New sulfonamides or sulfones and their use as neuroprotective and / or neurorestorative agents

Abstract

The present invention relates to compounds of general formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. The present invention also relates to the use of the compounds of the present invention as neuroprotective and / or neurorestorative agents, in particular for the treatment of nervous system disorders. (I)

Description

Technical Field

[0001] This invention relates to novel polycyclic sulfonamide or sulfone compounds, wherein the sulfonamide or sulfone group is combined with a bicyclic heteroaryl group. The compounds of this invention are useful as neuroprotective agents and / or nerve repair agents, particularly for the treatment of neurological disorders. Background Technology

[0002] Neurological disorders (NDs) are heterogeneous diseases affecting the body's autonomic, peripheral, and central nervous systems. Among central nervous system (CNS) diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), dementia, stroke, head trauma, brain tumors, pain, and epilepsy remain some of the most challenging diseases to address. Active compounds used to treat CNS disorders may also be associated with other diseases, such as those affecting the peripheral nervous system, eyes, spinal cord, and digestive system.

[0003] The incidence of neurodegenerative diseases (NDs) is projected to rise dramatically in the 21st century, primarily due to increased life expectancy and demographic changes. Some of these diseases are characterized by a gradual, age-related decline in neurological function. Medically, neurological disorders are a significant and common cause of disability-adjusted life years (DAS), or healthy life years lost due to death or disability, worldwide. The neurological system (CNS) represents the largest and fastest-growing area of ​​unmet medical needs, and it is being recognized as a global public health challenge and a major global health priority. Adequate neurological diagnosis is a significant challenge, and patients are increasingly concerned with developing new and effective treatments to address the pathophysiology or symptoms. Neurological disorders affect millions worldwide and cause permanent damage. They are progressive diseases, where symptoms worsen over time. While there is usually no definitive cure, supportive treatments exist. The primary goal of these treatments is to alleviate symptoms and maintain the patient's quality of life for as long as possible.

[0004] Neurons are cells that have undergone mitosis and must survive their entire lives. While young neurons possess normal self-repair and protective mechanisms, aging or external or internal damage can interfere with them, ultimately leading to neurodegeneration. These external / internal hazards include traumatic injury or excitotoxic compounds, reactive oxygen species (ROS), protein aggregates, and other toxic molecules. Fortunately, cells have an intrinsic mechanism that prevents death by activating elastic mechanisms or promoting regenerative pathways. Dysfunction or inadequacy of these self-healing mechanisms has also been described in neurodegenerative diseases.

[0005] In natural self-healing agents, glial cell-derived neurotrophic factor (GDNF) acts as a potent neurotrophic factor, promoting the survival of various neuronal populations, such as spinal motor neurons, retinal cells, central noradrenergic neurons, or sympathetic neurons. Similarly, GDNF (and other proteins in the GDNF family of neurotrophic factors, such as neuronal rankin, artemin, and persehin) act as powerful trophic factors, not only beneficial for survival and plasticity but also for the proliferation, differentiation, and protection of dopaminergic neurons, as well as dopamine synthesis and dopaminergic transmission in the developing and adult brain. GDNF can promote neuroprotection through the MAP kinase / ERK, Src kinase, and PI3 kinase / AKT pathways by inducing various neuroprotective signaling cascades, including activation of transcription factor Elk1 by activating the GFRα1-RET receptor complex.

[0006] The applications of these proteins are broad. Preclinical and clinical trials have been conducted to evaluate the effects of GDNF family neurotrophic factors on the prevention, treatment, or management of Parkinson's disease, chronic pain, Alzheimer's disease, amyotrophic lateral sclerosis, neuropathy, depression, and stroke. These proteins have even been suggested as male contraceptives. However, the clinical application of GDNF is hampered by its poor pharmacokinetic properties, its inability to cross the blood-brain barrier (requiring intracranial delivery via stereotactic surgery), its varying biological activities, and its high cost.

[0007] Small molecule compounds that target GDNF receptor complexes and mimic the biological effects of GDNF in neurons and penetrate the blood-brain barrier could be a way to overcome these problems and translate into greater therapeutic efficacy in clinical practice. The excellent tissue penetration of such compounds could promote the survival of all affected neuronal pathways.

[0008] The applicant was surprised to find that the new polycyclic sulfonamides or sulfones of formula (I) exhibited strong GFRα1-RET activity in luciferase assays, thus paving the way for overcoming the limitations of available therapeutic solutions. Summary of the Invention

[0009] The object of this invention is the compound of formula (I). (I) Or its pharmaceutically acceptable salts and / or solvates; Among them, W and R A -R D R 1 -R 4 A 1 -A 5 and R 10As defined below and / or as defined in the claims.

[0010] According to one embodiment, the compound is selected from the compounds in Table 1 herein and their pharmaceutically acceptable salts and / or solvates.

[0011] Another object of the present invention is a pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0012] Another object of the present invention is to use the compounds or pharmaceutical compositions according to the present invention as medicines. Another object of the present invention is to use the compounds or pharmaceutical compositions according to the present invention for treating neurological disorders.

[0013] Another object of the present invention is a method for preparing the compounds according to the present invention.

[0014] definition

[0015] In this invention, the following terms have the following meanings: Chemical definition When a chemical substituent is a combination of chemical groups, the point at which the substituent attaches to the molecule is the last chemical group listed to the right of the substituent's name. For example, an arylalkyl substituent is attached to the rest of the molecule via the alkyl portion, and it can be represented as "aryl-alkyl-".

[0016] Unless otherwise indicated, the compounds are named BIOVIA Draw 2021 (Dassault, France).

[0017] The definitions of optional or mandatory substitution of a specified group in this document apply both to the substituted group as it is considered itself and to the same group contained in another chemical section, both of which can be substituted as described herein. For example, "R x Indicates hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl-O- or cycloalkyl-(C 1 -C 8 )alkyl-NH-; wherein the alkyl "Optionally replaced by at least one F" Meaning R xAny alkyl group present in the structure may optionally be substituted with at least one F, including the (C1-C8) alkyl group itself (e.g., CF3), alkyl groups contained in the (C1-C8) alkyl-O- (e.g., OCF3), and alkyl groups contained in the cycloalkyl-(C1-C8) alkyl-NH- (e.g., cyclopropyl-CH2-CHF-CH2-NH-).

[0018] "Alkoxy" refers to an alkyl-O group.

[0019] "Alkyl" refers to a saturated straight-chain or branched hydrocarbon chain, typically containing 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms. Alkyl groups can be monovalent or polyvalent (i.e., "alkylene", which is a divalent alkyl group and is covered within the definition of "alkyl"). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl), and hexyl and its isomers. Specific examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl (including methylene, ethylene, n-propylene, n-butylene, and n-butylene).

[0020] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms have been replaced by a substituent (e.g., alkyl or aryl). "Amino" refers to the -NH2 group.

[0021] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbon group comprising at least one aromatic ring and containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group can be monovalent or polyvalent (e.g., divalent). The aryl group can have a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently linked. The aromatic ring may optionally include one or two additional rings (cycloalkyl, heterocycloalkyl, or heteroaryl) fused thereto. The definition of "aryl" includes partially hydrogenated derivatives of the carbocyclic systems listed herein, provided that at least one ring is aromatic. The aryl group may optionally be substituted with at least one group, such as, for example, a halogen (e.g., F or Cl), a (C1-C8) alkyl (e.g., methyl), or a nitrile (CN). Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylene, 5- or 6-naphthyl, naphth-1- or -2-yl, 4-, 5-, 6- or 7-indenyl, 1-, 2-, 3-, 4- or 5-acenaphthyl, 3-, 4- or 5-dihydroacenaphthyl, 1- or 2-pentenyl, 4- or 5-indenyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2, 3, 4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrene. A specific example of an aryl group is the phenyl.

[0022] "Benzylene" refers to a phenyl group bonded to a carbon atom via an outer carbon-carbon double bond, specifically a =CH-Ph bond. This portion is typically cyclic, such as a heterocyclic alkyl group.

[0023] “Cycloalkyl” refers to a cyclic alkyl group, typically containing 3 to 15 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. The cycloalkyl group can be monovalent or polyvalent (e.g., divalent). The definition of “cycloalkyl” covers polycyclic cycloalkyl groups (e.g., bicyclic) and bridged cycloalkyl structures, including rings linked by one atom (“spirocyclic”) or by two atoms. The definition of “cycloalkyl” covers cycloalkyl groups, including cycloalkyl groups substituted with at least one non-cycloalkyl group, such as (C1-C8)alkyl groups (preferably, (C1-C4)alkyl groups, such as methyl groups). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[4.4.0]decyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.1.1]hexane, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, decahydronaphthyl, 1,2,3,4-tetrahydronaphthyl and octahydropentenyl.

[0024] According to common terminology in the chemical field, the "C" before a group name... x -C y "or "(C x -C y ")" means that the group contains x to y carbon atoms.

[0025] "Halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0026] "Heteroalkyl" means an alkyl group as defined herein, wherein one or more carbon atoms are substituted with heteroatoms selected from oxygen, nitrogen, and sulfur, and wherein the resulting heteroalkyl group contains at least one carbon atom. In a heteroalkyl group, the heteroatom is bonded to only carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom, typically at least two carbon atoms. The heteroalkyl group can be monovalent or polyvalent (e.g., divalent). Nitrogen and sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized (e.g., sulfur can be oxidized to SO or SO2). The heteroalkyl group may also contain one or more =O and / or =S groups. In one embodiment, at least two carbon atoms are substituted with heteroatoms. In one embodiment, the heteroalkyl group is bonded to another group or molecule via a carbon atom, i.e., the bonded atom is not selected from the heteroatoms contained therein. In one embodiment, the heteroalkyl group is bonded to another group or molecule via one of the heteroatoms contained in another group or molecule. When substituted with one or more other groups, unless otherwise specified, the heteroalkyl group can be substituted via a carbon atom or via a heteroatom (e.g., nitrogen). Non-limiting examples of heteroalkyl groups include alkoxy groups, ethers and polyethers (e.g., polyethylene glycol), secondary and tertiary amines, as well as polyamines, thioethers and polysulfides, and combinations thereof.

[0027] "Heteroaryl" refers to an aromatic ring or aromatic ring system comprising 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, having one or two fused or covalently linked rings, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more rings are substituted with oxygen, nitrogen, and / or sulfur atoms. The heteroaryl can be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatomium may optionally be quaternized (e.g., the heteroatom is substituted with oxo(=O) (for sulfur) or (→O) (for nitrogen). The definition of "heteroaryl" encompasses partially hydrogenated derivatives of the carbocyclic systems listed herein, as well as cyclic systems comprising one or more fused non-aromatic cycloalkyl and / or heterocyclic alkyl rings, provided that at least one ring is aromatic. In one embodiment, the heteroaryl is bonded to another group or molecule via a carbon atom, i.e., the bonding atom is not selected from the heteroatoms contained therein. In one embodiment, the heteroaryl group is attached to another group or molecule by one of the heteroatoms contained in another group or molecule. When substituted by one or more other groups, the heteroaryl group may be substituted by a carbon atom or by a heteroatom (e.g., nitrogen) unless otherwise specified. The heteroaryl group may optionally be substituted by at least one group, such as, for example, a halogen (e.g., F or Cl), a (C1-C8) alkyl (preferably, a (C1-C4) alkyl, such as methyl), or a nitrile (CN).Non-limiting examples of heteroaryl groups include pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxtriazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyridazinyl, oxazinyl, dioxazinyl, thiazinyl, triazinyl, tetraazinyl, imidazo[2,1-] b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienoyl, thieno[2,3-d][1,3-thiazolyl, thieno[2,3-d]imidazolyl, tetrazol[1,5-a]pyridyl, indole, indoleazinyl, isoindole, benzofuranyl, isobenzofuranyl, benzothiophene, isobenzothiophene, indole Azolyl, benzimidazolyl, 1,3-benzoxazole, 1,2-benzoisoxazole, 2,1-benzoisoxazole, 1,3-benzothiazolyl, 1,2-phenylisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzotriazolyl Thiadiazolyl, thienopyridyl, purinyl, imidazo[1,2-a]pyridyl, 6-oxopyridin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxopyridin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolane, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, and quinoxalolinyl. Non-limiting examples of heteroaryl groups containing at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl and benzo[a]. [d] [1,3]dioxolanecycloyl, indololinyl, 2,3-dihydroxybenzo[] [b] [1,4]dioxanehexenyl, 3,4-dihydro- 2H- benzo[a] [b] [1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro- 2H -Benzo[b][1,4]thiazine and 2,3-dihydrobenzo[b][1,4]oxothiothiazide ring.

[0028] "Heteroarylene" refers to a heteroarylene group that is partially bonded to a carbon atom via an external carbon-carbon double bond, i.e., =CH-heteroarylene bonded to a carbon atom. The part is usually cyclic, such as, for example, a heterocyclic alkyl group.

[0029] "Heterocyclic alkyl" refers to a cyclic heteroalkyl group, typically containing 2 to 15 carbon atoms, preferably 2 to 11 carbon atoms, more preferably 2 to 7 carbon atoms, and even more preferably 2 to 6 carbon atoms. Heterocyclic alkyl groups can be monovalent or polyvalent (e.g., divalent). Heterocyclic alkyl groups are typically 3 to 7-membered, preferably 5 or 6-membered. Heterocyclic alkyl groups are typically monocyclic or bicyclic, preferably monocyclic. This definition covers polycyclic heterocyclic alkyl groups (e.g., bicyclic) and bridged heterocyclic alkyl structures, including rings bonded together by one atom ("spirocyclic") or by two atoms. Nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized (e.g., the heteroatom is substituted by oxo(=O) (for sulfur atoms) or (→O) (for nitrogen atoms). In one embodiment, a heterocyclic alkyl aryl group is bonded to another group or molecule via a carbon atom, i.e., the bonded atom is not selected from the heteroatoms contained therein. In one embodiment, a heterocyclic alkyl group is bonded to another group or molecule via one of the heteroatoms contained in another group or molecule. When substituted by one or more other groups, unless otherwise specified, heterocyclic alkyl groups may be substituted by a carbon atom or by a heteroatom (e.g., nitrogen). Heterocyclic alkyl groups may optionally be substituted by at least one group, such as, for example, a halogen (e.g., F or Cl), a (C1-C8) alkyl (preferably, a (C1-C4) alkyl, such as methyl), a nitrile (CN), or =O. Non-limiting examples of heterocyclic alkyl groups include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azirheptanane, azirheptanane, octahydro- 1H -Isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquinoline), hexahydropyrazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoleline, 1,2,3,4-tetrahydroquinoline, and oxacyclobutane.

[0030] A "prodrug" is a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention) whose in vivo biotransformation product is a therapeutic agent (active drug). A typical characteristic of prodrugs is increased bioavailability and readily metabolized in vivo into the active compound. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0031] A "solvent" is a molecular complex that comprises a compound and one or more molecules of one or more solvents in stoichiometric or substoichiometric amounts, typically pharmaceutically acceptable solvents such as ethanol. The term "hydrate" refers to a solvate when the solvent is water (H2O).

[0032] A "subunit" refers to a CH group contained in the outer carbon-carbon double bond that is bonded to another moiety. The moiety is usually cyclic, such as a heterocyclic alkyl group.

[0033] General definition

[0034] The word “approximately” in this text is used to mean about, roughly, around, or within a certain range. The term “approximately” before a number indicates a value plus or minus 10%. When the term “approximately” is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the stated value by 10%.

[0035] "Administration" or its variants (e.g., "Administration" or "administering") means the provision of a therapeutic agent, alone or as part of a pharmaceutically acceptable composition, to a patient for the treatment of a condition, symptom, or disease.

[0036] In accordance with common patent application drafting terminology, the term "comprising" or variations thereof (e.g., "comprising of", "including") is used herein. Therefore, "comprising" preceding "object" and followed by "component" indicates that the object requires the presence of a component (typically as a component of a composition), but does not exclude the presence of any additional components (multiple components). Furthermore, unless otherwise stated, "comprising" or variations thereof as used herein also encompass the narrower expression "consistently constitutes," the narrower expression "composes of," and any variations thereof (e.g., "consists of", "consisting of"), and can therefore be substituted.

[0037] "GDNF family receptor α-1," also known as "GFRα1" or "GDNFRα1," and also called "RET ligand 1" or "TGF-β-related neurotrophic factor receptor 1," is a protein in the GDNFR family that acts as a receptor for GDNF. It mediates GDNF-induced autophosphorylation and activation of the RET receptor. In humans, GFRα1 is... GFRA1 Gene encoding. An exemplary amino acid sequence of human GFRα1 is given in SEQ ID NO:1, wherein amino acid residue 124 corresponds to the signal peptide and amino acid residues 430-465 correspond to the propeptide removed in the mature form.

[0038] SEQ ID NO:1

[0039] MFLATLYFALPLLDLLLSAEVSGGDRLDCVKASDQCLKEQSCSTKYRTLRQCVAGKETNFSLASGLEAKDECRSAMEALKQKSLYNCRCKRGMKKEKNCLRIYWSMYQSLQGNDLL EDSPYEPVNSRLSDIFRVVPFISDVFQQVEHIPKGNNCLDAAKACNLDDICKKYRSAYITPCTTSVSNDVCNRRKCHKALRQFFDKVPAKHSYGMLFCSCRDIACTERRRQTIVPV CSYEEREKPNCLNLQDSCKTNYICRSRLADFFTNCQPESRSVSSCLKENYADCLLAYSGLIGTVMTPNYIDSSSLSVAPWCDCSNSGNDLEECLKFLNFFKDNTCLKNAIQAFGNG SDVTVWQPAFPVQTTTATTTTALRVKNKPLGPAGSENEIPTHVLPPCANLQAQKLKSNVSGNTHLCISNGNYEKEGLGASSHITTKSMAAPPSCGLSPLLVLVVTALSTLLSLTETS

[0040] "Human" refers to male or female human subjects at any developmental stage, including newborns, infants, adolescents, teenagers, and adults.

[0041] "Neuroprotective" refers to the protection of neurons from damage, events, or conditions that typically lead to loss of neuronal function and ultimately neuronal death. Such damage, events, or conditions include, but are not limited to, neuronal stress (e.g., caused by hypoxia or ischemia); traumatic injury; and exposure to toxic molecules such as misfolded proteins, protein aggregates, excitotoxic substances, reactive oxygen species, endoplasmic reticulum stress factors, mitochondrial stress factors, Golgi antagonists, etc. The term also characterizes the detectable biological activity of a compound in reducing the amount or level of neuronal loss of function and / or neuronal death.

[0042] "Neuroreparative" refers to the recovery or rescue of neurons, particularly their function, from the effects of damage, events, or conditions that would normally lead to loss of neuronal function (if not neuronal death).

[0043] "Patient" refers to a subject who is awaiting treatment or receiving medical care, or who has been / is / will be the subject of a medical procedure, or whose development is being monitored for a disease or condition (e.g., a neurological disorder).

[0044] "Pharmaceutical acceptable" means that the components of the composition are compatible with each other and are harmless to the subject of administration.

[0045] "Pharmaceutically acceptable carriers" are excipients that do not produce harmful, allergic, or other adverse reactions when administered to animals, preferably humans. This includes any and all solvents, dispersion media, coating agents, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents. For human use, the formulation should meet the sterility, pyrogenicity, general safety, and purity standards required by regulatory authorities (e.g., the FDA or EMA). Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., sodium carboxymethyl cellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0046] "Pharmaceutical composition" means a composition comprising at least one therapeutic agent (e.g., a compound according to the invention) and at least one pharmaceutically acceptable carrier.

[0047] "Proto-oncogene tyrosine protein kinase receptor Ret," or simply "RET," also known as "cadherin family member 12," is a receptor tyrosine kinase involved in a variety of cellular mechanisms, including cell proliferation, neuronal navigation, cell migration, and cell differentiation. RET is activated following: (i) binding of GDNF family neurotrophic factors (e.g., GDNF, neurorankin, artemin, or persehin) to GDNFR family receptors (e.g., GFRα1, GFRα2, GFRα3, or GFRα4), followed by (ii) complex formation between RET and the GDNF family receptor, (iii) dimerization, and (iv) trans-autophosphorylation. An exemplary amino acid sequence of human RET is given in SEQ ID NO:2, where amino acid residue 128 corresponds to the signal peptide.

[0048] SEQ ID NO: 2

[0049]

[0050] In accordance with common patent application drafting terminology, this document uses “selected from” to describe a list of elements in which one or more items have been selected. Any use of “selected from” in the specification may be replaced with “selected from the group comprising…” or “selected from the group consisting of…”, and these substitutions shall not change their meaning.

[0051] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, and further preferably a human. In one embodiment, the subject is a "patient" as defined herein. In one embodiment, the subject is infected with a disease, preferably diagnosed with a disease. In one embodiment, the subject is at risk of disease progression. Examples of risk factors include, but are not limited to, genetic susceptibility or a family history of disease.

[0052] "Therapeutic agent," "active pharmaceutical ingredient," and "active ingredient" refer to compounds intended for therapeutic use and relating to health. In particular, a therapeutic agent (e.g., a compound according to the invention) may be indicated for the treatment of a disease (e.g., a neurological disorder). An active ingredient may also be indicated for enhancing the therapeutic activity of another therapeutic agent.

[0053] A "therapeutic effective amount" (or "effective amount") refers to an amount of a therapeutic agent (e.g., a compound according to the invention) sufficient to achieve the desired therapeutic, preventive, or prophylactic effect in a patient to whom it is administered, without causing significant negative or adverse side effects. A therapeutic effective amount may be administered before the onset of disease for preventive or prophylactic purposes. Alternatively or additionally, a therapeutic effective amount may be administered after the onset of disease for therapeutic purposes.

[0054] "Treatment," "treatment," or "relief" refers to therapeutic treatment and preventive or preventative measures aimed at preventing or alleviating (reducing) a target pathological condition or symptom (referred to herein as "disease") (e.g., a neurological condition). Those requiring treatment include those who already have the disease, as well as those who are susceptible to it or require prevention of the condition or disease. A patient is successfully "treated" for a disease if, after receiving a therapeutic dose of a therapeutic agent (e.g., a compound according to the invention), they exhibit observable and / or measurable relief, or the absence of any of, or one or more, of the following: a reduction in pathogen count; a reduction in the percentage of pathogenic cells in the total cell count; and / or partial relief of one or more symptoms associated with the specific disease; a reduction in morbidity and mortality; and an improvement in quality of life. The parameters used to assess successful treatment and improvement of a disease are readily measurable through routine procedures familiar to physicians. Detailed Implementation

[0055] compound

[0056] The object of this invention is the compound of formula (I). (I) Or its pharmaceutically acceptable salts and / or solvates; in W represents CH or N; R A R B R C and R D Each can independently represent hydrogen, F, Cl, CH3, CF3, CHF2, or CH2F. The condition is R A R B R C and R D At least one of them does not represent hydrogen (i.e., phenyl or pyridyl is substituted; in other words, phenyl or pyridyl cannot be unsubstituted). R 1 Represents hydrogen or (C1-C8) alkyl, wherein the alkyl group is optionally substituted with at least one OH, (C1-C3) alkoxy, or F; and R 2 R 3 and R 4 It represents hydrogen; Or R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein -CH2-CH2- is optionally substituted by at least one F, OH, or OCH3; and R 2 and R 3 Each represents hydrogen; A 1 and A 2 Each can be represented independently as N or C; and A 3 A 4 and A 5 Each represents N and NR independently. 11 C or CR 12 ; The condition is A 1 A 2 A 3 A 4 and A 5 At least one of them represents N or NR. 11 ; in Each R 11Independently representing hydrogen, (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, or heteroaryl-(C1-C8)alkyl-; and Each R 12 Independently representing hydrogen, (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl- or heteroaryl-(C1-C8)alkyl-; Where R 11 or R 12 The alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups (i.e., those composed of R) 11 or R 12 Any alkyl, cycloalkyl, heterocycloalkyl, or aryl group represented or as part of any of its substituents may optionally be represented by at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O-, or NR. 13 R 14 Replace; where R 13 and R 14 Each independently represents hydrogen or (C1-C8) alkyl; and R 10 Indicates NR 5 R 6 or C(R) 5 (R) 6 (R) 9 ); in R 5 It represents hydrogen, (C1-C8)alkyl, CH3 substituted with one to three (C1-C8)alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8)alkyl; Where R 5 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 17 R 18 CO2H, R 17 R 18 NC(O)-, R 17 O-NR 18 - Heterocyclic alkyl, aryl, or heteroaryl substituted; wherein R 17 and R 18 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, or heteroaryl groups (i.e., those composed of R) 5Any heterocyclic alkyl, aryl, or heteroaryl group represented or as part of any of its substituents may optionally be represented by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 19 R 20 CO2H, R 19 R 20 NC(O)-, R 19 O-NR 20 -、(C1-C8)alkyl-CO2-、R 19 R 20 N-(C1-C8)alkyl-, R 19 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 19 and R 20 Each can independently represent hydrogen or (C1-C8) alkyl; R 6 It represents hydrogen, (C1-C8)alkyl, CH3 substituted with one to three (C1-C8)alkyl groups, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl; Where R 6 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 21 R 22 CO2H, R 21 R 22 NC(O)-, R 21 O-NR 22 - Heterocyclic alkyl, aryl, or heteroaryl substituted; wherein R 21 and R 22 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, or heteroaryl groups (i.e., those composed of R) 6 Any heterocyclic alkyl, aryl, or heteroaryl group represented or as part of any of its substituents may optionally be represented by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 23 R 24 CO2H, R 23 R 24 NC(O)-, R 23 O-NR 24 -、(C1-C8)alkyl-CO2-、R 23 R 24N-(C1-C8)alkyl-, R 23 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 23 and R 24 Each can independently represent hydrogen or (C1-C8) alkyl; Or R 5 and R 6 Together with the carbon or nitrogen atoms they are bonded to, they form cycloalkyl or heterocycloalkyl groups. The cycloalkyl or heterocycloalkyl group (i.e., composed of R) 5 R 6 The cycloalkyl or heteroalkyl groups formed by the carbon atoms bonded to them are optionally bonded by at least one of the following: F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 25 R 26 CO2H, (C1-C8)alkyl-CO2-, R 25 R 26 NC(O)-, R 25 O-NR 26 -、R 25 R 26 N-(C1-C8)alkyl-, R 25 O2C-(C1-C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, aryl-cycloalkyl-O-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1-C8)alkyl-O-, heterocycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-NR 25 - Heterocyclic alkyl-NR 25 -,Aryl-NR 25 -、Heteroaryl-NR 25 - Cycloalkyl-(C1-C8)alkyl-NR 25 - Heterocyclic alkyl-(C1-C8)alkyl-NR 25 -, aryl-(C1-C8)alkyl-NR 25 - Heteroaryl-(C1-C8)alkyl-NR 25 - Benzylene, heteroarylene, aryl-(C1-C8)alkyl-ylidene- or heteroaryl-(C1-C8)alkyl-ylidene-substituted; wherein R 25 and R26 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, heteroaryl, benzylidene, or heteroarylene (i.e., as a derivative of R) 5 R 6 Any heterocyclic alkyl, aryl, heteroaryl, benzylidene, or heteroarylene group (any part of any substituent of the heterocyclic alkyl group formed with the nitrogen atom to which it is bonded) may optionally be a substituent of at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 27 R 28 CO2H, R 27 R 28 NC(O)-, R 27 O-NR 28 -、(C1-C8)alkyl-CO2-、R 27 R 28 N-(C1-C8)alkyl-, R 27 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C1-C8) alkyl; and R 9 It represents hydrogen, (C1-C8)alkyl, CH3 substituted with one to three (C1-C8)alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8)alkyl; Where R 9 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, NR 29 R 30 CO2H, R 29 R 30 NC(O)-, R 29 O-NR 30 - Heterocyclic alkyl, aryl, or heteroaryl substituted; wherein R 29 and R 30 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, or heteroaryl groups (i.e., those composed of R) 9 Any heterocyclic alkyl, aryl, or heteroaryl group (represented or as part of any of its substituents) is optionally represented by at least one F, Cl, CF3, OCF3, CN, OH, =O, →O, (C1-C8)alkoxy, or NR. 31 R 32 CO2H, R 31R 32 NC(O)-, R 31 O-NR 32 -、(C1-C8)alkyl-CO2-、R 31 R 32 N-(C1-C8)alkyl-, R 31 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 31 and R 32 Each can be used independently to represent hydrogen or (C1-C8) alkyl groups.

[0057] In any of the following embodiments involving specific limitations on the structure of compounds of formula (I), any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, benzylidene, or heteroarylene may be independently and optionally substituted as indicated herein by formula (I), unless otherwise specified.

[0058] In equation (I) above, as shown in this paper, the quinary ring (by A) 1 A 2 A 3 A 4 and A 5 Formation, in which A 1 A 2 A 3 A 4 and A 5 At least one of them represents N or NR. 11 The five-membered ring and the six-membered ring fused with the five-membered heteroaryl group (substituted with nitrogen from piperazine and SO2) are aromatic, as indicated by the circles at the center of each ring. Thus, the five-membered ring is a heteroaryl, and the six-membered ring is either an isoaryl or phenyl, depending specifically on the position of the nitrogen heteroatom(s). Furthermore, the five-membered and six-membered rings together form a bicyclic heteroaryl (specifically, a [6,5]bicyclic heteroaryl).

[0059] In a preferred embodiment of spinning, W represents CH. In a particular embodiment, W represents N.

[0060] According to one implementation, R A R B R C and R D At least one of them represents hydrogen. In one embodiment, R A R B R C and R D There is exactly one character representing hydrogen. In one embodiment, R... A R B R C and R DThere are exactly two characters representing hydrogen. In one embodiment, R... A R B R C and R D There are exactly three characters representing hydrogen.

[0061] In one implementation, R A and R C At least one of them represents hydrogen. In a preferred embodiment, R A Represents hydrogen. In a preferred embodiment, R C Represents hydrogen. In another preferred embodiment, R A and R C Each represents hydrogen.

[0062] According to one implementation, R A R B and R D At least one of them represents F or Cl. In one embodiment, R B and R D At least one of them represents F or Cl. In a particular embodiment, R B and R D Each can be represented independently as F or Cl. In a particular implementation, R B F is represented. In a particular implementation, R is represented by... B Represents Cl. In one particular implementation, R D F is represented. In a particular implementation, R is represented by... D Represents Cl. In one particular implementation, R A F is represented. In a preferred embodiment, R B F is represented. In a particular implementation, R is represented by... D Represents CH3. In a preferred embodiment, R D Represents Cl. In another preferred embodiment, R B Let F be an integer, and R be an integer. D It represents Cl.

[0063] As defined above based on equation (I), R 1 It can represent (C1-C8) alkyl, wherein the alkyl group is optionally substituted by at least one OH, (C1-C3) alkoxy, or F, i.e., R 1 The (C1-C8) alkyl group may optionally be substituted with at least one group, and said group may be OH, (C1-C3) alkoxy, or F. According to one embodiment, R 1The term represents a (C1-C8) alkyl group, wherein the alkyl group is substituted with at least one group selected from OH, (C1-C3) alkoxy, and F. According to a preferred embodiment, the alkyl group is not substituted.

[0064] According to one implementation, R 1 Represents hydrogen or (C1-C8) alkyl, wherein the alkyl group is optionally substituted by at least one OH, (C1-C3) alkoxy, or F; and R 2 R 3 and R 4 Represents hydrogen. In a preferred embodiment, R 1 Represents hydrogen or methyl. In another preferred embodiment, R 1 R 2 R 3 and R 4 Each represents hydrogen. In another preferred embodiment, R 1 It indicates a methyl group.

[0065] According to one implementation, R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-. In one embodiment, R 1 and R 4 Together they form -CH2-CH2-. In one embodiment, -CH2-CH2- may optionally be substituted by at least one F, OH, or OCH3. In a preferred embodiment, -CH2-CH2- is not substituted.

[0066] According to one implementation, A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula:

[0067] Where R 11 and R 12 Each is independent as defined herein based on formula (I); and the dashed line represents the fusion point of the five-membered heteroaryl group with the six-membered ring (heteroaryl or phenyl) fused with it.

[0068] In one implementation, A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula:

[0069] Each R 11 and R 12 Each is independently defined as described in this paper based on equation (I); and the dashed line represents the fusion point of the five-membered heteroaryl group and the six-membered ring fused with it.

[0070] In a preferred embodiment, A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula:

[0071] Each R 11 and R 12 Each is independently defined as described in this paper based on equation (I); and the dashed line represents the fusion point of the five-membered heteroaryl group and the six-membered ring fused with it.

[0072] In another preferred embodiment, A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula:

[0073] Each R 11 and R 12 Each is independently defined as described in this paper based on equation (I); and the dashed line represents the fusion point of the five-membered heteroaryl group and the six-membered ring fused with it.

[0074] In one implementation, A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula:

[0075] Each R 11 and R 12 Each is independently defined as described in this paper based on equation (I); and the dashed line represents the fusion point of the five-membered heteroaryl group and the six-membered ring fused with it.

[0076] In a preferred embodiment, A 1 A 2 A 3 A 4 and A5 Together they form a five-membered heteroaryl group selected from the following formula:

[0077] Each R 11 and R 12 Each is independently defined as described in this paper based on equation (I); and the dashed line represents the fusion point of the five-membered heteroaryl group and the six-membered ring fused with it.

[0078] In another preferred embodiment, A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula:

[0079] Each R 11 and R 12 Each is independently defined as described in this paper based on equation (I); and the dashed line represents the fusion point of the five-membered heteroaryl group and the six-membered ring fused with it.

[0080] In the above formula, the dashed line therefore represents a five-membered heteroaryl group (from A). 1 A 2 A 3 A 4 and A 5 The fusion point of the six-membered ring (heteroaryl or phenyl) fused with the five-membered heteroaryl group. Any possible orientation of the fusion is covered, i.e., either of the two dashed lines on the right or left side of the formula can represent the fusion point via A. 1 Or A 2 The fusion of any one of the groups is considered, regardless of the orientation of the diagram. In other words, the orientation of the drawn formula should not be interpreted as a structural constraint. Typically, the dashed line on the left corresponds to the phenyl group through A. 1 The fusion point of the group, the dashed line on the right corresponds to the phenyl group passing through A. 2 The fusion point of the group, that is, the orientation of the drawn formula is the same as the orientation of the drawn formula (i).

[0081] According to a preferred embodiment, the five-membered heteroaryl group (from A) 1 A 2 A 3 A 4 and A 5The bicyclic heteroaryl group is formed together with a six-membered ring (heteroaryl or phenyl) to form a bicyclic heteroaryl group selected from the following: [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, benzimidazole, benzotriazole, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, indazole, and indole. In a preferred embodiment, the bicyclic heteroaryl group is selected from benzimidazole, imidazo[1,5-a]pyridine, indazole, and indole.

[0082] According to one implementation, A 3 Indicates NR 11 or CR 12 , where R 11 and R 12 As defined in this paper based on equation (I). In one implementation, R 11 and / or R 12 Indicates / does not indicate hydrogen. According to one embodiment, A 4 Indicates NR 11 or CR 12 , where R 11 and R 12 As defined in this paper based on equation (I). In one implementation, R 11 and / or R 12 Indicates / does not indicate hydrogen.

[0083] According to one implementation, A 5 Indicates NR 11 or CR 12 , where R 11 and R 12 As defined herein based on equation (I). In one implementation, A 5 Indicates NR 11 or CR 12 , where R 11 and R 12 As defined in this paper based on equation (I), the condition is R. 11 and / or R 12 This does not represent hydrogen. In a preferred embodiment, A 5 Indicates NR 11 or CR 12 , where R 11 and R 12 As defined in this paper based on equation (I), the condition is R. 11 and R 12 Each does not represent hydrogen. In another preferred embodiment, R 11 and R 12Each of these can independently represent methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl (preferably 2-hydroxy-2-methyl-propyl), methoxyethyl, ethyl-OC(O)-, cyclobutyl, or cyclopropyl. In another preferred embodiment, R 11 and R 12 Each can be independently represented as methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, ethyl-OC(O)-, or cyclopropyl.

[0084] According to one implementation, A 3 and A 4 Each can independently represent N, NH, C, or CH. In one implementation, A 3 It represents N, NH, C, or CH. In one embodiment, A 4 It represents N, NH, C, or CH.

