TW202304909A - Small molecule inhibitors of mammalian slc34a1 function - Google Patents

Abstract

Disclosed are compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with elevated serum phosphate levels in a subject.

Description

Small molecule inhibitors of mammalian SLC34A1 function

Phosphorus is an essential mineral responsible for maintaining cellular energy and mineralizing bones. In humans, most phosphorus is present in bones and teeth as hydroxyapatite, and in cells as nucleic acids and components of phospholipid membranes. A small fraction of phosphate circulates in the serum under tight regulation by a complex action of specialized ion transporters and regulatory hormones that balance gastrointestinal phosphorus absorption, bone resorption, cellular flux, and Kidney excretion.

Three members of the NaPi2 family of solute carrier (SLC) sodium-phosphate cotransporters play important roles in phosphate homeostasis. NaPi2a/SLC34A1 and NaPi2c/SLC34A3 are located on the apical membrane of renal proximal tubules and function to reabsorb phosphate filtered by glomeruli. NaPi2b/SLC34A2 is present on the apical membrane of the small intestine, where it absorbs a portion of dietary phosphate. When the phosphate load is overloaded, bone-derived hormones, fibroblast growth factor 23 (FGF23) and parathyroid-derived parathyroid hormone (PTH) will down-regulate NaPi2a/SLC34A1 and NaPi2c/SLC34A3 to increase urinary phosphate excretion, and when phosphate When salt is at a trough, 1,25(OH) ₂ -vitamin D3 increases intestinal phosphate absorption by up-regulating NaPi2b/SLC34A2. Phosphate homeostasis is tightly controlled to maintain proper bone function while limiting the undesired effects of calcification of vascular and non-bone tissues caused by excess circulating phosphate.

One of the major life-threatening complications in patients with chronic kidney disease (CKD) is hyperphosphatemia, which is manifested by decreased renal function and impaired renal phosphate excretion. Hyperphosphatemia in patients with end-stage renal disease (ESRD) is an important risk factor for cardiovascular events, and in CKD patients, it is an independent risk factor for further decline in renal function and increased cardiovascular burden. FGF-23 levels rise as renal function declines, and this precedes the development of overt hyperphosphatemia. FGF-23 controls the cell surface expression of NaPi2a/SLC34A1 and NaPi2c/SLC34A3, reduces phosphate reabsorption levels and promotes phosphate excretion. This role of FGF-23 is especially important for preventing hyperphosphatemia in individuals with reduced renal function, but one of the deleterious consequences of high systemic FGF-23 levels is also the promotion of left ventricular hypertrophy and cardiac insufficiency.

Genetic studies and experiments support a role for NaPi2a/SLC34A1 and NaPi2c/SLC34A3 in regulating serum and excreted phosphate. Individuals with predicted loss-of-function variants of NaPi2a/SLC34A1 and NaPi2c/SLC34A3 develop hypophosphatemia and hyperphosphaturia. In addition, deletion of the NaPi2a/SLC34A1 gene, the major renal phosphate transporter in humans and mice, resulted in significant urinary phosphorus loss and impaired bone development, as well as reduced FGF-23 levels in mice. Common and loss-of-function variants in the FGF23 gene were also associated with phosphate levels, suggesting a genetic hypothesis linking altered NaPi2a/SLC34A1 activity, increased phosphate excretion, and decreased FGF-23 levels.

High levels of FGF-23 are independent predictors of cardiovascular mortality in both CKD and non-CKD patient populations. Given the relationship between phosphate excretion and FGF-23, it is believed that further reductions in phosphate reabsorption will also result in lower FGF-23 levels, thereby reducing CKD progression and cardiovascular events. Although restriction of dietary phosphate intake and use of parenteral phosphate sequestration agents are important clinical approaches to limit the phosphate burden in renally impaired individuals, the limited tolerability and clinical efficacy of these types of regimens (especially in non- ESRD patients) means that there remains a significant unmet need and desire for more effective methods of modulating systemic phosphate levels. Pharmacological inhibition of NaPi2a/SLC34A1 is a route to therapeutically increase phosphate excretion in patients with CKD, reducing possible cardiorenal risk in these patients by normalizing phosphate balance and FGF-23 levels .

One aspect of the present invention provides compounds, compositions and methods suitable for inhibiting the function of SLC34A1 in mammals. Another aspect of the invention provides compounds, compositions and methods useful for treating or preventing diseases or conditions associated with elevated phosphate levels in a subject in need thereof, comprising administering to the subject an effective amount of formula (I ) compound.

Another aspect of the present invention provides compounds, compositions and methods suitable for treating or preventing diseases or conditions associated with elevated levels of FGF-23 in an individual in need thereof, comprising administering to the individual an effective amount of the formula ( I) Compounds.

X ₁不存在或選自-O-、-SO ₂-、-C(O)-、-N(X ₂)-及-C(X ₃) ₂-； X ₂係選自-H、烷基及-SO ₂-X ₂''； X ₂''為烷基； 各X ₃獨立地選自-H及烷基； R ₁係選自視情況經取代之胺基烷基、視情況經取代之烷胺基烷基、視情況經取代之烷氧基烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基及視情況經取代之雜芳基；及 R ₂係選自-H、鹵素(例如氯)、腈及烷基； R ₂'係選自烷基、羥烷基、烯基、炔基、環烷基及芳基； R ₂''係選自H、烷基及醯基； 其限制條件為當X ₁為-O-或-N(X ₂)-且R ₁為含氮雜環基時，則該-O-或-N(X ₂)-不直接鍵結於該雜環基上之氮； 其限制條件為當X ₁不存在，R ₂為-Cl，R ₂'為-CH ₃且R ₂''為-H時，則R ₁不為

； 或其醫藥學上可接受之鹽。 Therefore, a kind of compound with formula (I) structure is provided herein:

X ₁ does not exist or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -; X ₂ is selected from -H, alkyl and -SO ₂ -X ₂ ''; X ₂ '' is alkyl; each X ₃ is independently selected from -H and alkyl; R ₁ is selected from optionally substituted aminoalkyl, optionally substituted Alkylaminoalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted hetero Aryl; and _R is selected from -H, halogen (such as chlorine), nitrile and alkyl; _R is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and aryl; R ₂ '' is selected from H, alkyl and acyl; the restriction is that when X ₁ is -O- or -N(X ₂ )- and R ₁ is a nitrogen-containing heterocyclic group, then the -O- or -N(X ₂ )-Nitrogen not directly bonded to the heterocyclic group; the restriction is that when X ₁ does not exist, R ₂ is -Cl, R ₂ ' is -CH ₃ and R ₂ '' is - H, then _R1 is not

; or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating or preventing chronic kidney disease (CKD), the method comprising administering to an individual an effective amount of a compound of formula (I).

