACQUITYBEH C18 1.7μm：Rt＝1.71min；m/z 498.3[M+H]+。

Example 232N- (6 '- ((3-oxa-7-azabicyclo [3.3.1] non-7-yl) methyl) -6-methoxy- [2,3' -bipyridin ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

N- (6 '- (chloromethyl) -6-methoxy- [2,3' -bipyridyl ] -5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (intermediate 16) (100 mg,0.23 mmol), potassium carbonate (64.49 mg,0.46 mmol), potassium iodide (76.81 mg,0.46 mmol) and 3-oxa-7-azabicyclo [3.3.1] nonane (35.09 mg,0.28 mmol) were suspended in DMF (5 mL).

The reaction was stirred at 45℃for 2 hours. The mixture was washed with DCM (20mL) was diluted and washed with saturated sodium bicarbonate (3 x 20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by ISCO flash column chromatography (4 g silica, 0-5% methanol/DCM gradient). The fractions containing the product were combined and concentrated to give N- (6' - ((3-oxa-7-azabicyclo [ 3.3.1) as an off-white solid]Non-7-yl) methyl) -6-methoxy- [2,3' -bipyridine]-5-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (77 mg,0.1436mmol,62.434% yield). 1HNMR (500 MHz, DMSO). Delta.9.48 (s, 1H), 9.15 (d, J=2.2 Hz, 1H), 8.40 (dd, J=8.2, 2.3Hz, 2H), 7.72 (d, J=7.0 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.60-7.54 (m, 3H), 3.92 (s, 3H), 3.82 (d, J=10.9 Hz, 2H), 3.68 (dt, J=11.1, 2.3Hz, 2H), 3.63-3.54 (m, 2H), 2.94 (d, J=10.7 Hz, 2H), 2.68 (s, 3H), 2.41 (d, J=10.8 Hz, 2H), 1.78 (d, J=12.0 Hz, 1H), 1.72 (s, 2H), 1.57 (d, J=12.1 Hz, 1H). ACQUITYBEH C18 1.7μm：Rt＝1.85min；m/z526.3[M+H]+。

Example 233N- (2-methoxy-6- (4- ((tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) methyl) phenyl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide

N- (6- (4- (chloromethyl) phenyl) -2-methoxypyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (example 224) (100 mg,0.23 mmol), potassium carbonate (96.95 mg,0.69 mmol), potassium iodide (76.98 mg,0.46 mmol) and hexahydro-1H-furo [3, 4-c) ]Pyrrole hydrochloride (41.38 mg,0.28 mmol) was suspended in DMF (5 mL) and the reaction was stirred at 45℃for 3 h. The mixture was diluted with DCM (15 mL) and washed with saturated sodium bicarbonate (3×20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by ISCO flash column chromatography (4 g silica, 0-5% methanol/DCM gradient). The fractions containing the product were combined and concentrated to give N- (2-methoxy-6- (4- ((tetrahydro-1H-furo [3, 4-c)) as an orange solid]Pyrrole-5 (3H) -yl) methyl) phenyl) pyridin-3-yl) -5-methyl-3-phenylisoxazole-4-carboxamide (75 m)g,0.1395mmol,60.548% yield). 1H NMR (500 MHz, DMSO). Delta.9.45 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.02 (d, J=7.8 Hz, 2H), 7.78-7.70 (m, 2H), 7.57 (dtd, J=7.4, 5.4,5.0,3.0Hz, 4H), 7.40 (d, J=7.9 Hz, 2H), 3.91 (s, 3H), 3.72 (d, J=7.2 Hz, 2H), 3.59 (s, 2H), 3.48-3.36 (m, 2H), 2.72 (s, 2H), 2.67 (s, 3H), 2.54 (d, J=8.6 Hz, 2H), 2.43-2.24 (m, 2H). ACQUITYBEH C18 1.7μm：Rt＝1.67min；m/z 511.3[M+H] ⁺ 。

Biological data

Compounds shown in table 1 in vitro radioligand binding assays and in vitro alpha 5-GABA described herein _A The R relative efficacy assay showed the following activities:

TABLE 1

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_A In vitro electrophysiological recording assay (alpha 5-GABAR relative efficacy)

The expression of α5β3γ2gaba was recorded on the QPatch system using the in vitro electrophysiological recording assay described herein before and after addition of the compound of example 1 (1 μm) _A Primary whole cell current trace of the same cell of the recipient. FIG. 1 shows that the same concentration of GABA induces less current in the presence of the compound of example 1, compared to alpha 5-GABA _A The expected effect of R NAM was consistent.

Electrophysiology-long-term potentiation assay of hippocampal slices

Figure 2 shows the rescue of etomidate-mediated long-term potentiation (LTP) defects by the compound of example 1 in mouse hippocampal brain sections.