[0085] Based on the definition in this paper based on equation (I), R 11 and / or R 12 It can represent a carboxylic acid or an ester, that is, an alkyl group substituted with an oxo (=O) and further substituted with a hydroxyl (OH) or alkoxy (alkyl-O-). According to one embodiment, R 11 and R 12 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, or heteroaryl-(C1-C8)alkyl-; where R 11 or R 12 The alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally replaced by at least one F, Cl, OH, =O, (C1-C8)alkyl (preferably (C1-C4)alkyl), (C1-C8)alkyl-O- (preferably (C1-C4)alkyl-O-), or NR. 13 R 14 , where R 13 and R 14 Each independently represents a hydrogen or (C1-C8) hydrocarbon group (preferably hydrogen or (C1-C4) alkyl). In one embodiment, R 11 and R 12 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl-; where R 11 or R 12 The alkyl or cycloalkyl group may optionally be converted to at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O- or NR. 13 R 14 Replace, where R 13 and R14 Each can independently represent hydrogen or (C1-C8) alkyl. In a particular embodiment, R 11 and R 12 Each can independently represent hydrogen, (C1-C8) alkyl, or cycloalkyl; where R 11 or R 12 The alkyl or cycloalkyl group may optionally be converted to at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O- or NR. 13 R 14 Replace, where R 13 and R 14 Each can independently represent hydrogen or (C1-C8) alkyl. In a particular embodiment, R 11 and R 12 Each can independently represent hydrogen, (C1-C4)alkyl, or (C3-C4)cycloalkyl; where R 11 or R 12 The alkyl or cycloalkyl group may optionally be converted to at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O- or NR. 13 R 14 Replace, where R 13 and R 14 Each can independently represent hydrogen or (C1-C8) alkyl. In one embodiment, R 11 and R 12 Each can independently represent hydrogen, (C1-C4)alkyl, or (C3-C4)cycloalkyl; where R 11 or R 12 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, OH, =O, (C1-C4)alkyl, (C1-C4)alkyl-O-, or NR. 13 R 14 Replace, where R 13 and R 14 Each can independently represent hydrogen or (C1-C4) alkyl. In a preferred embodiment, R 11 R12 and R12 each independently represent hydrogen, methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl (preferably 2-hydroxy-2-methyl-propyl), methoxyethyl, ethyl-OC(O)-, cyclobutyl, or cyclopropyl. In another preferred embodiment, R 11 and R 12 Each of these independently represents methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl (preferably 2-hydroxy-2-methyl-propyl), methoxyethyl, ethyl-OC(O)-, cyclobutyl, or cyclopropyl. In a preferred embodiment, R 11 and R 12Each can independently represent hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, ethyl-O-C(O)-, or cyclopropyl. In another preferred embodiment, R 11 and R 12 Each can be independently represented as methyl, ethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, ethyl-OC(O)-, or cyclopropyl.

[0086] According to one implementation, R 10 Indicates NR 5 R 6 According to a different implementation, R 10 Represents C(R) 5 (R) 6 (R) 9 ).

[0087] According to one aspect of the invention, R 10 Indicates NR 5 R 6 or C(R) 5 (R) 6 (R) 9 ), where R 5 R 6 and R 9 The definition is as follows.

[0088] According to one implementation, R 5 Represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl. In one embodiment, R 5 R represents hydrogen. In one embodiment, R... 5 The term represents (C1-C8) alkyl. In one embodiment, the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In one embodiment, the alkyl or cycloalkyl group is not substituted. In a particular embodiment, R... 5 This indicates methyl, trideuteryl (CD3), or ethyl. In another preferred embodiment, R 5 It indicates hydrogen, methyl, trideuteryl (CD3), or ethyl.

[0089] According to one implementation, R 6 Represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). According to a preferred embodiment, R 6 It does not represent hydrogen. In a preferred embodiment, R 6This indicates (C1-C8) alkyl or cycloalkyl. In one embodiment, the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In one embodiment, the alkyl or cycloalkyl group is optionally substituted with one or two halogens (preferably one or two F). In one embodiment, the alkyl or cycloalkyl group is not substituted. In another preferred embodiment, R... 6 It represents ethyl, propyl (preferably n-propyl), 3-fluoropropyl (preferably 3-fluoron-propyl), butyl (preferably tert-butyl) or difluorocyclobutyl (preferably 3,3-difluorocyclobutyl).

[0090] According to one implementation, R 5 and R 6 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl and / or R 6 This indicates (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In another preferred embodiment, R 5 Indicates hydrogen, methyl, trideuteryl (CD3) or ethyl and / or R 6 This indicates ethyl, propyl (preferably n-propyl), 3-fluoropropyl (preferably 3-fluoron-propyl), butyl (preferably tert-butyl), or difluorocyclobutyl (preferably 3,3-difluorocyclobutyl). In one embodiment, R 5 Represents hydrogen. In one particular implementation, R 5 Represents hydrogen, and R 6 It represents (C1-C8) alkyl (preferably butyl; more preferably tert-butyl). In a particular embodiment, R 5 and R 6 Each can be independently represented as (C1-C8) alkyl (preferably ethyl).

[0091] According to one implementation, R 5 and R 6 Together with the carbon or nitrogen atoms they are bonded to, they form cycloalkyl or heterocycloalkyl groups. In a preferred embodiment, R 5 and R 6 Together with the carbon atoms they are attached to, they form cycloalkyl groups. In a preferred embodiment, R 5 and R 6Together with the nitrogen atoms they are bonded to, they form pyrrolidine, piperidine, or piperazine. In one embodiment, the cycloalkyl or heterocycloalkyl group is optionally substituted with at least one halogen (preferably, F). In one embodiment, the cycloalkyl or heterocycloalkyl group is optionally substituted with at least one phenyl, benzyl, or phenylethyl group; wherein the phenyl, benzyl, or phenylethyl group is optionally substituted with at least one halogen (preferably, Cl or F; more preferably, Cl). In a particular embodiment, R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form pyrrolidines, pyrrolidines substituted with one or two halogens (preferably one or more F; more preferably two F), piperidine, phenylpiperidine, piperazine, or phenylethyl-piperazine substituted with one halogen (preferably one Cl; preferably, halogen-substituted phenyl). In another preferred embodiment, R 5 and R 6 Together with the nitrogen atoms they bind, they form cyclopentyl, difluoropyrrolidine (preferably 3,3-difluoropyrrolidine), phenyl-piperidine (preferably 4-phenyl-piperidine-1-yl), or (chlorophenyl)ethyl-piperazine (preferably 4-(4-chlorophenyl)ethyl]piperazine-1-yl).

[0092] In one implementation, R 9 Indicates hydrogen or (C1-C8) alkyl. In one embodiment, R 9 This indicates a (C1-C8) alkyl group. In one embodiment, the alkyl group is not substituted. In a preferred embodiment, R... 9 It represents hydrogen.

[0093] In one particular implementation, R 5 and R 6 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives), and R 9 Represents hydrogen. In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl and / or R 6 The term represents (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F), and R 9 Represents hydrogen. In another preferred embodiment, R 5 Indicates hydrogen, methyl, trideuteryl (CD3) or ethyl and / or R 6 The symbol represents ethyl, propyl (preferably n-propyl), 3-fluoropropyl (preferably 3-fluoron-propyl), butyl (preferably tert-butyl), or difluorocyclobutyl (preferably 3,3-difluorocyclobutyl), and R 9 R represents hydrogen. In one embodiment, R... 5Represents hydrogen. In one particular implementation, R 5 Represents hydrogen, and R 6 It represents (C1-C8) alkyl (preferably butyl; more preferably tert-butyl), and R 9 Represents hydrogen. In one particular implementation, R 5 and R 6 Each independently represents a (C1-C8) alkyl group (preferably ethyl), and R 9 It represents hydrogen.

[0094] According to one aspect of the invention, R 10 Indicates NR 5 R 6 , where R 5 and R 6 The definition is as follows.

[0095] According to one implementation, R 5 Represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl. In one embodiment, R 5 R represents hydrogen. In one embodiment, R... 5 The term represents (C1-C8) alkyl. In one embodiment, the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In one embodiment, the alkyl or cycloalkyl group is not substituted. In a particular embodiment, R... 5 This indicates methyl, trideuteryl (CD3), or ethyl. In another preferred embodiment, R 5 It indicates hydrogen, methyl, trideuteryl (CD3), or ethyl.

[0096] According to one implementation, R 6 Represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). According to a preferred embodiment, R 6 It does not represent hydrogen. In a preferred embodiment, R 6 The term represents (C1-C8) alkyl or cycloalkyl. In one embodiment, the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In one embodiment, the alkyl or cycloalkyl group is optionally substituted with one or two halogens (preferably one or two F). In one embodiment, the alkyl or cycloalkyl group is not substituted. In another preferred embodiment, R... 6 It represents ethyl, propyl (preferably n-propyl), 3-fluoropropyl (preferably 3-fluoron-propyl), butyl (preferably tert-butyl) or difluorocyclobutyl (preferably 3,3-difluorocyclobutyl).

[0097] According to one implementation, R 5 and R 6 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl and / or R 6 This indicates (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In another preferred embodiment, R 5 Indicates hydrogen, methyl, trideuteryl (CD3) or ethyl and / or R 6 This indicates ethyl, propyl (preferably n-propyl), 3-fluoropropyl (preferably 3-fluoron-propyl), butyl (preferably tert-butyl), or difluorocyclobutyl (preferably 3,3-difluorocyclobutyl). In one embodiment, R 5 Represents hydrogen. In one particular implementation, R 5 Represents hydrogen, and R 6 It represents (C1-C8) alkyl (preferably butyl; more preferably tert-butyl). In a particular embodiment, R 5 and R 6 Each can be independently represented as (C1-C8) alkyl (preferably ethyl).

[0098] According to one implementation, R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form heterocyclic alkyl groups. In a preferred embodiment, R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form pyrrolidine, piperidine, or piperazine. In one embodiment, the heterocyclic alkyl group is optionally substituted with at least one halogen (preferably, F). In one embodiment, the heterocyclic alkyl group is optionally substituted with at least one phenyl, benzyl, or phenylethyl group; wherein the phenyl, benzyl, or phenylethyl group is optionally substituted with at least one halogen (preferably, Cl or F; more preferably, Cl). In a particular embodiment, R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form pyrrolidines, pyrrolidines substituted with one or two halogens (preferably one or more F; more preferably two F), piperidines, phenylpiperidines, piperazines, or phenethylpiperazines substituted with one halogen (preferably one Cl; preferably, a halogen-substituted phenyl). In another preferred embodiment, R 5 and R 6Together with the nitrogen atoms they are bound to, they form difluoropyrrolidine (preferably 3,3-difluoropyrrolidine), phenyl-piperidine (preferably 4-phenyl-piperidine-1-yl), or (chlorophenyl)ethyl-piperazine (preferably 4-(4-chlorophenyl)ethyl]piperazine-1-yl).

[0099] According to one aspect of the invention, R 10 Represents C(R) 5 (R) 6 (R) 9 ); and R 5 R 6 and R 9 The definition is as follows.

[0100] According to one implementation, R 5 Represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl. In one embodiment, R 5 R represents hydrogen. In one embodiment, R... 5 The term represents (C1-C8) alkyl. In one embodiment, the alkyl or cycloalkyl group is optionally substituted with at least one halogen (preferably F). In one embodiment, the alkyl or cycloalkyl group is not substituted. In a particular embodiment, R... 5 This indicates methyl or ethyl. In another preferred embodiment, R 5 It indicates hydrogen, methyl, or ethyl.

[0101] According to one implementation, R 6 Represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). According to a preferred embodiment, R 6 It does not represent hydrogen. In a preferred embodiment, R 6 The term represents (C1-C8) alkyl. In one embodiment, the alkyl group may optionally be substituted with at least one halogen (preferably F). In a preferred embodiment, the alkyl group is not substituted. In another preferred embodiment, R... 6 It represents ethyl or butyl (preferably tert-butyl).

[0102] According to one implementation, R 5 and R 6 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives). In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl and / or R 6It represents (C1-C8) alkyl. In another preferred embodiment, R 5 Indicates hydrogen, methyl or ethyl and / or R 6 This indicates ethyl or butyl (preferably tert-butyl). In one embodiment, R... 5 Represents hydrogen. In one particular implementation, R 5 Represents hydrogen, and R 6 It represents (C1-C8) alkyl (preferably butyl; more preferably tert-butyl). In a particular embodiment, R 5 and R 6 Each can be independently represented as (C1-C8) alkyl (preferably ethyl).

[0103] According to one implementation, R 5 and R 6 Together with the carbon atoms they are attached to, they form cycloalkyl or heterocycloalkyl groups. In a preferred embodiment, R 5 and R 6 Together with the carbon atoms to which they are attached, they form cycloalkyl groups. In one embodiment, the cycloalkyl or heterocycloalkyl group is optionally substituted with at least one halogen (preferably F). In a preferred embodiment, the cycloalkyl or heterocycloalkyl group is not substituted. In another preferred embodiment, R... 5 and R 6 Together with the nitrogen atoms they are bound to, they form cyclopentyl groups.

[0104] In one implementation, R 9 Indicates hydrogen or (C1-C8) alkyl. In one embodiment, R 9 This indicates a (C1-C8) alkyl group. In one embodiment, the alkyl group is not substituted. In a preferred embodiment, R... 9 It represents hydrogen.

[0105] In one particular implementation, R 5 and R 6 Each independently represents hydrogen, (C1-C8)alkyl, cycloalkyl, or cycloalkyl-(C1-C8)alkyl- (including its deuterated derivatives), and R 9 Represents hydrogen. In a preferred embodiment, R 5 Indicates hydrogen or (C1-C8) alkyl and / or R 6 It represents (C1-C8) alkyl, and R 9 Represents hydrogen. In another preferred embodiment, R 5 Indicates hydrogen, methyl or ethyl and / or R 6 It represents ethyl or butyl (preferably tert-butyl), and R 9 R represents hydrogen. In one embodiment, R... 5Represents hydrogen. In one particular implementation, R 5 Represents hydrogen, and R 6 It represents (C1-C8) alkyl (preferably butyl; more preferably tert-butyl), and R 9 Represents hydrogen. In one particular implementation, R 5 and R 6 Each independently represents a (C1-C8) alkyl group (preferably ethyl), and R 9 It represents hydrogen.

[0106] According to one embodiment, at least one heterocyclic alkyl group present in the compound of formula (I) is a water-soluble group, that is, the presence of this group in the molecule increases its solubility in water compared to the same molecule that does not contain a heterocyclic alkyl group.

[0107] According to one embodiment, the compound of formula (I) is the compound of formula (Ia). (Ia) Or its pharmaceutically acceptable salts and / or solvates; Among them, W and R B R D R 1 -R 4 A 1 -A 5 R10 is as defined in this paper based on equation (I).

[0108] In one implementation, W in formula (Ia) represents CH. In one implementation, R in formula (Ia) B and R D Each can be represented independently as F or Cl. In a particular implementation, R B Let F be an integer, and R be an integer. D It represents Cl.

[0109] According to one embodiment, the compounds of formula (I) are selected from the compounds in Table 1 below and their pharmaceutically acceptable salts and / or solvates.

[0110] Table 1

[0111] All references to the compounds of the present invention (e.g., "compounds of formula (I)") herein include references to their salts, solvates, multicomponent complexes, and liquid crystals. All references to the compounds of the present invention herein include references to their polymorphs and crystal habits. All references to the compounds of the present invention herein include references to their isotopically labeled compounds (including their deuterated compounds). All references to the compounds of the present invention herein include references to their stereoisomers. All references to the compounds of the present invention herein include references to their pharmaceutically acceptable prodrugs.

[0112] In particular, the compounds of the present invention can be in the form of pharmaceutically acceptable salts. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable salts. Pharmaceutically acceptable salts include their acid addition salts and base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetates, adipicates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, cyclosulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, gluconates, glucurons, hexafluorophosphates, phenacetinates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodides / iodides, hydroxyethylsulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, sucroseates, stearates, succinates, tannates, tartrates, toluenesulfonates, trifluoroacetates, and sinetes. Suitable alkali salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzoxin, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, alkanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed. When the compound contains both acidic and basic groups, it can also form internal salts, and such compounds are within the scope of this invention. When the compound contains a hydrogen-donating heteroatom (e.g., NH), this invention also includes salts and / or isomers formed by transferring said hydrogen atom into the molecule via a basic group or atom. Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by one or more of the following methods: (i) by reacting the compound with a desired acid; (ii) by reacting the compound with a desired base; (iii) by removing an acid- or base-instable protecting group from a suitable precursor of the compound, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam) using a desired acid; and / or (iv) by reacting with a suitable acid or by means of a suitable ion exchange column to convert one salt of the compound into another. All these reactions are generally carried out in solution. The salt can be precipitated from solution and collected by filtration, or recovered by evaporating the solvent. The degree of ionization in the salt can vary from complete ionization to almost no ionization.

[0113] In particular, the compounds of the present invention can be in the form of pharmaceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharmaceutically acceptable salts and solvates.

[0114] In particular, the compounds of the present invention may include at least one asymmetric center and thus may exist in different stereoisomeric forms. Therefore, all references to the compounds of the present invention herein include references to all possible stereoisomers (including not only racemic compounds but also individual enantiomers and their non-racemic mixtures). Non-racemic mixtures may contain any amount of each different stereoisomer; for example, one stereoisomer may be dominant (e.g., a 90 / 10 or 80 / 20 mixture), or the enantiomer ratio may be close to that of a racemic mixture (e.g., a 40 / 60 mixture). When a compound is required as a single enantiomer, such a single enantiomer can be obtained by stereooriented synthesis, by resolution of the final product or any convenient intermediate, or by various chiral chromatographic methods known in the art. Resolution of the final product, intermediate, or starting material can be performed by any suitable method known in the art.

[0115] Pharmaceutical Composition

[0116] Another object of the present invention is a composition comprising the compounds according to the invention as described herein. According to one embodiment, the composition further comprises at least one pharmaceutically acceptable carrier, such that the composition is a "pharmaceutical composition" as defined herein.

[0117] In a first embodiment, the pharmaceutical composition comprises the compound according to the invention as the sole therapeutic agent. In a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent, such as, for example, a therapeutic agent suitable for treating neurological disorders.

[0118] Another object of the present invention is a medicine comprising the compounds according to the present invention as described herein.

[0119] Reagent test kit

[0120] Another object of the present invention is a kit (hereinafter referred to as the "kit") comprising a portion of a compound or composition according to the present invention as described herein. According to one embodiment, the kit comprises a preparation, such as, for example, packaging or a container. According to one embodiment, the kit includes instructions for use. The kit can be promoted, distributed, or sold as a unit for carrying out the methods of the present invention.

[0121] According to one embodiment, the kit comprises: a pharmaceutical composition containing a compound according to the invention, and another separate pharmaceutical composition containing at least one other therapeutic agent (e.g., a therapeutic agent suitable for treating neurological disorders).

[0122] Medical uses of compounds

[0123] Another object of the present invention is to use the compounds or compositions according to the invention as described herein as pharmaceuticals.

[0124] Another object of the present invention is the use of compounds or compositions according to the invention, as described herein, for the treatment of neurological disorders.

[0125] Another object of the present invention is a method for treating neurological disorders in a subject in need. Another object of the present invention is the use of the compounds or compositions according to the present invention as described herein in the preparation of a medicament for treating neurological disorders. Another object of the present invention is the use of the compounds or compositions according to the present invention as described herein for treating neurological disorders.

[0126] According to one embodiment, a method or use includes the step of administering a therapeutically effective amount of a compound, composition, or medicament according to the invention as described herein to a subject.

[0127] According to one embodiment, the neurological disorders treated by the method or use of the present invention are: - Diseases or conditions associated with defective neurological development, such as, for example, congenital megacolon, schizophrenia, ataxia-telangiectasia, age-related decline in neurological function, or neurodevelopmental disorders; - Neurodegenerative diseases or conditions, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, retinal neurodegenerative diseases, neuroophthalmological diseases, neurotrophic keratitis, Charcot-Marie-Tuss disease, spinal muscular atrophy, epilepsy (e.g., epilepsy syndrome, seizure syndrome, or chronic neurological disorders presenting as epilepsy), dementia, age-related decline in neurological function, prions, Creutzfeldt-Jakob disease, multiple system atrophy (ShyDrager syndrome), multiple sclerosis, or Guillain-Barré syndrome; - Diseases or conditions associated with nerve damage or neurotoxicity, such as head injury, brain injury, traumatic brain injury, peripheral nerve injury, traumatic peripheral nerve injury, peripheral neuropathy, complications of nerve transplantation, spinal cord injury, traumatic spinal cord injury, nerve transection or nerve injury, cerebrospinal cord transection, brain or nerve cell injury, syringomyelia, optic neuropathy, trauma, stroke, ischemia, ischemic stroke, neurotoxicity caused by alcohol or drug abuse (e.g., ecstasy, methamphetamine, etc.), or aphasia. - Neurodevelopmental disorders, such as Rett syndrome, X-linked intellectual disability, Fragile X syndrome, Down syndrome, autism spectrum disorder, congenital megacolon, Tourette syndrome, childhood learning disabilities, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Angelman syndrome, microsymptom, schizophrenia, language disorders, preterm birth, perinatal ischemic stroke, spina bifida, intellectual disability, non-syndromic X-linked intellectual disability, Onding syndrome or WAGR syndrome; - Neuropsychiatric disorders, such as depression, major depressive disorder, schizophrenia, schizophrenic-type disorder, schizophrenic affective disorder, paranoia, anxiety disorder, anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, post-traumatic stress disorder, bipolar disorder, anorexia nervosa, bulimia nervosa, anhedonia, apathy, dementia, substance-induced dementia, motor disorders and / or tic disorders characterized by motor and / or vocal tics (e.g., Tourette syndrome), substance use behavior, addiction, mood disorders, suicide, cancer-related psychiatric symptoms, Alzheimer's disease, Huntington's disease, frontotemporal dementia, or reward deficiency syndrome (RDS). -Motor disorders, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, motor disorders and tic disorders characterized by motor and / or vocal tics (e.g., Tourette syndrome), ataxia, ataxic muscle rigidity (spasticity), Charcot-Marie-Tuss disease, spinal muscular atrophy, Wednisch-Hoffmann disease, or chronic proximal spinal muscular atrophy; - Pain disorders, such as neuralgia, trigeminal neuralgia, chronic pain, inflammatory pain, arthritis-related pain, fibromyalgia, back pain, cancer-related pain, pain associated with digestive disorders, Crohn's disease, autoimmune diseases, endocrine disorders, diabetic neuropathy, phantom limb pain, spontaneous pain, chronic postoperative pain, chronic temporomandibular pain, burning pain, postherpetic neuralgia, AIDS-related pain, type I and II complex regional pain syndromes, trigeminal neuralgia, chronic back pain, spinal cord injury-related pain, drug-related and recurrent acute pain, neuropathic pain, or abnormal neuronal activity leading to neurodysthesia in diseases such as diabetes, MS, and motor neuron disease; - Ophthalmic diseases or eye conditions, such as retinal diseases, retinal neurodegenerative diseases, retinitis pigmentosa, non-arteritis anterior ischemic optic neuropathy (NAION), macular degeneration, age-related macular degeneration, glaucoma, diabetic retinopathy, optic neuropathy and retinal degeneration, neuroophthalmological diseases, age-related cataracts, primary open-angle glaucoma (POAG), retinal ganglion cell damage, high intraocular pressure, ischemic optic neuropathy, macular telangiectasia, cystoid macular edema, type 2 macular telangiectasia, neurotrophic keratitis, or strabismus; - Intestinal system disorders or gastrointestinal disorders, such as intestinal motility disorders, constipation, congenital megacolon, inflammatory bowel disease, intestinal neuronal dysplasia, ulcerative colitis, achalasia, esophageal spasm, duodenal ulcer, Zollinger-Ellison syndrome, hyperacidity, malabsorption, or intestinal inflammation; - Progressive muscular dystrophy, such as Duchenne dystrophy, Becker disease, Emory-Dreyfus disease, Landowy-Dejerine disease, scapulohumeral disease, limb girdle disease, Von Graefe-Fuchs disease, oculopharyngeal disease, congenital myotonia, congenital or acquired myopathy, Charcot-Marie-Tuss disease, Wednig-Hoffmann disease, or chronic proximal spinal muscular atrophy; - Diseases or conditions associated with impaired long-term or short-term memory, such as memory loss, benign amnesia, or Alzheimer's disease; - Autoimmune diseases, such as multiple sclerosis, autoimmune encephalomyelitis, autoimmune encephalitis, autoimmune hemolytic anemia, chronic lymphocytic leukemia, Churg-Strauss syndrome, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, thyroid-associated orbital disease, autoimmune thyroiditis, Guillain-Barré syndrome, or autoimmune thrombocytopenic purpura; - Neurological diseases or conditions, such as damage to cochlear sensory cells, auditory perception defects, hearing loss, or tinnitus; - Sleep disorders, such as narcolepsy, restless legs syndrome, obstructive sleep apnea, chronic insomnia, paradoxical sleep deprivation, or REM sleep deprivation; - Cerebrovascular or neurovascular diseases, such as early brain injury (EBI) following subarachnoid hemorrhage (SAH), cerebral ischemia, stroke, hypoxic-ischemic brain injury, perinatal arterial ischemic stroke, or neovascular age-related macular degeneration (nvAMD). - Substance abuse disorders, such as substance dependence, substance abuse and the aftereffects of substance abuse dependence, substance-induced mental disorders, substance withdrawal and substance-induced dementia or amnesia. - Neuronal responses to viral infections, trypanosomiasis, AIDS-related neurological deficits, obesity, temporomandibular joint dysfunction, aphasia, Bell's palsy, encephalitis, nephropathy or renal dysfunction, pheochromocytoma, metabolic syndrome, cancer, eczema, thrombocytopenia; developmental disorders; disseminated intravascular coagulation (DIC); myelodyplasia; immune thrombocytopenic purpura (ITP), HIV-induced ITP, neuro-oncological diseases or conditions, neuroimmunological diseases or conditions, type 2 polyendocrine adenomas, Hippel-Lindau disease (VHL), type 1 neurofibromatosis, scleroderma, epidermal and stromal wound healing disorders and / or scarring disorders; or - Diseases or conditions related to aging and / or growing old.

[0128] According to one implementation, the neurological disorder is epilepsy, such as Dravet syndrome, benign Roland's epilepsy, frontal lobe epilepsy, infantile myositis, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., epileptiform seizures), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonus, infantile epilepsy (SMEI), benign neonatal familial seizures (BFNC), West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, and migratory partial epilepsy. Epilepsy in infants, tuberous sclerosis syndrome (TSC), focal cortical dysplasia, type I anegyria, Miller-Dieker syndrome, Angelman syndrome, Fragile X syndrome, epilepsy in autism spectrum disorders, epilepsy in subcortical banded gray matter heterotopia, epilepsy in Walker-Warburg syndrome, epilepsy in Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, bilateral generalized myoclonus, menstrual epilepsy, Jacksonian seizure disorder, Unverricht-Lundborg disease, or photosensitive epilepsy.

[0129] According to one embodiment, as described herein, the composition or drug according to the invention is administered to a subject and can be formulated using methods well known in the art. Non-limiting examples of suitable forms for administration include solutions (e.g., sterile aqueous solutions), gels, dispersions, emulsions, suspensions, and solid forms (e.g., powders or liposomes) suitable for addition to a liquid prior to use to prepare a solution or suspension.

[0130] As described herein, the compositions or pharmaceuticals according to the invention may be administered using routes of administration well known in the art, such as parenteral, oral, inhalation, spray, rectal, nasal or via implanted receptacle.

[0131] However, it should be understood that the total daily dosage of a compound, composition, or drug will be determined by the attending physician within the bounds of reasonable medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disease being treated and its severity; the activity of the compound used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific therapeutic agent used; the duration of treatment; drugs used in combination with or concurrently with the specific therapeutic agent used; and similar factors well-known in the medical field. For example, it is entirely within the scope of the art to begin with a dose of the compound below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. The total dose required for each treatment can be administered via multiple doses or a single dose.

[0132] In one embodiment, the compound is administered at a dose of about 0.01 to 500 mg per kg of patient body weight per day, and may be given in single or multiple doses. Preferably, the dose level is about 0.1 to about 250 mg / kg per day; more preferably, about 0.5 to about 100 mg / kg per day. Suitable dose levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dose may be about 0.05 to 0.5, about 0.5 to 5, or about 5 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing about 1.0 to 1000 mg of active ingredient (particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 mg of active ingredient) for adjusting the dosage for the patient being treated according to symptoms. The compound may be administered once to four times daily, preferably once or twice daily. However, it should be understood that specific dose levels and frequencies can vary for any particular patient and depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, route and time of administration, excretion rate, drug composition, severity of the specific condition, and the host receiving treatment.

[0133] According to a first embodiment, as described herein, the composition or medicament according to the invention is administered as the sole therapeutic agent. According to a second embodiment, as described herein, the composition or medicament according to the invention is administered before, simultaneously with, and / or after at least another therapeutic agent. In one embodiment, the other therapeutic agent is suitable for treating neurological disorders.

[0134] Another object of the present invention is a method for promoting the survival and / or function of neuronal cells. Another object of the present invention is the use of compounds or compositions according to the invention, as described herein, to promote the survival and / or function of neuronal cells. According to one embodiment, the method or use includes the step of contacting neuronal cells with a therapeutically effective amount of a compound, composition, or drug according to the invention, as described herein. The method or use may be in vitro, ex vivo, or in vivo.

[0135] Another object of the present invention is a method for rescuing neuronal function after neuronal cells have been subjected to damage, events, or conditions detrimental to neuronal function. Another object of the present invention is a compound or composition according to the invention, as described herein, for rescuing neuronal function after neuronal cells have been subjected to damage, events, or conditions detrimental to neuronal function. Such damage, events, or conditions include, but are not limited to, neuronal stress such as hypoxia or ischemia; traumatic injury; and exposure to toxic molecules, such as anomalously misfolded proteins, protein aggregates, excitotoxic substances, reactive oxygen species, endoplasmic reticulum stress factors, mitochondrial stress, Golgi antagonists, etc. According to one embodiment, the method or use includes the step of contacting neuronal cells with a therapeutically effective amount of the compound, composition, or drug according to the invention, as described herein. The method or use may be in vitro, ex vivo, or in vivo.

[0136] Another object of the present invention is a method for binding or modulating GFRα1 using compounds or compositions according to the invention as described herein. Another object of the present invention is the use of compounds or compositions according to the invention as described herein for binding or modulating GFRα1. According to a preferred embodiment, the compound or composition is used to activate GFRα1. In one embodiment, GFRα1 is human GFRα2, preferably having SEQ ID NO:1.

[0137] Another object of the present invention is a method for activating the GFRα1 / RET signaling pathway using compounds or compositions according to the invention as described herein. Another object of the present invention is the use of compounds or compositions according to the invention as described herein for activating the GFRα1 / RET signaling pathway.

[0138] Another object of the present invention is a method for detecting GFRα1 in a sample using a compound or composition according to the invention as described herein. Another object of the present invention is the use of a compound or composition according to the invention as described herein for detecting GFRα1 in a sample. In one embodiment, GFRα1 is human GFRα2, preferably having SEQ ID NO:1. In one embodiment, the compound according to the invention may be fused with a detectable marker, such as a fluorophore or any other portion that can re-emit light upon photoexcitation, a radioactive marker, a contrast agent, etc.

[0139] Preparation process

[0140] Compound Synthesis

[0141] As described herein, the compounds of the present invention can be prepared by synthetic methods well known in the art.

[0142] Another object of the present invention is a method for preparing compounds according to the invention as described herein. According to one embodiment, the method is Buchwald-Hartwig amination.

[0143] According to one aspect of the invention, the compounds according to the invention are prepared starting from compounds of formula (II): (II) Where A 1 -A 5 and R 10 As defined in this paper based on equation (I), where X represents a halide or -CF3SO3.

[0144] The compounds of formula (II) described herein can be prepared by synthetic methods well known in the art.

[0145] According to one embodiment, the process includes the step of reacting a compound of formula (II) with a compound of formula (III) in the presence of a base and a metal catalyst to obtain the compound of the present invention: (II) Where A 1 -A 5 and R 10 As defined in this paper based on equation (I), and where X represents a halide or -CF3SO3, (III) Among them, W and R A -R D and R 1 -R 4As defined in this paper based on equation (I).

[0146] The base can be any suitable base known in the art. In one embodiment, the base is cesium carbonate (Cs₂CO₃), sodium carbonate (Na₂CO₃), or potassium carbonate (K₂CO₃). In a particular embodiment, the base is cesium carbonate (Cs₂CO₃). In one embodiment, the base is sodium tert-butoxide (t-BuONa), potassium tert-butoxide (t-BuOK), or potassium phosphate. In a particular embodiment, the base is sodium tert-butoxide (t-BuONa). The catalyst can be any suitable catalyst known in the art. In one embodiment, the catalyst is a palladium catalyst. In a particular embodiment, the catalyst is Pd(Oac)₂ and rac-BINAP(2, -bis(diphenylphosphine)-1, -Binaphthalene) system. In one particular embodiment, the catalyst is XPhos-Pd-G3. In one embodiment, X represents a halide. In one particular embodiment, X represents Br. In one embodiment, the reaction is carried out in a solvent. The solvent can be any suitable solvent known in the art. In one particular embodiment, the solvent is toluene. In one embodiment, the reaction is carried out under reflux.

[0147] According to another embodiment, the method includes: ( -1) In the presence of a base and a metal catalyst, the compound of formula (II) is reacted with a monoprotected piperazine of formula (MPP) (i.e., wherein only one of the NH groups is protected by the R group). P The steps of the protected piperazine reaction to obtain the compound of formula (IV) (II) Where A 1 -A 5 and R 10 As defined in this paper based on equation (I), and where X represents a halide or -CF3SO3, (MPP) Where R 1 -R 4 As defined in this paper based on equation (I); (IV) Where R 1 -R 4 A 1 -A 5 and R 10 As defined in this paper based on equation (I) and R P It is a protecting group; then ( -2) The step of deprotecting the compound of formula (IV) to obtain the compound of formula (V); (V) Where R 1 -R 4 A 1 -A 5 and R 10 As defined in this paper based on equation (I); and ( -3) The step of reacting the compound of formula (V) with the compound of formula (VI) in the presence of a peptide coupling agent and a base to obtain the compound of the present invention. (VI) Among them, W and R A -R D As defined in this paper based on equation (I).

[0148] In one implementation, step ( The base and / or catalyst in step (a-1) are as described above based on step (a-1). In one embodiment, X represents a halide. In a particular embodiment, X represents Br. The protecting group (RP) can be any suitable protecting group known in the art, such as, for example, tert-butoxycarbonyl (Boc). The protecting group can be in step (a-1). -2) is removed by any method known in the art suitable for the nature of the protecting group, such as the addition of a strong Brønsted acid (e.g., hydrochloric acid [HCl]). Step ( -3) The peptide coupling agent can be any suitable peptide coupling agent known in the art, such as, for example, 2-( 1H (-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU). Steps ( The base in step -3) can be any suitable base known in the art, such as an amine base. According to one embodiment, the amine is triethylamine (Et3N) or diisopropylethylamine (iPr2NEt). In one embodiment, step ( The reaction -3) is carried out in a solvent. The solvent can be any suitable solvent known in the art. In one particular embodiment, the solvent is dimethylformamide (DMF) and / or tetrahydrofuran (THF). In one particular embodiment, the solvent is dichloroethane (DCE) and / or acetonitrile (MeCN). In one embodiment, the reaction is carried out at room temperature (RT).

[0149] In one embodiment, the process further includes a post-processing step (b). In one embodiment, post-processing step (b) includes an extraction step using a solvent. In a particular embodiment, the solvent is ethyl acetate (EtOAc). In a particular embodiment, the solvent is water or a 1 N HCl solution. In a particular embodiment, the solvent is dichloromethane (DCM). In one embodiment, post-processing step (b) includes a filtration step. In a particular embodiment, filtration is performed on a Celite®. In one embodiment, post-processing step (b) includes a concentration step under reduced pressure. In one embodiment, the process further includes a purification step (c). Purification can be any suitable purification method known in the art. In one embodiment, purification step (c) includes purification by chromatography. In a particular embodiment, the chromatography is rapid chromatography (FC) (e.g., cHex / EtOAc gradient), preparative thin-layer chromatography (PTLC), or semi-preparative high-performance liquid chromatography (HPLC).

[0150] According to another aspect of the invention, the compounds according to the invention are prepared starting from compounds of formula (VII). (VII) Among them, W and R A -R D R 1 -R 4 R 10 and R 12 As defined in this paper based on equation (I).

[0151] This aspect particularly relates to the preparation of compounds according to the invention, wherein A 1 Let N and A represent... 2 Represents C, A 3 Indicates CH, A 4 Let N and A represent... 4 CR 12 .