Another aspect of the present invention relates to a method of treating or preventing medial calcification, the method comprising administering to an individual an effective amount of a compound of formula (I).

Another aspect of the present invention relates to a method of treating or preventing vascular calcification, the method comprising administering to an individual an effective amount of a compound of formula (I).

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety. In case of conflict, the present disclosure, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features, objects and advantages of the present invention will be apparent from the following embodiments and claims.

RELATED APPLICATIONS This application claims priority to US Provisional Patent Application Serial No. 63/173,781, filed April 12, 2021.

Definitions For convenience, before further describing the invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

To facilitate understanding of the present invention, certain terms and phrases are defined below and throughout this specification.

The article "a/an" is used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

As used in this specification and claims, the phrase "and/or" should be understood to mean "either or both" of the elements so combined, that is, in some cases in combination and in other cases. Elements that exist uncombined. Multiple elements listed with "and/or" should be construed in the same fashion, ie, "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" phrase, whether related or unrelated to those elements specifically identified. Thus, by way of non-limiting example, a reference to "A and/or B," when used in conjunction with an open-ended wording such as "comprising," may, in one embodiment, refer to only A (including elements other than B, as appropriate) ); in another embodiment, it may only refer to B (including elements other than A as appropriate); in another embodiment, it may refer to A and B (including other elements as appropriate); and so on.

As used in this specification and claims, "or" should be understood as having the same meaning as "and/or" defined above. For example, when separating items in a list, "or" or "and/or" should be construed inclusively, that is, including at least one and including more than one of some or a list of elements, and ( As applicable) other items not listed. Only terms indicating the opposite, such as "only one of" or "exactly one of" or "consisting of of)" shall mean including exactly one element of some or a list of elements. In general, as used herein, the term "or" is preceded by an exclusive term (such as "either", "one of", "the only of" or "exactly one of" ”), it should only be construed as indicating an exclusive alternative (that is, “one or the other, but not both”). "Consisting essentially of" when used in the context of a claim shall have its ordinary meaning as it is used in the field of patent law.

As used in this specification and claims, the phrase "at least one" of a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but Each and at least one of each element specifically listed in the list of elements is not necessarily included, and any combination of elements in the list of elements is not necessarily excluded. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, by way of non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B" or equivalently "at least one of A and/or B") In one embodiment, may refer to at least one (optionally including more than one) A without B (and optionally include elements other than B); in another embodiment, refer to at least one (optionally including more than one) a) B in the absence of A (and optionally including elements other than A); in yet another embodiment, at least one (optionally including more than one) A and at least one (optionally including more than one) B (and other elements as appropriate); etc.

It should also be understood that in any method claimed herein that includes more than one step or operation, the order of the steps or operations of the method need not be limited to the order in which the steps or operations of the method are recited, unless indicated to the contrary.

In the scope of the claim and in the above description, all transitional phrases such as "comprises", "comprises", "with", "has", "contains", "relates to", "contains", "by... Consists of" and similar phrases should be understood as open-ended, ie, meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" should be closed or semi-closed transitional phrases respectively, such as United States Patent Office Manual of Patent Examining Procedures (United States Patent Office Manual of Patent Examining Procedures) No. 2111.03 explained in the section.

Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds within the scope of the invention, including cis and trans isomers, R- and S -mirror isomers, diastereomers, (D)-isomers, (L )-isomers, their racemic mixtures and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

"Geometric isomers" means isomers that differ in the orientation of substituent atoms with respect to carbon-carbon double bonds, cycloalkyl rings, or bridged bicyclic ring systems. The atoms (other than H) on each side of the carbon-carbon double bond can be in E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" indicate configuration relative to the core molecule. Certain of the disclosed compounds may exist in or as "metameric" forms. Hysterisomers result from sterically hindered rotation about a single bond, where the steric strain barrier to the rotation is high enough to allow separation of the conformers. Compounds of the present invention may be prepared as individual isomers or resolved from isomeric mixtures by isomer-specific synthesis. Conventional resolution techniques include formation of the free base salts of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), formation of each isomer of the isomeric pair using an optically active amine Salts in the acid form (followed by fractional crystallization and regeneration of the free acid), esters or amides of each of the isomers of the isomeric pair formed using optically pure acids, amines or alcohols (followed by chromatography separation and removal of chiral auxiliaries), or resolution of isomeric mixtures of starting materials or final products using various well-known chromatographic methods.

For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary The group is cleaved to provide the pure desired enantiomer. Alternatively, where the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by a method well known in the art. The diastereomers thus formed are resolved by fractional crystallization or chromatographic means, and the pure enantiomers are subsequently recovered.

The percentage of purity in mole fraction is the number of moles of enantiomer (or diastereomer) relative to the mole of enantiomer (or diastereomer) plus the mole of its optical isomer ratio of numbers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer, on a molar fraction basis, is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90% in molar fractions , about 99%, or about 99.9% pure.