LTP is a measure of the increase in synaptic efficacy and is induced using a standard paradigm involving 4-theta burst stimulation (4-TBS). A plot of fEPSP slope (expressed as% of control fEPSP prior to 4-TBS) versus time is shown in FIG. 2A. After recording fEPSP (1/30 seconds), 4-TBS was delivered at zero time to induce control LTP (n=8). The extent of LTP was reduced by etomidate (3 μm; n=17), but was saved by co-addition of the compound of example 1 (1 μm; n=6).

The extent of LTP determined within 50-60 minutes after 4-TBS delivery is shown in the bar graph of FIG. 2B. Etomidate significantly reduced the fEPSP slope at 50-60 minutes compared to the control. Incubation of the sections with the compound of example 1 significantly increased the fEPSP slope (using one-way ANOVA with the Tukey test afterwards, p < 0.05) so that there was no difference in the extent of LTP from the control.

In vivo brain receptor occupancy assay

Evaluation of the Compounds of example 1 on rat brain alpha 5-GABA in the in vivo brain receptor occupancy assay described herein _A Occupancy of the R binding site. For doses of the compound of example 1 in the range of 3 to 30mg/kg (oral), rat brain α5-GABA _A R (i.e. in vivo [ in vivo ] ³ H]Inhibition of L655,708 binding) is dose dependent, estimated to occupy brain α5gaba at a dose of 10mg/kg _A 77% of the receptors (FIG. 3).

Further embodiment

The invention is further illustrated by the following numbered clauses:

p1. a compound of formula (I):

wherein the method comprises the steps of

Ring a is selected from: a1, A2 and A3:

R ¹ selected from: phenyl and 5-or 6-membered heteroaryl, wherein R ¹ Optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 ；

R ² Selected from: H. halo, C _1-4 Alkyl and C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 ，

Wherein the C is _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a3 、-SR ^a3 and-NR ^a3 R ^b3 ；

R ³ Selected from: c (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 ；

R ⁴ And R is ⁵ Independently selected from: H. c (C) _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl and C _3-6 cycloalkyl-C _1-3 Alkyl-;

R ⁶ Selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ³ 、R ⁴ 、R ⁵ Or R is ⁶ Any C in any of (3) _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 ；

X ¹ 、X ² And X ³ Independently selected from: n and CR ⁷ ；

R ⁷ Independently at each occurrence selected from: H. halo, -CN, 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 is ⁹ Each independently selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ⁷ 、R ⁸ Or R is ⁹ Any C in any of (3) _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 ；

Ring B is selected from the group consisting of optionally one or more R ¹⁰ Substituted C _6-10 Aryl and 5-to 12-membered heteroaryl, wherein when ring B is heteroaryl, ring B passes through the aryl of the heteroarylThe ring atoms in the ring are bonded to the remainder of the compound of formula (I);

R ¹⁰ independently at each occurrence selected from: 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 ，

Wherein said C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with 1 or more R ¹² Substitution;

R ¹¹ independently selected from: H. c (C) _1-6 Alkyl and C _1-6 Haloalkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more R ¹³ Substitution;

Q ¹ independently at each occurrence selected from: c (C) _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl-, 4-to 7-membered heterocyclyl-C _1-3 Alkyl-, phenyl-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-,

wherein 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-optionally substituted with one or more R ¹⁴ Substituted, and

wherein the phenyl, phenyl-C _1-3 Alkyl, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁵ Substitution;

L ¹ is a bond or is selected from-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 -；

R ¹² 、R ¹³ And R is ¹⁴ Each occurrence is independently selected from: 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 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a9 、-NR ^a9 R ^b9 and-SO ₂ R ^a9 ；

R ¹⁵ Independently at each occurrence selected from: 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 NR ^a10 R ^b10 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-NR ^a5 R ^b5 and-SO ₂ R ^a5 ；

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 And R is ^b10 Independently at each occurrence selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

or any-NR within a substituent ^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 A 4-to 6-membered heterocyclyl can be formed, wherein the 4-to 6-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl and C _1-4 A haloalkyl group.

P2. the compound of clause P1, wherein R ² Is C _1-4 Alkyl groups, e.g. where R ² Is methyl.

P3. the compound of any preceding clause, wherein R ¹ The method comprises the following steps:

wherein:

X ₄ is CH or N; and is also provided with

R ¹⁰¹ Is H or halo;

optionally, wherein R ¹ Selected from:

p4. the compound of clause P1, wherein ring a has a structure selected from:

p5. the compound of any preceding clause, wherein X ₁ And X ₂ Is CH, optionally wherein X ₃ Is N or CH.

P6. the compound of any preceding clause, wherein X ₃ Is N.

P7. the compound of any one of clauses P1 to P4, wherein X ₂ And X ₃ Is N and X ₁ Is CR (CR) ⁷ Optionally wherein X ¹ Is CH.