[0152] According to one embodiment, the process includes the step of reacting a compound of formula (VII) in the presence of a dehydrating agent to obtain the compound of the present invention: (VII) Among them, W and R A -R D R 1 -R 4 R 10 and R 12 As defined in this paper based on equation (I).

[0153] The dehydrating agent can be any suitable dehydrating agent known in the art, such as, for example, acetic anhydride (Ac2O) or phosphorus oxychloride (POCl3). In one embodiment, the dehydrating agent is phosphorus oxychloride (POCl3).

[0154] The compounds of formula (VII) described herein can be prepared by synthetic methods well known in the art.

[0155] According to one embodiment, the compound of formula (VII) herein is prepared by reacting the compound of formula (VIII) with formula R under one of the following conditions. 12 -C(=O)-LG compounds (where R) 12 Prepared as defined in this paper based on formula (I), and LG (which is the “leaving group” as defined below) by reaction: (VIII) Among them, W and R A -R D R 1 -R 4 and R 10 As defined in this paper based on equation (I), (i) LG represents ethoxy (-OCH2CH3), and R 12 Indicates hydrogen (preferably at a temperature of at least about 60°C); (ii) LG represents Cl, in the presence of a base; or (iii) LG represents OH in the presence of a peptide coupling agent.

[0156] The base can be any suitable base known in the art, such as, for example N,N -Diisopropylethylamine (DIPEA) or triethylamine (Et3N). The peptide coupling agent (or "amide bond forming agent") can be any suitable peptide coupling agent known in the art, such as, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium (TBTU) or 2-(2-pyridin-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate ester (TPTU).

[0157] The compounds of formula (VIII) described herein can be prepared by synthetic methods well known in the art.

[0158] According to one embodiment, the compound of formula (VIII) herein is prepared by a method comprising the following steps: (a) In the presence of a palladium complex and a base, the compound of formula (IX) reacts with formula R. P HN-CH2-BF3K (where R) P (Represents the reaction of compounds with protecting groups) (IX) Among them, W and R A -R D R 1 -R 4 and R 10 As defined in this paper based on equation (I); then (b) Deprotection steps.

[0159] The palladium complex can be any suitable palladium complex known in the art, such as, for example, di(1-adamantyl)-n-butylphosphine (CatacXium-Pd-G3). The base can be any suitable base known in the art, such as, for example, cesium carbonate (Cs₂CO₃). Protecting group (R) P The protecting group can be any suitable protecting group known in the art, such as, for example, tert-butoxycarbonyl (Boc). The deprotection step can be carried out, for example, by hydrochloric acid (HCl) in dioxane.

[0160] The compounds of formula (IX) in this article can be prepared by synthetic methods well known in the art.

[0161] According to one embodiment, the compound of formula (IX) herein is prepared by reacting a compound of formula (X) with a compound of formula (III) in the presence of a base. (X) Where R 10 As defined in this paper based on equation (I), (III) Among them, W and R A -R D and R 1 -R 4 As defined in this paper based on equation (I).

[0162] The base can be any suitable base known in the art, such as, for example, N,N-diisopropylethylamine (DIPEA).

[0163] Synthetic intermediates

[0164] Another object of the present invention is a compound of formula (II). (II) Where A 1 -A 5 and R 10 As defined in this paper based on equation (I), where X represents a halide or -CF3SO3.

[0165] Another object of the present invention is a compound of formula (III). (III) Among them, W and R A -R D and R 1 -R 4 As defined in this paper based on equation (I).

[0166] Another object of the present invention is a compound of formula (IV). (IV) Where R 1 -R 4 A 1 -A 5 and R 10 As defined in this paper based on equation (I), and R P Indicates a protecting group (e.g., Boc).

[0167] Another object of the present invention is a compound of formula (V). (V) Where R 1 -R 4 A 1 -A 5 and R 10 As defined in this paper based on equation (I).

[0168] Another object of the present invention is the compound of formula (VII). (VII) Among them, W and R A -R D R 1 -R 4 R 10 and R 12 As defined in this paper based on equation (I).

[0169] Another object of the present invention is compound (VIII). (VIII) Among them, W and R A -R D R 1 -R 4 and R 10 As defined in this paper based on equation (I).

[0170] Another object of the present invention is a compound of formula (IX). (IX) Among them, W and R A -R D R 1 -R4 and R 10 As defined in this paper based on equation (I).

[0171] Example

[0172] The present invention is further illustrated by the following embodiments.

[0173] Example 1: Synthesis of the compound

[0174] General Materials and Methods

[0175] abbreviation

[0176] List of abbreviations: Ac: Acetyl group Ar: Argon gas BINAP:(2, -bis(diphenylphosphine)-1, -Binaphthalene) cataCXium: bis(1-adamantyl)n-butylphosphine cPr: Cyclopropane cHex: Cyclohexane dba:(1 E 4 E 1,5-Diphenylpentan-1,4-dien-3-one DCM: Dichloromethane DCE: 1,2-Dichloroethane DMAP: 4-Dimethylaminopyridine DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DMF: Dimethylformamide Et: Ethyl FC: Rapid Chromatography m-CPBA: m-chloroperbenzoic acid PTLC: Preparative Thin-Layer Chromatography RP-FC: Reversed-phase rapid chromatography RT: Room temperature TBAF: Tetrabutylammonium fluoride TBTU: 2-( 1H (-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium TFA: Trifluoroacetic acid THF: Tetrahydrofuran XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene XPhos: Dicyclohexyl [ , , -tris(propyl-2-yl)[1, [-biphenyl]-2-yl]phosphine

[0177] Analytical methods

[0178] Recorded using a Bruker ULTRASHIELD 400 spectrometer 1 H NMR spectrum (400 MHz) and 19 F NMR spectra (376 MHz). The spectra were processed and analyzed using MestReNova. Data are presented in the following order: ppm chemical shift of the reference internal solvent signal, multiplicity, coupling constant J in Hertz, and proton number.

[0179] Reversed-phase HPLC / MS analysis was performed using a Waters Alliance 2795 HPLC system equipped with an autosampler, an online membrane degasser, a column oven (T°=45°C), a UV detector, and a ZQ quadrupole mass detector operating in ionization electrospray mode. The analyzed compounds (0.1 to 0.3 mg) were dissolved in a minimal amount of DMSO and diluted to volume with acetonitrile (total volume: 1 mL). Standard analytical parameters: flow rate: 1 mL / min, V0 注射 5 μL. Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1 × 15 50 mm). Gradient: (H2O + 0.04% v / v HCO2H (10 mM)) / CAN, from 95 / 5 to 0 / 100 in 2.5 min. Alkaline conditions: Waters Xbridge C18 column (3.5 μm, 2.1 × 50 mm). Gradient: (H2O + 0.06% v / v NH3 (aqueous) (10 mM)) / CAN, from 95 / 5 to 0 / 100 in 2.5 min.

[0180] General synthesis methods

[0181] General Scheme 1 (GP-1): Palladium-catalyzed coupling of thiols and aryl halides

[0182] Charge the desired aryl halide and XantPhos-Pd-G3 into the MW. Rinse the vial with Ar and add the desired degassing solvent. Add iPr2NEt and the desired thiol. Seal the vial and stir the mixture at 100°C for the desired time. After cooling to RT, concentrate the RM and residue under reduced pressure. Purify the residue by passing it through an FC (cHex / EtOAc gradient) to obtain the desired thioether.

[0183] General Scheme 2 (GP-2): Thioether Oxidation

[0184] Add m-CPBA to the solution of sulfide in DCM at 0°C. Stir the mixture at RT for the desired time. Add aqueous saturated Na₂S₂O₃, aqueous saturated NaHCO₃, and EtOAc. Stir the mixture vigorously for 10 minutes. Separate the layers and extract the aqueous phase with EtOAc. Wash the combined organic extracts (with brine), dry (with Na₂SO₄), filter, and concentrate under reduced pressure. Optionally purify the residue via an FC (cHex / EtOAc gradient) to obtain the desired sulfone.

[0185] General Solution 3 (GP-3): Using Pd(Oac) 2 / rac-BINAP or palladium pre-complex for Hartwig- Buchwald's association

[0186] Charge the desired aryl bromide; the desired piperazine; Cs₂CO₃, NaOt-Bu, or LiHMDS (1 M solution in THF); Pd(Oac)₂ and rac-BINAP or the desired palladium pre-complex into a microwave reaction vial. Rinse the vial with argon and add the degassed solvent. Seal the vial and reflux the reaction in a preheated heating block with stirring for the desired time. After cooling to RT, add EtOAc and filter the suspension through Celite® (EtOAc rinse). Concentrate the filtrate under reduced pressure. Purify the residue by FC or PTLC to obtain the desired product.

[0187] General Scheme 4 (GP-4): Sulfonamide Formation

[0188] A mixture of the desired sulfonyl chloride in the same solvent is added to a solution of the desired amine and Et3N or iPr2NEt in the desired solvent under RT. The reaction mixture is stirred under RT for the desired time. The reaction mixture is partitioned between EtOAc and aqueous saturated NH4Cl. The layers are separated, and the aqueous phase is extracted with EtOAc. The combined organic extracts are washed (with aqueous saturated NH4Cl, brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue is purified by FC (cHex / EtOAc gradient) or PTLC to obtain the desired product.

[0189] Synthesis of intermediate compounds

[0190] 4-(2-chloro-4-fluoro-benzoyl)piperazine-1-carboxylic acid tert-butyl ester (Boc-I 001)

[0191] Formula: 342.79

[0192] Molecular formula: C 16 H 20 ClFN2O3

[0193] TBTU (9.20 g, 28.6 mmol, 1 equivalent) was added to a solution of 2-chloro-4-fluorobenzoic acid (5.00 g, 28.6 mmol, 1 equivalent) in THF (89 mL) under RT. The mixture was stirred under RT for 15 min, and a solution of piperazine-1-carboxylic acid tert-butyl ester (6.40 g, 34.4 mmol, 1.2 equivalent) and Et3N (6.0 mL, 43 mmol, 1.5 equivalent) in THF (30 mL) was added dropwise. The mixture was stirred under RT for 60 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between 1 N HCl and EtOAc. The layers were separated and compared with EtOAc (2 Extract the aqueous phase. Wash the combined organic extracts (1N HCl aqueous solution, aqueous saturated NaHCO3, brine), dry (Na2SO4), filter and concentrate under reduced pressure to give 10.2 g of Boc-I 001 (100%) as an orange oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.32-7.29 (m, 1H), 7.18(dd, J = 8.5, 2.5 Hz, 1H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 3.92-3.79 (m, 1H), 3.73 (dt, J = 13.2, 5.7 Hz, 1H), 3.63-3.50 (m, 2H), 3.48-3.34 (m, 2H), 3.34-3.10 (m, 2H), 1.48 (s, 9H). MS (ESI+): [M+H]+ 343.1 / 345.1.

[0194] (2-Chloro-4-fluoro-phenyl)-piperazin-1-yl-methyl ketone (I-001)

[0195] Formula weight: 242.68

[0196] Molecular formula: C 11 H 12 ClFN2O

[0197] At RT, HCl (4 M solution in dioxane, 37 mL, 148 mmol, 5 equivalents) was added to a solution of crude Boc-I 001 (10.2 g, 28.6 mmol, 1 equivalent) in dioxane (37 mL). The mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. K2CO3 was added in portions until pH > 11. The layers were separated and analyzed with DCM (2... Extract the aqueous phase. Dry the combined organic extracts (Na2SO4), filter, and concentrate under reduced pressure. Purify the residue by passing it through an FC column (80 g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to give 5.24 g of I 001 (72%) as an orange solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (qd, J = 8.4, 5.6 Hz, 2H), 3.87-3.69 (m, 2H), 3.15 (t, J = 5.1 Hz, 2H), 2.94 (t, J = 5.2 Hz, 2H), 2.80 – 2.70 (m, 2H). MS (ESI + ): [M+H] + 243.1 / 245.1.

[0198] 3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (Boc-I- 002）

[0199] Formula weight: 368.83

[0200] Molecular formula: C 18 H 22 ClFN2O3

[0201] TBTU (18.1 g, 56.5 mol, 1.2 equivalents) was added to a solution of 2-chloro-4-fluorobenzoic acid (9.87 g, 56.5 mmol, 1.2 equivalents) in DMF (118 mL) under RT. The mixture was stirred under RT for 15 min, and a solution of 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (10.0 g, 47.1 mmol, 1 equivalent) and Et3N (9.8 mL, 71 mmol, 1.5 equivalents) in THF (118 mL) was added dropwise. The mixture was stirred under RT for 16 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between aqueous saturated NH4Cl and EtOAc. The layers were separated and compared with EtOAc (2 Extract the aqueous phase. Wash the combined organic extracts (with aqueous saturated NH4Cl, aqueous saturated NaHCO3, and brine), dry (with Na2SO4), filter, and concentrate under reduced pressure to give 21.3 g of Boc-I-002 (76% purity, 93%) as an orange oil. 1 H NMR (400MHz, chloroform-) d ) δ 7.33 (dd, J = 8.5, 5.9 Hz, 0.5H), 7.23-7.09 (m, 1.5H), 7.09-6.97 (m, 1H), 4.54-4.40 (m, 1H), 4.33 (s, 1H), 4.23-4.01 (m, 1H), 3.56-3.17(m, 1H), 3.17-2.93 (m, 2H), 2.11-1.70 (m, 4H), 1.47 (s, 9H). MS (ESI + ): [M+H] + 369.1 / 371.1.

[0202] (2-Chloro-4-fluoro-phenyl)-(3,8-diazabicyclo[3.2.1]octane-3-yl)methyl ketone (I-002)

[0203] Formula weight: 268.71

[0204] Molecular formula: C 13 H 14 ClFN2O

[0205] At RT, HCl (4 M solution in dioxane, 55 mL, 220 mmol, 5 equivalents) was added to a solution of Boc-I-002 (21.3 g, 76% pure, 43.9 mmol, 1 equivalent) in dioxane (55 mL). The mixture was stirred at RT for 60 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM. K2CO3 was added in portions until pH > 11. The layers were separated and analyzed with DCM (2... Extract the aqueous phase. Dry the combined organic extracts (Na2SO4), filter and concentrate under reduced pressure. Purify the residue by passing it through an FC column (220 g column, dry load, DCM / MeOH(7 N NH3) = 99 / 1 to 95 / 5) to give 10.3 g of I-002 (88%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.32(dd, J = 8.5, 5.9 Hz, 0.5H), 7.20-7.15 (m, 0.5H), 7.15-7.10 (m, 1H), 7.09-6.98 (m, 1H), 4.47-4.37 (m, 1H), 3.69-3.56 (m, 1H), 3.44-3.34 (m, 1.5H), 3.22(d, J = 11.9 Hz, 0.5H), 3.10-2.98 (m, 2H), 1.95-1.48 (m, 4H). MS (ESI + ): [M+H] + 269.1 / 271.0.

[0206] (2S)-4-(2-chloro-4-fluorobenzoyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (Boc-I-003)

[0207] Formula weight: 356.82

[0208] Molecular formula: C 17 H 22 ClFN2O3

[0209] At RT, TBTU (3.85 g, 12.0 mol, 1 equivalent) was added to a solution of 2-chloro-4-fluorobenzoic acid (2.09 g, 12.0 mmol, 1.2 equivalents) in THF (20 mL). The mixture was stirred at RT for 15 minutes, and then (…) was added dropwise. SA solution of 2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.00 g, 99.9 mmol, 1 equivalent) and Et3N (2.1 mL, 15 mmol, 1.5 equivalent) in DMF (20 mL). The mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was partitioned between aqueous 1 N HCl and EtOAc. The layers were separated and compared with EtOAc (2 N HCl). Extract the aqueous phase. Wash the combined organic extracts (aqueous 1 N HCl, aqueous saturated NaHCO3, brine), dry (Na2SO4), filter, and concentrate under reduced pressure. Purify the residue by passing it through an FC column (80 g column, dry loading, cHex / EtOAc = 90 / 10 to 50 / 50) to give 3.56 g of Boc-I-003 (98%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d (Multiple rotational isomers) δ 7.36–7.21 (m, 1H), 7.20–7.09 (m, 1H), 7.08–6.97 (m, 1H), 4.67–4.13 (m, 2H), 3.99–3.74 (m, 1H), 3.41–3.23 (m, 1H), 3.23–2.83 (m, 3H), 1.44 (s, 9H), 1.29–0.97 (m, 3H). MS (ESI) + ): [M+H] + 357.0 / 359.0.

[0210] (2-Chloro-4-fluoro-phenyl)-[(3S)-3-methylpiperazin-1-yl]methyl ketone (I-003)

[0211] Formula weight: 256.7

[0212] Molecular formula: C 12 H 14 ClFN2O

[0213] At 0°C, HCl (4 N in dioxane, 24 mL, 98 mmol, 10 equivalents) was added to a solution of Boc-I-003 (3.50 g, 9.79 mmol, 1 equivalent) in DCM (49 mL). The mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and DCM at 0°C. K2CO3 was added in portions until pH > 11. The layers were separated and compared with DCM (2... Extract the aqueous phase. Dry the combined organic extracts (Na2SO4), filter and concentrate under reduced pressure. Purify the residue by passing it through an FC column (80 g column, dry load, DCM / MeOH(7N NH3) = 99 / 1 to 90 / 10) to give 2.45 g of I-003 (97%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.32(ddd, J = 8.6, 5.9, 1.3 Hz, 0.5H), 7.25 (ddd, J = 8.5, 5.9, 1.4 Hz, 0.5H),7.21-7.13 (m, 1H), 7.09-7.01 (m, 1H), 4.69-4.56 (m, 1H), 3.31-2.75 (m, 5H),2.51 (m, 1H), 1.15 (dd, J = 6.3, 2.4 Hz, 1.5H), 0.98 (dd, J = 6.3, 4.5 Hz, 1.5H). MS (ESI) + ): [M+H] + 257.1 / 259.1.

[0214] 3-Bromo-2-chloro-5-[(4-phenyl-1-piperidinyl)sulfonyl]pyridine (I-004)

[0215] Formula: 415.73

[0216] Molecular formula: C 16 H 16 BrClN2O2S

[0217] At RT, 4-phenylpiperidine (732 mg, 4.54 mmol, 1.1 equivalent) and Et3N (0.86 mL, 6.2 mmol, 1.5 equivalent) were added to a solution of 3-bromo-2-chloropyridine-5-sulfonyl chloride (1.20 g, 4.12 mmol, 1 equivalent) in DCM (21 mL). The mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc and aqueous saturated NH4Cl. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by passing through an FC column (40 g column, dry loading, cHex / DCM (50 / 50) / EtOAc = 97 / 3 to 70 / 30) to give 1.60 g of I-004 (92% purity, 86%) as a light brown solid. 1 H NMR (400 MHz, chloroform-) d ) δ8.73 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.28– 7.22 (m, 1H), 7.22 – 7.14 (m, 2H), 4.04 – 3.97 (m, 2H), 2.57 – 2.47 (m,3H), 2.04 – 1.82 (m, 4H). MS (ESI + ): [M+H] + 415.0 / 417.0 / 419.0.

[0218] 3-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]pyridine-2-amine (I-005)

[0219] Formula weight: 396.3

[0220] Molecular formula: C 16 H 18 BrN3O2S

[0221] 28% aqueous NH4OH (1 mL) was added to a suspension of I-004 (500 mg, 1.11 mmol, 1 equivalent) in THF (2.5 mL) under RT. The mixture was stirred at 100°C for 3 hours under MW irradiation. The reaction mixture was concentrated under reduced pressure to give 0.51 g of I-005 (85% purity, 99%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ8.41 (d,J = 2.1 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.35 – 7.25 (m, 2H), 7.22(t, J = 7.2 Hz, 1H), 7.19 – 7.13 (m, 2H), 5.48 (s, 2H), 3.97 – 3.85 (m, 2H), 2.55 – 2.32 (m, 3H), 2.55 – 2.35 (m, 4H). MS (ESI + ): [M+H] + 395.9 / 397.9.

[0222] 8-Bromo-6-[(4-phenyl-1-piperidinyl)sulfonyl]imidazo[1,2-a]pyridine (I-006)

[0223] Formula weight: 420.32

[0224] Molecular formula: C 18 H 18 BrN3O2S

[0225] At RT, Na₂CO₃ (116 mg, 1.10 mmol, 2 equivalents) and chloroacetaldehyde (50% in water, 349 µL, 2.74 mmol, 5 equivalents) were added to a solution of I-005 (256 mg, 85% purity, 549 µmol, 1 equivalent) in EtOH (2.5 mL), and the mixture was stirred at 80°C for 16 hours. More Na₂CO₃ (116 mg, 1.10 mmol, 2 equivalents) and chloroacetaldehyde (50% in water, 349 µL, 2.74 mmol, 5 equivalents) were added, and the mixture was stirred again at 80°C for 24 hours. The reaction mixture was filtered through a sintered glass filter, and the filtrate was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc=95 / 5 to 50 / 50) to give 52 mg of I-006 (23%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.64 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.75(d, J = 1.3 Hz, 1H), 7.64 (d, J= 1.5 Hz, 1H), 7.27 – 7.20 (m, 2H), 7.18 –7.12 (m, 1H), 7.12 – 7.07 (m, 2H), 3.98 – 3.88 (m, 2H), 2.59 – 2.37 (m, 3H),1.94 – 1.73 (m, 4H). MS (ESI + ): [M+H] + 420.0 / 422.0.

[0226] 8-Bromo-6-[(4-phenyl-1-piperidinyl)sulfonyl]-[1,2,4]triazolo[1,5-a]pyridine (I-007)

[0227] Formula weight: 421.31

[0228] Molecular formula: C 17 H 17 BrN4O2S

[0229] At RT, N,N-dimethylformamide dimethylacetal (272 µL, 2.05 mmol, 3.7 equivalence) was added to a solution of I-005 (256 mg, 85% purity, 549 µmol, 1 equivalent) in anhydrous DMF (1 mL). The mixture was stirred at 130°C for 15 min and then concentrated under reduced pressure. The residue was dissolved at 0°C in MeOH (1.4 mL) and pyridine (103 µL, 1.28 mmol, 2.3 equivalence). Hydroxylamine-O-sulfonic acid (101 mg, 0.897 mmol, 1.6 equivalence) was added. After stirring at RT for 16 hours, saturated aqueous NaHCO3 (5 mL) and water (5 mL) were added, and the mixture was stirred at RT for 1 hour. The suspension was filtered through a sintered glass filter, the filter cake was washed (1 mL water), collected, and azeotropically reacted with toluene. The residue was dissolved in THF (3.2 mL) at 0°C, and trifluoroacetic anhydride (0.27 mL, 1.9 mmol, 3.4 equivalence) was added dropwise. The mixture was stirred at RT for 16 hours. The reaction mixture was partitioned between EtOAc and aqueous saturated NaHCO3. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (aqueous saturated NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50), followed by FC (24 g column, dry loading, DCM / EtOAc = 98 / 2 to 80 / 20) to give 132 mg of I-007 (49%) as a white solid. 1 H NMR (400 MHz, chloroform-)d ) δ 9.03 (d, J = 1.5 Hz, 1H), 8.47 (s, 1H), 7.97 (d, J = 1.5Hz, 1H), 7.29 – 7.21 (m, 2H), 7.18 – 7.13 (m, 1H), 7.12 – 7.05 (m, 2H), 4.03– 3.91 (m, 2H), 2.53 (td, J = 11.9, 2.8 Hz, 2H), 2.45 (tt, J = 12.0, 3.9 Hz,1H), 1.98 – 1.73 (m, 4H). MS (ESI + ): [M+H] + 421.0 / 422.9.

[0230] 3-Bromo-2-chloro-5-(2,2-dimethylpropylthio)pyridine (I-008)

[0231] Formula weight: 294.64

[0232] Molecular formula: C 10 H 13 BrClNS

[0233] I-008 was obtained in 94% yield as a pale yellow oil at 100°C using GP-1 with 3-bromo-2-chloro-5-iodopyridine (600 mg, 1.88 mmol, 1 equivalent), XantPhos-D-G3 (36 mg, 38 µmol, 0.02 equivalent), iPr2NEt (0.49 mL, 2.8 mmol, 1.5 equivalent), and 2,2-dimethylpropane-1-thiol (236 µL, 1.88 mmol, 1 equivalent) in dioxane (7.5 mL) for 1 hour. Purification was performed by FC (cHex / EtOAc = 99 / 1 to 90 / 10). 1 H NMR (400 MHz, chloroform-) d ) δ 8.24 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 2.87(s, 2H), 1.04 (s, 9H). MS (ESI + ): [M+H] + 294.0 / 296.0 / 298.0.

[0234] 3-Bromo-2-chloro-5-(2,2-dimethylpropylsulfonyl)pyridine (I-009)

[0235] Formula weight: 326.64

[0236] Molecular formula: C 10 H 13 BrClNO2S

[0237] Using GP-2, I-009 was obtained in 100% yield as a colorless oil by continuously applying I-008 (522 mg, 1.77 mmol, 1 equivalent) and m-CPBA (70% wet, 961 mg, 3.90 mmol, 2.2 equivalent) in DCM (9 mL) for 2 hours at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 8.80 (s, 1H), 8.38 (s, 1H), 3.05 (s, 2H), 1.21 (s, 9H). MS (ESI + ): [M+H] + 326.0 / 327.9 / 330.0.

[0238] 3-Bromo-5-(2,2-dimethylpropylsulfonyl)pyridine-2-amine (I-010)

[0239] Formula weight: 307.21

[0240] Molecular formula: C 10 H 15 BrN2O2S

[0241] 28% aqueous NH4OH (1.1 mL) was added to a suspension of I-009 (350 mg, 1.07 mmol, 1 equivalent) in dioxane (2.1 mL) under RT. The mixture was stirred at 100°C for 1.5 h under MW irradiation. The reaction mixture was concentrated under reduced pressure to give 324 mg of I-010 (99%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ8.48 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 5.50 (s, 2H), 3.01 (s,2H), 1.19 (s, 9H). MS (ESI + ): [M+H] + 307.1 / 309.0.

[0242] [8-[2-amino-5-(2,2-dimethylpropylsulfonyl)-3-pyridyl]-3,8-diazabicyclo[3.2.1]octyl [Alkyl-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-011)

[0243] Formula weight: 495.01

[0244] Molecular formula: C 23 H 28 ClFN4O3S

[0245] According to GP-3, I-011 was obtained in 22% yield by reflux in THF (8.9 mL) for 3 h using aryl bromide I-010 (274 mg, 892 µmol, 1 equivalent), piperazine I-002 (360 mg, 1.34 mmol, 1.5 equivalent), LiHMDS (2.23 mL, 2.23 mmol, 2.5 equivalent), and RuPhos-Pd-G2 (66 mg, 89 µmol, 0.10 equivalent). Purification was then performed by FC (cHex / EtOAc = 95 / 5 to 0 / 100) followed by FC (DCM / MeOH = 99 / 1 to 95 / 5). 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 8.30 (s, 1H), 7.45 – 7.30 (m, 1.5H), 7.27 – 7.03 (m,2.5H), 5.48 (s, 2H), 4.70 – 4.60 (m, 1H), 3.96 (s, 1H), 3.72 (s, 1H), 3.65 – 3.40 (m, 1H), 3.35 – 3.20 (m, 2H), 3.03 (s, 2H), 2.15 – 1.90 (m, 4H), 1.20 (s, 9H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.71, -108.84. MS (ESI + ):[M+H] + 495.1 / 497.1.

[0246] 1-[5-[(4-phenyl-1-piperidinyl)sulfonyl]indoline-1-yl]acetone (I-012)

[0247] Formula weight: 384.49

[0248] Molecular formula: C 21 H 24 N2O3S

[0249] According to GP-4, I-012 was obtained in 90% yield as a white solid by continuous resuscitation in DCM (5.8 mL) at RT for 16 h using 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (300 mg, 1.15 mmol, 1 equivalent), 4-phenylpiperidine (223 mg, 1.39 mmol, 1.2 equivalent), and Et3N (480 µL, 3.46 mmol, 3 equivalent). Purification was performed by FC (DCM / EtOAc = 100 / 0 to 40 / 60). 1 H NMR (400 MHz, chloroform-) d ) δ 8.34 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.29 (dd, J =8.2, 6.7 Hz, 2H), 7.24 – 7.17 (m, 1H), 7.17 – 7.11 (m, 2H), 4.16 (t, J = 8.6Hz, 2H), 3.95 – 3.85 (m, 2H), 3.28 (t, J = 8.6 Hz, 2H), 2.46 – 2.30 (m, 3H), 2.27 (s, 3H), 1.94 – 1.73 (m, 4H). MS (ESI + ): [M+H] + 385.0.

[0250] 5-[(4-phenyl-1-piperidinyl)sulfonyl]indoline (I-013)

[0251] Formula weight: 342.46

[0252] Molecular formula: C 19 H 22 N2O2S

[0253] At RT, 32% NaOH (0.35 mL, 5.2 mmol, 5 equivalents) was added to a solution of I-012 (400 mg, 1.04 mmol, 1 equivalent) in THF / MeOH / H2O (4 / 2 / 1, 5 mL). The mixture was stirred under reflux for 16 hours. Volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 315 mg of I-013 (88%) as a light brown solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.49 – 7.43 (m, 2H), 7.29 (dd, J = 8.1, 6.7Hz, 2H), 7.24 – 7.11 (m, 3H), 6.66 – 6.60 (m, 1H), 3.93 – 3.85 (m, 2H), 3.71(t, J = 8.6 Hz, 2H), 3.11 (t, J = 8.6 Hz, 2H), 2.48 – 2.30 (m, 3H), 1.98 –1.75 (m, 4H). MS (ESI + ): [M+H] + 343.1.

[0254] 7-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]indoline (I-014)

[0255] Formula weight: 421.35

[0256] Molecular formula: C 19 H 21 BrN2O2S

[0257] At 0°C, a solution of N-bromosuccinimide (246 mg, 1.38 mmol, 1 equivalent) in dioxane (4.6 mL) was added dropwise to a solution of I-013 (315 mg, 0.92 mmol, 1 equivalent) in acetic acid (630 µL). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2 N NaOH and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 303 mg of I-014 (78%) as a white solid. MS (ESI) + ): [M+H] + 421.0 / 423.0.

[0258] 7-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]-1H-indole (I-015)

[0259] Formula weight: 419.34

[0260] Molecular formula: C 19 H 19 BrN2O2S

[0261] DDQ (0.21 g, 0.93 mmol, 1.3 equivalents) was added to a solution of I-014 (303 mg, 720 µmol, 1 equivalent) in DCM (3.6 mL) at RT. The mixture was stirred at RT for 16 h and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 100 / 0 to 0 / 100) to give 215 mg of I-015 (71%) as a grayish-white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.67 (s, 1H), 8.12 (s, 1H), 7.82(d, J = 1.5 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 7.37 – 7.29 (m, 2H), 7.25 –7.12 (m, 3H), 6.82 (dd, J= 3.3, 2.1 Hz, 1H), 4.05 – 3.95 (m, 2H), 2.45 –2.30 (m, 3H), 2.00 – 1.80 (m, 4H). MS (ESI + ): [M+H] + 419.0 / 421.0.

[0262] 2-[[7-bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]indol-1-yl]methoxy]ethyl-trimethylsilane （I-016）

[0263] Formula weight: 549.6

[0264] Molecular formula: C 25 H 33 BrN2O3SSi

[0265] At 0°C, NaH (60% in mineral oil, 29 mg, 0.73 mmol, 2.7 equivalents) was added to a solution of I-015 (114 mg, 271 µmol, 1 equivalent) in anhydrous DMF (1.4 mL). The mixture was stirred at 0°C for 1 hour, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (72 µL, 0.41 mmol, 1.5 equivalents). The mixture was stirred at RT for 2 hours. The residue was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 149 mg of I-016 (100%) as a colorless oil. 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.09 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.21 – 7.11 (m, 3H), 6.82(d, J = 3.3 Hz, 1H), 5.88 (s, 2H), 3.83 – 3.75 (m, 2H), 3.51 (t, J= 7.9 Hz,2H), 2.50 – 2.40 (m, 1H), 2.35 – 2.22 (m, 2H), 1.90 – 1.75 (m, 2H), 1.75 –1.60 (m, 2H), 0.82 (t, J = 7.8 Hz, 2H), -0.10 (s, 9H). MS (ESI + ): [M+H] + 549.0 / 551.0.

[0266] 1-Acetyl-N-tert-butylindoline-5-sulfonamide (I-017)

[0267] Formula weight: 296.39

[0268] Molecular formula: C 14 H 20 N2O3S

[0269] According to GP-4, I-017 was obtained as a white solid in 93% yield by continuous administration of 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (3.00 g, 11.5 mmol, 1 equivalent) and tert-butylamine (3.03 mL, 28.9 mmol, 2.5 equivalent) in DCM (23 mL) for 16 hours at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 8.26 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 4.51 (s, 1H), 4.14 (t, J = 8.6Hz, 2H), 3.25 (t, J = 8.6 Hz, 2H), 2.25 (s, 3H), 1.22 (s, 9H). MS (ESI + ): [M+H] + 297.2.

[0270] N-tert-butylindoline-5-sulfonamide (I-018)

[0271] Formula weight: 254.35

[0272] Molecular formula: C 12 H 18 BrN2O2S

[0273] At RT, 32% NaOH (14.0 mL, 151 mmol, 12 equivalents) was added to a solution of I-017 (3.70 g, 12.5 mmol, 1 equivalent) in THF / MeOH / H2O (1 / 3 / 1, 60 mL). The mixture was stirred under reflux for 2 hours. Volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 50 / 50) to give 2.20 g of I-018 (69%) as a light brown solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.56 – 7.51 (m, 2H), 6.55 (d, J = 7.9 Hz, 1H), 4.38 (s, 1H), 3.66 (t, J = 8.6 Hz, 2H), 3.07 (t, J = 8.6 Hz, 2H), 1.22 (s, 9H). MS (ESI + ): [M+H] + 254.1.

[0274] 7-Bromo-N-tert-butyl-indoline-5-sulfonamide (I-019)

[0275] Formula weight: 333.24

[0276] Molecular formula: C 12 H 17 BrN2O2S

[0277] At 0°C, a solution of N-bromosuccinimide (1.43 g, 8.04 mol, 1 equivalent) in dioxane (20 mL) was added dropwise to a solution of I-018 (2.20 g, 8.04 mol, 1 equivalent) and acetic acid (2.3 mL, 40 mmol, 5 equivalent) in dioxane (20 mL). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2 N NaOH and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / EtOAc = 100 / 0 to 98 / 02) to give 2.17 g of I-019 (81%) as a white solid. 1 H NMR (400 MHz, chloroform-) d )δ 7.72 (s, 1H), 7.46 (s, 1H), 4.34 (s, 1H), 3.74 (t, J = 8.6 Hz, 2H), 3.20(t, J = 8.7 Hz, 2H), 1.25 (s, 9H). MS (ESI + ): [M+H] + 333.0 / 335.0.

[0278] 7-Bromo-N-tert-butyl-1H-indole-5-sulfonamide (I-020)

[0279] Formula weight: 331.23

[0280] Molecular formula: C 12 H 15 BrN2O2S

[0281] At RT, activated MnO2 (2.8 g, 33 mmol, 5 equivalents) was added to a solution of I-019 (2.17 g, 6.51 mmol, 1 equivalent) in DCE (33 mL). The mixture was stirred under reflux for 16 hours. More activated MnO2 (2.8 g, 33 mmol, 5 equivalents) was added, and the mixture was stirred under reflux for another 24 hours. The resulting suspension was filtered through diatomaceous earth (washed with DCM). The filtrate was concentrated under reduced pressure to give 1.50 g of I-020 (70%) as a pink solid. 1 H NMR (400MHz, chloroform-) d) δ 8.57 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.39 (s, 1H), 6.75 (s, 1H), 4.44 (s, 1H), 1.25 (s, 9H). MS (ESI + ): [M+H] + 331.0 / 333.0.

[0282] 1-(benzyloxymethyl)-7-bromo-N-tert-butyl-indole-5-sulfonamide (I-021)

[0283] Formula weight: 451.38

[0284] Molecular formula: C 20 H 23 BrN2O3S

[0285] At 0°C, NaH (48 mg, 1.2 mmol, 2 equivalents in mineral oil, 60%) was added to a solution of I-020 (200 mg, 0.604 mol, 1 equivalent) in anhydrous THF (3 mL). The mixture was stirred at 0°C for 15 min, and benzyloxymethyl chloride (84 µL, 0.61 mmol, 1 equivalent) was added. The mixture was stirred at RT for 16 h. The residue was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 149 mg of I-021 (67%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 8.09(s, 1H), 7.88 (s, 1H), 7.35 – 7.18 (m, 6H), 6.60 (d, J = 3.4 Hz, 1H), 5.90(s, 2H), 4.48 (s, 2H), 4.43 (s, 1H), 1.21 (s, 9H). MS (ESI + ): [M+H] + 451.1 / 453.1.