When a disclosed compound is named or depicted by a structure without indication of stereochemistry, and the compound has at least one chiral center, it is understood that the name or structure encompasses enantiomerism of the compound without the corresponding optical isomer A racemic mixture of a compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by a structure without indication of stereochemistry and has two or more chiral centers, it is understood that the name or structure encompasses the diastereomer without the other diastereomer. stereoisomers, multiple diastereomeric isomers without the other diastereomeric pair, mixture of diastereomeric isomers, mixture of diastereomeric pairs, one diastereomeric isomer relative to the other A mixture of enriched diastereomers, or a mixture of diastereomers in which one or more diastereomers are enriched relative to the other diastereomers. The present invention encompasses all such forms.

Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds resulting from the replacement of hydrogen with deuterium or tritium or the replacement of carbon with ¹³ C or ¹⁴ C enriched carbon are within the scope of the invention.

As used herein, the term "prodrug" encompasses a compound that is converted into a therapeutically active agent under physiological conditions. One common method for making prodrugs involves hydrolysis under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a substance such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. A pharmaceutically acceptable material, composition or vehicle that participates in carrying or transporting the chemical substance of the present invention from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially nonpyrogenic. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as Cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol Sugar alcohols, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) ) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) Other non-toxic and compatible substances used in pharmaceutical preparations. In certain embodiments, the pharmaceutical compositions of the invention are non-pyrogenic, that is, do not induce a significant increase in temperature when administered to a patient.

The term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid addition salts of one or more compounds. Such salts can be prepared in situ during the final isolation and purification of the compound or compounds, or by separately reacting one or more of the purified compounds in their free base form with a suitable organic or inorganic acid and isolating The resulting salt was prepared. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalene dicarboxylate, methanesulfonate salt, glucoheptonate, lactobionate and laurylsulfonate and the like. (See, eg, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66:1-19.)

In other cases, compounds useful in the methods of the invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic base addition salts of one or more compounds. Such salts can also be prepared in situ during the final isolation and purification of the compound or compounds, or by separately combining one or more of the purified compounds in their free acid form with, for example, a pharmaceutically acceptable metal cation. It is prepared by reacting a suitable base of hydroxide, carbonate or bicarbonate with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines suitable for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, pyridoxine, and the like (see, eg, Berge et al., supra).

The term "pharmaceutically acceptable co-crystal" refers to a solid co-former that does not form formal ionic interactions with small molecules.

A "therapeutically effective amount" (or "effective amount") of a compound for use in therapy is that amount which, when administered (to a mammal, preferably a human) as part of a desired dosage regimen, is the amount determined for the condition to be treated or A clinically acceptable standard for a condition or cosmetic purpose, such as the amount of a compound in a preparation to relieve symptoms, ameliorate a condition, or slow the onset of a disease condition at a reasonable benefit/risk ratio applicable to any medical treatment.

The term "prophylactic or therapeutic" treatment is art recognized and includes administering to a host one or more of the compositions of interest. Treatment is prophylactic, (i.e., it protects the host from suffering from the undesired condition) if it is administered before the clinical manifestation of the undesired condition (such as disease or other undesired condition in the host animal) ), and if it is administered after the manifestation of an undesired condition, the treatment is therapeutic, (ie, it is intended to reduce, ameliorate or stabilize the existing undesired condition or its side effects).

The term "patient" or "individual" refers to a mammal in need of particular treatment. In certain embodiments, the patient is a primate, dog, cat or horse. In certain embodiments, the patient is human.

Aliphatic chains include the classes of alkyl, alkenyl and alkynyl defined below. Aliphatic straight chains are limited to unbranched carbon chain moieties. As used herein, the term "aliphatic group" refers to a straight chain, branched chain or cycloaliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl.

If not specified, "alkyl" means a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms or up to 30 carbon atoms. By way of example, an alkyl group having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl as well as positional isomers of such moieties those parts of the body. Alkyl groups having 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, Twenty bases, twenty one bases, twenty two bases, twenty three bases and twenty four bases. In certain embodiments, straight or branched chain alkyl groups have 30 or fewer and more preferably 20 or fewer carbon atoms in their backbone (e.g., C ₁ -C 30 for straight chains; C 1 -C ₃₀ for branched chains; The chain is C ₃ -C ₃₀ ). Alkyl groups can be substituted or unsubstituted.

As used herein, the term "heteroalkyl" refers to an alkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms instead of carbon atoms.

As used herein, the term "haloalkyl" refers to an alkyl group as defined above substituted with at least one halogen.

As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above substituted with at least one hydroxy group.

As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, eg, 2 to 12 carbon atoms, which contains two points of attachment on its longest carbon chain to the rest of the compound. Non-limiting examples _of alkylene groups include methylene (-( _CH2 )-), ethylidene ₍ - _{( CH2CH2} )-), n-propylidene (-( _CH2CH2CH2 )-) , isopropylidene (-( _CH2CH ( _CH3 ))-) and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moieties, and are optionally substituted with one or more substituents.

"Cycloalkyl" means a monocyclic or bicyclic or bridged or spiro ring, or polycyclic saturated carbocyclic ring each having 3 to 12 carbon atoms. Preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbon atoms in the ring structure. Cycloalkyl groups can be substituted or unsubstituted.

As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above substituted with at least one halogen.

"Cycloheteroalkyl" means a cycloalkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms in place of a carbon atom. Preferred cycloheteroalkyl groups have 4 to 8 carbon atoms and heteroatoms in their ring structure, and more preferably 4 to 6 carbon atoms and heteroatoms in the ring structure. Cycloheteroalkyl groups can be substituted or unsubstituted.

Unless the carbon number is specified otherwise, as used herein, "lower alkyl" means an alkyl group as defined above but having one to ten carbon atoms, more preferably one to six carbon atoms in its main chain structure, Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and tertiary butyl. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In certain embodiments, substituents designated herein as alkyl are lower alkyl.

"Alkenyl" means any cyclic or acyclic, branched or Unbranched unsaturated carbon chain moiety. The alkenyl group of 6 to 26 carbon atoms consists of hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, Pentadecenyl, Hexadecenyl, Heptadecenyl, Octadecenyl, Nonadecenyl, Eicosenyl, Hexadecenyl, Dococenyl, Tritricenyl and Eicosanyl Tetraenyl is exemplified (in its many isomeric forms) where one or more unsaturated bonds can be located anywhere in the moiety and can have a (Z) or (E) configuration around one or more double bonds.