P8. the compound of any preceding clause, wherein R ³ Selected from: -OR ⁴ and-NR ⁵ R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein:

R ⁴ selected from: optionally by-NR ^a4 R ^b4 Substituted C _3-6 Cycloalkyl, C _1-4 Alkyl and C _2-4 An alkyl group;

R ^a4 and R is ^b4 Independently selected from: h and C _1-4 An alkyl group; and is also provided with

R ⁵ And R is ⁶ Independently selected from: h and C _1-4 An alkyl group.

P9. the compound of any one of clauses P1 to P7, wherein:

(i)R ³ is-OR ⁴ Optionally wherein R ⁴ Selected from: c (C) _1-4 Alkyl and C _3-6 Cycloalkyl; or alternatively

(ii)R ³ Selected from: methoxy group, Or alternatively

(iii)R ³ Selected from: methoxy andor alternatively

(iv)R ³ Is methoxy.

P10. the compound of any one of clauses P1 to P9, wherein:

(i) Ring B' is selected from: phenyl and a monocyclic or bicyclic 5-to 12-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ Substitution; or alternatively

(ii) Ring B is selected from: 5-or 6-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ Substitution; or alternatively

(iii) Ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 9-or 10-membered heteroaryl;

optionally, wherein the heteroaryl in any of (i), (ii) and (iii) contains 1 ring nitrogen atom and optionally 1 to 3 ring heteroatoms selected from O, S and N.

P11. the compound of any one of clauses P1 to P9, wherein ring B is selected from:

wherein p' is 0 or 1;

p "is 0, 1 or 2;

p' "is 0, 1, 2 or 3; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I).

P12. the compound of any one of clauses P1 to P11, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring carbon atom in an aromatic ring in ring B.

P13. the compound of any one of clauses P1 to P11, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring nitrogen atom in an aromatic ring in ring B.

P14. the compound of any one of clauses P1 to P9, wherein:

(i) Ring B is:

wherein p "is 0, 1 or 2, optionally wherein p'" is 0; or alternatively

(ii) Ring B is selected from:

wherein p is 0, 1, 2 or 3, and wherein +.>Represents an attachment point to the remainder of the compound of formula (I); or alternatively

(iii) Ring B is selected from:

wherein p is 0 or 1; and is also provided withRepresents an attachment point to the remainder of the compound of formula (I); optionally, wherein p is 1.

P15. the compound of any preceding clause, wherein:

(i)R ¹⁰ independently at each occurrence selected from: 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 -；

Wherein Q is ¹⁰² Selected from 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

wherein the 4-to 6-membered heterocyclyl is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is selected from: pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, C _1-4 Alkyl, -OR ^a10 and-NR ^a10 R ^b10 ；

L ¹⁰² Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 -; or alternatively

(ii)R ¹⁰ Selected from: -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 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group; or alternatively

(iii)R ¹⁰ Selected from: -NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group; or alternatively

(iv)R ¹⁰ Selected from: fluorine, chlorine, cyano, nitro, oxo, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, ammoniaRadicals, -NH (Me), -N (Me) ₂ 、 />

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P16. the compound of any one of clauses P1 to P9, wherein ring B is selected from:

p17. the compound of clause 1, wherein the compound is selected from the list of compounds 1 in the specification, or a pharmaceutically acceptable salt thereof.

P18. a pharmaceutical composition comprising a compound of any one of clauses P1 to P17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

P19. the compound of any one of clauses P1 to P17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause P8, for use as a medicament.

P20. the compound of any one of clauses P1 to P17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause P18, for use in the prevention or treatment of a disease caused by alpha 5-GABA _A Receptor mediated diseases or medical disorders.

P22. the compound of any one of clauses P1 to P17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause P18, for use in the prevention or treatment of a disease associated with a 5-GABA _A Receptor-mediated diseases or medical disorders related cognitive functionCan be used in disorders.

P22A method for preventing or treating a disorder caused by alpha 5-GABA in a subject _A A method of R-mediated disease or medical disorder, comprising administering to the subject an effective amount of a compound of any one of clauses P1 to P17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause P18.

P23. the compound used as described in clause P20 or clause P21, or the method as described in clause P22, wherein the compound is a compound prepared from alpha 5-GABA _A The R-mediated disease or medical disorder is selected from: alzheimer's disease, parkinson's disease, huntington's disease, cognitive dysfunction (e.g., cognitive dysfunction associated with chemotherapy, narcotics, bacterial or viral infections (e.g., HIV), memory deficits, age-related cognitive dysfunction (e.g., mild cognitive impairment, MCI), bipolar disorder, autism, down's syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, amyotrophic Lateral Sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorders, schizophreniform disorders, substance-induced psychotic disorders or paranoid disorders), psychosis, post-traumatic stress disorders, anxiety disorders, generalized anxiety disorders, panic disorders, delusional disorders, obsessive-compulsive disorders, acute stress disorders, drug addiction, alcohol disorders (e.g., alcohol addiction), drug withdrawal symptoms, movement disorders, restless leg syndrome, cognitive deficit disorder, multi-infarct dementia, vascular dementia, mood disorders, depression, neuropsychiatric conditions, attention-deficit/hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive dysfunction associated with trauma or dysfunction associated with brain injury, cognitive dysfunction associated with brain dysfunction and cognitive dysfunction;

Optionally, a compound as defined in any one of clauses P1 to P17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in clause P18, for use in the treatment or prevention of post-operative cognitive dysfunction, such as anesthesia-induced cognitive dysfunction.