[0286] 1-(benzyloxymethyl)-N-tert-butyl-7-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo] [3.2.1]Octan-8-yl]Indole-5-sulfonamide (I-022)

[0287] Formula weight: 639.18

[0288] Molecular formula: C 33 H 36 ClFN4O4S

[0289] According to GP-3, I-022 was obtained in 60% yield by reflux in toluene (2 mL) for 3 h using aryl bromide I-021 (183 mg, 405 µmol, 1 equivalent), piperazine I-002 (218 mg, 811 µmol, 2 equivalent), Cs₂CO₃ (396 mg, 1.22 mmol, 3 equivalent), Pd(Oac)₂ (9.1 mg, 41 µmol, 0.10 equivalent), and rac-BINAP (30 mg, 49 µmol, 0.12 equivalent). Purification was performed by FC (cHex / EtOAc = 95 / 5 to 0 / 100). 1 H NMR (400 MHz, chloroform-) d , 2 sets of rotating anisotropy configuration ) δ 7.93 (s, 1H), 7.45 – 7.15 (m, 8H), 7.15 – 7.00 (m, 2H), 6.68 (d, J =3.3 Hz, 1H), 6.25 – 5.95 (m, 2H), 4.60 – 4.46 (m, 3H), 4.38 (s, 1H), 4.06 (s,1H), 3.81 (s, 1H), 3.70 – 3.40 (m, 1H), 3.33 – 3.25 (m, 1H), 3.20 – 3.05 (m,1H), 2.20 – 1.85 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.24 (s, 9H). 19 F NMR (376MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.14, -109.29. MS (ESI + ): [M+H] + 639.4 / 641.3.

[0290] 1-(benzyloxymethyl)-N-tert-butyl-7-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo] [3.2.1]Octan-8-yl]-N-(trideuterylmethyl)indole-5-sulfonamide (I-023)

[0291] Formula weight: 656.22

[0292] Molecular formula: C 34 H 35 ClD3FN4O4S

[0293] At 0°C, NaH (60% in mineral oil, 11 mg, 0.28 mmol, 2 equivalents) was added to a solution of I-022 (90 mg, 141 µmol, 1 equivalent) in anhydrous DMF (1.4 mL). The mixture was stirred at RT for 30 min, and then iodomethane-d3 (19 µL, 0.28 mmol, 2 equivalents) was added. The mixture was stirred at RT for 30 min. The residue was partitioned in aqueous saturated NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 89 mg of I-023 (96%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.85 (s, 1H), 7.45 – 7.15 (m, 9H), 7.15 – 7.05 (m, 1H), 6.67 (d, J = 3.3 Hz, 1H), 6.25 – 5.95 (m, 2H), 4.60 – 4.40 (m, 3H), 4.05 (s,1H), 3.80 (s, 1H), 3.68 – 3.40 (m, 1H), 3.32 & 3.28 (s, 1H), 3.20 – 3.05 (m,1H), 2.15 – 1.85 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.36 (s, 9H). 19 F NMR (376MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.17, -109.33. MS (ESI + ): [M+H] + 656.4 / 658.4.

[0294] 7-Bromo-N-tert-butyl-1-cyclopropyl-indole-5-sulfonamide (I-024)

[0295] Formula weight: 371.29

[0296] Molecular formula: C 15 H 19 BrN2O2S

[0297] In air, I-020 (150 mg, 0.45 mmol, 1 equivalent), Cu(OAc)2 (82 mg, 0.45 mol, 1 equivalent), and 2, were added to a MW vial. - Bipyridine (71 mg, 0.45 mmol, 1 equivalent), cyclopropylboronic acid (78 mg, 0.91 mmol, 2 equivalents), and Na₂CO₃ (96 mg, 0.91 mL, 2 equivalents). DCE (1.1 mL) was added, the vial was sealed, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was partitioned between aqueous saturated NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 22 mg of I-024 (13%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.08 (s, 1H), 7.87 (s, 1H), 7.23 (d, J = 3.3 Hz, 1H), 6.51 (d, J = 3.5 Hz, 1H), 4.45 (s, 1H), 3.85 – 3.75 (m, 1H), 1.24 (s, 9H), 1.24 – 1.14 (m, 4H). MS (ESI + ): [M+H] + 371.0 / 373.1.

[0298] 1-Acetyl-N-tert-butyl-N-methyl-indoline-5-sulfonamide (I-025)

[0299] Formula weight: 310.41

[0300] Molecular formula: C 15 H 22 N2O3S

[0301] According to GP-4, 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (1.00 g, 3.85 mmol, 1 equivalent), N-methyl-tert-butylamine (0.58 mL, 4.6 mmol, 1.2 equivalent) and Et3N (0.80 mL, 5.8 mmol, 1.5 equivalent) were continuously applied at RT in DCM (7.7 mL) for 2 hours to give a white solid I-025 in 76% yield. 1 H NMR (400MHz, chloroform-)d ) δ 8.29 (d, J = 8.5 Hz, 1H), 7.71 – 7.62 (m, 2H), 4.16 (t, J = 8.6Hz, 2H), 3.27 (t, J = 8.6 Hz, 2H), 2.96 (s, 3H), 2.28 (s, 3H), 1.37 (s, 9H).MS (ESI + ): [M+H] + 311.1.

[0302] N-tert-butyl-N-methyl-indoline-5-sulfonamide (I-026)

[0303] Formula weight: 268.38

[0304] Molecular formula: C 13 H 20 N2O2S

[0305] At RT, NaOH (580 mg, 14.5 mmol, 4.5 equivalents) was added to a solution of I-025 (1.00 g, 3.22 mmol, 1 equivalent) in THF / MeOH / H2O (1 / 1 / 1, 18 mL). The mixture was stirred under reflux for 5 hours. Volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 525 mg of I-026 (67%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.62 – 7.43 (m, 2H), 6.57 (d, J = 8.8 Hz, 1H), 4.11 (s, 1H), 3.68(td, J = 8.6, 1.7 Hz, 2H), 3.09 (t, J = 8.5 Hz, 2H), 2.90 (s, 3H), 1.38 (s,9H). MS (ESI + ): [M+H] + 269.2.

[0306] 7-Bromo-N-tert-butyl-N-methyl-indoline-5-sulfonamide (I-027)

[0307] Formula weight: 347.27

[0308] Molecular formula: C 13 H 19 BrN2O2S

[0309] At 0°C, a solution of N-bromosuccinimide (379 mg, 2.13 mmol, 1.1 equivalent) in dioxane (4 mL) was added dropwise to a solution of I-026 (520 mg, 1.94 mmol, 1 equivalent) and acetic acid (0.55 mL, 9.7 mmol, 5 equivalent) in dioxane (4 mL). The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2 N NaOH and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 630 mg of I-027 (94%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.68 – 7.64 (m, 1H), 7.43 – 7.40 (m, 1H), 4.36 (s, 1H), 3.75 (t, J = 8.7Hz, 2H), 3.21 (t, J = 8.7 Hz, 2H), 2.90 (s, 3H), 1.38 (s, 9H). MS (ESI + ): [M+H] + 347.0 / 349.0.

[0310] 7-Bromo-N-tert-butyl-N-methyl-1H-indole-5-sulfonamide (I-028)

[0311] Formula weight: 345.26

[0312] Molecular formula: C 13 H 17 BrN2O2S

[0313] DDQ (0.62 g, 2.7 mmol, 1.5 equivalent) was added to a solution of I-027 (630 mg, 1.81 mmol, 1 equivalent) in DCM (9.1 mL) under RT. The mixture was stirred under RT for 16 h and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 96 / 4 to 60 / 40) to give 483 mg of I-028 (73%) as a light brown solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.62 (s, 1H), 8.14 (s, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.41 (t, J = 2.8 Hz, 1H), 6.76 (dd, J = 3.2, 2.1 Hz, 1H), 2.99 (s, 3H), 1.40 (s, 9H). MS (ESI + ): [M+H] + 345.0 / 347.0.

[0314] 7-Bromo-N-tert-butyl-N,1-dimethyl-indole-5-sulfonamide (I-029)

[0315] Formula weight: 359.28

[0316] Molecular formula: C 14 H 19 BrN2O2S

[0317] At 0°C, NaH (17 mg, 0.41 mmol, 1.5 equivalent in mineral oil, 60% in DMF (1.1 mL)) was added to a solution of I-028 (100 mg, 275 µmol, 1 equivalent). The mixture was stirred at RT for 30 min, and iodomethane (43 µL, 0.69 mmol, 2.5 equivalent) was added. The mixture was stirred at RT for 30 min. The residue was partitioned between aqueous saturated NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 80 / 20) to give 103 mg of I-029 (95%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.06 (d,J = 1.7 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.12 (d, J =3.2 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 4.21 (s, 3H), 2.98 (s, 3H), 1.39 (s,9H). MS (ESI + ): [M+H] + 359.1 / 361.1.

[0318] 7-Bromo-N-tert-butyl-N-methyl-1-(2-trimethylsilylethoxymethyl)indole-5-sulfonamide (I- 030）

[0319] Formula weight: 475.52

[0320] Molecular formula: C 19 H 31 BrN2O3SSi

[0321] At 0°C, NaH (60% in mineral oil, 25 mg, 0.62 mmol, 1.5 equivalent) was added to a solution of I-028 (150 mg, 413 µmol, 1 equivalent) in anhydrous DMF (2.1 mL). The mixture was stirred at RT for 30 min, and then 2-(trimethylsilyl)ethoxymethyl chloride (183 µL, 1.03 mmol, 2.5 equivalent) was added. The mixture was stirred at RT for 1 h. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 80 / 20) to give 190 mg of I-030 (94%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 8.12 (d, J = 1.7 Hz, 1H), 7.89 (d, J = 1.7Hz, 1H), 7.36 (d, J = 3.3 Hz, 1H), 6.70 (d, JMS (ESI) + ): [M+H] + 475.1 / 477.1.

[0322] N-tert-butyl-7-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-N- Methyl-1-(2-trimethylsilylethoxymethyl)indole-5-sulfonamide (I-031)

[0323] Formula weight: 663.32

[0324] Molecular formula: C 32 H 44 ClFN4O4SSi

[0325] According to GP-3, I-031 was obtained in 13% yield by reflux in toluene (1.8 mL) for 3 h using aryl bromide I-030 (183 mg, 366 µmol, 1 equivalent), piperazine I-002 (118 mg, 439 µmol, 1.2 equivalent), t-BuONa (105 mg, 1.10 mmol, 3 equivalent), and XPhos-Pd-G3 (31 mg, 37 µmol, 0.10 equivalent). Purification was performed by FC (cHex / EtOAc = 95 / 5 to 0 / 100). 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.90 – 7.84 (m,1H), 7.47 – 7.40 (m, 0.5H), 7.31 – 7.05 (m, 4.5H), 6.67 (d, J = 3.3 Hz, 1H),6.15 – 5.89 (m, 2H), 4.66 – 4.56 (m, 1H), 4.11 (s, 1H), 3.89 (s, 1H), 3.81 –3.54 (m, 3H), 3.47 – 3.39 (m, 1H), 3.32 – 3.19 (m, 1H), 3.00 & 2.99 (s, 3H), 2.25 – 1.90 (m, 3.5H), 1.78 – 1.68 (m, 0.5H), 1.39 (s, 9H), 0.99 – 0.85 (m, 2H), 0.00 & -0.02 (s, 9H). 19F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.17, -109.35. MS (ESI + ): [M+H] + 663.3 / 665.3.

[0326] 1-(5-Thioalkylindoline-1-yl)acetone (I-032)

[0327] Formula weight: 193.27

[0328] Molecular formula: C 10 H 11 NOS

[0329] At RT, water (1.3 mL) and PPh3 (3.62 g, 13.8 mmol, 3.5 equivalents) were added fractionally to a solution of 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride (1.02 g, 3.95 mmol, 1 equivalent) in THF (40 mL). The mixture was stirred at 50°C for 4 hours. After cooling to RT, water and EtOAc were added. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 98 / 2 to 20 / 80) to give 550 mg of I-032 (72%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.90 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 1.9Hz, 1H), 7.06 (dd, J = 8.4, 1.9 Hz, 1H), 5.19 (s, 1H), 4.06 (t, J = 8.5 Hz, 2H), 3.09 (t, J = 8.5 Hz, 2H), 2.13 (s, 3H). MS (ESI + ): [M+H] + 194.1.

[0330] 1-[5-(2,2-dimethylpropylthio)indoline-1-yl]acetone (I-033)

[0331] Formula weight: 263.4

[0332] Molecular formula: C 15 H 21 NOS

[0333] At RT, NaH (60% in mineral oil, 137 mg, 3.42 mmol, 1.2 equivalent) was added to a solution of I-032 (550 mg, 2.84 mmol, 1 equivalent) in anhydrous DMF (2.8 mL). The mixture was stirred at RT for 30 min, and 1-bromo-2,2-dimethylpropane (0.43 mL, 3.42 mmol, 1.2 equivalent) was added dropwise. The mixture was stirred at 80°C for 1.5 h. After cooling to RT, the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 642 mg of I-033 (86%) as a white solid. 1 HNMR (400 MHz, chloroform-) d ) δ 8.13 (d, J = 8.3 Hz, 1H), 7.27 – 7.17 (m, 2H), 4.07(t, J = 8.5 Hz, 2H), 3.19 (t, J = 8.5 Hz, 2H), 2.87 (s, 2H), 2.24 (s, 3H), 1.04 (s, 9H). MS (ESI + ): [M+H] + 263.1.

[0334] 1-[5-(2,2-dimethylpropylsulfonyl)indoline-1-yl]acetone (I-034)

[0335] Formula weight: 295.4

[0336] Molecular formula: C 15 H 21 NO3S

[0337] Using GP-2, I-034 was obtained in 100% yield as a colorless oil by continuously applying I-033 (640 mg, 2.43 mmol, 1 equivalent) and m-CPBA (70% wet, 1.32 g, 5.34 mmol, 2.2 equivalent) in DCM (12 mL) for 1 hour at RT. 1H NMR (400 MHz, chloroform-) d ) δ 8.34 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 4.17 (t, J = 8.6 Hz, 2H), 3.28 (t, J =8.6 Hz, 2H), 3.03 (s, 2H), 2.28 (s, 3H), 1.19 (s, 9H). MS (ESI + ): [M+H] + 296.2.

[0338] 5-(2,2-Dimethylpropylsulfonyl)indoline (I-035)

[0339] Formula weight: 253.36

[0340] Molecular formula: C 13 H 19 NO2S

[0341] At RT, NaOH (487 mg, 12.2 mmol, 5 equivalents) was added to a solution of I-034 (720 mg, 2.44 mmol, 1 equivalent) in THF / MeOH / H2O (1 / 1 / 1, 15 mL). The mixture was stirred under reflux for 2.5 h. Volatiles were removed under reduced pressure. The residue was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give 620 mg of I-035 (100%) as a white solid. 1 HNMR (400 MHz, chloroform-) d ) δ 7.68 – 7.47 (m, 2H), 6.60 (d, J = 8.7 Hz, 1H), 4.23(s, 1H), 3.71 (td, J = 8.6, 1.4 Hz, 2H), 3.11 (t, J = 8.6 Hz, 2H), 3.01 (s,2H), 1.18 (s, 9H). MS (ESI + ): [M+H] + 254.1.

[0342] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)indoline (I-036)

[0343] Formula weight: 332.26

[0344] Molecular formula: C 13 H 18 BrNO2S

[0345] At 0°C, a solution of N-bromosuccinimide (479 mg, 2.69 mmol, 1.1 equivalent) in dioxane (5 mL) was added dropwise to a solution of I-035 (620 mg, 2.45 mmol, 1 equivalent) and acetic acid (0.700 mL, 12.2 mmol, 5 equivalent) in dioxane (5 mL). The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2N NaOH and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine) and dried (with NaOH). 2S O4), filtered and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to give 751 mg of I-036 (88%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.73 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 4.49 (s, 1H), 3.78 (t, J = 8.7 Hz, 2H), 3.23 (t, J = 8.7 Hz, 2H), 3.00 (s, 2H), 1.19 (s,9H). MS (ESI + ): [M+H] + 332.0 / 334.0.

[0346] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1H-indole (I-037)

[0347] Formula weight: 330.24

[0348] Molecular formula: C 13 H 16 BrNO2S

[0349] At RT, DDQ (0.73 g, 3.2 mmol, 1.5 equivalent) was added to a solution of I-036 (745 mg, 2.13 mmol, 1 equivalent) in DCM (11 mL). The mixture was stirred at RT for 16 h and refluxed for 2 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 96 / 4 to 60 / 40) to give 640 mg of I-037 (86%) as a light brown solid. 1 H NMR (400 MHz, chloroform-) d δ¹H NMR (400 MHz, chloroform-d) δ 8.74 (s, ¹H), 8.22 (s, ¹H), 7.90 (s, ¹H), 7.44 (s, ¹H), 6.80 (s, ¹H), 3.10 (s, 2H), 1.22 (s, 9H). MS (ESI) + ): [M+H] + 330.0 / 332.0.

[0350] 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)indol-1-yl]methoxy]ethyl-trimethyl-silane (I- 038）

[0351] Formula weight: 460.5

[0352] Molecular formula: C 19 H 30 BrNO3SSi

[0353] At 0°C, NaH (60 mg, 40 mg, 0.99 mmol, 1.5 equivalent in mineral oil) was added to a solution of I-037 (230 mg, 662 µmol, 1 equivalent) in anhydrous DMF (3.3 mL). The mixture was stirred at RT for 30 min, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (293 µL, 1.65 mmol, 2.5 equivalent). The mixture was stirred at RT for 1 h. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 97 / 3 to 70 / 30) to give 297 mg of I-038 (97%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 8.21 (d,J = 1.7 Hz, 1H), 7.97 (d, J = 1.7Hz, 1H), 7.39 (d, J = 3.3 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 5.94 (s, 2H), 3.63 – 3.53 (m, 2H), 3.13 (s, 2H), 1.25 (s, 9H), 0.96 (dd, J = 8.6, 7.6 Hz,2H), 0.00 (s, 9H). MS (ESI + ): [M+H] + 460.1 / 462.1.

[0354] (2-Chloro-4-fluoro-phenyl)-[8-[5-(2,2-dimethylpropylsulfonyl)-1-(2-trimethylsilylethoxy) [3.2.1]octane-3-yl]methyl[indol-7-yl]-3,8-diazabicyclo[3.2.1]octane-3-yl]methyl ketone (I-039)

[0355] Formula weight: 648.3

[0356] Molecular formula: C 32 H 43 ClFN3O4SSi

[0357] According to GP-3, I-039 was obtained in 13% yield by reflux in toluene (1.8 mL) for 4 h using aryl bromide I-038 (271 mg, 592 µmol, 1 equivalent), piperazine I-002 (191 mg, 711 µmol, 1.2 equivalent), t-BuONa (171 mg, 1.78 mmol, 3 equivalent), and XPhos-Pd-G3 (50 mg, 59 µmol, 0.10 equivalent). Purification was performed by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.95 (s, 1H), 7.48– 7.41 (m, 0.5H), 7.35 – 7.04 (m, 4.5H), 6.71 & 6.70 (s, 1H), 6.17 – 5.88 (m,2H), 4.65 & 4.62 (s, 1H), 4.15 (s, 1H), 3.92 (s, 1H), 3.83 – 3.51 (m, 3H), 3.51 – 3.34 (m, 1H), 3.32 – 3.20 (m, 1H), 3.08 (s, 2H), 2.28 – 1.91 (m,3.5H), 1.80 – 1.65 (m, 0.5H), 1.20 (s, 9H), 0.96 – 0.84 (m, 2H), 0.00 & -0.02(s, 9H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.11, -109.29. MS (ESI + ):[M+H] + 648.3 / 650.2.

[0358] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1-methyl-indole (I-040)

[0359] Formula weight: 344.27

[0360] Molecular formula: C 14 H 18 BrNO2S

[0361] At 0°C, NaH (60% in mineral oil, 35 mg, 0.86 mmol, 1.5 equivalent) was added to a solution of I-037 (190 mg, 575 µmol, 1 equivalent) in anhydrous DMF (2.3 mL). The mixture was stirred at RT for 30 min, and iodomethane (90 µL, 1.44 mmol, 2.5 equivalent) was added dropwise. The mixture was stirred at RT for 30 min. The residue was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 97 / 3 to 70 / 30) to give 198 mg of I-040 (100%) as a white solid. 1 H NMR (400 MHz, chloroform-) d) δ 8.14 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.16 (d, J =3.2 Hz, 1H), 6.63 (d, J = 3.1 Hz, 1H), 4.23 (s, 3H), 3.08 (s, 2H), 1.21 (s,9H). MS (ESI + ): [M+H] + 344.1 / 346.1.

[0362] 7-Bromo-1-cyclopropyl-5-(2,2-dimethylpropylsulfonyl)indole (I-041)

[0363] Formula weight: 370.3

[0364] Molecular formula: C 16 H 20 BrNO2S

[0365] Under air, I-037 (200 mg, 606 µmol, 1 equivalent) and Cu(OAc)2 monohydrate (121 mg, 606 µmol, 1 equivalent) were added to a MW vial. - Bipyridine (95 mg, 606 μmol, 1 equivalent), cyclopropylboronic acid (104 mg, 1.21 mmol, 2 equivalents), and Na₂CO₃ (128 mg, 1.21 mmol, 2 equivalents). DCE (2 mL) was added, the vial was sealed, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 98 / 2 to 70 / 30) to give 114 mg of I-041 (51%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 8.09 (d, J = 1.7 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 3.3 Hz, 1H), 6.55 (d, J= 3.3 Hz, 1H), 3.86 – 3.78 (m, 1H), 3.06 (s, 2H), 1.23 – 1.14 (m, 4H), 1.20 (s, 9H). MS (ESI + ): [M+H] + 370.0 / 372.0.

[0366] 7-Bromo-1H-indazole-5-sulfonyl chloride (I-042)

[0367] Formula weight: 295.54

[0368] Molecular formula: C7H4BrClN2O2S

[0369] In the first 100 mL flask: at 0°C, add dropwise SOCl2 (5.5 mL, 76 mmol, 8 equivalents) to a solution of CuCl (112 mg, 1.13 mmol, 0.12 equivalents) in water (30 mL) [Note: exothermic and gas release]. Stir the resulting green solution at RT for 1 hour. In another 500 mL flask: at 0°C, add dropwise NaNO2 (716 mg, 10.4 mmol, 1.1 equivalents) in water (30 mL) to a solution of 7-bromo-1H-indazole-5-amine (2.00 g, 9.43 mmol, 1 equivalent) in water (80 mL) and 37% HCl (35 mL). Stir the mixture at 0°C for 30 minutes, at which point add the first solution. Stir the resulting mixture at RT for 2 hours. Filter the dark suspension through a sintered glass filter and wash the filter cake with water (30 mL). The filter cake was dissolved in EtOAc, the organic solution was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 1.1 g of I-042 (41%) as a brown solid, which was immediately used in the next step. 1 H NMR (400 MHz, chloroform-) d ) δ8.52 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H).

[0370] 7-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]-1H-indazole (I-043)

[0371] Formula weight: 420.32

[0372] Molecular formula: C 18 H 18 BrN3O2S

[0373] According to GP-4, I-043 was obtained as a white solid in 50% yield by continuous administration of I-042 (130 mg, 220 µmol, 1 equivalent), 4-phenylpiperidine (71 mg, 0.44 mmol, 2 equivalent) and Et3N (0.15 mL, 1.1 mmol, 5 equivalent) in DCM (3 mL) for 16 hours at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 10.46 (s, 1H), 8.33 (s,1H), 8.25 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 1.4 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.24 – 7.18 (m, 1H), 7.17 – 7.10 (m, 2H), 4.03 – 3.95 (m, 2H), 2.48 – 2.33(m, 3H), 1.96 – 1.82 (m, 4H). MS (ESI + ): [M+H] + 420.0 / 422.0.

[0374] 2-[[7-bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]indazole-1-yl]methoxy]ethyl-trimethylsilane A mixture of 2-[[7-bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]indazole-2-yl]methoxy]ethyl-trimethyl-silane Things (I-044)

[0375] Formula weight: 550.58

[0376] Molecular formula: C 24 H 32 BrN3O2SSi

[0377] At 0°C, NaH (60% in mineral oil, 10 mg, 0.25 mmol, 2.3 equivalents) was added to a solution of I-043 (50.0 mg, 111 µmol, 1 equivalent) in anhydrous THF (1.7 mL). The mixture was stirred at 0°C for 30 min, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (44 µL, 0.25 mmol, 2.3 equivalents). The mixture was stirred at RT for 16 h. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with water and brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 60 / 40) to give 30 mg of I-044 as a colorless oil (59%, an unreasonable 3 / 1 mixture of isomers). Major isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.44 (s, 1H), 8.26 (d, J = 1.4 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.25 – 7.18 (m, 1H), 7.17 – 7.07 (m, 2H), 5.82 (s, 2H), 4.09 – 3.89 (m, 2H), 3.77 – 3.69 (m, 2H), 2.64 – 2.28 (m, 3H), 2.05 – 1.77 (m, 4H), 1.04 – 0.94 (m, 2H), 0.00 (s, 9H). Minor isomers 1 H NMR (400MHz, chloroform-) d ) δ 8.23 ​​– 8.14 (m, 2H), 8.01 (d, J = 1.5 Hz, 1H), 7.29 (t, J= 7.3Hz, 2H), 7.25 – 7.18 (m, 1H), 7.17 – 7.07 (m, 2H), 6.11 (s, 2H), 4.09 – 3.89(m, 2H), 3.67 – 3.57 (m, 2H), 2.64 – 2.28 (m, 3H), 2.05 – 1.77 (m, 4H), 0.94– 0.85 (m, 2H), -0.05 (s, 9H). MS (ESI + ): [M+H] + 550.1 / 550.2.

[0378] 7-Bromo-N-tert-butyl-1H-indazole-5-sulfonamide (I-045)

[0379] Formula weight: 332.22

[0380] Molecular formula: C 11 H 14 BrN3O2S

[0381] According to GP-4, I-042 (525 mg, 1.78 mmol, 1 equivalent) and at RT t -BuNH2 (1.9 mL, 18 mmol, 10 equivalents) was used in DCM (9 mL) for 16 hours to obtain I-045 as a white solid in 49% yield. 1 H NMR (400 MHz, DMSO-) d 6 ) δ 13.92 (s, 1H), 8.42 (s, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.98 (t, J = 1.4 Hz, 1H), 7.53 (s, 1H), 1.09 (s, 9H). MS (ESI + ): [M+H] + 332.0 / 334.0.

[0382] 7-Bromo-N-tert-butyl-1-(2-trimethylsilylethoxymethyl)indazole-5-sulfonamide (I-046)

[0383] Formula weight: 462.48

[0384] Molecular formula: C 17 H 28 BrN3O3SSi

[0385] At 0°C, NaH (67 mg, 1.7 mmol, 3 equivalents in mineral oil, 185 mg, 557 µmol, 1 equivalent) was added to a solution of I-045 (185 mg, 557 µmol, 1 equivalent) in anhydrous DMF (2.8 mL). The mixture was stirred at RT for 30 min, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (98 µL, 0.56 mmol, 1 equivalent). The mixture was stirred at RT for 16 h. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 99 / 1 to 80 / 20) to give 53 mg of I-046 (21%) as a colorless oil. 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.45 (s, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.61 (s,1H), 6.01 (s, 2H), 3.55 (t, J = 7.7 Hz, 2H), 1.08 (s, 9H), 0.77 (t, J = 7.7Hz, 2H), -0.16 (s, 9H). MS (ESI + ): [M+H] + 462.0 / 464.0.

[0386] 7-Bromo-N-tert-butyl-1-cyclopropyl-indazole-5-sulfonamide (I-047)

[0387] Formula weight: 372.28

[0388] Molecular formula: C 14 H 18 BrN3O2S

[0389] Under air, I-045 (100 mg, 301 µmol, 1 equivalent), Cu(OAc)2 (55 mg, 0.30 mmol, 1 equivalent), and 2, were added to a MW vial. - Bipyridine (47 mg, 0.30 mmol, 1 equivalent), cyclopropylboronic acid (52 mg, 0.60 mmol, 2 equivalents), and Na₂CO₃ (64 mg, 0.60 mol, 2 equivalents). DCE (2 mL) was added, the vial was sealed, and the reaction mixture was stirred at 70°C for 3 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 42 mg of I-047 (37%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.17 (d, J = 1.7 Hz, 1H), 7.98 (d, J =1.6 Hz, 1H), 7.94 (s, 1H), 4.87 (s, 1H), 4.03 (tt, J = 7.3, 3.7 Hz, 1H), 1.42– 1.32 (m, 2H), 1.22 – 1.12 (s, 11H). MS (ESI + ): [M+H] + 372.0 / 374.0.

[0390] 7-Bromo-5-(3,3-difluoropyrrolidone-1-yl)sulfonyl-1H-indazole (I-048)

[0391] Formulae: 366.18

[0392] Molecular formula: C 11 H 10 BrF2N3O2S

[0393] According to GP-4, I-048 was obtained as a white solid in 18% yield by continuous administration of I-042 (300 mg, 1.02 mmol, 1 equivalent), 3,3-difluoropyrrolidine hydrochloride (175 mg, 1.22 mmol, 1.2 equivalent) and Et3N (0.35 mL, 2.0 mmol, 2 equivalent) in THF (5 mL) for 16 hours at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 8.33 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 3.59 (t, J= 12.8 Hz, 2H), 3.47 (d, J = 7.6 Hz,2H), 2.37 – 2.22 (m, 2H). MS (ESI + ): [M+H] + 366.0 / 368.0.

[0394] 2-[[7-bromo-5-(3,3-difluoropyrrolidone-1-yl)sulfonyl-indazole-1-yl]methoxy]ethyl-trimethylsilyl Alkane and 2-[[7-bromo-5-(3,3-difluoropyrrolidone-1-yl)sulfonyl-indazol-2-yl]methoxy]ethyltrimethyl-silane Mixture (I-049)

[0395] Formula weight: 496.44

[0396] Molecular formula: C 17 H 24 BrF2N3O3SSi

[0397] At 0°C, NaH (60% in mineral oil, 8.8 mg, 0.22 mmol, 1.2 equivalent) was added to a solution of I-048 (66 mg, 0.18 mmol, 1 equivalent) in anhydrous THF (1.8 mL). The mixture was stirred at 0°C for 30 min, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (39 µL, 0.22 mmol, 1.2 equivalent). The mixture was stirred at RT for 16 h. More NaH (60% in mineral oil, 7.3 mg, 0.18 mmol, 1 equivalent) and 2-(trimethylsilyl)ethoxymethyl chloride (32 µL, 0.18 mmol, 1 equivalent) were added, and the reaction mixture was stirred at RT for another 3 h. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 64 mg of I-049 as a colorless oil (69%, an unreasonable 2 / 1 mixture of isomers). Major isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.22 (d, J = 1.5 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J= 1.5 Hz, 1H), 6.09 (s, 2H), 3.74 –3.42 (m, 6H), 2.41 – 2.19 (m, 2H), 0.92 – 0.85 (m, 2H), -0.08 (s, 9H). Minor isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.45 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 5.81 (s, 2H), 3.74 – 3.42 (m, 6H), 2.41 – 2.19 (m,2H), 1.00 – 0.94 (m, 2H), -0.02 (s, 9H). MS (ESI + ): [M+H] + 496.0 / 497.9.

[0398] 7-Bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1H-indazole (I-050)

[0399] Formula weight: 483.81

[0400] Molecular formula: C 19 H 20 BrClN4O2S

[0401] According to GP-4, I-050 was obtained as a white solid in 37% yield by continuous administration of I-042 (1.25 g, 4.23 mmol, 1 equivalent), 1-[2-(4-chlorophenyl)ethyl]piperazine (952 mg, 4.23 mmol, 1 equivalent) and Et3N (0.71 mL, 5.1 mmol, 1.2 equivalent) in THF / DCM (40 mL) for 16 hours at RT. 1 H NMR (400 MHz, chloroform-) d ) δ10.64 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 3.09 (s, 4H), 2.75 – 2.50 (m, 8H).MS (ESI + ):[M+H] +483.0 / 485.0 / 487.0.

[0402] 2-[[7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-indazole-1-yl]methoxy]ethyl 2-[[7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-indazole-2-yl]methyl Mixture of [oxy]ethyl-trimethyl-silanes (I-051)

[0403] Formula weight: 614.07

[0404] Molecular formula: C 25 H 34 BrClN4O3SSi

[0405] At 0°C, NaH (60% in mineral oil, 35 mg, 0.87 mmol, 2 equivalents) was added to a solution of I-050 (210 mg, 434 µmol, 1 equivalent) in anhydrous DMF (2.2 mL). The mixture was stirred at 0°C for 30 min, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (0.15 mL, 0.87 mmol, 2 equivalents). The mixture was stirred at RT for 16 h. The mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with water and brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give 220 mg of I-051 as an orange oil (83%, a mixture of insignificant 2 / 1 isomers). Major isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.19– 8.12 (m, 2H), 7.96 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.6 Hz,2H), 6.10 (s, 2H), 3.61 (t, J = 8.2 Hz, 2H), 3.20 – 2.85 (m, 4H), 2.75 – 2.45(m, 8H), 0.93 (t, J = 8.2 Hz, 2H), -0.05 (s, 9H). Minor isomers 1 H NMR (400MHz, chloroform-) d )δ 8.43 (s, 1H), 8.21 (s, 1H), 7.82 (s, 1H), 7.22 (d, J= 7.6 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 5.82 (s, 2H), 3.70 (t, J = 8.3 Hz, 2H), 3.20 –3.00 (s, 4H), 2.75 – 2.50 (m, 8H), 1.04 – 0.95 (m, 2H), 0.02 (s, 9H). MS (ESI + ): [M+H] + 613.2 / 615.2 / 617.2.

[0406] 7-Bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1-cyclopropyl-indazole (I-052)

[0407] Formula weight: 523.87

[0408] Molecular formula: C 22 H 24 BrClN4O2S

[0409] Under air, I-050 (250 mg, 517 µmol, 1 equivalent), Cu(OAc)2 (94 mg, 0.52 mmol, 1 equivalent), and 2, - Bipyridine (81 mg, 0.52 mol, 1 equivalent), cyclopropylboronic acid (88.7 mg, 1.03 mmol, 2 equivalents), and Na₂CO₃ (110 mg, 1.04 mmol, 2 equivalents). DCE (2 mL) was added, the vial was sealed, and the reaction mixture was stirred at 75°C for 16 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 30 / 70) to give 130 mg of I-052 (48%) as a brown solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.13 (d, J = 1.6 Hz, 1H), 8.07(s, 1H), 7.94 (s, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 4.14 (tt, J= 7.5, 3.8 Hz, 1H), 3.10 (br s, 4H), 2.80 – 2.50 (m, 8H), 1.52 –1.42 (m, 2H), 1.32 – 1.22 (m, 2H). MS (ESI + ): [M+H] + 523.1 / 525.1 / 527.1.

[0410] 7-Bromo-5-iodo-1H-indazole (I-053)

[0411] Formula weight: 322.93

[0412] Molecular formula: C7H4BrIN2

[0413] At 0°C, a solution of NaNO2 (1.15 g, 16.6 mmol, 1.1 equivalent) in water (17 mL) was added dropwise to a solution of 7-bromo-1H-indazole-5-amine (3.20 g, 15.1 mmol, 1 equivalent) in 6 N HCl (30 mL). The mixture was stirred at 0°C for 30 minutes, at which point it was added dropwise to a solution of KI (12.5 g, 75.5 mmol, 5 equivalent) in water (26 mL) at 0°C. The resulting thick suspension was stirred at RT for 1.5 hours, then at 90°C for 1 hour. After cooling to RT, EtOAc was added, and the two-phase suspension was filtered through diatomaceous earth (EtOAc washing). The filtrate layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, 3... The sample was dried (Na2S2O3, brine) and filtered and concentrated under reduced pressure. The residue was purified by passing it through an FC column (80 g column, dry load, cHex / EtOAc = 97 / 3 to 70 / 30) to give 3.63 g of I-053 (74%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 10.39 (s, 1H), 8.15 – 8.05 (m, 2H), 7.87 – 7.78 (m, 1H). MS (ESI + ): [M+H] + 322.9 / 324.9.