"Alkynyl" means a hydrocarbyl moiety of the alkenyl category, but having one or more double bonds in the moiety.

As used herein, the term "aryl" includes 3 to 12 membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms thereof is a heteroatom (ie, heteroaryl). Preferably, the aryl group includes 5 to 12 membered rings, more preferably 6 to 10 membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one of the rings is aromatic , for example the other cyclic ring can be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and/or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl includes substituted or unsubstituted aromatic 3 to 12 membered ring structures, more preferably 5 to 12 membered rings, more preferably 5 to 10 membered rings, the ring structures including one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyridine, pyridoxine, and pyrimidine, and the like. Aryl and heteroaryl groups can be monocyclic, bicyclic or polycyclic.

As used herein, the term "halo", "halo" or "halogen" means halogen and includes, for example and without limitation, fluorine, chlorine, bromine, iodine, and the like, in radioactive and non-radioactive forms. In a preferred embodiment, the halo group is selected from the group consisting of fluorine, chlorine and bromine.

、啡㗁噻、吡咯、咪唑、吡唑、異噻唑、異㗁唑、吡啶、吡𠯤、嘧啶、嗒𠯤、吲哚𠯤、異吲哚、吲哚、吲唑、嘌呤、喹𠯤、異喹啉、喹啉、酞𠯤、㖠啶、喹喏啉、喹唑啉、㖕啉、喋啶、咔唑、咔啉、啡啶、吖啶、嘧啶、啡啉、吩𠯤、啡砷𠯤、吩噻𠯤、呋呫、啡㗁𠯤、吡咯啶、氧雜環戊烷、硫雜環戊烷、㗁唑、哌啶、哌𠯤、嗎啉、內酯、內醯胺(諸如氮雜環丁酮及吡咯啶酮)、磺內醯胺、磺內酯及其類似基團。雜環可在一或多個位置處經如上文所述之該等取代基取代，該等取代基例如為鹵素、烷基、芳烷基、烯基、炔基、環烷基、羥基、胺基、硝基、硫氫基、亞胺基、醯胺基、磷酸酯、膦酸酯、亞膦酸酯、羰基、羧基、矽基、胺磺醯基、亞磺醯基、醚、烷硫基、磺醯基、酮、醛、酯、雜環基、芳族或雜芳族部分、-CF ₃、-CN及其類似基團。 The term "heterocyclyl/heterocyclic group" refers to a 3-12-membered ring structure, more preferably a 5-12-membered ring, more preferably a 5-10-membered ring, and the ring structure includes one to four heteroatoms. A heterocycle can be monocyclic, bicyclic, spirocyclic or polycyclic. Heterocyclic groups include, for example, thiophene, thiane, furan, pyran, isobenzofuran, thiophene, thiophene

, phenthiazothia, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrimidine, pyrimidine, indole, isoindole, indole, indazole, purine, quinone, isoquinone phenoline, quinoline, phthaloline, phenanthroline, quinoxaline, quinazoline, phenoline, pteridine, carbazole, carboline, phenanthidine, acridine, pyrimidine, phenanthroline, phenoline, phenanthrene arsenic 𠯤, phen Thiazine, furoxane, phenanthrene, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperidine, morpholine, lactone, lactam (such as azetidinone and pyrrolidone), sulamides, sultones and similar groups. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amine nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphonite, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio group, sulfonyl group, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, _-CF3 , -CN and the like.

The term "substituted" refers to moieties having substituents that replace a hydrogen on one or more carbons of the backbone. It is to be understood that "substituted" or "substituted" includes the implied proviso that such substitutions are consistent with the permissible valences of the substituted atoms and substituents, and that the substitutions result in stable compounds, e.g. row, cyclization, elimination, etc. for transformation. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituent of an organic compound described herein that satisfies the valence of the heteroatom. Substituents may include any of those described herein, for example, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate, or thio Formate), alkoxy, phosphonyl, phosphate, phosphonate, phosphonite, amine, amido, amidino, imino, cyano, nitro, azide sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituent on the substituted alkyl is selected from C _1-6 alkyl, C _3-6 cycloalkyl, halogen, carbonyl, cyano or hydroxyl. In a more preferred embodiment, the substituent on the substituted alkyl group is selected from fluorine, carbonyl, cyano or hydroxyl. Those skilled in the art will appreciate that substituents may themselves be substituted as appropriate. Unless specifically stated as "unsubstituted," references to a chemical moiety herein are to be understood as including substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted and unsubstituted variations.

As used herein, when a definition of each expression such as alkyl, m, n, etc. occurs more than once in any structure, it is intended to be independent of its definition elsewhere in the same structure.

As used herein, "small molecule" refers to a small organic or inorganic molecule having a molecular weight of less than about 3,000 Daltons. Generally, small molecules suitable for use in the present invention have a molecular weight of less than 3,000 Daltons (Da). Small molecules can, for example, be at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da , about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

In some embodiments, "small molecule" refers to an organic, inorganic or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, small molecules are organic compounds with dimensions of about 1 nm. In some embodiments, the small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

An "effective amount" is an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is that amount to achieve the desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount can be administered in one or more administrations, administrations or doses. A therapeutically effective amount of a composition depends on the composition chosen. The compositions can be administered one or more times daily to one or more times per week, including every other day. Those skilled in the art will appreciate that certain factors may affect the dosage and duration necessary to effectively treat a subject, including, but not limited to, the severity of the disease or condition, previous therapy, the general health of the subject and/or the age and presence of other illnesses. Furthermore, treatment of a subject with a therapeutically effective amount of a composition described herein may comprise a single treatment or a series of treatments.

The terms "reduce", "reduce/reduced/reduction", "reduce" and "inhibit" are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for the avoidance of any doubt, the terms "reduce/reduction" or "lower" or "inhibit" generally mean a reduction of at least 10% compared to a reference level, such as a reduction of at least about 20% compared to a reference level, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least About 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the absence of a given entity or parameter at all, or a similar Any reduction between 10-99% compared to the situation without the given treatment.