P24. the compound of any one of clauses P1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause P18For use in the prevention or treatment of disorders mediated by alpha 5-GABA _A Rs-mediated neurological or neuropsychiatric disorders (e.g., treating or preventing cognitive dysfunction associated with a neurological or neuropsychiatric disorder);

optionally wherein the neurological disorder is a neurological developmental disorder (e.g., attention deficit disorder (ADHD), down's syndrome, learning disorder, cerebral palsy, autism, or speech disorder);

optionally wherein the neurodegenerative disorder (e.g., alzheimer's disease, dementia, parkinson's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS) or creutzfeldt-jakob disease (CJD));

for example, wherein the neurological disorder is huntington's disease.

P25. the compound of any one of clauses P1 to P17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause P18, for use in the treatment or prevention of a psychotic and/or neurological symptom (particularly cognitive dysfunction) caused by or associated with: viral or bacterial infection.

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

Ring a is selected from: a1, A2 and A3:

R ¹ selected from: phenyl and 5-or 6-membered heteroaryl, wherein R ¹ Optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 ；

R ² Selected from: H. halo, C _1-4 Alkyl and C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 ，

Wherein the C is _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a3 、-SR ^a3 and-NR ^a3 R ^b3 ；

R ³ Selected from: c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-;

R ⁴ and R is ⁵ Independently selected from: H. c (C) _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl-, 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms-C _1-3 Alkyl-;

R ⁶ selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ³ 、R ⁴ 、R ⁵ Or R is ⁶ Any C in any of (3) _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 ；X ¹ 、X ² And X ³ Independently selected from: n and CR ⁷ ；

R ⁷ Independently at each occurrence selected from: H. halo, -CN, 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 is ⁹ Each independently selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ⁷ 、R ⁸ Or R is ⁹ Any of (3)Any C of (2) _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 ；

Ring B is selected from the group consisting of optionally one or more R ¹⁰ Substituted C _6-10 Aryl and 5-to 12-membered heteroaryl, wherein when ring B is heteroaryl, ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the aromatic ring of the heteroaryl;

R ¹⁰ independently at each occurrence selected from: 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 ，

Wherein said C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with 1 or more R ¹² Substitution;

R ¹¹ independently selected from: H. c (C) _1-6 Alkyl and C _1-6 Haloalkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more R ¹³ Substitution;

Q ¹ independently at each occurrence selected from: c (C) _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-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-,

wherein said C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl-, 4-to7-membered heterocyclyl and 4-to 7-membered heterocyclyl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁴ Substituted, and

wherein the phenyl, phenyl-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁵ Substitution;

L ¹ is a bond or is selected from-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 -；

R ¹² 、R ¹³ And R is ¹⁴ Each occurrence is independently selected from: 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 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a9 、-NR ^a9 R ^b9 and-SO ₂ R ^a9 ；

R ¹⁵ Independently at each occurrence selected from: 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 NR ^a10 R ^b10 ；

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-NR ^a11 R ^b11 and-SO ₂ R ^a11 ；

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 is ^b11 Independently at each occurrence selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

or any-NR within a 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 A 4-to 6-membered heterocyclyl can be formed, wherein the 4-to 6-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

the conditions are (i) and (ii):

(i) When ring A is A2 and R ² When H is H, then R ³ not-NR ⁵ R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

(ii) The compound of formula (I) is not

2. The compound of clause 1, wherein R ² Is C _1-4 Alkyl groups, e.g. where R ² Is methyl.

3. The compound of any preceding clause, wherein R ¹ The method comprises the following steps:

wherein:

X ₄ is CH or N; and is also provided with

R ¹⁰¹ Is H or halo;

optionally, wherein R ¹ Selected from:

4. the compound of clause 1, wherein ring a has a structure selected from the group consisting of:

5. the compound of any preceding clause, wherein X ₁ And X ₂ Is CH, optionally wherein X ₃ Is N or CH.

6. The compound of any preceding clause, wherein X ₃ Is N.

7. The compound of any one of clauses 1 to 4, wherein X ₂ And X ₃ Is N and X ₁ Is CR (CR) ⁷ Optionally wherein X ¹ Is CH.