[0414] 2-[(7-bromo-5-iodo-indazole-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(7-bromo-5-iodo-indazole- A mixture of 2-yl)methoxy]ethyl-trimethyl-silanes (I-054)

[0415] Formula weight: 453.19

[0416] Molecular formula: C 13 H 18 BrIN2OSi

[0417] At 0°C, NaH (60% in mineral oil, 290 mg, 7.24 mmol, 2 equivalents) was added to a solution of I-053 (1.17 g, 3.62 mol, 1 equivalent) in anhydrous THF (18 mL). The mixture was stirred at RT for 30 min, and 2-(trimethylsilyl)ethoxymethyl chloride (0.96 mL, 5.43 mmol, 1.5 equivalents) was added dropwise. The mixture was stirred at RT for 2 h. The mixture was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 1.64 g of I-054 as an orange oil (98%, an unreasonable 2 / 1 mixture of isomers). Major isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.03 (d, J =1.4 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J = 1.4 Hz, 1H), 6.03 (s, 2H), 3.59 –3.53 (m, 2H), 0.91 – 0.85 (m, 2H), -0.07 (s, 9H). Minor isomers 1 H NMR (400MHz, chloroform-) d ) δ 8.14 (s, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.76 (d, J = 1.3 Hz,1H), 5.75 (s, 2H), 3.68 – 3.62 (m, 2H), 0.98 – 0.92 (m, 2H), -0.02 (s, 9H).MS (ESI + ): [M+H] + 452.9 / 454.9.

[0418] 2-[[7-bromo-5-(2,2-dimethylpropylthio)indazol-1-yl]methoxy]ethyl-trimethyl-silane and A mixture of 2-[[7-bromo-5-(2,2-dimethylpropylthio)indazole-2-yl]methoxy]ethyl-trimethyl-silane (I- 055）

[0419] Formula weight: 429.49

[0420] Molecular formula: C 18 H 29 BrN2OSSi

[0421] Using GP-1, I-055 was obtained as a pale yellow oil in 95% yield at 100°C using I-054 (500 mg, 1.10 mmol, 1 equivalent), XantPhos-Pd-G3 (105 mg, 110 µmol, 0.10 equivalent), iPr2NEt (0.38 mL, 2.2 mmol, 2 equivalent), and 2,2-dimethylpropane-1-thiol (139 µL, 1.10 mmol, 1 equivalent) in toluene (5.5 mL) for 2 hours. Purification was performed by FC (cHex / EtOAc = 99 / 1 to 90 / 10). MS (ESI) + ): [M+H] + 429.1 / 431.1.

[0422] 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazole-1-yl]methoxy]ethyl-trimethyl-silane and A mixture of 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazole-2-yl]methoxy]ethyl-trimethyl-silane (I- 056）

[0423] Formula weight: 461.49

[0424] Molecular formula: C 18 H 29 BrN2O3SSi

[0425] Using GP-2, I-056 (a mixture of 2 / 1 isomers, not important) was obtained as a white solid in 71% yield by continuous RT in DCM (5.2 mL) with I-055 (449 mg, 1.05 mmol, 1 equivalence) and m-CPBA (70% wet, 569 mg, 2.31 mmol, 2.2 equivalences) for 16 hours. Purification was performed by FC (cHex / EtOAc = 95 / 5 to 50 / 50). Major isomers... 1 H NMR (400 MHz, chloroform-) d ) δ 8.32 (d, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J= 1.5 Hz, 1H), 6.10 (s, 2H), 3.64 – 3.55 (m, 2H), 3.08 (s, 2H), 1.21 (s, 9H), 0.92 – 0.86 (m, 2H), -0.07 (s, 9H). Minor isomers 1 H NMR (400MHz, chloroform-) d ) δ 8.45 (s, 1H), 8.37 (d, J = 1.5 Hz, 1H), 7.95 (d, J MS (ESI) + ): [M+H] + 461.0 / 463.0.

[0426] 7-Bromo-5-iodo-1-methyl-indazole (I-057)

[0427] Formula weight: 336.96

[0428] Molecular formula: C8H6BrIN2

[0429] At 0°C, NaH (60% in mineral oil, 44 mg, 1.10 mmol, 1.5 equivalent) was added to a solution of I-053 (237 mg, 0.734 mmol, 1 equivalent) in anhydrous THF (3.7 mL). The mixture was stirred at RT for 30 min, and iodomethane (0.11 mL, 1.8 mmol, 2.5 equivalent) was added dropwise. The mixture was stirred at RT for 1 h. The mixture was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 80 / 20) to give 70 mg of I-057 (28%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ7.99 (d, J = 1.5 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J= 1.4 Hz, 1H), 4.39 (s,3H). MS (ESI + ): [M+H] + 336.8 / 338.8.

[0430] 7-Bromo-5-(2,2-dimethylpropylthio)-1-methyl-indazole (I-058)

[0431] Formula weight: 313.26

[0432] Molecular formula: C 13 H 17 BrN2S

[0433] Using GP-1, I-058 was obtained in 69% yield as a pale yellow oil at 100°C using I-057 (70 mg, 0.21 mmol, 1 equivalent), XantPhos-Pd-G3 (5.9 mg, 6.2 µmol, 0.03 equivalent), iPr2NEt (70 µL, 0.42 mmol, 2 equivalent), and 2,2-dimethylpropane-1-thiol (26 µL, 0.21 mmol, 1 equivalent) in toluene (1 mL) for 2 hours. Purification was performed by FC (DCM / EtOAc = 99 / 1 to 80 / 20). 1 H NMR (400 MHz, chloroform-) d δ7.87 (s, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 4.38 (s,3H), 2.89 (s, 2H), 1.03 (s, 9H). MS (ESI + ): [M+H] + 313.1 / 315.1.

[0434] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1-methyl-indazole (I-059)

[0435] Formula weight: 345.26

[0436] Molecular formula: C 13 H 17 BrN2O2S

[0437] Using GP-2, I-059 was obtained as a white solid in 81% yield by continuous RT in DCM (0.7 mL) with I-058 (45 mg, 0.14 mmol, 1 equivalent) and m-CPBA (77% wet, 71 mg, 0.32 mmol, 2.2 equivalent) for 1 hour. Purification was performed by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1 H NMR (400 MHz, chloroform-) d ) δ 8.29 (d, J = 1.5 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 4.47 (s, 3H), 3.06(s, 2H), 1.20 (s, 9H). MS (ESI + ): [M+H] + 345.0 / 347.0.

[0438] 7-Bromo-5-(2,2-Dimethylpropylthio)-1H-indazole (I-060)

[0439] Formula weight: 299.23

[0440] Molecular formula: C 12 H 15 BrN2S

[0441] Using GP-1, I-060 was obtained as a white solid in 83% yield at 100°C using I-053 (630 mg, 1.95 mmol, 1 equivalent), XantPhos (56 mg, 0.70 mmol, 0.05 equivalent), Pd2(dba)3 (36 mg, 39 µmol, 0.05 equivalent), iPr2NEt (0.68 mL, 3.9 mmol, 2 equivalent), and 2,2-dimethylpropane-1-thiol (245 µL, 1.95 mmol, 1 equivalent) in toluene (10 mL). Purification was performed by FC (DCM / EtOAc = 99 / 1 to 90 / 10). 1 H NMR (400 MHz, chloroform-) d ) δ 8.12 (s, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 5.63 (br s, 1H), 2.93 (s, 2H), 1.07 (s, 9H). MS (ESI+ ): [M+H] + 299.1 / 301.1.

[0442] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1H-indazole (I-061)

[0443] Formula weight: 331.23

[0444] Molecular formula: C 12 H 15 BrN2O2S

[0445] Using GP-2, I-061 was obtained in 100% yield as a white solid by continuous resuscitation in DCM (8 mL) with I-060 (485 mg, 1.62 mmol, 1 equivalent) and m-CPBA (77% wet, 875 mg, 3.56 mmol, 2.2 equivalent) for 16 hours at RT. Purification was performed by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1 H NMR (400 MHz, chloroform-) d ) δ 8.40 (d, J = 1.4 Hz, 1H), 8.35 (s, 1H), 8.09 (d, J = 1.4 Hz, 1H), 3.11 (s, 2H), 1.24(s, 9H). MS (ESI + ): [M+H] + 331.0 / 333.0.

[0446] 7-Bromo-1-cyclopropyl-5-(2,2-dimethylpropylsulfonyl)indazole (I-062)

[0447] Formula weight: 371.29

[0448] Molecular formula: C 15 H 19 BrN2O2S

[0449] Under air, I-061 (250 mg, 755 µmol, 1 equivalent), Cu(OAc)2 (137 mg, 0.75 mmol, 1 equivalent), and 2, - Bipyridine (118 mg, 0.75 mol, 1 equivalent), cyclopropylboronic acid (130 mg, 1.51 mmol, 2 equivalents), and Na₂CO₃ (160 mg, 1.51 mmol, 2 equivalents). DCE (3.8 mL) was added, and the reaction mixture was stirred at 70°C for 3 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 118 mg of I-062 (42%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.28 – 8.24 (m, 1H), 8.08 – 8.04 (m, 2H), 4.16 – 4.08 (m, 1H), 3.06 (s, 2H), 1.48 – 1.40 (m, 2H), 1.30 – 1.24 (m, 2H), 1.21 (s, 9H). MS (ESI + ): [M+H] + 371.1 / 373.1.

[0450] 2-[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazole-1-yl]ethoxy-tert-butyldimethylsilane (I- 063）

[0451] Formula weight: 489.54

[0452] Molecular formula: C 20 H 33 BrN2O3SSi

[0453] At 0°C, NaH (60% in mineral oil, 45 mg, 1.12 mmol, 1.2 equivalent) was added to a solution of I-061 (310 mg, 0.936 mmol, 1 equivalent) in anhydrous DMF (4.7 mL). The mixture was stirred at RT for 30 min, and (2-bromoethoxy)-tert-butyl-dimethylsilane (0.30 mL, 1.4 mmol, 1.5 equivalent) was added dropwise. The mixture was stirred at RT for 16 h. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 96 / 4 to 60 / 40) to give 133 mg of I-063 (29%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 8.45 (d, J = 1.7 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 5.16 (t, J = 5.8 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 3.22 (s,2H), 1.35 (s, 9H), 0.88 (s, 9H), 0.00 (s, 6H). MS (ESI + ): [M+H] + 489.2 / 491.1.

[0454] [8-[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-(2,2-dimethylpropylsulfonyl)in [Azol-7-yl]-3,8-diazabicyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-064)

[0455] Formula weight: 677.34

[0456] Molecular formula: C 33 H 46 ClFN4O4SSi

[0457] According to GP-3, I-064 was obtained in 56% yield by reflux in toluene (1.4 mL) for 4 h using aryl bromide I-063 (133 mg, 272 µmol, 1 equivalent), piperazine I-002 (102 mg, 380 µmol, 1.4 equivalent), Cs₂CO₃ (266 mg, 0.815 mmol, 3 equivalent), Pd(OAc)₂ (6.1 mg, 27 µmol, 0.10 equivalent), and BINAP (20 mg, 33 µmol, 0.12 equivalent). Purification was performed by FC (cHex / EtOAc = 95 / 5 to 0 / 100). 1 H NMR (400 MHz, chloroform-) d , 2 sets of rotating anisotropy configuration ) δ 8.29 (s, 1H), 8.15 (s, 1H), 7.57 – 7.47 (m, 0.5H), 7.40 – 7.15 (m,3.5H), 5.15 – 4.90 (m, 2H), 4.77 & 4.74 (s, 1H), 4.40 – 4.22 (m, 3H), 4.07 &4.02 (s, 1H), 3.95 – 3.70 (m, 1H), 3.57 & 3.54 (s, 1H), 3.43 – 3.32 (m, 1H),3.15 (s, 2H), 2.42 – 1.98 (m, 3.5H), 1.85 – 1.75 (m, 0.5H), 1.29 (s, 9H), 0.83 (s, 9H), 0.00 (s, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers δ -108.96, -109.10. MS (ESI) + ): [M+H] + 677.4 / 679.4.

[0458] 2-Bromo-6-nitro-4-[(4-phenyl-1-piperidinyl)sulfonyl]aniline (I-065)

[0459] Formula weight: 440.31

[0460] Molecular formula: C 17 H 18 BrN3O4S

[0461] According to GP-4, I-065 was obtained as a white solid in 95% yield by continuous recombinant human 4-amino-3-bromo-5-nitrobenzenesulfonyl chloride (811 mg, 2.57 mmol, 1 equivalent), 4-phenylpiperidine (828 mg, 5.13 mmol, 2 equivalent), and Et3N (1.8 mL, 13 mmol, 5 equivalent) in DCM (27 mL) for 16 hours. Purification was performed by FC (DCM / EtOAc = 98 / 2 to 60 / 40). 1 H NMR (400 MHz, chloroform-) d ) δ 8.60 (d, J = 2.1 Hz, 1H), 8.11 (d, J =2.1 Hz, 1H), 7.37 – 7.29 (m, 2H), 7.27 – 7.22 (m, 1H), 7.21 – 7.15 (m, 2H), 4.01 – 3.94 (m, 2H), 2.55 – 2.40 (m, 3H), 2.00 – 1.79 (m, 4H). MS (ESI + ): [M+H] + 440.0 / 442.0.

[0462] 3-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]benzene-1,2-diamine (I-066)

[0463] Formula weight: 410 / 33

[0464] Molecular formula: C 17 H 20 BrN3O2S

[0465] At 0°C, iron powder (325 mesh, 411 mg, 7.36 mmol, 4 equivalents) and AcOH (0.64 mL, 11.0 mmol, 6 equivalents) were added to a solution of I-065 (810 mg, 1.84 mmol, 1 equivalent) in MeOH (9.2 mL). The mixture was stirred at 60°C for 16 hours. After cooling to RT, EtOAc was added, and the suspension was filtered through diatomaceous earth (EtOAc / MeOH washing). The filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc=98 / 2 to 50 / 50) to give 377 mg of I-066 (50%) as a gray solid.1 H NMR (400 MHz, DMSO- d 6 ) δ 7.30 – 7.24 (m, 2H), 7.22 – 7.14 (m, 3H),7.00 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 5.48 (s, 2H), 5.34 (s,2H), 3.74 – 3.59 (m, 2H), 2.50 – 2.44 (m, 1H), 2.29 (td, J = 11.9, 2.4 Hz,2H), 1.86 – 1.76 (m, 2H), 1.72 – 1.56 (m, 2H). MS (ESI + ): [M+H] + 410.0 / 412.0.

[0466] 7-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]-1H-benzotriazole (I-067)

[0467] Formula weight: 421.31

[0468] Molecular formula: C 17 H 17 BrN4O2S

[0469] At 0°C, a solution of NaNO2 (48 mg, 0.70 mmol, 1.5 equivalent) in water (0.4 mL) was added to a solution of I-066 (192 mg, 468 µmol, 1 equivalent) in AcOH (1.5 mL). The reaction mixture was stirred at RT for 16 h. Water and EtOAc were added. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give 190 mg of I-067 (96%) as a gray solid. 1 H NMR (400 MHz, DMSO-) d 6 ) δ 8.30 (d, J = 1.4 Hz, 1H), 7.82 (d, J= 1.2 Hz, 1H), 7.35– 7.09 (m, 5H), 3.90 – 3.75 (m, 2H), 2.53 – 2.42 (m, 1H), 2.37 (td, J = 12.1,2.6 Hz, 2H), 1.87 – 1.75 (m, 2H), 1.75 – 1.62 (m, 2H). MS (ESI + ): [M+H] + 420.9 / 422.9.

[0470] 2-[[7-bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]benzotriazol-1-yl]methoxy]ethyl-trimethyl- Silane, 2-[[4-bromo-6-[(4-phenyl-1-piperidinyl)sulfonyl]benzotriazol-2-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-6-[(4-phenyl-1-piperidinyl)sulfonyl]benzotriazol-1-yl]methoxy]ethyl-trimethyl-silane Mixture (I-068)

[0471] Formulas: 551,57

[0472] Molecular formula: C 23 H 31 BrN4O3SSi

[0473] At 0°C, NaH (60% in mineral oil, 36 mg, 0.89 mmol, 1.8 equivalent) was added to a solution of I-067 (217 mg, 494 µmol, 1 equivalent) in anhydrous DMF (2.5 mL). The mixture was stirred at 0°C for 30 min, and 2-(trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.59 mmol, 1.2 equivalent) was added. The mixture was stirred at RT for 16 h, at which point more 2-(trimethylsilyl)ethoxymethyl chloride (0.11 mL, 0.59 mmol, 1.2 equivalent) was added. After an additional hour at RT, the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with water, brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give 210 mg of I-068 as a colorless oil (77%, an unreasonable 3 / 2 / 1 mixture of isomers). MS (ESI) + ): [M+H] + 551.0 / 553.0.

[0474] 7-Bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]-1H-benzimidazole (I-069)

[0475] Formula: 420,32

[0476] Molecular formula: C 18 H 18 BrN3O2S

[0477] At RT, I-065 (310 mg, 704 µmol, 1 equivalent) was administered... i Add NH4Cl (377 mg, 7.04 mmol, 10 equivalents) and iron powder (325 mesh, 393 mg, 7.04 mmol, 10 equivalents) to a solution of PrOH (3.5 mL) and formic acid (3.5 mL). Stir the mixture at 80°C for 2.5 hours. After cooling to RT, add... i PrOH, and the suspension was filtered through diatomaceous earth ( i (PrOH wash). The filtrate was concentrated under reduced pressure. The residue was partitioned between DCM and saturated aqueous NaHCO3. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 98 / 2 to 0 / 100) to give 140 mg of I-069 (47%) as a brown solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.30 (s, 1H), 8.59 (s, 1H), 7.99 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.32 – 7.23 (m, 2H), 7.23 – 7.11 (m, 3H), 3.85 – 3.77 (m, 2H), 2.50 – 2.40 (m, 1H), 2.33 (td, J = 11.9, 2.5 Hz, 2H),1.87 – 1.75 (m, 2H), 1.75 – 1.60 (m, 2H). MS (ESI + ): [M+H] + 420.1 / 422.0.

[0478] 2-[[7-bromo-5-[(4-phenyl-1-piperidinyl)sulfonyl]benzimidazol-1-yl]methoxy]ethyl-trimethyl- Silane and 2-[[4-bromo-6-[(4-phenyl-1-piperidinyl)sulfonyl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane Mixture of alkanes (I-070)

[0479] Formula weight: 550.58

[0480] Molecular formula: C 24 H32 BrN3O3SSi

[0481] At 0°C, NaH (60% in mineral oil, 29 mg, 0.71 mmol, 1.5 equivalent) was added to a solution of I-069 (200 mg, 476 µmol, 1 equivalent) in anhydrous DMF (2.4 mL). The mixture was stirred at 0°C for 30 min, and 2-(trimethylsilyl)ethoxymethyl chloride (84 µL, 0.48 mmol, 1 equivalent) was added dropwise. The mixture was stirred at RT for 24 h, at which point more NaH (60% in mineral oil, 15 mg, 0.62 mmol, 1.3 equivalent) and 2-(trimethylsilyl)ethoxymethyl chloride (84 µL, 0.48 mmol, 1 equivalent) were added. After an additional 4 h at RT, the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give 150 mg of I-070 as a yellow solid (57%, an unreasonable 3 / 2 mixture of isomers). MS (ESI) + ): [M+H] + 550.2 / 552.2

[0482] 7-Bromo-1-methyl-5-[(4-phenyl-1-piperidinyl)sulfonyl]benzimidazole (I-071)

[0483] Formula weight: 434.35

[0484] Molecular formula: C 19 H 20 BrN3O2S

[0485] At RT, K₂CO₃ (115 mg, 0.833 mmol, 1 equivalent) and iodomethane (30 µL, 0.50 mmol, 1.5 equivalent) were added to a solution of I-069 (140 mg, 0.333 mmol, 1 equivalent) in anhydrous DMF (0.7 mL). The mixture was stirred at 80°C for 2 hours. After cooling to RT, the mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 90 / 10 to 20 / 80) to give 32 mg of I-071 (22%) as a white solid.1 H NMR (400 MHz, chloroform-) d ) δ 8.18 (s, 1H), 7.97 (s, 1H), 7.87 (s,1H), 7.32 – 7.24 (m, 2H), 7.24 – 7.17 (m, 1H), 7.16 – 7.09 (m, 2H), 4.20 (s,3H), 4.02 – 3.93 (m, 2H), 2.45 – 2.30 (m, 3H), 1.98 – 1.76 (m, 4H). MS (ESI + ): [M+H] + 434.1 / 436.1.

[0486] 4-Amino-3-bromo-N-tert-butyl-5-nitro-benzenesulfonamide (I-072)

[0487] Formula weight: 352.2

[0488] Molecular formula: C0H 14 BrN3O4S

[0489] A solution of 2-bromo-6-nitroaniline (590 mg, 2.72 mmol, 1 equivalent) in HSO3Cl (3 mL) was stirred for 1.5 h at 100°C. After cooling to RT, the RM was carefully poured onto ice [Note: exothermic, gas release]. After the ice melted, DCM was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting arylsulfonyl chloride was dissolved in DCM (5 mL) and the solution was added dropwise to RT. t -BuNH2 (1.4 mL, 14 mmol, 5 equivalents) was in a solution of DCM (5 mL). The mixture was stirred at RT for 16 hours. It was partitioned between 1 N HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 795 mg of I-072 (83%) as a brown solid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.43 (d, J = 2.2 Hz, 1H), 8.13 (d, J= 2.2 Hz, 1H), 7.70 (s, 2H), 7.56 (s, 1H), 1.12 (s, 9H). MS (ESI + ): [M+H] + 352.0 / 354.0.

[0490] 7-Bromo-N-tert-butyl-1H-benzimidazole-5-sulfonamide (I-073)

[0491] Formula weight: 332.22

[0492] Molecular formula: C 11 H 14 BrN3O2S

[0493] At RT, I-072 (350 mg, 994 µmol, 1 equivalent) was administered... i Add NH4Cl (532 mg, 9.93 mmol, 10 equivalents) and iron powder (325 mesh, 555 mg, 9.93 mmol, 10 equivalents) to a solution of PrOH (5 mL) and formic acid (5 mL). Stir the mixture at 80°C for 2.5 hours. After cooling to RT, add... i PrOH, and the suspension was filtered through diatomaceous earth ( i (PrOH wash). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry load, cHex / EtOAc = 98 / 2 to 0 / 100) to give 309 mg of I-073 as a yellow solid (80% purity, 75%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.15 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.86 (d, J = 1.6 Hz,1H), 7.57 (s, 1H), 1.09 (s, 9H). MS (ESI + ): [M+H] + 331.9 / 334.0.

[0494] 7-Bromo-N-tert-butyl-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-sulfonamide (I-074)

[0495] Formula weight: 462.48

[0496] Molecular formula: C 17 H 28 BrN3O3SSi

[0497] At RT, iPr2NEt (222 µL, 1.28 mmol, 1.6 equivalent) and 2-(trimethylsilyl)ethoxymethyl chloride (246 µL, 1.39 mmol, 1.8 equivalent) were added to a solution of I-073 (200 mg, 772 µmol, 1 equivalent) in DCM (7.7 mL). The mixture was stirred at RT for 24 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give 220 mg of I-074 (62%) as a yellow solid. ¹H NMR (400 MHz, DMSO- d 6 ) δ 8.68 (s, 1H), 8.17 (d, J =1.5 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.62 (s, 1H), 5.75 (s, 2H), 3.52 –3.45 (m, 2H), 1.09 (s, 9H), 0.85 – 0.78 (m, 2H), -0.10 (s, 9H). MS (ESI + ): [M+H] + 462.0 / 463.9.

[0498] 7-Bromo-N-tert-butyl-1-cyclopropyl-benzimidazole-5-sulfonamide (I-075)

[0499] Formula weight: 372.28

[0500] Molecular formula: C 14 H 18 BrN3O2S

[0501] Under air, I-073 (351 mg, 1.06 mmol, 1 equivalent), Cu(OAc)2 (211 mg, 1.06 mmol, 1 equivalent), and 2, - Bipyridine (165 mg, 1.06 mmol, 1 equivalent), cyclopropylboronic acid (100 mg, 1.16 mmol, 1.1 equivalent), and Na₂CO₃ (224 mg, 2.11 mmol, 2 equivalent). DCE (1.1 mL) was added, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) and then purified by PTLC (2 plates, 2 migrations in DCM / MeOH = 98 / 2) to give 19 mg of I-075 (5%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.28 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 4.58 (s, 1H), 3.80 – 3.70 (m, 1H), 1.35 – 1.10 (m, 13H). MS (ESI + ): [M+H] + 372.1 / 374.0.

[0502] 4-Amino-3-bromo-N-tert-butyl-N-methyl-5-nitro-benzenesulfonamide (I-076)

[0503] Formula: 366.23

[0504] Molecular formula: C 11 H 16 BrN3O4S

[0505] A solution of 2-bromo-6-nitroaniline (610 mg, 2.81 mmol, 1 equivalent) in HSO3Cl (3 mL) was stirred for 1.5 hours at 100°C. After cooling to RT, the RM was carefully poured onto ice [Note: exothermic, gas release]. After the ice melted, DCM was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The obtained arylsulfonyl chloride was dissolved in DCM (5 mL), and the solution was added dropwise to a solution of N-methyl-tert-butylamine (0.51 mL, 4.2 mmol / L, 1.5 equivalent) and Et3N (0.59 mL, 4.2 mmol / L, 1.5 equivalent in DCM (5 mL)). The mixture was stirred at RT for 16 hours. It was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 75 / 25) to give 433 mg of I-076 (42%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.59 (d, J = 2.2 Hz, 1H), 8.09 (d, J =2.1 Hz, 1H), 2.95 (s, 3H), 1.39 (s, 9H). MS (ESI + ): [M+H] + 366.1 / 368.2.

[0506] 7-Bromo-N-tert-butyl-N-methyl-1H-benzimidazole-5-sulfonamide (I-077)

[0507] Formula: 346.24

[0508] Molecular formula: C 12 H 16 BrN3O2S

[0509] At RT, I-076 (433 mg, 1.18 mmol, 1 equivalent) was administered... i Add NH4Cl (632 mg, 11.8 mmol, 10 equivalents) and iron powder (325 mesh, 660 mg, 11.8 mol, 10 equivalents) to a solution of PrOH (6 mL) and formic acid (6 mL). Stir the mixture at 80°C for 3 hours. After cooling to RT, add... iPrOH, and the suspension was filtered through diatomaceous earth ( i (PrOH wash). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry load, cHex / EtOAc = 80 / 20 to 0 / 100) to give 117 mg of I-077 (29%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d δ8.45 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 1.4 Hz, 1H), 2.99 (s,3H), 1.37 (s, 9H). MS (ESI + ): [M+H] + 346.0 / 348.0.

[0510] 7-Bromo-N-tert-butyl-N-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazole-5-sulfonamide A mixture of 7-bromo-N-tert-butyl-N-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-sulfonamide Things (I-078)

[0511] Formula weight: 476.5

[0512] Molecular formula: C 18 H 30 BrN3O3SSi

[0513] At RT, 2-(trimethylsilyl)ethoxymethyl chloride (72 µL, 0.41 mmol, 1.2 equivalence) was added to a solution of I-077 (117 mg, 338 µmol, 1 equivalent) and iPr2NEt (65 µL, 0.37 mmol, 1.1 equivalent) in anhydrous DCM (3.4 mL). The mixture was stirred at RT for 16 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give 118 mg of I-078 as a yellow oil (73%, an unreasonable 55 / 45 mixture of isomers). MS (ESI) + ): [M+H] + 476.0 / 478.0.

[0514] 2-Bromo-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-6-nitroaniline (I-079)

[0515] Formula weight: 503.8

[0516] Molecular formula: C 18 H 20 BrClN4O4S

[0517] A solution of 2-bromo-6-nitroaniline (1.00 g, 4.61 mmol, 1 equivalent) in HSO3Cl (3.1 mL) was stirred for 1.5 h at 100°C. After cooling to RT, the RM was carefully poured onto ice [Note: exothermic, gas release]. After the ice melted, DCM was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting arylsulfonyl chloride was dissolved in DCM (10 mL), and the solution was added dropwise to a solution of 1-[2-(4-chlorophenyl)ethyl]piperazine (1.24 g, 5.53 mmol, 1.2 equivalent) and Et3N (0.96 mL, 6.9 mmol, 1.5 equivalent) in DCM (10 mL). The mixture was stirred at RT for 16 h. It was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 94 / 6 to 40 / 60) to give 1.60 g of I-079 (69%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.54 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.25 – 7.00 (m, 4H), 3.08 (s, 4H), 2.75 – 2.50(m, 8H). MS (ESI + ): [M+H] + 503.0 / 505.0 / 507.0.

[0518] 7-Bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1H-benzimidazole (I-080)

[0519] Formula: 483.81

[0520] Molecular formula: C 19 H 20 BrClN4O2S

[0521] At RT, I-079 (1.60 g, 3.18 mmol, 1 equivalent) was administered... i NH4Cl (1.7 g, 32 mmol, 10 equivalents) and iron powder (325 mesh, 1.8 g, 32 mmol, 10 equivalents) were added to a solution of PrOH (15 mL) and formic acid (15 mL). The mixture was stirred at 80°C for 6 hours. After cooling to RT, volatiles were removed under reduced pressure. The residue was partitioned between water and EtOAc. K2CO3 was added until pH > 11. The suspension was filtered through diatomaceous earth (DCM / MeOH 95 / 5 wash). The filtrate layer was separated, the organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, DCM / MeOH = 98 / 2 to 90 / 10) to give 605 mg of I-080 (39%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.29 (br s, 1H), 8.57 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.31 –7.11 (m, 4H), 2.90 (s, 4H), 2.63 (t, J = 7.5 Hz, 2H), 2.55 – 2.40 (m, 6H). MS(ESI + ): [M+H] + 483.0 / 485.0 / 487.0.

[0522] 2-[[7-bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-benzimidazol-1-yl]methoxy [[4-bromo-6-[4-[2-(4-chlorophenyl)ethyl]piperazine-1-yl]sulfonyl-benzimidyl] A mixture of [azol-1-yl]methoxy]ethyl-trimethyl-silanes (I-081)

[0523] Formula weight: 614.07

[0524] Molecular formula: C 25 H 34 BrClN4O3SSi

[0525] At RT, 2-(trimethylsilyl)ethoxymethyl chloride (88 µL, 0.50 mmol, 1.2 equivalence) was added to a solution of I-080 (200 mg, 413 µmol, 1 equivalent) and iPr2NEt (0.11 mL, 0.62 mmol, 1.5 equivalent) in anhydrous DCM (4.1 mL). The mixture was stirred at RT for 16 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 100 / 0 to 96 / 4) to give 177 mg of I-081 as an orange oil (70%, an unreasonable 2 / 1 mixture of isomers). MS (ESI) + ): [M+H] + 613.2 / 615.2 / 617.2.

[0526] 7-Bromo-5-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-1-cyclopropyl-benzimidazole (I-082)

[0527] Formula weight: 523.87

[0528] Molecular formula: C 22 H 24 BrClN4O2S

[0529] Under air, I-080 (245 mg, 0.51 mmol, 1 equivalent), Cu(OAc)2 (92 mg, 0.51 mmol, 1 equivalent), and 2, were added to a MW vial. - Bipyridine (79 mg, 0.51 mmol, 1 equivalent), cyclopropylboronic acid (87 mg, 1.0 mmol, 2 equivalents), and Na₂CO₃ (107 mg, 1.0 mmol, 2 equivalents). DCE (5.1 mL) was added, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) and then purified by PTLC (3 plates, 3 migrations in cHex / EtOAc / EtOH = 70 / 23 / 7) to give 27 mg of I-082 (10%) as a white solid. 1 H NMR (400 MHz, chloroform-) d) δ 8.14 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.22 (d, J = 7.9Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 3.82 – 3.72 (m, 1H), 3.15 – 3.00 (m, 4H), 2.75 – 2.50 (m, 8H), 1.42 – 1.19 (m, 4H). MS (ESI + ): [M+H] + 523.0 / 525.0 / 527.0.

[0530] 4-(2,2-Dimethylpropylthio)-2-nitroaniline (I-083)

[0531] Formula weight: 240.32

[0532] Molecular formula: C 11 H 16 N2O2S

[0533] I-083 was obtained in 83% yield as an orange oil by using GP-1 at 100°C with 4-bromo-2-nitroaniline (800 mg, 3.69 mmol, 1 equivalent), XantPhos-D-G3 (70 mg, 74 µmol, 0.02 equivalent), iPr2NEt (0.96 mL, 5.5 mmol, 1.5 equivalent), and 2,2-dimethylpropane-1-thiol (469 µL, 3.87 mmol, 1.05 equivalent) in toluene (15 mL) for 1 hour. Purification was performed by FC (cHex / EtOAc = 97 / 3 to 70 / 30). 1 H NMR (400 MHz, DMSO-) d 6 ) δ 8.16 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 8.7, 2.2 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.05 (s, 2H), 2.82 (s, 2H), 1.02 (s, 9H). MS(ESI + ): [M+H] + 241.1.

[0534] 4-(2,2-Dimethylpropylsulfonyl)-2-nitroaniline (I-084)

[0535] Formula weight: 272.32

[0536] Molecular formula: C 11 H 16 N2O4S

[0537] Using GP-2, I-084 was obtained as a white solid in 97% yield by continuously applying I-083 (390 mg, 1.62 mmol, 1 equivalent) and m-CPBA (70% wet, 880 mg, 3.57 mmol, 2.2 equivalent) in DCM (16 mL) for 1 hour at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 8.71 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.8, 2.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.54 (s, 2H), 3.03 (s, 2H), 1.21 (s,9H). MS (ESI + ): [M+H] + 273.2.

[0538] 2-Bromo-4-(2,2-dimethylpropylsulfonyl)-6-nitroaniline (I-085)

[0539] Formula weight: 351.22

[0540] Molecular formula: C 11 H 15 BrN2O4S

[0541] N-bromosuccinimide (308 mg, 1.73 mmol, 1.1 equivalent) was added to a solution of I-084 (429 mg, 1.57 mmol, 1 equivalent) in DMF (7.9 mL) at RT. The mixture was stirred at RT for 16 hours. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 97 / 3 to 70 / 30) to give 419 mg of I-085 (76%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ8.72 (d,J = 2.2 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.25 (br s, 2H), 3.05 (s,2H), 1.24 (s, 9H). MS (ESI + ): [M+H] + 351.0 / 353.0.

[0542] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1H-benzimidazole (I-086)

[0543] Formula weight: 331.23

[0544] Molecular formula: C 12 H 15 BrN2O2S

[0545] At RT, I-085 (419 mg, 1.19 mmol, 1 equivalent) was administered... i NH4Cl (638 mg, 11.9 mmol, 10 equivalents) and iron powder (325 mesh, 666 mg, 11.9 mmol / L, 10 equivalents) were added to a solution of PrOH (6 mL) and formic acid (6 mL). The mixture was stirred at 80°C for 3 hours. After cooling to RT, NH4Cl (638 mg, 11.9 mmol / L, 10 equivalents) was added. i PrOH, and the suspension was filtered through diatomaceous earth ( i (PrOH wash). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry load, DCM / MeOH = 98 / 2 to 80 / 20) to give 356 mg of I-086 (88%) as a light brown solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ13.28 (s, 1H), 8.58 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 1.6 Hz,1H), 3.36 (s, 2H), 1.09 (s, 9H). MS (ESI + ): [M+H] + 331.0 / 333.0.

[0546] 2-[[7-bromo-5-(2,2-dimethylpropylsulfonyl)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silicon Alkane and 2-[[4-bromo-6-(2,2-dimethylpropylsulfonyl)benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane Mixture (I-087)

[0547] Formula weight: 461.49

[0548] Molecular formula: C 18 H 29 BrN2O3SSi

[0549] At RT, 2-(trimethylsilyl)ethoxymethyl chloride (114 µL, 0.645 mmol, 1.5 equivalent) was added to a solution of I-086 (150 mg, 430 µmol, 1 equivalent) and iPr2NEt (150 µL, 0.860 mmol, 2 equivalent) in anhydrous DCM (2.2 mL). The mixture was stirred at RT for 16 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 93 / 7 to 30 / 70) to give 138 mg of I-087 as a yellow oil (70%, an unreasonable 2 / 1 mixture of isomers). Major isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.25 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 1.6Hz, 1H), 5.60 (s, 2H), 3.58 – 3.52 (m, 2H), 3.10 (s, 2H), 1.23 (s, 9H), 1.05– 0.78 (m, 2H), -0.03 (s, 9H). Minor isomers 1 H NMR (400 MHz, chloroform-) d ) δ 8.35(d, J = 1.6 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J MS (ESI) + ): [M+H] + 461.0 / 463.0.