The term "increased/increase" or "enhancement" or "activation" is generally used herein to mean an increase of a statistically significant amount; for the avoidance of any doubt, the term "increase" or "enhancement" or "activation" means An increase of at least 10% compared to a reference level, such as an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70% compared to a reference level %, or at least about 80%, or at least about 90%, or up to and including a 100% increase or any increase between 10-100%, or at least about 2 times, or at least about 3 times, or at least About 4-fold, or at least about 5-fold, or at least about 10-fold increase, or any increase between 2-fold and 10-fold, or more.

As used herein, the term "modulate" includes both upregulation and downregulation, such as enhancing or inhibiting a response.

As defined herein, a "radiopharmaceutical" refers to a pharmaceutical containing at least one radioactive isotope that emits radiation. Radiopharmaceuticals are routinely used in nuclear medicine for the diagnosis and/or treatment of various diseases. Radiolabeled agents, such as radiolabeled antibodies, contain a radioisotope (RI) that acts as the source of radiation. As considered herein, the term "radioisotope" includes metallic radioisotopes as well as non-metallic radioisotopes. The radioisotope is selected based on the medical application of the radiolabeled agent. When the radioisotope is a metal radioisotope, a chelating agent is typically used to bind the metal radioisotope to the remainder of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is usually attached to the rest of the molecule either directly or via a linking group.

For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 67th Edition, 1986-87, inside cover.

X ₁不存在或選自-O-、-SO ₂-、-C(O)-、-N(X ₂)-及-C(X ₃) ₂-； X ₂係選自-H、烷基及-SO ₂-X ₂''； X ₂''為烷基； 各X ₃獨立地選自-H及烷基； R ₁係選自視情況經取代之胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜環基、芳基及雜芳基；及 R ₂係選自-H、鹵素(例如氯)及烷基； R ₂'係選自烷基、烯基、炔基、環烷基及芳基；及 R ₂''係選自H、烷基及醯基； 其限制條件為當X ₁為-O-或-N(X ₂)-且R ₁為含氮雜環基時，則該-O-或-N(X ₂)-不直接鍵結於該雜環基上之氮； 其限制條件為當X ₁不存在，R ₂為-Cl，R ₂'為-CH ₃且R ₂''為-H時，則R ₁不為

； 或其醫藥學上可接受之鹽。 Compounds of the Invention One aspect of the present invention relates to a compound having the structure of formula (I):

X ₁ does not exist or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -; X ₂ is selected from -H, alkyl And -SO ₂ -X ₂ ''; X ₂ '' is an alkyl group; each X ₃ is independently selected from -H and an alkyl group; R ₁ is selected from optionally substituted aminoalkyl, alkylaminoalkane radical, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R ₂ is selected from -H, halogen (such as chlorine) and alkyl; R ₂ ' is selected from alkyl, Alkenyl, alkynyl, cycloalkyl and aryl; and R ₂ '' is selected from H, alkyl and acyl; the restriction is that when X ₁ is -O- or -N(X ₂ )- and R When ₁ is a nitrogen-containing heterocyclic group, the -O- or -N(X ₂ )- is not directly bonded to the nitrogen of the heterocyclic group; the limitation is that when X ₁ does not exist, R ₂ is -Cl , when R ₂ 'is -CH ₃ and R ₂ '' is -H, then R ₁ is not

; or a pharmaceutically acceptable salt thereof.

X ₁不存在或選自-O-、-SO ₂-、-C(O)-、-N(X ₂)-及-C(X ₃) ₂-； X ₂係選自-H、烷基及-SO ₂-X ₂''； X ₂''為烷基； 各X ₃獨立地選自-H及烷基； R ₁係選自視情況經取代之胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜環基、芳基及雜芳基；及 R ₂係選自-H、鹵素(例如氯)及烷基； R ₂'係選自烷基、烯基、炔基、環烷基及芳基；及 R ₂''係選自H、烷基及醯基； 其限制條件為當X ₁為-O-或-N(X ₂)-且R ₁為含氮雜環基時，則該-O-或-N(X ₂)-不直接鍵結於該雜環基上之氮； 其限制條件為當X ₁不存在，R ₂為-Cl，R ₂'為-CH ₃且R ₂''為-H時，則R ₁不為

； 或其醫藥學上可接受之鹽。 Another aspect of the present invention relates to a compound having the structure of formula (I):

X ₁ does not exist or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -; X ₂ is selected from -H, alkyl And -SO ₂ -X ₂ ''; X ₂ '' is an alkyl group; each X ₃ is independently selected from -H and an alkyl group; R ₁ is selected from optionally substituted aminoalkyl, alkylaminoalkane radical, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R ₂ is selected from -H, halogen (such as chlorine) and alkyl; R ₂ ' is selected from alkyl, Alkenyl, alkynyl, cycloalkyl and aryl; and R ₂ '' is selected from H, alkyl and acyl; the restriction is that when X ₁ is -O- or -N(X ₂ )- and R When ₁ is a nitrogen-containing heterocyclic group, the -O- or -N(X ₂ )- is not directly bonded to the nitrogen of the heterocyclic group; the limitation is that when X ₁ does not exist, R ₂ is -Cl , when R ₂ 'is -CH ₃ and R ₂ '' is -H, then R ₁ is not

; or a pharmaceutically acceptable salt thereof.

In certain embodiments, X ₁ is absent, or selected from -SO ₂ -, -C(O)-, and -C(X ₃ ) ₂ -. In certain embodiments, _Xi is absent.

In certain embodiments, R ₁ is unsubstituted heterocyclyl.

。 In certain embodiments, wherein _R is selected from unsubstituted azetidinyl, unsubstituted pyrrolidinyl, unsubstituted piperoneyl, unsubstituted piperoneyl, unsubstituted Substituted morpholinyl, unsubstituted dioxythiomorpholinyl, unsubstituted tetrahydrofuryl and unsubstituted tetrahydropyranyl, for example _R is selected from

.