8. The compound of any preceding clause, wherein R ³ Selected from: -OR ⁴ and-NR ⁵ R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein:

R ⁴ selected from: optionally by-NR ^a4 R ^b4 Substituted C _3-6 Cycloalkyl, C _1-4 Alkyl and C _2-4 An alkyl group;

R ^a4 and R is ^b4 Independently selected from: h and C _1-4 An alkyl group; and is also provided with

R ⁵ And R is ⁶ Independently selected from: h and C _1-4 An alkyl group.

9. As in any one of clauses 1 to 7A compound of claim, wherein R ³ is-OR ⁴ Optionally wherein R ⁴ Selected from: c (C) _1-4 Alkyl and C _3-6 Cycloalkyl groups.

10. The compound of any one of clauses 1 to 7, wherein:

(i)R ³ selected from: methoxy group, Or alternatively

(ii)R ³ Selected from: methoxy group, Or->

(iii)R ³ is-OR ⁴ Wherein R is ⁴ Is a 4-to 6-membered heterocyclic group containing 1 epoxy atom or a 4-to 6-membered heterocyclic group containing 1 epoxy atom-C _1-3 Alkyl radicals, e.g. R ³ The method comprises the following steps:

11. the compound of any one of clauses 1 to 7, wherein R ³ Selected from: methoxy and

12. the compound of any one of clauses 1 to 7, wherein R ³ Is methoxy.

13. The compound of any one of clauses 1 to 12, wherein ring B is selected from: phenyl and a monocyclic or bicyclic 5-to 12-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ And (3) substitution.

14. The compound of any one of clauses 1 to 12, wherein ring B is selected from: 5-or 6-membered heteroaryl, each of which isOptionally by one or more R ¹⁰ And (3) substitution.

15. The compound of any one of clauses 1 to 12, wherein ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 9-or 10-membered heteroaryl.

16. The compound of any one of clauses 13 to 15, wherein the heteroaryl contains 1 ring nitrogen atom and optionally 1 to 3 ring heteroatoms selected from O, S and N.

17. The compound of any one of clauses 1 to 12, wherein ring B is selected from:

wherein p' is 0 or 1;

p "is 0, 1 or 2;

p' "is 0, 1, 2 or 3; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I).

18. The compound of any one of clauses 1 to 17, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring carbon atom in an aromatic ring in ring B.

19. The compound of any one of clauses 1 to 17, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring nitrogen atom in an aromatic ring in ring B.

20. The compound of any one of clauses 1 to 12, wherein ring B is:

wherein p "is 0, 1 or 2, optionally wherein p'" is 0.

21. The compound of any one of clauses 1 to 12, wherein ring B is selected from:

wherein p is 0, 1, 2 or 3, and wherein +.>Represents the point of attachment to the remainder of the compound of formula (I).

22. The compound of any one of clauses 1 to 12, wherein ring B is selected from:

wherein p is 0 or 1; and is also provided withRepresents an attachment point to the remainder of the compound of formula (I); optionally, wherein p is 1.

23. The compound of any preceding clause, wherein R ¹⁰ Independently at each occurrence selected from: 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 -；

Wherein Q is ¹⁰² Selected from 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

wherein the 4-to 6-membered heterocyclyl is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is selected from: pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, C _1-4 Alkyl, -OR ^a10 and-NR ^a10 R ^b10 ；

L ¹⁰² Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 -。

24. The compound of any one of clauses 1 to 22, wherein R ¹⁰ Selected from: -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 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group.

25. The compound of any one of clauses 1 to 22, wherein R ¹⁰ Selected from: -NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group.

26. The compound of any one of clauses 1 to 22, wherein R ¹⁰ Selected from: fluoro, chloro, cyano, nitro, oxo, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, amino, -NH (Me), -N (Me) ₂ 、

/>

/>

27. The compound of any one of clauses 1 to 12, wherein ring B is selected from:

optionally, wherein ring B is

28. The compound of clause 1, wherein the compound is selected from compound list 1 in the specification, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound of any one of clauses 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. The compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 29, for use as a medicament.

31. The compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 29, for use in the prevention or treatment of a disorder consisting of alpha 5-GABA _A Receptor mediated diseases or medical disorders.

32. The compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 29, for use in preventing or treating a disease associated with alpha 5-GABA _A Receptor mediumFor use in cognitive dysfunction associated with a disease or medical disorder.

33. Prevention or treatment of a disease caused by alpha 5-GABA in a subject _A A method of R-mediated disease or medical disorder, comprising administering to the subject an effective amount of a compound of any one of clauses 1-28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause 29.