[0550] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1-methylbenzimidazole (I-088)

[0551] Formula weight: 345.26

[0552] Molecular formula: C 13 H 17 BrN2O2S

[0553] Iodomethane (0.11 mL, 1.8 mmol, 3 equivalents) was added to a suspension of I-086 (200 mg, 592 µmol, 1 equivalent) and K₂CO₃ (245 mg, 1.8 mmol, 3 equivalents) in anhydrous DMF (3 mL) at RT. The mixture was stirred at RT for 1.5 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by PTLC (3 plates, 2 migrations at cHex / EtOAc = 25 / 75) to give 67 mg of I-088 (33%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.30 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J = 1.5Hz, 1H), 4.21 (s, 3H), 3.09 (s, 2H), 1.20 (s, 9H). MS (ESI + ): [M+H] + 345.0 / 347.1.

[0554] 7-Bromo-1-cyclopropyl-5-(2,2-dimethylpropylsulfonyl)benzimidazole (I-089)

[0555] Formula weight: 371.29

[0556] Molecular formula: C 15 H 19 BrN2O2S

[0557] Under air, I-086 (270 mg, 0.815 mmol, 1 equivalent), Cu(OAc)2 (148 mg, 0.810 mmol, 1 equivalent), and 2, were added to a MW vial. - Bipyridine (127 mg, 0.815 mL, 1 equivalent), cyclopropylboronic acid (140 mg, 1.63 mmol, 2 equivalents), and Na₂CO₃ (173 mg, 1.63 mmol, 2 equivalents). DCE (4.1 mL) was added, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was partitioned between saturated aqueous NH₄Cl and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 70 / 30) to give 20 mg of I-089 (7%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.27 (s, 1H), 8.08 (s, 1H), 8.01 (s,1H), 3.76 (tt, J = 7.3, 3.8 Hz, 1H), 3.08 (s, 2H), 1.38 – 1.14 (m, 13H). MS(ESI + ): [M+H] + 371.1 / 373.1.

[0558] 2-Bromo-N-ethyl-6-nitroaniline (I-090)

[0559] Formula weight: 245.07

[0560] Molecular formula: C8H9BrN2O2

[0561] A mixture of 1-bromo-2-fluoro-3-nitrobenzene (1.00 g, 4.55 mmol, 1 equivalent) and ethylamine (2 M, 11 mL, 23 mmol, 5 equivalent in THF) was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 869 mg of I-090 (78%) as a yellow oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.81 (dd, J = 8.4, 1.6 Hz, 1H), 7.61(dd, J = 7.7, 1.6 Hz, 1H), 6.63 (t, J= 8.1 Hz, 1H), 5.90 (br s, 1H), 3.26(q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). MS (ESI + ): [M+H] + 245.0 / 247.1.

[0562] 2-Bromo-N-ethyl-4-iodo-6-nitroaniline (I-091)

[0563] Formula weight: 370.97

[0564] Molecular formula: C8H8BrIN2O2

[0565] Under RT, N-iodosuccinimide (544 mg, 2.42 mmol, 1 equivalent) was added to a solution of I-090 (494 mg, 2.02 mmol, 1 equivalent) in AcOH (3.1 mL). The mixture was stirred at 50°C for 16 hours (in the dark). Volatiles were removed under reduced pressure. The residue was dissolved in EtOAc, and the resulting solution was washed (1 N Na2S2O3, saturated aqueous NaHCO3 water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 99 / 1 to 90 / 10) to give 713 mg of I-091 (93%) as an orange oil. 1 HNMR (400 MHz, chloroform-) d ) δ 8.17 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 6.05 (s, 1H), 3.34 (qd, J = 7.2, 5.4 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS(ESI + ): [M+H] + 370.9 / 372.9.

[0566] 7-Bromo-1-ethyl-5-iodo-benzimidazole (I-092)

[0567] Formula weight: 350.98

[0568] Molecular formula: C9H8BrIN2

[0569] Under RT, I-091 (713 mg, 1.88 mmol, 1 equivalent) was administered at... i NH4Cl (1.01 g, 18.8 mmol, 10 equivalents) and iron powder (325 mesh, 1.05 g, 18.8 mol, 10 equivalents) were added to a solution of PrOH (9.5 mL) and formic acid (9.5 mL). The mixture was stirred at 80°C for 4 hours. After cooling to RT, EtOAc was added, and the suspension was filtered through diatomaceous earth (washed with EtOAc). The filtrate was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, DCM / MeOH = 98 / 2 to 90 / 10) to give 446 mg of I-092 (67%) as a light brown solid. 1 H NMR (400 MHz, chloroform-) d 8.09 (d, J = 1.5 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J = 1.3 Hz, 1H), 4.56 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H). MS (ESI + ): [M+H] + 350.9 / 352.9.

[0570] 7-Bromo-5-(2,2-Dimethylpropylthio)-1-ethylbenzimidazole (I-093)

[0571] Formula weight: 327.28

[0572] Molecular formula: C 14 H 19 BrN2S

[0573] I-093 was obtained in 58% yield by incubation at 110°C in toluene (2.1 mL) with I-092 (150 mg, 0.42 mmol, 1 equivalent), XantPhos-Pd-G3 (20 mg, 21 µmol, 0.05 equivalent), iPr2NEt (0.15 mL, 0.85 mmol, 2 equivalent), and 2,2-dimethylpropane-1-thiol (52 µL, 0.43 mmol, 1 equivalent) for 1.5 h. Purification was performed by FC (DCM / MeOH = 99 / 1 to 95 / 5). 1 H NMR (400 MHz, chloroform-) d) δ 7.87 (s, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 2.92(s, 2H), 1.54 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H). MS (ESI + ): [M+H] + 327.1 / 329.1.

[0574] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1-ethylbenzimidazole (I-094)

[0575] Formula weight: 359.28

[0576] Molecular formula: C 14 H 19 BrN2O2S

[0577] Using GP-2, I-094 was obtained as a white solid in 81% yield by continuous exposure to DCM (1.2 mL) at RT with I-093 (81 mg, 0.25 mmol, 1 equivalent) and m-CPBA (70% wet, 134 mg, 0.54 mmol, 2.2 equivalent) for 16 hours. Purification was performed by FC (DCM / MeOH = 99 / 1 to 95 / 5). 1 H NMR (400 MHz, chloroform-) d ) δ 8.24 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 4.56 (q, J = 7.2 Hz,2H), 3.01 (s, 2H), 1.51 (t, J = 7.2 Hz, 3H), 1.13 (s, 9H). MS (ESI + ): [M+H] + 359.0 / 361.0.

[0578] 2,6-Dichloropyridine-4-sulfonyl chloride (I-095)

[0579] Formula weight: 246.5

[0580] Molecular formula: C5H2Cl3NO2S

[0581] In the first 250 mL flask: SOCl2 (6.0 mL, 83 mmol, 4.5 equivalents) was added dropwise to water (37 mL) at 0°C [Note: exothermic and gas release]. The resulting solution was stirred at RT for 1 hour, and CuCl (91 mg, 0.92 mmol, 0.05 equivalents) was added. The resulting green solution was stirred at 0°C for 10 minutes. In another 250 mL flask: NaNO2 (1.42 g, 20.6 mmol, 1.12 equivalents) in water (15 mL) was added dropwise to a solution of 4-amino-2,6-dichloropyridine (3.00 g, 18.4 mmol, 1 equivalent) in 37% HCl (31 mL) at 0°C. The mixture was stirred at 0°C for 45 minutes, at which point the resulting mixture was added dropwise to the first solution, maintaining the temperature at 0°C. The mixture was stirred at RT for 2 hours. The suspension was filtered through a sintered glass filter, and the filter cake was washed with water (20 mL). The filter cake was dissolved in EtOAc, the organic solution was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 3.50 g of I-095 (78%) as a brown solid, which was immediately used in the next step. 1 H NMR (400 MHz, chloroform-) d ) δ 7.78 (s, 2H).

[0582] 2,6-Dichloro-4-[(4-phenyl-1-piperidinyl)sulfonyl]pyridine (I-096)

[0583] Formula weight: 371.28

[0584] Molecular formula: C 16 H 16 Cl2N2O2S

[0585] According to GP-4, I-096 was obtained in 80% yield as an orange solid by continuous administration of I-095 (333 mg, 1.35 mmol, 1 equivalent), 4-phenylpiperidine (261 mg, 1.62 mmol, 1.2 equivalent), and Et3N (0.28 mL, 2.0 mmol, 1.5 equivalent) in DCM (6.8 mL) for 16 hours at RT. Purification was performed by FC (cHex / EtOAc = 100 / 0 to 80 / 20). 1 HNMR (400 MHz, chloroform-) d) δ 7.59 (s, 2H), 7.39 – 7.29 (m, 2H), 7.26 – 7.06 (m,3H), 4.07 – 3.91 (m, 2H), 2.63 – 2.45 (m, 3H), 2.13 – 1.74 (m, 4H). MS (ESI + ): [M+H] + 371.1 / 373.1.

[0586] (2-Chloro-4-fluoro-phenyl)-[8-[6-chloro-4-[(4-phenyl-1-piperidinyl)sulfonyl]-2-pyridinyl]-3,8- Diazabicyclo[3.2.1]octane-3-yl]methyl ketone (I-097)

[0587] Formula weight: 603.53

[0588] Molecular formula: C 29 H 29 Cl2FN4O3S

[0589] A solution of I-096 (400 mg, 1.08 mmol, 1 equivalent), I-002 (318 mg, 1.19 mmol, 1.1 equivalent), and iPr2NEt (0.28 mL, 1.6 mmol, 1.5 equivalent) in NMP (4 mL) was stirred for 16 hours at 100°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 100 / 0 to 50 / 50) to give 406 mg of I-097 (62%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.43 – 7.29 (m, 2.5H), 7.26 –7.21 (m, 1.5H), 7.20 – 6.98 (m, 4H), 6.92 – 6.85 (m, 1H), 6.74 (d, J= 1.1Hz, 1H), 4.74 – 4.50 (m, 3H), 4.00 – 3.90 (m, 2H), 3.60 – 3.38 (m, 1H), 3.23– 3.10 (m, 2H), 2.65 – 2.45 (m, 3H), 2.20 – 1.80 (m, 7.5H), 1.80 – 1.65 (m, 0.5H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.76, -108.90. MS (ESI + ): [M+H] + 603.1 / 605.1.

[0590] (2-Chloro-4-fluoro-phenyl)-[8-[6-hydrazino-4-[(4-phenyl-1-piperidinyl)sulfonyl]-2-pyridinyl]-3, 8-Diazabicyclo[3.2.1]octane-3-yl]methyl ketone (I-098)

[0591] Formula weight: 599.12

[0592] Molecular formula: C 29 H 32 ClFN6O3S

[0593] A solution of I-097 (200 mg, 0.331 mmol, 1 equivalent) and hydrazine hydrate (83 mg, 1.7 mmol, 5 equivalent) in n-butanol (1.6 mL) was stirred at 130°C for 72 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 99 / 1 to 90 / 10) to give 50 mg of I-098 (25%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.57 – 7.28 (m, 2.5H), 7.26 –6.95 (m, 5.5H), 6.39 (s, 1H), 6.24 (s, 1H), 4.65 (s, 1H), 4.58 – 4.41 (m,2H), 4.00 – 3.85 (m, 2H), 3.63 – 3.40 (m, 1H), 3.32 – 3.03 (m, 2H), 2.64 –2.42 (m, 3H), 2.10 – 1.65 (m, 8H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers) δ -109.03, -109.17. MS (ESI + ): [M+H] + 599.2 / 601.1.

[0594] [8-[6-amino-4-[(4-phenyl-1-piperidinyl)sulfonyl]-2-pyridinyl]-3,8-diazabicyclo [3.2.1]Octan-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-099)

[0595] Formula: 584,1

[0596] Molecular formula: C 29 H 31 ClFN5O3S

[0597] I-097 (161 mg, 0.267 mmol, 1 equivalent), benzophenone imine (91 mg, 0.40 mmol, 1.5 equivalent), NaOt-Bu (43 mg, 0.48 mmol, 1.8 equivalent), Pd2(dba)3 (12 mg, 13 µmol, 0.05 equivalent), and rac-BINAP (17 mg, 27 µmol, 0.1 equivalent) were loaded into a microwave-safe solution. The solution was rinsed with Ar and degassed toluene (1.3 mL) was added. The reaction mixture was stirred under microwave irradiation at 140°C for 1 hour. After cooling to RT, MeOH (0.4 mL) and 1 N HCl (0.4 mL) were added, and the mixture was stirred vigorously for 0.5 hours. EtOAc and water were added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 106 mg of I-099 (68%) as a white solid. 1 HNMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.43 – 7.28 (m, 2.5H), 7.25 – 7.00 (m,5.5H), 6.22 (s, 1H), 6.14 (s, 1H), 4.63 (s, 1H), 4.57 – 4.39 (m, 4H), 3.95 –3.85 (m, 2H), 3.65 – 3.38 (m, 1H), 3.23 & 3.20 (d, J = 5.1 Hz, 1H), 3.15 –3.00 (m, 1H), 2.65 – 2.42 (m, 3H), 2.05 – 1.61 (m, 8H). 19F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.11, -109.25. MS (ESI + ): [M+H] + 584.2 / 586.1.

[0598] [8-[6-(aminomethyl)-4-[(4-phenyl-1-piperidinyl)sulfonyl]-2-pyridinyl]-3,8-diazabicyclo [3.2.1]Octan-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-100)

[0599] Formula weight: 598.13

[0600] Molecular formula: C 30 H 33 ClFN5O3S

[0601] In a MW vial, I-097 (300 mg, 0.497 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (306 mg, 1.29 mmol, 2.6 equivalent), Cs₂CO₃ (810 mg, 2.49 mmol, 5 equivalent), and cataCXium-Pd-G₃ (11 mg, 15 µmol, 0.03 equivalent) were added. The vial was rinsed with Ar and degassed dioxane / water (1 / 1, 4 mL) was added. The vial was sealed and the mixture was stirred at 100°C for 22 hours. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to obtain an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (1.7 mL) at RT and HCl (4 N in dioxane, 0.85 mL, 3.4 mmol, 7 equivalents) was added. The mixture was stirred at RT for 5 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with Na2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 92 mg of I-100 (31%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.48 – 7.27 (m, 2.5H),7.26 – 6.97 (m, 5.5H), 6.89 (s, 1H), 6.77 (s, 1H), 4.77 & 4.75 (s, 1H), 4.62– 4.40 (m, 2H), 4.11 – 3.83 (m, 4H), 3.63 – 3.38 (m, 1H), 3.28 – 3.06 (m,2H), 2.62 – 2.41 (m, 3H), 2.23 – 1.64 (m, 10H). 19 F NMR (376 MHz, chloroform-) d , 2 sets of spins Transisomer ) δ -108.93, -109.06. MS (ESI + ): [M+H] + 598.1 / 600.1.

[0602] 2,6-Dichloro-N,N-Diethyl-pyridine-4-sulfonamide (I-101)

[0603] Formula weight: 283.17

[0604] Molecular formula: C9H 12 Cl2N2O2S

[0605] According to GP-4, I-101 was obtained as a yellow solid in 79% yield by continuous exposure to DCM (20 mL) at RT for 16 h using I-095 (1.00 g, 4.06 mmol, 1 equivalent), diethylamine (0.50 mL, 4.9 mmol, 1.2 equivalent), and Et3N (0.85 mL, 6.1 mmol, 1.5 equivalent). Purification was performed by FC (cHex / EtOAc = 100 / 0 to 80 / 20). 1 H NMR (400 MHz, chloroform-) d ) δ 7.60 (s, 2H), 3.30 (q, J = 7.1 Hz, 4H), 1.20 (t, J = 7.1Hz, 6H). MS (ESI + ): [M+H] + 283.0 / 285.1.

[0606] 2-Chloro-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-N,N-di Ethyl-pyridine-4-sulfonamide (I-102)

[0607] Formula weight: 515.43

[0608] Molecular formula: C 22 H 25 Cl2FN4O3S

[0609] A solution of I-101 (910 mg, 3.22 mmol, 1 equivalent), I-002 (1.04 g, 3.86 mmol, 1.2 equivalent), and iPr2NEt (0.84 mL, 4.8 mmol, 1.5 equivalent) in NMP (8 mL) was stirred for 16 hours at 120°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 1.42 g of I-102 (86%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.32 (m, 0.5H), 7.24 –6.96 (m, 2.5H), 6.87 (s, 1H), 6.78 (s, 1H), 4.73 – 4.43 (m, 3H), 3.59 – 3.34(m, 1H), 3.28 (q, J = 7.2 Hz, 4H), 3.20 – 3.05 (m, 2H), 2.22 – 1.93 (m,3.5H), 1.75 – 1.65 (m, 0.5H), 1.19 (t, J = 7.2 Hz, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.83, -108.97. MS (ESI + ): [M+H] + 515.1 / 517.1.

[0610] 2-(aminomethyl)-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8- [I-103]-N,N-diethyl-pyridine-4-sulfonamide

[0611] Formula weight: 510.02

[0612] Molecular formula: C23 H 29 ClFN5O3S

[0613] I-102 (1.42 g, 2.75 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (1.96 g, 8.26 mmol, 3 equivalents), Cs₂CO₃ (5.39 g, 16.5 mmol, 5 equivalents), and cataCXium-Pd-G₃ (60 mg, 83 µmol, 0.03 equivalents) were packed into a MW vial. The vial was rinsed with Ar and degassed dioxane / water (1 / 114 mL) was added. The vial was sealed and the mixture was stirred at 100°C for 20 hours. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to obtain an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (14 mL) at RT and HCl (4 N in dioxane, 6.9 mL, 28 mmol, 10 equivalences) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K₂CO₃ added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 805 mg of I-10⁻¹⁰³ (57%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.32 (m, 0.5H), 7.25 –6.95 (m, 2.5H), 6.88 (s, 1H), 6.80 (s, 1H), 4.73 (d, 1H), 4.60 – 4.44 (m,2H), 3.90 (s, 2H), 3.60 – 3.34 (m, 1H), 3.33 – 3.01 (m, 6H), 2.38 – 1.92 (m,5.5H), 1.76 – 1.64 (m, 0.5H), 1.17 (t, J = 7.1 Hz, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.02, -109.15. MS (ESI + ): [M+H] + 510.2 / 512.2.

[0614] N-tert-butyl-2,6-dichloro-pyridine-4-sulfonamide (I-104)

[0615] Formula weight: 283.17

[0616] Molecular formula: C9H 12 Cl2N2O2S

[0617] According to GP-4, I-104 was obtained as a yellow solid in 78% yield by continuous reaction at RT in DCM (41 mL) with I-095 (2.00 g, 8.11 mmol, 1 equivalent), t-BuNH2 (1.0 mL, 10 mmol, 1.2 equivalent), and Et3N (1.7 mL, 12 mmol, 1.5 equivalent) for 16 h. Purification was performed by FC (cHex / EtOAc = 97 / 3 to 70 / 30). 1 H NMR (400MHz, chloroform-) d ) δ 7.68 (s, 2H), 4.85 (s, 1H), 1.30 (s, 9H). MS (ESI + ): [M+H] + 283.0 / 285.1.

[0618] N-tert-butyl-2-chloro-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8- [I-105]pyridine-4-sulfonamide

[0619] Formula weight: 515.43

[0620] Molecular formula: C 22 H 25 Cl2FN4O3S

[0621] A solution of I-104 (1.78 g, 6.30 mmol, 1 equivalent), I-002 (2.03 g, 7.56 mmol, 1.2 equivalent), and iPr2NEt (1.65 mL, 9.5 mmol, 1.5 equivalent) in NMP (16 mL) was stirred for 16 hours at 120°C. After cooling to RT, the mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 2.77 g of I-105 (85%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.33 (m, 0.5H), 7.24 –6.98 (m, 2.5H), 6.96 (s, 1H), 6.89 (s, 1H), 4.81 (s, 1H), 4.68 – 4.59 (m,1H), 4.59 – 4.46 (m, 2H), 3.57 – 3.35 (m, 1H), 3.18 – 3.05 (m, 2H), 2.17 –1.94 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.29 (s, 9H). 19 F NMR (376 MHz, chloroform-) d , 2 Group rotational isomers ) δ -108.83, -108.97. MS (ESI + ): [M+H] + 515.1 / 517.1.

[0622] 2-(aminomethyl)-N-tert-butyl-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]] Octane-8-yl]pyridine-4-sulfonamide (I-106)

[0623] Formula weight: 510.02

[0624] Molecular formula: C 23 H 29 ClFN5O3S

[0625] In a sealable flask, I-105 (2.67 g, 5.17 mmol, 1 equivalent), potassium N-Boc-aminomethyltrifluoroborate (1.47 g, 6.21 mmol, 1.2 equivalent), Cs₂CO₃ (8.43 g, 25.9 mmol, 5 equivalent), and cataCXium-Pd-G₃ (113 mg, 155 µmol, 0.03 equivalent) were charged. The flask was rinsed with Ar and degassed dioxane / water (1 / 126 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (26 mL) at RT and HCl (4 N in dioxane, 13 mL, 52 mmol, 10 equivalences) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K₂CO₃ added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 1.09 g of I-10⁶ (41%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.30 (m, 0.5H), 7.25– 6.95 (m, 3.5H), 6.91 (s, 1H), 4.90 (br s, 1H), 4.72 (s, 1H), 4.62 – 4.37(m, 2H), 3.92 (s, 2H), 3.57 – 3.35 (m, 1H), 3.23 – 3.02 (m, 2H), 2.44 (br s,2H), 2.15 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.27 (s, 9H). 19 F NMR (376MHz, chloroform-) d , Two sets of rotational isomers ) δ -109.02, -109.17. MS (ESI + ): [M+H]+ 510.2 / 512.2.

[0626] 2,6-Dichloro-4-(3,3-difluoropyrrolidone-1-yl)sulfonyl-pyridine (I-107)

[0627] Formula weight: 317.14

[0628] Molecular formula: C9H8Cl2F2N2O2S

[0629] According to GP-4, I-107 was obtained as a yellow solid in 45% yield using I-095 (1.24 g, 4.53 mmol, 1 equivalent), 3,3-difluoropyrrolidine hydrochloride (975 mg, 6.79 mmol, 1.5 equivalent), and Et3N (1.9 mL, 14 mmol, 3 equivalent) in DCM (18 mL) at RT for 2 hours. Purification was performed by FC (cHex / EtOAc = 97 / 3 to 70 / 30). 1 H NMR (400 MHz, chloroform-) d ) δ 7.63 (s, 2H), 3.68 (t, J = 12.5 Hz, 2H), 3.58 (t, J = 7.3 Hz, 2H), 2.42 (tt, J = 13.6, 7.3 Hz, 2H). 19 F NMR (376 MHz, chloroform-) d ) δ -100.1. MS (ESI + ): [M+H] + 317.0 / 319.0.

[0630] [8-[6-chloro-4-(3,3-difluoropyrrolidin-1-yl)sulfonyl-2-pyridyl]-3,8-diazabicyclo [3.2.1]Octan-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-108)

[0631] Formula: 549.39

[0632] Molecular formula: C 22 H 21 Cl2F3N4O3S

[0633] A solution of I-107 (635 mg, 2.00 mmol, 1 equivalent), I-002 (646 mg, 2.40 mmol, 1.2 equivalent), and iPr2NEt (0.52 mL, 3.0 mmol, 1.5 equivalent) in NMP (8 mL) was stirred for 16 hours at 100°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 92 / 8 to 20 / 80) to give 1.01 g of I-108 (92%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.45 – 7.35 (m, 0.5H), 7.27 –7.00 (m, 2.5H), 6.91 (s, 1H), 6.75 (s, 1H), 4.77 – 4.48 (m, 3H), 3.65 (t, J =12.7 Hz, 2H), 3.60 – 3.38 (m, 3H), 3.25 – 3.10 (m, 2H), 2.40 (tt, J = 13.7,7.1 Hz, 2H), 2.21 – 1.95 (m, 3.5H), 1.80 – 1.65 (m, 0.5H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -99.23, -99.24, -108.76, -108.89. MS (ESI + ): [M+H] + 549.1 / 551.1.

[0634] [8-[6-(aminomethyl)-4-(3,3-difluoropyrrolidone-1-yl)sulfonyl-2-pyridyl]-3,8-diazadi Cyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-109)

[0635] Formula weight: 543.99

[0636] Molecular formula: C 23 H 25 ClF3N5O3S

[0637] I-108 (4.48 g, 8.15 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (2.51 g, 10.6 mmol, 1.3 equivalent), Cs₂CO₃ (6.64 g, 20.4 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (178 mg, 245 µmol, 0.03 equivalent) were charged into a sealable flask. The flask was rinsed with Ar and a degassed dioxane / water mixture (1 / 1, 82 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (35 mL) at RT and HCl (4 N in dioxane, 17 mL, 69 mmol, 8.5 equivalence) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, DCM / MeOH(7N NH3) = 99 / 1 to 90 / 10) to give 2.93 g of I-109 (66%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.45 – 7.35(m, 0.5H), 7.27 – 6.98 (m, 2.5H), 6.92 & 6.91 (s, 1H), 6.77 (s, 1H), 4.73 (s,1H), 4.65 – 4.45 (m, 2H), 3.92 (s, 2H), 3.69 – 3.39 (m, 5H), 3.29 – 2.99 (m,2H), 2.37 (tt, J = 13.7, 7.2 Hz, 2H), 2.20 – 1.96 (m, 3.5H), 1.84 (s, 2H), 1.80 – 1.68 (m, 0.5H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers) δ -98.88, -98.90, -108.96, -109.08. MS (ESI + ): [M+H] + 544.1 / 546.2.

[0638] 2,6-Dichloro-N-(3-fluoropropyl)pyridine-4-sulfonamide (I-110)

[0639] Formula weight: 287.14

[0640] Molecular formula: C8H9Cl2FN2O2S

[0641] According to GP-4, I-110 was obtained as a yellow solid in 72% yield by continuous administration of I-095 (1.50 g, 6.09 mmol, 1 equivalent), 3-fluoropropane-1-amine hydrochloride (829 mg, 7.30 mmol, 1.2 equivalent) and Et3N (2.5 mL, 18 mmol, 3 equivalent) in DCM (30 mL) for 16 hours at RT. Purification was performed by FC (cHex / EtOAc = 94 / 6 to 40 / 60). 1 H NMR (400 MHz, chloroform-) d ) δ 7.66 (s, 2H), 4.92 (t, J = 5.9 Hz, 1H), 4.55 (dt, J = 47.1, 5.4 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 1.96 (dp, J = 27.8, 5.9 Hz, 2H). MS (ESI) + ): [M+H] + 287.0 / 289.0.

[0642] 2-Chloro-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-N-(3- Fluoropropylpyridine-4-sulfonamide (I-111)

[0643] Formula weight: 519.39

[0644] Molecular formula: C 21 H 22 Cl2F2N4O3S

[0645] A solution of I-110 (1.26 g, 4.39 mmol, 1 equivalent), I-002 (1.42 g, 5.27 mmol, 1.2 equivalent), and iPr2NEt (1.2 mL, 6.6 mmol, 1.5 equivalent) in NMP (20 mL) was stirred for 16 hours at 120°C. After cooling to RT, the mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 1.99 g of I-111 (87%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 4.32 (m, 0.5H), 7.25 –6.96 (m, 2.5H), 6.93 (s, 1H), 6.83 (s, 1H), 4.93 (s, 1H), 4.65 (s, 1H), 4.61– 4.41 (m, 4H), 3.62 – 3.35 (m, 1H), 3.29 – 3.01 (m, 4H), 2.20 – 1.85 (m, 5.5H), 1.75 – 1.65 (m, 0.5H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.73,-108.87, -221.10, -221.13. MS (ESI + ): [M+H] + 519.1 / 521.1.

[0646] 2-(aminomethyl)-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8- [I-112]-N-(3-fluoropropyl)pyridine-4-sulfonamide

[0647] Formula weight: 513.99

[0648] Molecular formula: C 22 H 26 ClF2N5O3S

[0649] In a sealable flask, I-109 (1.99 g, 3.84 mmol, 1 equivalent), potassium N-Boc-aminomethyltrifluoroborate (1.18 g, 4.99 mmol, 1.3 equivalent), Cs₂CO₃ (3.12 g, 9.59 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (83.8 mg, 115 µmol, 0.03 equivalent) were charged. The flask was rinsed with Ar and degassed dioxane / water (1 / 1, 20 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 2 hours. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (20 mL) at RT and HCl (4 N in dioxane, 9.6 mL, 38 mmol, 10 equivalences) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 1.39 g of I-112 (63%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.43 – 7.33 (m, 0.5H), 7.23 – 6.96 (m, 2.5H), 6.94 (s, 1H), 6.85 (s, 1H), 4.70 (s, 1H), 4.61 – 4.34(m, 4H), 3.86 (s, 2H), 3.60 – 3.35 (m, 1H), 3.24 – 3.00 (m, 4H), 2.41 (br s,2H), 2.15 – 1.80 (m, 5.5H), 1.75 – 1.65 (m, 0.5H). MS (ESI + ): [M+H] + 514.2 / 516.2.

[0650] 2,6-Dichloro-N-(3,3-difluorocyclobutyl)pyridine-4-sulfonamide (I-113)

[0651] Formula weight: 317.14

[0652] Molecular formula: C9H8Cl2F2N2O2S

[0653] According to GP-4, I-113 was obtained as a white solid in 49% yield by continuous recombinant human oxidase (RT) in DCM (66 mL) with I-095 (3.27 g, 13.3 mmol, 1 equivalent), 3,3-difluorocyclobutylamine hydrochloride (2.00 g, 13.9 mmol, 1.05 equivalent) and Et3N (4.6 mL, 33 mmol, 2.5 equivalent) for 16 h. Purification was performed by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1 H NMR (400 MHz, chloroform-) d ) δ 7.67 (s, 2H), 5.22 (d, J = 7.4 Hz, 1H), 3.90 –3.80 (m, 1H), 3.10 – 2.90 (m, 2H), 2.64 – 2.43 (m, 2H). 19 F NMR (376 MHz, chloroform-) d ) δ -84.80 (d, J F-F = 201.6 Hz), -97.86 (d, J F-F = 201.6 Hz). MS (ESI + ): [M+H] + 317.1 / 319.0.

[0654] 2-Chloro-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-N-(3, 3-Difluorocyclobutyl)pyridine-4-sulfonamide (I-114)

[0655] Formula weight: 549.39

[0656] Molecular formula: C 22 H 21 Cl2F3N4O3S

[0657] A solution of I-113 (2.08 g, 6.56 mmol, 1 equivalent), I-002 (1.94 g, 7.21 mmol, 1.1 equivalent), and iPr2NEt (1.7 mL, 9.8 mmol, 1.5 equivalent) in NMP (24 mL) was stirred for 16 hours at 120°C. After cooling to RT, the mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 3.1 g of I-114 (86%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.47 – 7.37 (m, 0.5H), 7.28 – 7.02(m, 2.5H), 6.92 (s, 1H), 6.85 (s, 1H), 5.75 – 5.60 (m, 1H), 4.76 – 4.45 (m,3H), 3.78 (s, 1H), 3.60 – 3.38 (m, 1H), 3.25 – 3.10 (m, 2H), 3.00 – 2.80 (m,2H), 2.62 – 2.42 (m, 2H), 2.20 – 1.95 (m, 3.5H), 1.80 – 1.65 (m, 0.5H).MS(ESI + ): [M+H] + 549.2 / 551.2.

[0658] 2-(aminomethyl)-6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8- [I-115]-N-(3,3-difluorocyclobutyl)pyridine-4-sulfonamide

[0659] Formula weight: 543.99

[0660] Molecular formula: C 23 H 25 ClF3N5O3S

[0661] I-114 (3.10 g, 5.64 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (1.61 g, 6.77 mmol, 1.2 equivalent), Cs₂CO₃ (4.6 g, 14 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (123 mg, 169 µmol, 0.03 equivalent) were charged into a sealable flask. The flask was rinsed with Ar and degassed dioxane / water (1 / 156 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to obtain an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (14 mL) at RT and HCl (4 N in dioxane, 14 mL, 56 mmol, 10 equivalences) was added. The mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 900 mg of I-115 (29%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.45 – 7.30 (m, 0.5H), 7.24– 6.97 (m, 2.5H), 6.90 (s, 1H), 6.84 (s, 1H), 5.80 (s, 1H), 4.67 (s, 1H),4.61 – 4.40 (m, 2H), 4.30 (s, 2H), 3.74 (s, 1H), 3.57 – 3.37 (m, 1H), 3.20 –3.05 (m, 2H), 2.92 – 2.75 (m, 2H), 2.57 – 2.38 (m, 2H), 2.15 – 1.90 (m,3.5H), 1.85 – 1.65 (m, 2.5H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -84.36(d,J F-F = 200.3 Hz), -98.55 & -98.53 (d, J F-F = 200.6 Hz), -108.79, -108.94. MS(ESI + ): [M+H] + 544.1 / 546.2.

[0662] 1-[2-(4-chlorophenyl)ethyl]-4-[(2,6-dichloro-4-pyridyl)sulfonyl]piperazine (I-116)

[0663] Formula: 434.77

[0664] Molecular formula: C 17 H 18 Cl3N3O2S

[0665] According to GP-4, I-116 was obtained as a white solid in 54% yield by continuous RT in DCM (33 mL) with I-095 (1.64 g, 6.65 mmol, 1 equivalent), 1-[2-(4-chlorophenyl)ethyl]piperazine (1.64 g, 7.32 mmol, 1.1 equivalent), and Et3N (1.4 mL, 10 mmol, 1.5 equivalent) for 16 h. Purification was performed by FC (cHex / EtOAc = 95 / 5 to 50 / 50). 1 H NMR (400 MHz, chloroform-) d ) δ 7.56 (s, 2H), 7.26 (d, J = 7.9 Hz, 2H), 7.11(d, J = 7.9 Hz, 2H), 3.17 (s, 4H), 2.72 (s, 2H), 2.63 (s, 6H). MS (ESI + ): [M+H] + 434.1 / 436.0 / 438.0.

[0666] [8-[6-chloro-4-[4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-2-pyridyl]-3,8-di [3.2.1]octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-117)

[0667] Formula weight: 667.02

[0668] Molecular formula: C 30 H 31 Cl3FN5O3S

[0669] A solution of I-116 (1.56 g, 3.59 mmol, 1 equivalent), I-002 (1.06 g, 3.95 mmol, 1.1 equivalent), and iPr2NEt (0.94 mL, 5.4 mmol, 1.5 equivalent) in NMP (13 mL) was stirred for 16 hours at 120°C. After cooling to RT, the mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 1.6 g of I-117 (66%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.45 – 7.35 (m, 0.5H), 7.30 –7.20 (m, 2.5H), 7.21 – 7.00 (m, 4H), 6.85 (s, 1H), 6.70 (s, 1H), 4.70 – 4.50(m, 3H), 3.62 – 3.38 (m, 1H), 3.25 – 3.05 (m, 6H), 2.80 – 2.70 (m, 2H), 2.70 – 2.55 (m, 6H), 2.20 – 1.95 (m, 3.5H), 1.80 – 1.70 (s, 0.5H). MS (ESI + ): [M+H] + 666.3 / 668.4 / 670.4.

[0670] [8-[6-(aminomethyl)-4-[4-[2-(4-chlorophenyl)ethyl]piperazin-1-yl]sulfonyl-2-pyridyl]-3, 8-Diazabicyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-118)

[0671] Formula quantity: 661.62

[0672] Molecular formula: C 31 H 35 Cl2FN6O3S

[0673] In a sealable flask, I-117 (1.57 g, 2.35 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (670 mg, 2.82 mmol, 1.2 equivalent), Cs₂CO₃ (1.92 g, 5.88 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (51 mg, 71 µmol, 0.03 equivalent) were charged. The flask was rinsed with Ar and degassed dioxane / water (1 / 1, 18 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give an inseparable mixture of starting material and intermediates protected by Boc to the desired product. It was dissolved in dioxane (11 mL) at RT and HCl (4 N in dioxane, 2.7 mL, 11 mmol, 4.6 equivalence) was added. The mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / MeOH = 99 / 1 to 90 / 10) to give 1.1 g of I-118 (63%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.32 (m, 0.5H), 7.28 – 7.17 (m, 2.5H), 7.16 – 6.95 (m, 4H), 6.88 (s, 1H), 6.71 (s, 1H), 4.74 (s,1H), 4.60 – 4.40 (m, 2H), 4.07 – 3.90 (m, 2H), 3.60 – 3.30 (m, 1H), 3.28 –3.00 (m, 6H), 2.75 – 2.65 (m, 2H), 2.65 – 2.52 (m, 6H), 2.20 – 1.90 (m,3.5H), 1.75 – 1.60 (m, 0.5H), 1.24 – 1.15 (m, 2H). 19 F NMR (376 MHz, chloroform-) d , 2 groups Rotational isomers ) δ -108.95, -109.07. MS (ESI + ): [M+H] + 661.3 / 663.3.