In certain embodiments, R ₁ is substituted heterocyclyl.

In certain embodiments, R ₁ is -NR ₃ R ₄ ; and R ₃ and R ₄ combine to form substituted azetidinyl, substituted pyrrolidinyl, substituted piperrolidinyl, substituted piperone, substituted morpholinyl or substituted dioxythiomorpholinyl.

； R _a、R _b、R _i及R _j獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c、R _d、R _e、R _f、R _g及R _h獨立地選自-H、鹵素、-CN、-CF ₃、-OH、-CO ₂H、-NH ₂、烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-OR ₅、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、-SO ₂R ₇、-NHSO ₂R ₇、-SO ₂NR ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇、烷基-SO ₂NR ₅R ₆及-NHC(O)NR ₇，或 R _c與R _d以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基，或 R _e與R _f以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基，或 R _c與R _e以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基，或 R _d與R _f以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基，或 R _c與R _i一起形成亞甲基橋，或 R _d與R _j一起形成亞甲基橋，或 R _c與R _g一起形成亞甲基橋，或 R _d與R _h一起形成亞甲基橋； R ₅及R ₆在每次出現時獨立地選自-H、-CF ₃、烷基、胺基烷基、羥烷基、甲氧基烷基、環烷基、雜烷基、鹵烷基、芳基及雜芳基， 或其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基；其限制條件為R _a、R _b、R _c、R _d、R _e、R _f、R _g、R _h、R _i及R _j中之至少一者不為-H。在某些實施例中，R ₁為

； R _a、R _b、R _i及R _j獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c、R _d、R _e、R _f、R _g及R _h獨立地選自-H、鹵素、-CN、-CF ₃、-OH、-CO ₂H、-NH ₂、烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、-SO ₂R ₇、-SO ₂NR ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇及烷基-SO ₂NR ₅R ₆，或 R _c與R _d以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基，或R _e與R _f以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基； R ₅及R ₆在每次出現時獨立地選自-H、烷基、雜烷基、鹵烷基、芳基及雜芳基，或其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基；其限制條件為R _a、R _b、R _c、R _d、R _e、R _f、R _g、R _h、R _i及R _j中之至少一者不為-H。 In certain embodiments, _R is

; R _{a ,} R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , Re , R _f , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -OR ₅ , -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R ₆ , -SO ₂ R ₇ , -NHSO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C (O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ , Alkyl-SO ₂ NR ₅ R ₆ and -NHC (O)NR ₇ , or R _c and R _d and the carbon atom to which it is bonded together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl, or R _e Form unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl together with R _f and the carbon atom to which it is bonded, or R _c and R _e and the bonded carbon atom The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl group, or R _d and R _f together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkane group, or R _c and R _i together form a methylene bridge, or R _d and R _j together form a methylene bridge, or R _c and R _g together form a methylene bridge, or R _d and _Rh together form a methylene bridge Methyl bridge; _R5 and _R6 are independently selected from each occurrence of -H, _-CF3 , alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl , haloalkyl, aryl, and heteroaryl, or with the restriction that -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R In the case of ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ and the nitrogen atom to which it is bonded together can form an unsubstituted or substituted C ₄ -C ₆ heterocyclic ring and R ₇ at each occurrence is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that R _a , R _b , R _c , R _d , R _e , R At least one of _f , R _g , _Rh , R _i and R _j is not -H. In certain embodiments, _R is

; R _{a ,} R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , Re , R _f , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C (O)NR ₅ R ₆ , -SO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C (O)R ₇ , alkyl-NR ₅ C(O)NR ₅ R ₆ , alkyl-SO ₂ R ₇ and alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d and their bonded The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl, or R _e and R _f together with the carbon atom to which they are bonded form an unsubstituted or substituted Substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl, aryl And heteroaryl, or its restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ In the case of C(O)NR ₅ R ₆ , the R ₅ and R ₆ and the nitrogen atom to which they are bonded together can form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ in each The second occurrence is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; with the proviso that R _a , R _{b ,} R _c , R _d , Re , R _f , R _g , _Rh , at least one of R _i and R _j is not -H.

In certain embodiments, R _a , R _b , R _i , and R _j are independently selected from -H, halogen, -CN, -CF _{3 ,} and alkyl; and R _c , R _d , Re , R _{f ,} R _g and R _h are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkane Aminoalkyl, Alkoxyalkyl, Cycloalkyl, Heteroalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , Alkyl-C (O)NR ₅ R ₆ , alkyl-NR ₅ C(O)R ₆ and alkyl-C(O)R ₇ .

In certain embodiments _, each of Ra, _{Rb ,} Ri, and _Rj is -H; and _Rc , _Rd , _Re , _Rf , _Rg , and _Rh are independently selected from -H, halogen, -OH, -CO ₂ H, -alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)R ₆ .

。 In certain embodiments _, each of Ra, _Rb , _Ri , and _Rj is -H; and _Rc , _Rd , _Re , _Rf , _Rg , and _Rh are independently selected from -H, -F , -OH, -CH ₂ OH, CH ₂ OCH ₃ , -CH ₂ NH ₂ , -CO ₂ H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C( O)NH ₂ , -C(O)N(H)(CH ₃ ), -C(O)N(CH ₃ ) ₂ , alkyl-C(O)N(H)(CH ₃ ), -CH ₂ -C(O)N(CH ₃ ) ₂ , -N(H)C(O)CH ₃ , -N(CH ₃ )C(O)CH ₃ , -CH ₂ -N(H)C(O)CH _3. -CH ₂ -N(CH ₃ )C(O)CH ₃ , -CH(CH ₂ ) ₂ and

.