34. The compound for use of clause 31 or clause 32, or the method of clause 33, wherein the compound is a peptide consisting of alpha 5-GABA _A The R-mediated disease or medical disorder is selected from: alzheimer's disease, parkinson's disease, huntington's disease, cognitive dysfunction (e.g., cognitive dysfunction associated with chemotherapy, narcotics, bacterial or viral infections (e.g., HIV), memory deficits, age-related cognitive dysfunction (e.g., mild cognitive impairment, MCI), bipolar disorder, autism, down's syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, amyotrophic Lateral Sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorders, schizophreniform disorders, substance-induced psychotic disorders or paranoid disorders), psychosis, post-traumatic stress disorders, anxiety disorders, generalized anxiety disorders, panic disorders, delusional disorders, obsessive-compulsive disorders, acute stress disorders, drug addiction, alcohol disorders (e.g., alcohol addiction), drug withdrawal symptoms, movement disorders, restless leg syndrome, cognitive deficit disorder, multi-infarct dementia, vascular dementia, mood disorders, depression, neuropsychiatric conditions, attention-deficit/hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive dysfunction associated with trauma or dysfunction associated with brain injury, cognitive dysfunction associated with brain dysfunction and cognitive dysfunction;

Optionally, a compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause 29, for use in treating or preventing post-operative cognitive dysfunction, such as anesthesia-induced cognitive dysfunction.

35. The compound of any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, or asThe pharmaceutical composition of clause 29, for use in the prevention or treatment of a disorder mediated by alpha 5-GABA _A Rs-mediated neurological or neuropsychiatric disorders (e.g., treating or preventing cognitive dysfunction associated with a neurological or neuropsychiatric disorder);

optionally wherein the neurological disorder is a neurological developmental disorder (e.g., attention deficit disorder (ADHD), down's syndrome, learning disorder, cerebral palsy, autism, or speech disorder);

optionally wherein the neurodegenerative disorder (e.g., alzheimer's disease, dementia, parkinson's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS) or creutzfeldt-jakob disease (CJD));

for example, wherein the neurological disorder is huntington's disease.

36. A compound according to any one of clauses 1 to 28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to clause 29, for use in the treatment or prevention of a psychotic and/or neurological symptom (particularly cognitive dysfunction) caused by or associated with: viral or bacterial infection.

Claims (27)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

Ring a is selected from: a1, A2 and A3:

R ¹ selected from: phenyl and 5-or 6-membered heteroaryl, wherein R ¹ Optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a1 、-SR ^a1 and-NR ^a1 R ^b1 ；

R ² Selected from: H. halogenated radical,C _1-4 Alkyl, C _1-4 Haloalkyl, -OR ^a2 、-SR ^a2 and-NR ^a2 R ^b2 ，

Wherein the C is _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a3 、-SR ^a3 and-NR ^a3 R ^b3 ；

R ³ Selected from: c (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 heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group-C containing 1 or more epoxy atoms _1-3 Alkyl-;

R ⁴ and R is ⁵ Independently selected from: H. c (C) _1-4 Alkyl, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-3 Alkyl-, 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms, and 4-to 7-membered heterocyclic group containing 1 or more epoxy atoms-C _1-3 Alkyl-;

R ⁶ selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ³ 、R ⁴ 、R ⁵ Or R is ⁶ Any C in any of (3) _1-4 Alkyl, C _3-6 Cycloalkyl or C _3-6 cycloalkyl-C _1-3 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OR ^a4 、-SR ^a4 and-NR ^a4 R ^b4 ；

X ¹ 、X ² And X ³ Independently selected from: n and CR ⁷ ；

R ⁷ Independently at each occurrence selected from: H. halo, -CN, 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 is ⁹ Each independently selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group;

wherein R is ⁷ 、R ⁸ Or R is ⁹ Any C in any of (3) _1-4 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halo, -CN, -OR ^a5 、-S(O) _x R ^a5 (wherein x is 0, 1 or 2) and-NR ^a5 R ^b5 ；

Ring B is selected from the group consisting of optionally one or more R ¹⁰ Substituted C _6-10 Aryl and 5-to 12-membered heteroaryl, wherein when ring B is heteroaryl, ring B is bonded to the remainder of the compound of formula (I) through a ring atom in the aromatic ring of the heteroaryl;

R ¹⁰ independently at each occurrence selected from: 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 ，

Wherein said C _1-6 Alkyl, C _2-6 Alkenyl and C _2-6 Alkynyl is optionally substituted with 1 or more R ¹² Substitution;

R ¹¹ independently selected from: H. c (C) _1-6 Alkyl and C _1-6 Haloalkyl, wherein said C _1-6 Alkyl is optionally substituted with one or more R ¹³ Substitution;

Q ¹ independently at each occurrence selected from: c (C) _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-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-,

wherein 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-optionally substituted with one or more R ¹⁴ Substituted, and

wherein the phenyl, phenyl-C _1-3 Alkyl-, 5-or 6-membered heteroaryl and 5-or 6-membered heteroaryl-C _1-3 Alkyl-optionally substituted with one or more R ¹⁵ Substitution;