[0674] 2,6-Dichloro-4-(2,2-dimethylpropylthio)pyridine (I-119)

[0675] Formula weight: 250.19

[0676] Molecular formula: C 10 H 13 Cl2NS

[0677] I-119 was obtained in 95% yield as a pale yellow oil by incubation at 100°C in dioxane (22 mL) with 2,6-dichloro-4-iodopyridine (1.50 g, 5.48 mmol, 1 equivalent), XantPhos-D-G3 (104 mg, 110 µmol, 0.02 equivalent), iPr2NEt (1.43 mL, 8.2 mmol, 1.5 equivalent), and 2,2-dimethylpropane-1-thiol (722 µL, 5.75 mmol, 1.05 equivalent) for 1.5 h. Purification was performed by FC (cHex / EtOAc = 100 / 0 to 80 / 20). 1 H NMR (400 MHz, chloroform-) d ) δ 7.08 (s, 2H), 2.92 (s, 2H), 1.11 (s, 9H).

[0678] 2,6-Dichloro-4-(2,2-dimethylpropylsulfonyl)pyridine (I-120)

[0679] Formula weight: 282.19

[0680] Molecular formula: C 10 H 13 Cl2NO2S

[0681] Using GP-2, I-120 was obtained in 100% yield as a colorless oil by continuously applying I-119 (1.30 g, 5.20 mmol, 1 equivalent) and m-CPBA (70% wet, 2.82 g, 11.4 mmol, 2.2 equivalent) in DCM (26 mL) for 16 hours at RT. 1 H NMR (400 MHz, chloroform-) d) δ 7.75 (s, 2H), 3.07 (s, 2H), 1.27 (s, 9H). MS(ESI + ): [M+H] + 282.1 / 284.1.

[0682] [8-[6-chloro-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3,8-diazabicyclo[3.2.1]octyl [Alkyl-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-121)

[0683] Formula weight: 514.44

[0684] Molecular formula: C 23 H 26 Cl2FN3O3S

[0685] A solution of I-120 (1.07 g, 3.79 mmol, 1 equivalent), I-002 (1.22 g, 4.55 mmol, 1.2 equivalent), and iPr2NEt (0.99 mL, 5.7 mmol, 1.5 equivalent) in NMP (7.6 mL) was stirred for 16 hours at 100°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 92 / 8 to 20 / 80) to give 1.68 g of I-121 (86%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.40 (dd, J = 8.5, 5.8 Hz,0.5H), 7.24 (dd, J = 8.5, 2.4 Hz, 0.5H), 7.20 – 6.98 (m, 3H), 6.90 – 6.86 (m,1H), 4.82 – 4.45 (m, 3H), 3.60 – 3.35 (m, 1H), 3.23 – 3.11 (m, 2H), 3.05 &3.04 (s, 2H), 2.20 – 1.95 (m, 3.5H), 1.78 – 1.65 (m, 0.5H), 1.25 (s, 9H). 19 FNMR (376 MHz, chloroform-) d , Two sets of rotational isomers) δ -108.77, -108.91. MS (ESI + ): [M+H] + 514.1 / 516.2.

[0686] [8-[6-amino-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3,8-diazabicyclo[3.2.1]octyl [Alkyl-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-122)

[0687] Formula weight: 495.01

[0688] Molecular formula: C 23 H 28 ClFN4O3S

[0689] I-121 (230 mg, 0.447 mmol, 1 equivalent), benzophenone imine (152 mg, 0.671 mmol, 1.5 equivalent), NaOt-Bu (77 mg, 0.81 mmol, 1.8 equivalent), Pd2(dba)3 (20 mg, 22 µmol, 0.05 equivalent), and rac-BINAP (28 mg, 45 µmol, 0.1 equivalent) were packed into a microwave-safe vial. The vial was rinsed with Ar and degassed toluene (2.2 mL) was added. The reaction mixture was stirred under microwave irradiation at 140°C for 1 hour. After cooling to RT, MeOH (1 mL) and 1 NHCl (1 mL) were added, and the mixture was stirred vigorously for 0.5 hours. EtOAc and water were added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give 174 mg of I-122 as a yellow solid (50% purity, 39%). MS (ESI) + ): [M+H] + 495.1 / 497.1.

[0690] [8-[6-(aminomethyl)-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3,8-diazabicyclo [3.2.1]Octan-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-123)

[0691] Formula weight: 509.04

[0692] Molecular formula: C 24 H 30 ClFN4O3S

[0693] In a sealable flask, I-121 (1.68 g, 3.27 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (929 mg, 3.92 mmol, 1.2 equivalent), Cs₂CO₃ (2.66 g, 8.16 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (71 mg, 98 µmol, 0.03 equivalent) were charged. The flask was rinsed with Ar and degassed dioxane / water (1 / 1, 25 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 98 / 2 to 50 / 50) to give an inseparable mixture of starting material and intermediates protected by Boc to the desired product. It was dissolved in dioxane (14 mL) at RT and HCl (4 N in dioxane, 7.1 mL, 29 mmol, 8.7 equivalence) was added. The mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / MeOH = 99 / 1 to 90 / 10) to give 1.15 g of I-123 (69%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.37 (dd, J = 8.5, 5.8 Hz,0.5H), 7.20 (dd, J = 8.5, 2.4 Hz, 0.5H), 7.16 – 6.95 (m, 3H), 6.87 (s, 1H), 4.74 & 4.72 (s, 1H), 4.60 – 4.40 (m, 2H), 3.90 (s, 2H), 3.57 – 3.34 (m, 1H),3.26 – 3.04 (m, 2H), 3.01 & 3.00 (s, 2H), 2.20 – 1.90 (m, 5.5H), 1.75 – 1.65(m, 0.5H), 1.21 (s, 9H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.84, -108.96. MS (ESI + ): [M+H] + 509.2 / 511.2.

[0694] 2-[tert-butyl(diphenyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazide] Heterobicyclo[3.2.1]octane-8-yl]-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]acetamide (I-124)

[0695] Formula weight: 805.47

[0696] Molecular formula: C 42 H 50 ClFN4O5SSi

[0697] TBTU (54 mg, 0.18 mmol / L, 1.2 equivalents) was added to a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetic acid (56 mg, 0.18 mmol, 1.2 equivalents) in DMF (0.5 mL). The mixture was stirred at RT for 10 min, and a solution of I-123 (75 mg, 0.15 mmol, 1 equivalent) and Et3N (51 µL, 0.37 mmol, 2.5 equivalents) in THF (0.5 mL) was added. The mixture was stirred at RT for 3 h. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (water, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was passed through an FC (12 Purification was performed on a g column, dry load (cHex / EtOAc = 98 / 2 to 50 / 50) to give 69 mg of I-124 as a yellow solid (48%). 1 H NMR (400 MHz, chloroform-) d , 2 groups Rotational isomers ) δ 7.90 – 7.80 (m, 0.5H), 7.65 – 7.55 (m, 3.5H), 7.48 – 7.29 (m,6H), 7.25 – 6.90 (m, 5H), 4.95 – 4.30 (m, 5H), 4.19 (s, 2H), 3.55 – 3.25 (m,1H), 3.15 – 2.95 (m, 4H), 2.10 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H), 1.23 (s, 9H), 1.08 (s, 9H). 19 F NMR (376 MHz, chloroform-) d, Two sets of rotational isomers ) δ -108.73, -108.85. MS (ESI + ): [M+H] + 805.5 / 807.5.

[0698] [8-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]-7-(2,2-dimethylpropylsulfonyl)imidazolium [1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluorophenyl)methyl ketone (I- 125）

[0699] Formula weight: 787.46

[0700] Molecular formula: C 42 H 48 ClFN4O4SSi

[0701] At RT, POCl3 (53 µL, 0.57 mmol, 6.6 equivalents) was added to a solution of I-124 (69 mg, 86 µmol, 1 equivalent) and Et3N (0.16 mL, 1.1 mmol, 13 equivalents) in DCE (1.1 mL). The mixture was stirred at 80°C for 16 h. After cooling to RT, the reaction mixture was carefully poured into saturated aqueous NaHCO3 and the mixture was stirred vigorously for 15 min. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic extracts were washed (saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 40 / 60) to give 54 mg of I-125 (60%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.87 – 7.75 (m, 1.5H), 7.67 – 7.55 (m,3.5H), 7.45 – 7.37 (m, 7H), 7.20 – 6.80 (m, 3H), 6.32 (s, 1H), 5.75 – 5.50(m, 2H), 4.50 – 4.37 (m, 1H), 3.91 (s, 1H), 3.80 – 3.60 (m, 1H), 3.57 – 3.17(m, 1H), 3.10 – 2.85 (m, 4H), 2.20 – 1.85 (m, 3.5H), 1.70 – 1.60 (m, 0.5H),1.21 (s, 9H), 1.05 & 1.03 (s, 9H). 19F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.60, -108.73. MS (ESI + ): [M+H] + 787.5 / 789.5.

[0702] 2-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(2,2- [dimethylpropylsulfonyl]-2-pyridyl]methylamino]-2-oxo-ethyl acetate (I-126)

[0703] Formula weight: 609.11

[0704] Molecular formula: C 28 H 34 ClFN4O6S

[0705] Ethyl oxaloyl chloride (0.14 mL, 1.3 mmol, 1 equivalent) was added to a solution of I-123 (436 mg, 0.856 mmol, 1 equivalent) and Et3N (0.18 L, 1.3 mmol, 1.5 equivalent) in DCM (4.3 mL) at RT. The mixture was stirred at RT for 2 hours. The reaction mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 471 mg of I-126 (90%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , 2 sets of rotational isomers body ) δ 8.08 (s, 1H), 7.41 – 7.35 (m, 0.5H), 7.24 – 7.18 (m, 0.5H), 7.16 – 6.98 (m, 2H), 6.95 – 6.90 (m, 2H), 4.72 (s, 1H), 4.63 – 4.50 (m, 4H), 4.42 – 4.32(m, 2H), 3.57 – 3.35 (m, 1H), 3.20 – 3.10 (m, 2H), 3.01 & 3.00 (s, 2H), 2.20– 1.95 (m, 3.5H), 1.78 – 1.68 (m, 0.5H), 1.42 – 1.35 (m, 3H), 1.22 (s, 9H).MS (ESI + ): [M+H] + 609.2 / 611.2.

[0706] 3-[tert-butyl(diphenyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazide] Heterobicyclo[3.2.1]octane-8-yl]-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]propionamide (I-127)

[0707] Formula weight: 819.5

[0708] Molecular formula: C 43 H 52 ClFN4O5SSi

[0709] β-propiolactone (32 µL, 0.51 mmol, 1 equivalent) was added to a solution of I-123 (200 mg, 0.393 mmol, 1 equivalent) in DCE (2 mL) at RT. The mixture was stirred at RT for 16 h. Imidazole (134 mg, 1.96 mmol, 5 equivalent), DMAP (4.8 mg, 36 µmol, 0.1 equivalent), and tert-butyldiphenylchlorosilane (0.2 mL, 0.8 mmol, 2 equivalent) were added, and the mixture was stirred again for 24 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NH4Cl. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (saturated aqueous NH4Cl, saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry load, cHex / EtOAc = 90 / 10 to 0 / 100) to give 176 mg of I-127 (55%) as white foam. 1 HNMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.70 – 7.60 (m, 3.5H), 7.50 – 7.32 (m,6.5H), 7.27 – 6.95 (m, 4H), 6.92 (s, 1H), 4.70 (s, 1H), 4.62 – 4.45 (m, 4H), 4.00 (t, J = 5.8 Hz, 2H), 3.57 – 3.31 (m, 1H), 3.25 – 3.03 (m, 2H), 3.01 (s,2H), 2.52 (t, J = 5.7 Hz, 2H), 2.15 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.24 (s, 9H), 1.02 (s, 9H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers δ -108.91, -109.05. MS (ESI) + ): [M+H] + 819.5 / 821.5.

[0710] [8-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-7-(2,2-dimethylpropylsulfonyl)imidazolium [1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluorophenyl)methyl ketone (I- 128）

[0711] Formula weight: 801.48

[0712] Molecular formula: C 43 H 50 ClFN4O4SSi

[0713] At RT, POCl3 (97 µL, 1.0 mmol, 5 equivalents) was added to a solution of I-127 (170 mg, 207 µmol, 1 equivalent) and Et3N (0.29 mL, 2.1 mmol, 10 equivalents) in DCE (2.1 mL). The mixture was stirred at 80°C for 3 hours. After cooling to RT, the reaction mixture was carefully poured into saturated aqueous NaHCO3, and the mixture was stirred vigorously for 15 minutes. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic extracts were washed (saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 93 / 7 to 30 / 70) to give 144 mg of I-128 (87%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.80 (s, 1H), 7.69 (s, 1H), 7.61 – 7.50 (m,4H), 7.50 – 7.30 (m, 6H), 7.26 – 6.94 (m, 3H), 6.28 & 6.25 (s, 1H), 4.70 –4.55 (m, 1H), 4.30 – 4.15 (m, 2H), 4.00 (s, 1H), 3.90 – 3.60 (m, 4H), 3.50 –3.10 (m, 2H), 2.97 (s, 2H), 2.10 – 1.90 (m, 3.5H), 1.75 – 1.65 (m, 0.5H),1.20 (s, 9H), 1.01 – 0.97 (m, 9H). 19F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.58, -108.76. MS (ESI + ): [M+H] + 801.5 / 803.5.

[0714] 2,6-Dichloro-4-cyclopentylthioalkylpyridine (I-129)

[0715] Formula weight: 248.17

[0716] Molecular formula: C 10 H 11 Cl2NS

[0717] I-129 was obtained in 54% yield as a pale yellow oil by using GP-1 at 100°C with 2,6-dichloro-4-iodopyridine (500 mg, 1.83 mmol, 1 equivalent), XantPhos-D-G3 (35 mg, 37 µmol, 0.02 equivalent), iPr2NEt (0.48 mL, 2.7 mmol, 1.5 equivalent), and cyclopentylthiol (205 µL, 1.92 mmol, 1.05 equivalent) in dioxane (7.3 mL) for 1 hour. Purification was performed by FC (cHex / EtOAc = 100 / 0 to 70 / 30). 1 H NMR (400MHz, chloroform-) d ) δ 7.04 (s, 2H), 3.75 – 3.60 (m, 1H), 2.30 – 2.05 (m, 2H), 1.90 –1.55 (m, 6H). MS (ESI + ): [M+H] + 248.1 / 250.1.

[0718] 2,6-Dichloro-4-cyclopentylsulfonyl-pyridine (I-130)

[0719] Formula weight: 280.17

[0720] Molecular formula: C 10 H 11 Cl2NO2S

[0721] Using GP-2, I-130 was obtained as a colorless oil in 82% yield by continuous exposure to DCM (5 mL) at RT with I-129 (243 mg, 0.979 mmol, 1 equivalent) and m-CPBA (70% wet, 0.99 g, 4.00 mmol, 4.1 equivalent) for 4 hours. Purification was performed by FC (cHex / EtOAc = 100 / 0 to 95 / 5). 1 H NMR (400 MHz, chloroform-) d ) δ 7.71 (s,2H), 3.60 – 3.45 (m, 1H), 2.15 – 2.00 (m, 2H), 2.00 – 1.75 (m, 4H), 1.75 –1.65 (m, 2H). MS (ESI + ): [M+H] + 280.1 / 282.1.

[0722] [8-(6-chloro-4-cyclopentylsulfonyl-2-pyridyl)-3,8-diazabicyclo[3.2.1]octane-3-yl]-(2- Chloro-4-fluoro-phenyl)methyl ketone (I-131)

[0723] Formula weight: 512.42

[0724] Molecular formula: C 23 H 24 Cl2FN3O3S

[0725] A solution of I-130 (226 mg, 0.807 mmol, 1 equivalent), I-002 (260 mg, 0.968 mmol, 1.2 equivalent), and iPr2NEt (0.28 mL, 1.6 mmol, 2 equivalent) in NMP (4 mL) was stirred for 16 hours at 100°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 0.33 g of I-131 (86%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.42 – 7.33 (m, 0.5H), 7.26 –7.18 (m, 0.5H), 7.18 – 6.92 (m, 3H), 6.85 (s, 1H), 4.66 (s, 1H), 4.62 – 4.48(m, 2H), 3.61 – 3.34 (m, 2H), 3.20 – 3.08 (m, 2H), 2.20 – 1.75 (m, 9.5H), 1.75 – 1.60 (m, 2.5H). MS (ESI + ): [M+H] + 512.1 / 514.1.

[0726] [8-[6-(aminomethyl)-4-cyclopentylsulfonyl-2-pyridyl]-3,8-diazabicyclo[3.2.1]octane- 3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-132)

[0727] Formula weight: 507.02

[0728] Molecular formula: C 24 H 28 ClFN4O3S

[0729] In a sealable flask, I-131 (330 mg, 0.644 mmol, 1 equivalent), potassium N-Boc-aminomethyltrifluoroborate (229 mg, 0.966 mmol, 1.5 equivalent), Cs₂CO₃ (0.52 g, 1.6 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (14 mg, 19 µmol, 0.03 equivalent) were charged. The flask was rinsed with Ar and degassed dioxane / water (1 / 1, 3.2 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 16 hours. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (3.2 mL) at RT and HCl (4 N, 1.6 mL, 6.4 mmol, 10 equivalences in dioxane) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM and K2CO3 was added in portions until pH > 11. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / MeOH = 99 / 1 to 90 / 10) to give 120 mg of I-132 (37%) as a yellow solid. MS (ESI) +): [M+H] + 507.2 / 509.2.

[0730] 2,6-Dichloro-4-[(4-methoxyphenyl)methylthioalkyl]pyridine (I-133)

[0731] Formula weight: 300.2

[0732] Molecular formula: C 13 H 11 Cl2NOS

[0733] I-133 was obtained in 99% yield as a pale yellow oil by incubation at 100°C in dioxane (30 mL) with 2,6-dichloro-4-iodopyridine (2.02 g, 7.37 mmol, 1 equivalent), XantPhos-D-G3 (70 mg, 74 µmol, 0.01 equivalent), iPr2NEt (2.6 mL, 15 mmol, 2 equivalent), and 4-methoxybenzylthiol (1.07 mL, 7.68 mmol, 1.05 equivalent) for 1.5 h. Purification was performed by FC (cHex / EtOAc = 99 / 1 to 80 / 20). 1 H NMR (400 MHz, chloroform-) d ) δ 7.39 – 7.27 (m, 2H), 7.05 (s, 2H), 6.95 – 6.81 (m, 2H), 4.18 (s, 2H), 3.81 (s, 3H). MS (ESI + ): [M+H] + 300.1 / 302.1.

[0734] 2,6-Dichloro-4-[(2,6-dichloro-4-pyridinyl)dithioalkyl]pyridine (I-134)

[0735] Formula weight: 358.09

[0736] Molecular formula: C 10 H4Cl4N2S2

[0737] TFA (28 mL) was added to a solution of I-133 (2.40 g, 7.28 mmol, 1 equivalent) in anisole (6.5 mL). The mixture was stirred under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water and EtOAc, with NaHCO3 added in portions until the residual acid was neutralized. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The alkaline aqueous phase was acidified to pH 2 with 2 N HCl, and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The combined organic residues were purified by FC (80 g column, dry loading, cHex / EtOAc = 98 / 2 to 80 / 20) to give 900 mg of I-134 (69%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 δ 7.47 (s, 4H). MS (ESI) + ): [M+H] + 356.9 / 359.0 / 360.9.

[0738] 2,6-Dichloropyridine-4-thiol (I-135)

[0739] Formula weight: 180.06

[0740] Molecular formula: C5H3Cl2NS

[0741] At 0°C, NaBH4 (421 mg, 11.1 mmol, 5 equivalents) was added dropwise to a solution of I-134 (798 mg, 2.29 mmol, 1 equivalent) in THF / EtOH (1 / 1, 22 mL). The reaction mixture was stirred at RT for 3 hours. Saturated aqueous NH4Cl was added dropwise, followed by EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure to give 707 mg of I-135 (86%) as a white solid. 1 HNMR (400 MHz, DMSO- d 6 δ 7.27 (s, 2H). MS (ESI) + ): [M+H] + 180.1 / 182.1.

[0742] 2,6-Dichloro-4-(1-Ethylpropylthio)pyridine (I-136)

[0743] Formula weight: 250.19

[0744] Molecular formula: C 10 H 13 Cl2NS

[0745] At RT, 3-bromopentane (0.47 mL, 3.8 mmol, 2 equivalents) and K₂CO₃ (522 mg, 3.78 mmol, 2 equivalents) were successively added to a solution of I-135 (340 mg, 1.89 mmol, 1 equivalent) in DMF (9 mL). The mixture was stirred at RT for 16 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 99 / 1) to give 300 mg of I-136 (64%) as a colorless oil. 1 H NMR (400MHz, chloroform-) d ) δ 7.05 (s, 2H), 3.24 (p, J = 6.3 Hz, 1H), 1.85 – 1.60 (m, 4H), 1.03 (t, J = 7.4 Hz, 6H). MS (ESI + ): [M+H] + 250.1 / 252.1.

[0746] 2,6-Dichloro-4-(1-ethylpropylsulfonyl)pyridine (I-137)

[0747] Formula weight: 282.19

[0748] Molecular formula: C 10 H 13 Cl2NO2S

[0749] Using GP-2, I-137 was obtained as a white solid in 91% yield by continuous 1.5 hours in DCM (6 mL) with I-136 (300 mg, 1.20 mmol, 1 equivalent) and m-CPBA (70% wet, 0.65 g, 2.6 mmol, 2.2 equivalent) at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 7.69 (s, 2H), 2.88 (tt,J = 7.1, 4.7 Hz, 1H),1.98 – 1.63 (m, 4H), 1.06 (t, J = 7.5 Hz, 6H). MS (ESI + ): [M+H] + 282.1 / 284.1.

[0750] [8-[6-chloro-4-(1-ethylpropylsulfonyl)-2-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3- [I-138]-(2-chloro-4-fluoro-phenyl)methyl ketone

[0751] Formula weight: 514.44

[0752] Molecular formula: C 23 H 26 Cl2FN3O3S

[0753] A solution of I-137 (323 mg, 1.12 mmol, 1 equivalent), I-002 (392 mg, 1.46 mmol, 1.3 equivalent), and iPr2NEt (0.39 mL, 2.2 mmol, 2 equivalent) in NMP (5.6 mL) was stirred for 3 hours at 120°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 0.47 g of I-138 (80%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.38 (dd, J = 8.5, 5.6 Hz,0.5H), 7.22 (dd, J = 8.3, 2.5 Hz, 0.5H), 7.18 – 6.98 (m, 2H), 6.96 & 6.95 (s,1H), 6.83 (s, 1H), 4.66 (s, 1H), 4.61 – 4.49 (m, 2H), 3.60 – 3.34 (m, 1H),3.22 – 3.08 (m, 2H), 2.90 – 2.78 (m, 1H), 2.20 – 1.94 (m, 3.5H), 1.94 – 1.66(m, 4.5H), 1.05 (t, J= 7.4 Hz, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers δ -108.78, -108.92. MS (ESI) + ): [M+H] + 514.1 / 516.1.

[0754] [8-[6-(aminomethyl)-4-(1-ethylpropylsulfonyl)-2-pyridyl]-3,8-diazabicyclo[3.2.1] Octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-139)

[0755] Formula weight: 509.04

[0756] Molecular formula: C 24 H 30 ClFN4O3S

[0757] Add I-138 (473 mg, 0.901 mmol, 1 equivalent), potassium N-Boc-aminomethyltrifluoroborate (320 mg, 1.35 mmol, 1.5 equivalent), Cs₂CO₃ (0.73 g, 2.25 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (20 mg, 27 µmol, 0.03 equivalent) to a sealable flask. Rinse the flask with Ar and add degassed dioxane / water (1 / 1, 7 mL). The flask was sealed, and the mixture was stirred at 100°C for 16 hours, during which time more N-Boc-aminomethyltrifluoroborate potassium (160 mg, 0.675 mmol, 0.75 equivalents), Cs₂CO₃ (0.36 g, 1.12 mmol, 1.25 equivalents), and cataCXium-Pd-G₃ (10 mg, 13 µmol, 0.015 equivalents) were added. The reaction mixture was stirred at 100°C for another 2 hours. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was dissolved in dioxane (3.3 mL) at RT, and HCl (4 N in dioxane, 1.7 mL, 6.7 mmol, 7.5 equivalents) was added. The mixture was stirred at RT for 16 hours and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in batches until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry load, DCM / MeOH = 99 / 1 to 90 / 10) to give 283 mg of I-139 (61%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d, 2 sets of rotational isomers ) δ 7.42 – 7.32 (m, 0.5H), 7.24 – 7.17(m, 0.5H), 7.16 – 6.91 (m, 3H), 6.86 (s, 1H), 4.78 (s, 1H), 4.63 – 4.40 (m,2H), 3.97 & 3.96 (s, 2H), 3.60 – 3.35 (m, 1H), 3.27 – 3.02 (m, 2H), 3.00 –2.40 (br s, 2H), 2.90 – 2.80 (m, 1H), 2.20 – 1.94 (m, 3.5H), 1.94 – 1.65 (m,4.5H), 1.03 (t, J= 7.3 Hz, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.96, -109.09. MS (ESI + ): [M+H] + 509.2 / 511.2.

[0758] 2,6-Dichloro-4-[rac-(1R)-1-methylpropyl]thioalkyl-pyridine (I-140)

[0759] Formula weight: 236.16

[0760] Molecular formula: C9H 11 Cl2NS

[0761] At RT, rac-2-bromobutane (0.42 mL, 3.9 mmol, 1 equivalent) and K₂CO₃ (537 mg, 3.89 mmol, 2 equivalent) were successively added to a solution of I-135 (350 mg, 1.94 mmol, 1 equivalent) in DMF (9 mL). The mixture was stirred at RT for 16 h and then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 99 / 1) to give 291 mg of I-140 (63%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.04 (s, 2H), 3.45 – 3.33 (m, 1H), 1.80 – 1.60 (m, 2H), 1.39 (d, J = 6.7 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H). MS (ESI + ): [M+H] + 236.1 / 238.1.

[0762] 2,6-Dichloro-4-[rac-(1R)-1-methylpropyl]sulfonyl-pyridine (I-141)

[0763] Formula weight: 268.16

[0764] Molecular formula: C9H 11 Cl2NO2S

[0765] Colorless I-141 was obtained in 100% yield by using GP-2, with I-140 (291 mg, 1.23 mmol, 1 equivalent) and m-CPBA (70% wet, 0.67 g, 2.7 mmol, 2.2 equivalent) in DCM (6 mL) for 2 hours at RT. 1 H NMR (400 MHz, chloroform-) d ) δ 7.69 (s, 2H), 3.08 – 2.96 (m, 1H), 2.06 – 1.94 (m, 1H), 1.58 – 1.44 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H). MS(ESI + ): [M+H] + 268.0 / 270.0.

[0766] (2-Chloro-4-fluoro-phenyl)-[8-[6-chloro-4-[rac-(1R)-1-methylpropyl]sulfonyl-2-pyridyl]-3, 8-Diazabicyclo[3.2.1]octane-3-yl]methyl ketone (I-142)

[0767] Formula weight: 500.41

[0768] Molecular formula: C 22 H 24 Cl2FN3O3S

[0769] A solution of I-141 (347 mg, 1.23 mmol, 1 equivalent), I-002 (429 mg, 1.60 mmol, 1.3 equivalent), and iPr2NEt (0.43 mL, 2.5 mmol, 2 equivalent) in NMP (6.1 mL) was stirred for 3 hours at 120°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 40 / 60) to give 0.52 g of I-142 (80%) as a white solid. 1 H NMR (400 MHz, chloroform-) d, 2 sets of rotational isomers) δ 7.42 – 7.33 (m, 0.5H), 7.25 –7.18 (m, 0.5H), 7.17 – 6.98 (m, 2H), 6.95 (s, 1H), 6.83 (s, 1H), 4.72 – 4.46(m, 3H), 3.60 – 3.35 (m, 1H), 3.22 – 3.08 (m, 2H), 3.05 – 2.90 (m, 1H), 2.20 – 1.95 (m, 4.5H), 1.75 – 1.65 (m, 0.5H), 1.58 – 1.42 (m, 1H), 1.31 (d, J =6.8 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers δ -108.77, -108.91. MS (ESI) + ): [M+H] + 500.1 / 502.1.

[0770] [8-[6-(aminomethyl)-4-[rac-(1R)-1-methylpropyl]sulfonyl-2-pyridyl]-3,8-diazadi Cyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-143)

[0771] Formula weight: 495.01

[0772] Molecular formula: C 23 H 28 ClFN4O3S

[0773] Add I-142 (518 mg, 0.983 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (350 mg, 1.48 mmol, 1.5 equivalent), Cs₂CO₃ (0.80 g, 2.46 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (21 mg, 30 µmol, 0.03 equivalent) to a sealable flask. Rinse the flask with Ar and add degassed dioxane / water (1 / 1, 8 mL). The flask was sealed, and the mixture was stirred at 100°C for 2 hours, during which time more N-Boc-aminomethyltrifluoroborate potassium (175 mg, 0.737 mmol, 0.75 equivalents), Cs₂CO₃ (0.400 g, 1.23 mmol, 1.25 equivalents), and cataCXium-Pd-G₃ (10 mg, 15 µmol, 0.015 equivalents) were added. The reaction mixture was stirred at 100°C for another 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was dissolved in dioxane (3.6 mL) at RT, and HCl (4 N in dioxane, 1.8 mL, 7.2 mmol, 7.3 equivalents) was added. The mixture was stirred at RT for 16 hours and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in batches until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry load, DCM / MeOH = 99 / 1 to 90 / 10) to give 314 mg of I-143 (63%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d, 2 sets of rotational isomers) δ 7.42 – 7.32 (m, 0.5H), 7.25 – 7.18(m, 0.5H), 7.17 – 6.90 (m, 3H), 6.86 (s, 1H), 4.79 (s, 1H), 4.62 – 4.40 (m,2H), 4.00 & 3.98 (s, 2H), 3.58 – 3.35 (m, 1H), 3.27 – 3.05 (m, 2H), 3.05 –2.90 (m, 1H), 3.00 – 2.20 (br s, 2H), 2.20 – 1.90 (m, 4.5H), 1.75 – 1.65 (m,0.5H), 1.55 – 1.40 (m, 1H), 1.35 – 1.20 (m, 3H), 1.01 (t, J = 8.1 Hz, 3H). 19 FNMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.95, -109.06. MS (ESI + ): [M+H] + 495.2 / 497.2.

[0774] [4-[6-chloro-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]piperazin-1-yl]-(2-chloro-4-fluoro-benzene) Methyl ketone (I-144)

[0775] Formula weight: 488.4

[0776] Molecular formula: C 21 H 24 Cl2FN3O3S

[0777] A solution of I-120 (200 mg, 0.709 mmol, 1 equivalent), I-001 (206 mg, 0.851 mmol, 1.2 equivalent), and iPr2NEt (0.19 mL, 1.1 mmol, 1.5 equivalent) in NMP (2.6 mL) was stirred for 18 hours at 100°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 92 / 8 to 20 / 80) to give 291 mg of I-144 (84%) as a white solid. 1H NMR (400 MHz, chloroform-) d ) δ 7.34 (dd, J = 8.5, 5.8 Hz, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (td, J = 8.2, 2.5 Hz, 1H), 7.04 (d, J = 1.0 Hz, 1H), 6.96 (d, J = 1.1 Hz, 1H), 4.10 – 3.60 (m, 6H), 3.50 – 3.25 (m, 2H), 3.03 (s, 2H), 1.25 (s, 9H). 19 F NMR (376 MHz, chloroform-) d δ -108.64. MS (ESI) + ): [M+H] + 488.1 / 490.2.

[0778] [4-[6-(aminomethyl)-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]piperazin-1-yl]-(2-chloro- 4-Fluoro-phenyl)methyl ketone (I-145)

[0779] Formula: 483

[0780] Molecular formula: C 22 H 28 ClFN4O3S

[0781] I-144 (280 mg, 0.573 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (163 mg, 0.688 mmol, 1.2 equivalent), Cs₂CO₃ (467 mg, 1.43 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (13 mg, 17 µmol, 0.03 equivalent) were charged into a sealable flask. The flask was rinsed with Ar and degassed dioxane / water (1 / 1, 4.5 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 1 hour. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 93 / 7 to 30 / 70) to give an inseparable mixture of starting material and intermediate protected by Boc to the desired product. It was dissolved in dioxane (3.1 mL) at RT and HCl (4 N in dioxane, 1.2 mL, 4.6 mmol, 8.1 equivalence) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, DCM / MeOH(7N NH3)) = 98 / 2 to 80 / 20) to give 200 mg of I-145 (71%) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.25 (dd, J = 8.5, 5.8 Hz, 1H), 7.12 (dd, J = 8.4, 2.4 Hz, 1H), 7.01 (td, J = 8.2, 2.5 Hz, 1H), 6.96 (d, J = 1.2 Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 4.00 – 3.98 (m, 1H), 3.83(s, 2H), 3.83 – 3.50 (m, 5H), 3.40 – 3.20 (m, 2H), 2.94 (s, 2H), 1.15 (s,9H). 19 F NMR (376 MHz, chloroform-) dδ -108.86. MS (ESI) + ): [M+H] + 483.2 / 485.2.

[0782] [(3S)-4-[6-chloro-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3-methyl-piperazin-1-yl]- (2-Chloro-4-fluoro-phenyl)methyl ketone (I-146)

[0783] Formula weight: 502.43

[0784] Molecular formula: C 22 H 26 Cl2FN3O3S

[0785] A solution of I-120 (200 mg, 0.709 mmol, 1 equivalent), I-003 (200 mg, 0.780 mmol, 1.1 equivalent), and iPr2NEt (0.19 mL, 1.1 mmol, 1.5 equivalent) in NMP (2.6 mL) was stirred for 18 hours at 120°C. After cooling to RT, the mixture was partitioned between 1 N HCl and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (1 N HCl, water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 95 / 5 to 50 / 50) to give 217 mg of I-146 (61%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.27 (m, 1H), 7.25 –7.15 (m, 1H), 7.12 – 7.04 (m, 1H), 7.00 (s, 1H), 6.90 & 6.88 (s, 1H), 4.80 –4.40 (m, 2H), 4.25 – 4.05 (m, 1H), 3.57 – 3.00 (m, 4H), 3.00 (s, 2H), 1.40 –1.05 (m, 3H), 1.23 (s, 9H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers δ -108.45, -108.66. MS (ESI) + ): [M+H] + 502.1 / 504.1.

[0786] [(3S)-4-[6-(aminomethyl)-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]-3-methyl-piperazine- 1-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-147)

[0787] Formula weight: 497.03

[0788] Molecular formula: C 23 H 30 ClFN4O3S

[0789] I-146 (217 mg, 0.432 mmol, 1 equivalent), N-Boc-aminomethyltrifluoroborate potassium (123 mg, 0.518 mmol, 1.2 equivalent), Cs₂CO₃ (352 mg, 1.08 mmol, 2.5 equivalent), and cataCXium-Pd-G₃ (9.4 mg, 13 µmol, 0.03 equivalent) were charged into a sealable flask. The flask was rinsed with Ar and degassed dioxane / water (1 / 1, 3.5 mL) was added. The flask was sealed and the mixture was stirred at 100°C for 2 hours. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 90 / 10 to 0 / 100) to give an inseparable mixture of the starting material and intermediates protected by Boc to the desired product. It was dissolved in DCM (1.6 mL) at RT and HCl (4 N in dioxane, 0.82 mL, 3.3 mmol, 7.6 equivalents) was added. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between water and DCM, with K2CO3 added in portions until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 98 / 2 to 80 / 20) to give 84 mg of I-147 (39%) as a pale yellow solid. 1 H NMR (500 MHz, chloroform-) d(Multiple rotational isomers) δ 7.50 – 7.25 (m, 1H), 7.24 – 6.95 (m, 3H), 6.95 – 6.85 (m, 1H), 4.80 – 4.40 (m, 2H), 4.25– 4.05 (m, 1H), 3.94 (s, 2H), 3.57 – 3.40 (m, 1H), 3.37 – 3.05 (m, 3H), 3.01 (s, 2H), 2.28 (br s, 2H), 1.35 – 1.05 (m, 3H), 1.21 (s, 9H). 19 F NMR (470 MHz, chloroform- d (Multiple rotational isomers) δ -108.73, -108.75, -108.79, -108.97. MS (ESI) + ): [M+H] + 497.1 / 499.2.