In certain embodiments _, each of Ra, _Rb , _Ri , and _Rj is -H; and _Rc , _Rd , _Re , _Rf , _Rg , and _Rh are independently selected from -H, -F , -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ CH _3. -CH ₂ F, -NHSO ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -NHC(O)NHCH ₃ , -NHC(O)CH ₃ , -C(O)NH ₂ , -C(O) NHCH ₃ , -C(O)NHCH ₂ CH ₃ , -C(O)NHCH(CH ₃ ) ₂ , -C(O)NHCH ₂ CH ₂ OCH ₃ , -CH ₂ NHC(O)CH ₃ , -CH ₂ NHC(O)CH ₂ CH ₃ , -CH ₂ NHC(O)CH ₂ NH ₂ , -CH ₂ NHC(O)C(CH ₃ ) ₂ CH ₃ , -CH ₂ NHC(O)C(CH ₃ ) ₂ NH ₂ , -CH ₂ NHC(O)C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ NHC(O)C(CH ₃ ) ₂ CH ₂ OCH ₃ , -CH ₂ NHC(O)C(CH ₃ ) ₂ OCH ₃ , —CH ₂ C(O)NH ₂ , —CH ₂ C(O)NHCH ₃ , and —CH ₂ C(O)N(CH ₃ ) ₂ .

。在某些實施例中，R ₁係選自：

。在某些實施例中，R ₁係選自：

。在其他實施例中，R ₁係選自：

。 In certain embodiments _, each of Ra, _Rb , _Ri , and _Rj is -H; and _Rc , _Rd , _Re , _Rf , _Rg , and _Rh are independently selected from -H, -F , -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ CH _3. -CH ₂ F, -O-cyclopropyl, -C(O)NH-cyclopropyl, -C(O)NH-oxetanyl, -C(O)NH-tetrahydrofuryl, - C(O)NH-tetrahydropyranyl, -CH ₂ NHC(O)-cyclopropyl,

. In certain embodiments, _R is selected from:

. In certain embodiments, _R is selected from:

. In other embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

.

。 In certain embodiments, _R is

.

.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

In certain embodiments _, R _a , R _b , Re , R _f , R _g , _Rh , R _{i ,} and R _j are independently selected from -H, halogen, -CN, -CF _{3 ,} and alkyl; and R _c and R _d together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl.

In certain embodiments, _Rc and _Rd together with the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperolyl, oxetanyl , tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, _-CF3 , alkyl, and acetyl.

In certain embodiments, R _a , R _b , R _c , R _d , R _g , _Rh , R _i , and R _j are independently selected from -H, halogen, -CN, -CF _{3 ,} and alkyl; and R _e and R _f together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl.

In certain embodiments, Re _and R _f together with the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperhydrinyl, oxetanyl , tetrahydrofuranyl, tetrahydropyranyl and cyclobutanyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, _-CF3 , alkyl, and acetyl.

。 In certain embodiments, _R is selected from:

.

In certain embodiments, each of Ra, _Rb , _Rg , Rh, _Ri , _{and Rj} is _-H ; one of Re _{and Rf} is -H and the other of Re _{and Rf} One is -OH; and R _c and R _d together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclic group.

In certain embodiments, each of Ra, _Rb , _Rd , _Rg , _{Rh , Ri ,} and _Rj is -H; _Rf is _-OH ; The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl group.

In certain embodiments, each of R _a , R _b , R _c , R _g , Rh , R _{i ,} and R _j is -H; _{R e} is _-OH ; The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl group.

In certain embodiments, each of Ra, _Rb , _Rd , _Rg , _Rh , and _{Rj is} -H; one of Re _{and Rf} is -H and the other of Re _{and Rf} One is -OH; and R _c and R _i together form a methylene bridge.

In certain embodiments, each of R _a , R _b , R _c , R _g , _Rh and R _i is -H; one of R _e and R _f is -H and the other of R _e and R _f One is -OH; and R _d and R _j together form a methylene bridge.

In certain embodiments, each of R _a , R _b , R _c , R _g , _Rh and R _i is -H; one of R _e and R _f is -H and the other of R _e and R _f One is -OH; and _Rj and _Rd together form a methylene bridge.

In certain embodiments, each of Ra, _Rb , _Rd , _Rf , _{Rh ,} and _Ri is -H; one of Re _{and Rf} is -H and the other of Re _{and Rf} One is -OH; and _Rc and _Rg together form a methylene bridge.

In certain embodiments, each of R _a , R _b , R _c , R _g , _Rh and R _i is -H; one of R _e and R _f is -H and the other of R _e and R _f One is -OH; and R _d and _Rh together form a methylene bridge.

。 In certain embodiments, _R is selected from

.

； R _a、R _b、R _i及R _j獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c、R _d、R _g及R _h獨立地選自-H、鹵素、-CN、-CF ₃、-CO ₂H、-烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、 _-SO ₂R ₇、-SO ₂N R ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇及烷基-SO ₂NR ₅R ₆，或 R _c與R _d以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基； R ₅及R ₆在每次出現時獨立地選自-H、烷基、雜烷基、鹵烷基、芳基及雜芳基，或其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基； 其限制條件為R _a、R _b、R _c、R _d、R _g、R _h、R _i及R _j中之至少一者不為-H。 In certain embodiments, _R is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -CO ₂ H, -alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, Aryl, Heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R _{6 ,} -SO ₂ R _7. -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl- _{NR 5} C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C (O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ and Alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d together with the carbon atom to which it is bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl group, or its restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O ) In the case of NR ₅ R ₆ , said R ₅ and R ₆ together with the nitrogen atom to which it is bonded may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ at each occurrence selected from alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl; the limitation is that at least one of R _a , R _b , R _c , R _d , R _g , _Rh , R _i and R _j One is not -H.

In certain embodiments, R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -CO ₂ H, -alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkane radical, heteroalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , alkyl-C(O)NR ₅ R ₆ , alkyl-NR ₅ C(O)R ₆ and alkyl-C(O)R ₇ .

In certain embodiments, each of R _a , R _b , R _i and R _j is -H; and R _c , R _d , R _g and _Rh are independently selected from -H, halogen, -CO ₂ H, - Alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , alkane Group-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)R ₆ .