L ¹ is a bond or is selected from-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 -；

R ¹² 、R ¹³ And R is ¹⁴ Each occurrence is independently selected from: 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 ，

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a9 、-NR ^a9 R ^b9 and-SO ₂ R ^a9 ；

R ¹⁵ Independently at each occurrence selected from: 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 NR ^a10 R ^b10 ，

Wherein said C _1-4 The alkyl group is optionally substituted with 1 or 2 substituents selected from the group consisting of: halo, -CN, -OR ^a11 、-NR ^a11 R ^b11 and-SO ₂ R ^a11 ；

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 is ^b11 Independently at each occurrence selected from: H. c (C) _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

or any-NR within a 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 A 4-to 6-membered heterocyclyl can be formed, wherein the 4-to 6-membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl and C _1-4 A haloalkyl group, a halogen atom,

the conditions are (i) and (ii):

(i) When ring A is A2 and R ² When H is H, then R ³ not-NR ⁵ R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the And

(ii) The compound of formula (I) is not

2. The compound of claim 1, wherein R ² Is C _1-4 Alkyl groups, e.g. where R ² Is methyl.

3. The compound of claim 1 or claim 2, wherein R ¹ The method comprises the following steps:

wherein:

X ₄ is CH or N; and is also provided with

R ¹⁰¹ Is H or halo;

optionally, wherein R ¹ Selected from:

4. the compound of claim 1, wherein ring a has a structure selected from the group consisting of:

5. a compound as claimed in any preceding claim wherein X ₁ And X ₂ Is CH, optionally wherein X ₃ Is N or CH.

6. A compound as claimed in any preceding claim wherein X ₃ Is N.

7. The compound of any one of claims 1 to 4, wherein X ₂ And X ₃ Is N and X ₁ Is CR (CR) ⁷ Optionally wherein X ¹ Is CH.

8. A compound as claimed in any preceding claim whereinR ³ Selected from: -OR ⁴ and-NR ⁵ R ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Optionally, wherein:

R ⁴ selected from: is-NR ^a4 R ^b4 Substituted C _3-6 Cycloalkyl, C _1-4 Alkyl and C _2-4 An alkyl group;

R ^a4 and R is ^b4 Independently selected from: h and C _1-4 An alkyl group; and is also provided with

R ⁵ And R is ⁶ Independently selected from: h and C _1-4 An alkyl group.

9. The compound of any one of claims 1 to 7, wherein:

(i)R ³ is-OR ⁴ Wherein R is ⁴ Selected from: c (C) ₁ -4 alkyl and C _3-6 Cycloalkyl; or alternatively

(ii)R ³ is-OR ⁴ Wherein R is ⁴ Is a 4-to 6-membered heterocyclic group containing 1 epoxy atom or a 4-to 6-membered heterocyclic group containing 1 epoxy atom-C _1-3 An alkyl group; or alternatively

(iii)R ³ Selected from: methoxy group, Or alternatively

(iv)R ³ Is thatOr alternatively

(v)R ³ Selected from: methoxy andor alternatively

(vi)R ³ Is methoxy.

10. The compound of any one of claims 1 to 9, wherein:

(i) Ring B is selected from: phenyl and a monocyclic or bicyclic 5-to 12-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ Substitution; or alternatively

(ii) Ring B is selected from: 5-or 6-membered heteroaryl, each of which is optionally substituted with one or more R ¹⁰ Substitution; or alternatively

(iii) Ring B is selected from: optionally by one or more R ¹⁰ Substituted bicyclic 9-or 10-membered heteroaryl;

optionally, wherein the heteroaryl in any of (i), (ii) and (iii) contains 1 ring nitrogen atom and optionally 1 to 3 ring heteroatoms selected from O, S and N.

11. The compound of any one of claims 1 to 9, wherein ring B is selected from:

wherein p' is 0 or 1;

p "is 0, 1 or 2;

p' "is 0, 1, 2 or 3; and is also provided with

Represents the point of attachment to the remainder of the compound of formula (I).

12. The compound of any one of claims 1 to 11, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring carbon atom in an aromatic ring in ring B.

13. The compound of any one of claims 1 to 11, wherein ring B is bonded to the remainder of the compound of formula (I) through a ring nitrogen atom in an aromatic ring in ring B.

14. The compound of any one of claims 1 to 9, wherein:

(i) Ring B is:

wherein p "is 0, 1 or 2, optionally wherein p" is 0; or alternatively

(ii) Ring B is selected from:

wherein p is 0, 1, 2 or 3, and wherein +.>Represents an attachment point to the remainder of the compound of formula (I); or alternatively

(iii) Ring B is selected from:

wherein p is 0 or 1; and is also provided withRepresents an attachment point to the remainder of the compound of formula (I); optionally, wherein p is 1; or alternatively

(iv) Ring B is:

wherein the method comprises the steps ofRepresents the point of attachment to the remainder of the compound of formula (I).