[0790] 1-(7-bromo-5-iodo-indazol-1-yl)-2-methyl-prop-2-propanol (I-148)

[0791] Formula weight: 395.03

[0792] Molecular formula: C 11 H 12 BrIN2O

[0793] At 0°C, 2,2-dimethylethylene oxide (497 µL, 5.57 mmol, 2 equivalents) was added to a solution of I-053 (900 mg, 2.79 mmol, 1 equivalent) in anhydrous DMF (11 mL). The mixture was stirred at 100°C for 16 hours. The mixture was partitioned between water and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (80 g column, dry loading, cHex / EtOAc = 100 / 0 to 0 / 100) to give 240 mg of I-148 (22%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 7.99 (d, J = 1.4 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J = 1.3 Hz, 1H), 4.79(s, 2H), 1.10 (s, 6H). MS (ESI +): [M+H] + 394.9 / 396.9.

[0794] [2-(7-bromo-5-iodo-indazol-1-yl)-1,1-dimethyl-ethoxy]-tert-butyl-dimethyl-silane (I-149)

[0795] Formula weight: 509.3

[0796] Molecular formula: C 17 H 26 BrIN2OSi

[0797] At 0°C, 2,6-dimethylpyridine (142 µL, 1.22 mmol, 2 equivalents) and tert-butyldimethylsilyltrifluoromethanesulfonate (209 µL, 0.911 mmol, 1 equivalent) were added to a solution of I-148 (240 mg, 0.608 mmol, 1 equivalent) in anhydrous DCM (1.2 mL). The mixture was stirred at 0°C for 2 hours. Water was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic extracts were washed (with water and brine), dried (using Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by passing it through an FC column (24 g column, dry loading, cHex / EtOAc = 100 / 0 to 80 / 20) to give 260 mg of I-149 (84%) as a yellow oil. 1 H NMR (400 MHz, chloroform-) d ) δ 8.00 (d, J = 1.4 Hz, 1H), 7.92(s, 1H), 7.79 (d, J = 1.4 Hz, 1H), 4.79 (s, 2H), 1.31 (s, 6H), 0.67 (s, 9H), 0.00 (s, 6H).

[0798] 3-[7-bromo-1-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyl]indazol-5-yl]sulfonane Methyl propionate (I-150)

[0799] Formula weight: 501.55

[0800] Molecular formula: C 21 H 33 BrN2O3SSi

[0801] I-149 (260 mg, 0.511 mmol, 1 equivalent) and XPhos-Pd-G3 (48 mg, 51 µmol, 0.1 equivalent) were loaded into a MW vial. The vial was washed with Ar and degassed dioxane (2.5 mL) was added. DIPEA (0.18 mL, 1.0 mmol, 2 equivalent) and methyl 3-mercaptopropionate (61 mg, 0.51 mmol, 1.00 equivalent) were added. The vial was sealed and the mixture was stirred at 100°C for 1.5 h. The mixture was concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 100 / 0 to 80 / 20) to give 186 mg of I-150 (83%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d ) δ 7.98 (s, 1H), 7.78 (d, J = 1.5 Hz, 1H), 7.66 (d, J = 1.5Hz, 1H), 4.83 (s, 2H), 3.70 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 2.62 (t, J =7.3 Hz, 2H), 1.35 (s, 6H), 0.66 (s, 9H), 0.02 (s, 6H). MS (ESI + ): [M+H] + 501.3 / 503.3.

[0802] 7-Bromo-1-[2-[tert-butyl(dimethyl)silyl]oxy-2-methylpropyl]indazole-5-thiol (I-151)

[0803] Formula weight: 415.46

[0804] Molecular formula: C 17 H 27 BrN2OSSi

[0805] At -78°C, t-BuOK (1 M solution in THF, 742 µL, 0.742 mmol, 2 equivalents) was added to a solution of I-150 (286 mg, 0.371 mmol, 1 equivalent) in THF (3.7 mL). The mixture was warmed to RT over 3 hours. Aqueous saturated NH4Cl and EtOAc were added. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (24 g column, dry loading, cHex / EtOAc = 100 / 0 to 80 / 20) to give 124 mg of I-151 (80%) as a colorless oil. 1 H NMR (400MHz, chloroform-) d ) δ 7.90 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz,1H), 4.79 (s, 2H), 3.52 (s, 1H), 1.30 (s, 6H), 0.67 (s, 9H), 0.00 (s, 6H). MS(ESI + ): [M+H] + 415.1 / 417.1.

[0806] [2-[7-bromo-5-(2,2-dimethylpropylsulfonyl)indazole-1-yl]-1,1-dimethylethoxy]-tert-butyl β-dimethylsilane (I-152)

[0807] Formula weight: 517.6

[0808] Molecular formula: C 22 H 37 BrN2O3SSi

[0809] At -0°C, NaH (14.3 mg, 0.358 mmol, 1.2 equivalent in mineral oil, 60%) was added to a solution of I-151 (124 mg, 0.298 mmol, 1 equivalent) in DMF (0.6 mL). The mixture was stirred at 0°C for 0.5 h. 1-Bromo-2,2-dimethylpropane (54 mg, 0.36 mmol, 1.20 equivalent) was added, and the mixture was stirred at 80°C for 1 h. After cooling to RT, the mixture was partitioned between MTBE and water. The layers were separated, and the aqueous phase was extracted with MTBE. The combined organic extracts were washed (with brine), dried (with Na2SO4), filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (1.5 mL), and m-CPBA (70% wet, 184 mg, 0.746 mmol, 2.5 equivalent) was added. The mixture was stirred at RT for 1 h. Aqueous Na₂S₂O₃ and aqueous saturated NaHCO₃ were added, and the mixture was stirred vigorously at RT for 0.5 h. EtOAc was added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (with brine), dried (with Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 100 / 0 to 50 / 50) to give 106 mg of I-152 (69%) as a white solid. 1 H NMR (400 MHz, chloroform-) d ) δ 8.31 (d, J = 1.6 Hz, 1H),8.18 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 4.88 (s, 2H), 3.06 (s, 2H), 1.36 (s,6H), 1.22 (s, 9H), 0.61 (s, 9H), 0.00 (s, 6H). MS (ESI + ): [M+H] + 517.1 / 519.1.

[0810] [8-[1-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyl]-5-(2,2-dimethylpropyl] [Sulfoyl]indazole-7-yl]-3,8-diazabicyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluoro-phenyl)methyl ketone (I-153)

[0811] Formula weight: 705.4

[0812] Molecular formula: C 35 H 50 ClFN4O4SSi

[0813] According to GP-3, aryl bromide I-152 (106 mg, 205 µmol, 1 equivalent), piperazine I-002 (71.5 mg, 266 µmol, 1.3 equivalent), Cs₂CO₃ (200 mg, 0.614 mmol, 3 equivalent), Pd(OAc)₂ (4.6 mg, 21 µmol, 0.10 equivalent) and rac I-153 was obtained in 67% yield by reflux of BINAP (15 mg, 25 µmol, 0.12 equivalents) in toluene (1 mL) for 2 h. Purification was performed by FC (cHex / EtOAc = 100 / 0 to 85 / 15). 1 H NMR (400 MHz, chloroform-) d , 2 Group rotational isomers ) δ 8.13 (s, 1H), 8.01 (s, 1H), 7.42 – 7.00 (m, 4H), 5.01 – 4.50(m, 3H), 4.10 – 3.95 (m, 1H), 3.90 – 3.20 (m, 3H), 3.02 & 3.01 (s, 2H), 2.23– 1.86 (m, 4.5H), 1.75 – 1.65 (m, 0.5H), 1.28 – 1.11 (m, 18H), 0.78 (s, 3H), 0.69 (s, 3H), 0.04 (s, 3H), -0.01 (s, 3H). 19 F NMR (376 MHz, chloroform-) d , 2 sets of rotational isomers body ) δ -108.80, -108.95. MS (ESI + ): [M+H] + 705.5 / 707.4.

[0814] 7-Bromo-5-iodo-1-(2-methoxyethyl)indazole (I-154)

[0815] Formula weight: 381.01

[0816] Molecular formula: C 10 H 10 BrIN2O

[0817] At 0°C, NaH (149 mg, 3.72 mmol, 1.2 equivalents in mineral oil) was added to a solution of I-053 (1.00 g, 3.10 mmol, 1 equivalent) in anhydrous DMF (15.5 mL). The mixture was stirred at RT for 0.5 h, and 2-bromoethyl methyl ether (0.58 mL, 6.2 mmol, 2 equivalents) was added dropwise. The mixture was stirred at RT for 2 h. Saturated NH4Cl and EtOAc were added. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (40 g column, dry loading, cHex / EtOAc = 100 / 0 to 85 / 15) to give 437 mg of I-154 (37%) as a colorless oil. 1 H NMR (400 MHz, chloroform-) d )δ 8.01 (d, J = 1.4 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 1.4 Hz, 1H), 4.97 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.33 (s, 3H). MS (ESI + ): [M+H] + 380.9 / 382.9.

[0818] 7-Bromo-5-(2,2-dimethylpropylthio)-1-(2-methoxyethyl)indazole (I-155)

[0819] Formula weight: 357.31

[0820] Molecular formula: C 15 H 21 BrN2OS

[0821] I-155 was obtained in 95% yield as a pale yellow oil by incubation at 100°C with I-154 (890 mg, 2.54 mmol, 1 equivalent), XantPhos-Pd-G3 (44.3 mg, 46.7 µmol, 0.03 equivalent), iPr2NEt (0.76 mL, 3.5 mmol, 1.5 equivalent), and 2,2-dimethylpropane-1-thiol (0.83 mL, 2.3 mmol, 1 equivalent) in dioxane (12 mL) for 1.5 h. Purification was performed by FC (cHex / EtOAc = 99 / 1 to 90 / 10).1 H NMR (400MHz, chloroform-) d ) δ 7.93 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 1.5 Hz, 1H), 4.96 (t, J = 6.1 Hz, 2H), 3.84 (t, J = 6.1 Hz, 2H), 3.34 (s, 3H), 2.89(s, 2H), 1.04 (s, 9H). MS (ESI + ): [M+H] + 357.0 / 359.0.

[0822] 7-Bromo-5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxyethyl)indazole (I-156)

[0823] Formula weight: 389.31

[0824] Molecular formula: C 15 H 21 BrN2O3S

[0825] Using GP-2, I-156 was obtained in 100% yield as a white solid by continuous RT in DCM (11 mL) with I-155 (790 mg, 2.21 mmol, 1 equivalent) and m-CPBA (77% wet, 1.09 g, 4.86 mmol, 2.2 equivalent) for 1 hour. Purification was performed by FC (cHex / EtOAc = 97 / 3 to 70 / 30). 1 H NMR (400 MHz, chloroform-) d ) δ 8.30 (d, J = 1.5 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 5.05 (t, J = 5.8 Hz, 2H), 3.87 (t, J = 5.9 Hz, 2H), 3.33 (s, 3H), 3.06 (s, 2H), 1.21 (s, 9H). MS(ESI + ): [M+H] + 389.0 / 391.0.

[0826] 8-[5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxyethyl)indazole-7-yl]-3,8-diazabicyclo [3.2.1] Octane-3-carboxylic acid tert-butyl ester (I-157)

[0827] Formula weight: 520.68

[0828] Molecular formula: C 26 H 40 N4O5S

[0829] According to GP-3, aryl bromide I-156 (500 mg, 1.28 mmol, 1 equivalent), 3-boc-3,8-diazabicyclo[3.2.1]octane (327 mg, 1.54 mmol, 1.2 equivalent), Cs2CO3 (1.26 g, 3.85 mmol, 3 equivalent), Pd(OAc)2 (28.8 mg, 128 µmol, 0.10 equivalent) and rac -BINAP (96.0 mg, 154 µmol, 0.12 equivalents) was refluxed in toluene (6.4 mL) for 4 h to obtain I-157 in 91% yield. Purification was performed by FC (cHex / EtOAc = 100 / 0 to 50 / 50). 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 8.15 (s, 1H), 7.99 (d, J = 1.4Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 5.15 – 4.80 (m, 2H), 4.03 – 3.78 (m, 6H), 3.45 – 3.25 (m, 2H), 3.31 (s, 3H), 3.02 (s, 2H), 2.10 – 1.75 (m, 4H), 1.50 (s, 9H), 1.16 (s, 9H). MS (ESI + ): [M+H] + 521.3.

[0830] 7-(3,8-diazabicyclo[3.2.1]octane-8-yl)-5-(2,2-dimethylpropylsulfonyl)-1-(2-methoxy) (I-158) Indazole (I-158)

[0831] Formula weight: 420.57

[0832] Molecular formula: C 21 H 32 N4O3S

[0833] HCl (4 M solution in dioxane, 2.92 mL, 11.7 mmol, 10 equivalents) was added to a solution of I-157 (609 mg, 1.17 mmol, 1 equivalent) in DCM (5.8 mL) at RT. The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was partitioned between DCM and water, and K2CO3 was added until pH > 11. The layers were separated, and the aqueous phase was extracted with DCM. The organic extract was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, DCM / MeOH = 99 / 1 to 90 / 10) to give 400 mg of I-158 (80%) as a white solid. 1 HNMR (400 MHz, chloroform-) d ) δ 8.14 (s, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.28 (d, J =1.5 Hz, 1H), 4.98 (t, J = 5.9 Hz, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.90 – 3.85(m, 2H), 3.37 – 3.30 (m, 2H), 3.31 (s, 3H), 3.03 (s, 2H), 2.89 (dd, J = 12.5,2.5 Hz, 2H), 2.11 – 1.94 (m, 4H), 1.16 (s, 9H). MS (ESI + ): [M+H] + 421.2.

[0834] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(2,2- (dimethylpropylsulfonyl)-2-pyridyl]methyl]-3-hydroxy-3-methylbutyramide (I-159)

[0835] Formula weight: 609.15

[0836] Molecular formula: C 29 H 38 ClFN4O5S

[0837] DIPEA (0.21 mL, 1.2 mmol, 2 equivalents) and HATU (269 mg, 0.707 mmol, 1.2 equivalents) were added to a solution of hydroxyisovalerate (89 µL, 0.71 mmol, 1.2 equivalents) in DMF (3 mL). The mixture was stirred at RT for 30 min, and I-123 (300 mg, 0.589 mmol, 1 equivalent) was added. The mixture was stirred at RT for 16 h. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (20 g column, dry loading, cHex / EtOAc = 50 / 50) to give 250 mg of I-159 (70%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.42 – 7.18 (m, 1H), 7.18 – 6.98 (m, 2H), 6.97 (s,1H), 6.92 – 6.85 (m, 2H), 4.74 (s, 1H), 4.61 – 4.48 (m, 4H), 3.57 – 3.35 (m,1H), 3.20 – 3.07 (m, 2H), 3.01 & 3.00 (s, 2H), 2.43 (s, 2H), 2.15 – 1.95 (m,4H), 1.30 (s, 6H), 1.21 (s, 9H). MS (ESI + ): [M+H] + 609.3 / 611.3.

[0838] 3-[tert-butyl(dimethyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazide] Heterobicyclo[3.2.1]octane-8-yl]-4-(2,2-dimethylpropylsulfonyl)-2-pyridyl]methyl]-3-methylbutyramide （I-160）

[0839] Formula weight: 723.41

[0840] Molecular formula: C 35 H 52 ClFN4O5SSi

[0841] At RT, 2,6-dimethylpyridine (100 µL, 0.821 mmol, 2 equivalents) and tert-butyldimethylsilyltrifluoromethanesulfonate (0.11 mL, 0.49 mmol, 1.2 equivalents) were added to a solution of I-159 (250 mg, 0.410 mmol, 1 equivalent) in DCM (0.8 mL). The mixture was stirred at RT for 2.5 h, at which point more 2,6-dimethylpyridine (100 µL, 0.821 mmol, 2 equivalents) and tert-butyldimethylsilyltrifluoromethanesulfonate (0.11 mL, 0.49 mmol, 1.2 equivalents) were added, and the mixture was stirred at RT for 16 h. Water was added. The layers were separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were washed (with brine), dried (using Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc=100 / 0 to 50 / 50) to give 140 mg of I-160 (47%) as a white solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.50 – 7.20 (m, 1H),7.20 – 6.95 (m, 4H), 6.88 (s, 1H), 4.72 (s, 1H), 4.60 – 4.40 (m, 4H), 3.60 –3.30 (m, 1H), 3.22 – 3.06 (m, 2H), 3.00 & 2.99 (s, 2H), 2.44 (s, 2H), 2.15 –1.95 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.37 (s, 6H), 1.22 (m, 9H), 0.81 &0.79 (s, 9H), 0.11 (m, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers δ -108.97, -109.10. MS (ESI) + ): [M+H] + 723.4 / 725.4.

[0842] [8-[3-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propyl]-7-(2,2-dimethylpropyl] [sulfonyl]imidazo[1,5-a]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octane-3-yl]-(2-chloro-4-fluoro-benzene) Methyl ketone (I-161)

[0843] Formula weight: 705.4

[0844] Molecular formula: C 35 H 50 ClFN4O4SSi

[0845] At RT, POCl3 (240 µL, 976 µmol, 5 equivalents) was added to a solution of I-160 (140 mg, 193 µmol, 1 equivalent) and Et3N (0.27 mL, 1.9 mmol, 10 equivalents) in DCE (1 mL). The mixture was stirred at 80°C for 2 hours. After cooling to RT, the reaction mixture was carefully poured into saturated aqueous NaHCO3, and the mixture was stirred vigorously for 15 minutes. EtOAc was added and the layers were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic extracts were washed (saturated aqueous NaHCO3, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by FC (12 g column, dry loading, cHex / EtOAc = 98 / 2 to 60 / 40) to give 121 mg of I-161 (89%) as a yellow solid. MS (ESI) + ): [M+H] + 705.5 / 707.4.

[0846] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(2,2- (dimethylpropylsulfonyl)-2-pyridyl]methyl]propionamide (I-162)

[0847] Formula weight: 565.1

[0848] Molecular formula: C 27 H 34 ClFN4O4S

[0849] At RT, Et3N (55 µL, 0.39 mmol, 2 equivalents) and propionyl chloride (33 µL, 0.49 mmol, 2 equivalents) were added to a solution of I-123 (100 mg, 0.196 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at RT for 2 hours. 1 N HCl and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 90 mg of I-162 (81%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.45 – 7.20 (m, 1H), 7.19 –6.99 (m, 2H), 6.95 (s, 1H), 6.93 (s, 1H), 6.40 (br s, 1H), 4.81 – 4.42 (m,5H), 3.60 – 3.35 (m, 1H), 3.20 – 3.10 (m, 2H), 3.02 & 3.01 (s, 2H), 2.30 (q, J = 7.7 Hz, 2H), 2.20 – 1.95 (m, 3.5H), 1.75 – 1.65 (m, 0.5H), 1.32 – 1.08 (m, 12H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.75, -108.88. MS (ESI + ): [M+H] + 565.2 / 567.3.

[0850] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(2,2- (dimethylpropylsulfonyl)-2-pyridyl]methyl]-3-methylbutyramide (I-163)

[0851] Formula weight: 593.15

[0852] Molecular formula: C 29 H 38 ClFN4O4S

[0853] At RT, Et3N (55 µL, 0.39 mmol, 2 equivalents) and isovaleryl chloride (31 µL, 0.25 mmol, 1.3 equivalents) were added to a solution of I-123 (100 mg, 0.196 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at RT for 1 hour. 1 N HCl and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 110 mg of I-163 (94%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.45 – 7.20 (m, 1H), 7.18 – 6.97 (m, 2H), 6.97 (s, 1H), 6.95 (s, 1H), 6.45 (br s, 1H), 4.79 – 4.42(m, 5H), 3.60 – 3.38 (m, 1H), 3.22 – 3.10 (m, 2H), 3.01 (s, 2H), 2.20 – 1.90(m, 6.5H), 1.80 – 1.70 (m, 0.5H), 1.22 (s, 9H), 0.99 – 0.95 (m, 6H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.71, -108.84. MS (ESI + ): [M+H] + 593.3 / 595.3.

[0854] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(2,2- (dimethylpropylsulfonyl)-2-pyridyl]methyl]cyclobutane carboxamide (I-164)

[0855] Formula weight: 591.14

[0856] Molecular formula: C 29 H 36 ClFN4O4S

[0857] At RT, Et3N (55 µL, 0.39 mmol, 2 equivalents) and cyclobutylcarbonyl chloride (29 µL, 0.25 mmol, 1.3 equivalents) were added to a solution of I-123 (100 mg, 0.196 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at RT for 1 hour. 1 N HCl and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 100 mg of I-164 (86%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.45 – 7.20 (m, 1H), 7.20 – 7.00 (m, 2H), 6.96 (s, 1H), 6.94 (s, 1H), 6.41 (br s, 1H), 4.81 – 4.40(m, 5H), 3.60 – 3.38 (m, 1H), 3.23 – 3.13 (m, 2H), 3.13 – 3.04 (m, 1H), 3.02& 3.01 (s, 2H), 2.37 – 1.82 (m, 9.5H), 1.78 – 1.68 (m, 0.5H), 1.23 (s, 9H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -108.68, -108.81. MS (ESI + ): [M+H] + 591.3 / 593.2.

[0858] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(3,3- [Difluoropyrrolidine-1-yl]sulfonyl-2-pyridyl]methyl]acetamide (I-165)

[0859] Formula weight: 586.03

[0860] Molecular formula: C 25 H 27 ClF3N5O4S

[0861] At RT, Et3N (51 µL, 0.37 mmol, 2 equivalents) and acetyl chloride (16 µL, 0.22 mmol, 1.2 equivalents) were added to a solution of I-109 (100 mg, 0.184 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at RT for 1 hour. 1 N HCl and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 109 mg of I-165 (100%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers ) δ 7.45 – 7.20 (m, 1H), 7.20– 7.00 (m, 2H), 6.86 (br s, 1H), 6.79 (s, 1H), 6.36 (s, 1H), 4.80 – 4.40 (m,5H), 3.61 (t,J = 12.8 Hz, 2H), 3.55 – 3.35 (m, 3H), 3.25 – 3.05 (m, 2H), 2.36 (tt, J = 13.7, 7.3 Hz, 2H), 2.15 – 2.00 (m, 6.5H), 1.78 – 1.68 (m, 0.5H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -99.13, -99.15, -108.74, -108.86. MS (ESI + ): [M+H] + 586.2 / 588.2.

[0862] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(3,3- [Difluoropyrrolidone-1-yl]sulfonyl-2-pyridyl]methyl]propionamide (I-166)

[0863] Formula weight: 600.05

[0864] Molecular formula: C 26 H 29 ClF3N5O4S

[0865] At RT, Et3N (51 µL, 0.37 mmol, 2 equivalents) and propionyl chloride (19 µL, 0.22 mmol, 1.2 equivalents) were added to a solution of I-109 (100 mg, 0.184 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at RT for 1 h. 1 N HCl and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 110 mg of I-166 (100%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.42 – 7.20 (m, 1H), 7.17– 6.95 (m, 2H), 6.88 (s, 1H), 6.82 (s, 1H), 6.49 (br s, 1H), 4.81 – 4.45 (m,5H), 3.65 – 3.35 (m, 5H), 3.25 – 3.10 (m, 2H), 2.45 – 2.25 (m, 4H), 2.15 –2.00 (m, 3.5H), 1.80 – 1.70 (m, 0.5H), 1.30 – 1.22 (m, 3H). 19 F NMR (376 MHz, chloroform-) d , Two sets of rotational isomers ) δ -99.20, -108.66, -108.79. MS (ESI + ): [M+H] + 600.2 / 602.2.

[0866] N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazabicyclo[3.2.1]octane-8-yl]-4-(3,3- [Difluoropyrrolidine-1-yl)sulfonyl-2-pyridyl]methyl]-3-methylbutyramide (I-167)

[0867] Formula quantity: 628.11

[0868] Molecular formula: C 28 H 33 ClF3N5O4S

[0869] At RT, Et3N (51 µL, 0.37 mmol, 2 equivalents) and isovaleryl chloride (27 µL, 0.22 mmol, 1.2 equivalents) were added to a solution of I-109 (100 mg, 0.184 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at RT for 1 hour. 1 N HCl and EtOAc were added. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed (1 N HCl, brine), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 115 mg of I-167 (100%) as a yellow solid. 1 H NMR (400 MHz, chloroform-) d , Two sets of rotational isomers) δ 7.45 – 7.20 (m, 1H), 7.20 – 6.99 (m, 2H), 6.90 (s, 1H), 6.82 (s, 1H), 6.46 (br s, 1H), 4.80 – 4.40(m, 5H), 3.65 – 3.35 (m, 5H), 3.25 – 3.10 (m, 2H), 2.50 – 2.30 (m, 3H), 2.20 – 2.00 (m, 5.5H), 1.80 – 1.70 (m, 0.5H), 1.00 – 0.90 (m, 6H). 19 F NMR (376MHz, chloroform-) d , Two sets of rotational isomers ) δ -99.17, -108.64, -108.77. MS (ESI + ): [M+H] + 628.3 / 630.3.

[0870] 3-[tert-butyl(diphenyl)silyl]oxy-N-[[6-[3-(2-chloro-4-fluorobenzoyl)-3,8-diazide] Heterobicyclo[3.2.1]octane-8-yl]-4-(3,3-difluoropyrrolidone-1-yl)sulfonyl-2-pyridyl]methyl]propionamide (I- 168）

[0871] Formula weight: 854.45

[0872] Molecular formula: C 42 H 47 ClF3N5O5SSi

[0873] HATU (168 mg, 0.441 mmol, 1.2 equivalents) was added to a solution of 3-[tert-butyl(diphenyl)silyl]oxypropionic acid (121 mg, 0.368 mmol, 1 equivalent) and DIPEA (128 µL, 0.735 mmol, 2 equivalents) in DMF (1.8 mL) under RT. The mixture was stirred under RT for 0.5 h, and I-109 (200 mg, 0.368 mmol, 1 equivalent) was added. The mixture was stirred under RT for 16 h. Aqueous saturated NH4Cl and EtOAc were added. The layers were separated, and the aqueous phase was extrac...

Claims

1. Compounds of formula (I) (I) Or its pharmaceutically acceptable salts and / or solvates; in W represents CH or N; R A R B R C and R D Each can independently represent hydrogen, F, Cl, CH3, CF3, CHF2, or CH2F. The condition is R A R B R C and R D At least one of them does not represent hydrogen; R 1 Represents hydrogen or (C1-C8) alkyl, wherein the alkyl group is optionally substituted with at least one OH, (C1-C3) alkoxy, or F; and R 2 R 3 and R 4 It represents hydrogen; Or R 1 and R 4 Together they form -CH2-O-CH2- or -CH2-CH2-, wherein the -CH2-CH2- is optionally substituted by at least one F, OH, or OCH3; and R 2 and R 3 Each represents hydrogen; A 1 and A 2 Each can be represented independently as N or C; and A 3 A 4 and A 5 Each represents N and NR independently. 11 C or CR 12 ; The condition is A 1 A 2 A 3 A 4 and A 5 At least one of them represents N or NR. 11 ; in Each R 11 Independently representing hydrogen, (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, or heteroaryl-(C1-C8)alkyl-; and Each R 12 Independently representing hydrogen, (C1-C8)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl- or heteroaryl-(C1-C8)alkyl-; Where R 11 or R 12 The alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally surrounded by at least one F, Cl, OH, =O, (C1-C8)alkyl, (C1-C8)alkyl-O-, or NR. 13 R 14 Replace; where R 13 and R 14 Each independently represents hydrogen or (C1-C8) alkyl; and R 10 Indicates NR 5 R 6 or C(R) 5 (R) 6 (R) 9 ); in R 5 It represents hydrogen, (C1-C8)alkyl, CH3 substituted with one to three (C1-C8)alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8)alkyl; Where R 5 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, or NR. 17 R 18 CO2H, R 17 R 18 NC(O)-, R 17 O-NR 18 - Heterocyclic alkyl, aryl, or heteroaryl substituted; wherein R 17 and R 18 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, or heteroaryl group is optionally surrounded by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 19 R 20 CO2H, R 19 R 20 NC(O)-, R 19 O-NR 20 -、(C1-C8)alkyl-CO2-、R 19 R 20 N-(C1-C8)alkyl-, R 19 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 19 and R 20 Each can independently represent hydrogen or (C1-C8) alkyl; R 6 It represents hydrogen, (C1-C8)alkyl, CH3 substituted with one to three (C1-C8)alkyl groups, cycloalkyl, heterocycloalkyl, aryl or cycloalkyl-(C1-C8)alkyl; Where R 6 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, or NR. 21 R 22 CO2H, R 21 R 22 NC(O)-, R 21 O-NR 22 - Heterocyclic alkyl, aryl, or heteroaryl substituted; wherein R 21 and R 22 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, or heteroaryl group is optionally surrounded by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 23 R 24 CO2H, R 23 R 24 NC(O)-, R 23 O-NR 24 -、(C1-C8)alkyl-CO2-、R 23 R 24 N-(C1-C8)alkyl-, R 23 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 23 and R 24 Each can independently represent hydrogen or (C1-C8) alkyl; Or R 5 and R 6 Together with the carbon or nitrogen atoms they are bonded to, they form cycloalkyl or heteroalkyl groups. The cycloalkyl or heterocycloalkyl group is optionally oxidized by at least one of the following: F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, NR 25 R 26 CO2H, (C1-C8)alkyl-CO2-, R 25 R 26 NC(O)-, R 25 O-NR 26 -、R 25 R 26 N-(C1-C8)alkyl-, R 25 O2C-(C1-C8)alkyl-, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-(C1-C8)alkyl-, heterocycloalkyl-(C1-C8)alkyl-, aryl-(C1-C8)alkyl-, heteroaryl-(C1-C8)alkyl-, aryl-cycloalkyl-O-, cycloalkyl-O-, heterocycloalkyl-O-, aryl-O-, heteroaryl-O-, cycloalkyl-(C1-C8)alkyl-O-, heterocycloalkyl-(C1-C8)alkyl-O-, aryl-(C1-C8)alkyl-O-, heteroaryl-(C1-C8)alkyl-O-, cycloalkyl-NR 25 - Heterocyclic alkyl-NR 25 -,Aryl-NR 25 -、Heteroaryl-NR 25 - Cycloalkyl-(C1-C8)alkyl-NR 25 - Heterocyclic alkyl-(C1-C8)alkyl-NR 25 -, aryl-(C1-C8)alkyl-NR 25 - Heteroaryl-(C1-C8)alkyl-NR 25 - substituted with benzylidene, heteroarylene, aryl-(C1-C8)alkyl-ylidene, or heteroaryl-(C1-C8)alkyl-ylidene; wherein R 25 and R 26 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, heteroaryl, benzylidene, or heteroarylene group is optionally surrounded by at least one F, Cl, (C1-C8) alkyl, CF3, CHF2, CH2F, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, or NR. 27 R 28 CO2H, R 27 R 28 NC(O)-, R 27 O-NR 28 -、(C1-C8)alkyl-CO2-、R 27 R 28 N-(C1-C8)alkyl-, R 27 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 27 and R 28 Each independently represents hydrogen or (C1-C8) alkyl; and R 9 It represents hydrogen, (C1-C8)alkyl, CH3 substituted with one to three (C1-C8)alkyl groups, cycloalkyl, heterocycloalkyl, aryl, or cycloalkyl-(C1-C8)alkyl; Where R 9 The alkyl or cycloalkyl group may optionally be replaced by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, (C1-C8) alkoxy, or NR. 29 R 30 CO2H, R 29 R 30 NC(O)-, R 29 O-NR 30 - Heterocyclic alkyl, aryl, or heteroaryl substituted; wherein R 29 and R 30 Each can independently represent hydrogen or (C1-C8) alkyl; The heterocyclic alkyl, aryl, or heteroaryl group is optionally surrounded by at least one F, Cl, (C1-C8) alkyl, CF3, OCF3, CN, OH, =O, →O, (C1-C8) alkoxy, or NR. 31 R 32 CO2H, R 31 R 32 NC(O)-, R 31 O-NR 32 -、(C1-C8)alkyl-CO2-、R 31 R 32 N-(C1-C8)alkyl-, R 31 O2C-(C1-C8)alkyl-, heterocyclic alkyl, heteroaryl, aryl or aryl-(C1-C8)alkyl-substituted; wherein R 31 and R 32 Each can be used independently to represent hydrogen or (C1-C8) alkyl groups.

2. The compound according to claim 1, wherein R A R B R C and R D At least one of them represents hydrogen, preferably R A and R C At least one of them represents hydrogen, more preferably R C It represents hydrogen.

3. The compound according to claim 1 or 2, wherein R A R B and R D At least one of them represents F or Cl, preferably R B and R D At least one of them represents F or C1; more preferably R B and R D Each can be represented independently as F or Cl; more preferably R. B Let F be an integer, and R be an integer. D It represents Cl.

4. The compound according to any one of claims 1 to 3, wherein R 1 Indicates hydrogen or (C1-C8) alkyl; preferably R 1 It indicates hydrogen or methyl.

5. The compound according to any one of claims 1 to 3, wherein R 1 and R 4 Together they form -CH2-CH2-; wherein the -CH2-CH2- is optionally replaced by at least one F, OH or OCH3; preferably R 1 and R 4 Together they form -CH2-CH2-.

6. The compound according to any one of claims 1 to 5, wherein A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula: Where R 11 and R 12 Each independently as defined in claim 1; and The dashed lines represent the fusion points of the five-membered heteroaryl group and the six-membered ring fused with it.

7. The compound according to claim 6, wherein A 1 A 2 A 3 A 4 and A 5 Together they form a five-membered heteroaryl group selected from the following formula. Where R 11 and R 12 Each independently as defined in claim 1; and The dashed lines represent the fusion points of the five-membered heteroaryl group and the six-membered ring fused with it.

8. The compound according to any one of claims 1 to 7, wherein A 5 Indicates NR 11 or CR 12 , where R 11 and R 12 As defined in claim 1, the condition is R 11 and R 12 Does not represent hydrogen; preferably R 11 and R 12 Each can be independently represented as methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, hydroxybutyl, methoxyethyl, ethyl-OC(O)-, cyclobutyl or cyclopropyl.

9. The compound according to any one of claims 1 to 8, wherein R 10 Indicates NR 5 R 6 ,in: R 5 Indicates hydrogen or (C1-C8) alkyl; preferably R 5 Indicates hydrogen, methyl, trideuteryl (CD3), or ethyl; and / or R 6 It represents (C1-C8) alkyl or cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with at least one F; preferably R 6 Indicates ethyl, propyl, 3-fluoropropyl, butyl, or difluorocyclobutyl; or R 5 and R 6 Together with the nitrogen atoms they are bonded to, they form heterocyclic alkyl groups; preferably R 5 and R 6 Together with the nitrogen atoms they bind to, they form difluoropyrrolidine, phenyl-piperidine, or (chlorophenyl)ethylpiperazine.

10. The compound according to any one of claims 1 to 8, wherein R 10 Represents C(R) 5 (R) 6 (R) 9 ),in: R 5 Indicates hydrogen or (C1-C8) alkyl; preferably R 5 Indicates hydrogen, methyl, or ethyl; and / or R 6 Indicates (C1-C8) alkyl; preferably R 6 Indicates ethyl or butyl; or R 5 and R 6 Together with the carbon atoms they are attached to, they form cycloalkyl groups; preferably cyclopentyl groups; and / or R 9 It represents hydrogen.

11. The compound according to any one of claims 1 to 10, wherein the compound is selected from: And its pharmaceutically acceptable salts and / or solvates.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

13. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, used as a medicine.

14. The compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, for treating neurological disorders.

15. A method for preparing the compound according to any one of claims 1 to 11, wherein the method comprises: - A step of reacting a compound of formula (II) with a compound of formula (III) in the presence of an alkaline and metal catalyst to obtain a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. (II) in A 1 -A 5 and R 10 As defined in claim 1, and X represents a halide or -CF3SO3. (III) Among them, W and R A -R D and R 1 -R 4 As defined in claim 1; or - A step of reacting the compound of formula (VII) in the presence of a dehydrating agent to obtain the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate. (VII) Among them, W and R A -R D R 1 -R 4 R 10 and R 12 As defined in claim 1, Preferably, the dehydrating agent is phosphorus oxychloride (POCl3).

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