15. A compound as claimed in any preceding claim, wherein:

(i)R ¹⁰ independently at each occurrence selected from: 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 -；

Wherein Q is ¹⁰² Selected from 4-to 6-membered heterocyclyl and 5-or 6-membered heteroaryl,

Wherein the 4-to 6-membered heterocyclyl is selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, = O, C _1-4 Alkyl, -OR ^a8 、-NR ^a8 R ^b8 and-C (O) R ^a8 ，

Wherein the 5-or 6-membered heteroaryl is selected from: pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of: halo, C _1-4 Alkyl, -OR ^a10 and-NR ^a10 R ^b10 ；

L ¹⁰² Is a bond or is selected from: c (C) _1-3 Alkylene, -O-and-NR ^a7 -; or alternatively

(ii)R ¹⁰ Selected from: -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 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group; or alternatively

(iii)R ¹⁰ Selected from: -NR ^a81 R ^b81 and-C _1-3 alkyl-NR ^a81 R ^b81 Wherein R is ^a81 And R is ^b81 Independently selected from H and C _1-3 An alkyl group; or alternatively

(iv)R ¹⁰ Selected from: fluoro, chloro, cyano, nitro, oxo, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, amino, -NH (Me), -N (Me) ₂ 、

Wherein the method comprises the steps ofIndicating the point of attachment to ring B.

16. The compound of any one of claims 1 to 9, wherein ring B is selected from:

Optionally, wherein ring B is

17. The compound of claim 1, wherein the compound is selected from compound list 1 in the specification, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use as a medicament.

20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prevention or treatment of a disorder consisting of a 5-GABA _A Receptor mediated diseases or medical disorders.

21. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prevention or treatment of a disease associated with a 5-GABA _A For use in cognitive dysfunction associated with a receptor-mediated disease or medical disorder.

22. Prevention or treatment of a disease caused by alpha 5-GABA in a subject _A A method of R-mediated disease or medical disorder, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18.

23. The compound for use as claimed in claim 20 or claim 21, or the method as claimed in claim 22, wherein the compound is prepared from alpha 5-GABA _A The R-mediated disease or medical disorder is selected from: alzheimer's disease, parkinson's disease, huntington's disease, cognitive dysfunction (e.g., cognitive dysfunction associated with chemotherapy, narcotics, bacterial or viral infections (e.g., HIV)), memory deficits, age-related cognitive dysfunction (e.g., mild cognitive impairment, MCI), bipolar disorder, autism, down's syndrome, type I neurofibromatosis, sleep disorders, circadian rhythm disorders, amyotrophic Lateral Sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorders, schizophreniform disorders, substance-induced psychotic disorders or paranoid disorders), psychosis, post-traumatic stress disorders, anxiety disorders, generalized anxiety disorders, panic disorders, delusional disorders, obsessive-compulsive disorders, acute stress disorders, drug addiction, alcohol disorders (e.g., alcohol addiction), drug withdrawal symptoms, movement disorders, restless leg syndrome, cognitive deficit disorder, multi-infarct dementia, vascular dementia, mood disorders, depression, neuropsychiatric conditions, attention-deficit/hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive dysfunction associated with trauma or injury to the brain, cognitive dysfunction associated with trauma or dysfunction, cognitive dysfunction associated with cognitive dysfunction and Dup15, and cognitive dysfunction associated with the brain tumor and dysfunction;

Optionally, wherein the compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, is for use in the treatment or prevention of post-operative cognitive dysfunction, such as anesthesia-induced cognitive dysfunction.

24. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prevention or treatment of a disorder consisting of a 5-GABA _A R-mediated neurological or neuropsychiatric disorders (e.g., treating or preventing cognitive dysfunction associated with a neurological or neuropsychiatric disorder);

optionally wherein the neurological disorder is a neurological developmental disorder (e.g., attention deficit disorder (ADHD), down's syndrome, learning disorder, cerebral palsy, autism, or speech disorder);

optionally wherein the neurological disorder is a neurodegenerative disorder (e.g., alzheimer's disease, dementia, parkinson's disease, huntington's disease, amyotrophic Lateral Sclerosis (ALS), or creutzfeld-jakob disease (CJD)); for example, wherein the neurodegenerative disease is huntington's disease.

25. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the treatment or prevention of psychotic and/or neurological symptoms (particularly cognitive dysfunction) caused by or associated with: viral or bacterial infection.

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

27. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the treatment or prevention of a cognitive disorder associated with a psychotic disorder;

optionally, wherein the compound or composition is for use in the treatment or prevention of cognitive disorders associated with schizophrenia.