。 In certain embodiments, each of R _a , R _b , R _i and R _j is -H; and R _c , R _d , R _g and _Rh are independently selected from -H, -F, -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ NH ₂ , -CO ₂ H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(O)NH ₂ , -C( O)N(H)(CH ₃ ), -C(O)N(CH ₃ ) ₂ , Alkyl-C(O)N(H)(CH ₃ ), -CH ₂ -C(O)N(CH ₃ ) ₂ , -N(H)C(O)CH ₃ , -N(CH ₃ )C(O)CH ₃ , -CH ₂ -N(H)C(O)CH ₃ , -CH ₂ -N( CH ₃ )C(O)CH ₃ , -CH(CH ₂ ) ₂ and

.

。在其他實施例中，R ₁係選自：

。 In certain embodiments, _R is selected from:

. In other embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

In certain embodiments, R _a , R _b , R _g , _Rh , R _i , and R _j are independently selected from —H, halogen, —CN, —CF _{3 ,} and alkyl; and R _c and R _d and The carbon atoms to which they are bonded together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl.

In certain embodiments, _Rc and _Rd together with the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperolyl, oxetanyl , tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, _-CF3 , alkyl, and acetyl.

。 In certain embodiments, _R is selected from:

.

； R _a、R _b、R _i及R _j獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c、R _d、R _g及R _h獨立地選自-H、鹵素、-CN、-CF ₃、-CO ₂H、-烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、-SO ₂R ₇、-SO ₂NR ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇及烷基-SO ₂NR ₅R ₆； R _k係選自-H、烷基及環烷基； R ₅及R ₆在每次出現時獨立地選自-H、烷基、雜烷基、鹵烷基、芳基及雜芳基，或其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基； 其限制條件為R _a、R _b、R _c、R _d、R _g、R _h、R _i、R _j及R _k中之至少一者不為-H。 In certain embodiments, _R is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -CO ₂ H, -alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, Aryl, Heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R ₆ , -SO ₂ R _7. -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C (O)NR ₅ R ₆ , alkyl-SO ₂ R ₇ and alkyl-SO ₂ NR ₅ R ₆ ; R _k is selected from -H, alkyl and cycloalkyl; R ₅ and R ₆ appear in each are independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl, or are limited to -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR In the case of ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ together with the nitrogen atom to which they are bonded may form Unsubstituted or substituted C ₄ -C ₆ heterocyclyl; and R ₇ at each occurrence is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl; provided that R _a , R _b , R _c , R _d , R _g , Rh _h , R _i , R _j and R _k are not -H.

In certain embodiments, each of Ra, _Rb , _Rc , _Rd , _Rg , _Rh , _Ri , and _Rj is -H _; and _Rk is selected from alkyl and cycloalkyl.

。 In certain embodiments, _R is selected from:

.

；且R _k係選自烷基及環烷基，例如R ₁為：

。 In certain embodiments, _R is

and _R is selected from alkyl and cycloalkyl, for example R _is :

.

； R _a、R _b、R _i及R _j獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c、R _d、R _g及R _h獨立地選自-H、鹵素、-CN、-CF ₃、-OH、-CO ₂H、-NH ₂、烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-OR ₅、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、-SO ₂R ₇、-NHSO ₂R ₇、-SO ₂NR ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇、烷基-SO ₂NR ₅R ₆及-NHC(O)NR ₇，或 R _c與R _d以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基，或 R _c與R _g或R _d與R _h以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基； R ₅及R ₆在每次出現時獨立地選自-H、-CF ₃、烷基、胺基烷基、羥烷基、甲氧基烷基、環烷基、雜烷基、鹵烷基、芳基及雜芳基，或 其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基； 其限制條件為R _a、R _b、R _c、R _d、R _g、R _h、R _i及R _j中之至少一者不為-H。 In certain embodiments, _R is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkane radical, heteroalkyl, aryl, heteroaryl, -OR ₅ , -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O )NR ₅ R ₆ , -SO ₂ R ₇ , -NHSO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ , Alkyl-SO ₂ NR ₅ R ₆ and -NHC(O)NR ₇ , Or R _c and R _d and the carbon atom to which they are bonded together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl, or R _c and R _g or R _d Together with _Rh and the carbon atom to which it is bonded, an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl is formed; R ₅ and R ₆ are independently at each occurrence selected from -H, -CF ₃ , alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or restrictions thereof Between -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ In some cases, the R ₅ and R ₆ and the nitrogen atom to which they are bonded together may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ is selected from the group consisting of alkyl, hetero Alkyl, haloalkyl, aryl and heteroaryl; provided that at least one of R _a , R _b , R _c , R _d , R _g , _Rh , R _i and R _j is not -H .

； R _a、R _b、R _i及R _j獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c、R _d、R _g及R _h獨立地選自-H、鹵素、-CN、-CF ₃、-OH、-CO ₂H、-NH ₂、烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、-SO ₂R ₇、-SO ₂NR ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇及烷基-SO ₂NR ₅R ₆，或 R _c與R _d以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基； R ₅及R ₆在每次出現時獨立地選自-H、烷基、雜烷基、鹵烷基、芳基及雜芳基，或其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基； 其限制條件為R _a、R _b、R _c、R _d、R _g、R _h、R _i及R _j中之至少一者不為-H。 In certain embodiments, _R is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkane radical, heteroalkyl, aryl, heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R _6. -SO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl- _{NR 5} C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ and Alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d together with the carbon atom to which they are bonded form a Substituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl , aryl and heteroaryl, or the restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl In the case of -NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ together with the nitrogen atom to which it is bonded may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ is selected at each occurrence from alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl; with the proviso that R _a , R _b , R _c , R _d , R _g , _Rh , R _i and at least one of R _j is not -H.

In certain embodiments, R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; and R _c , R _d , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkane Oxyalkyl, Cycloalkyl, Heteroalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , Alkyl-C(O)NR ₅ R _6. Alkyl-NR ₅ C(O)R ₆ and Alkyl-C(O)R ₇ .

In certain embodiments, _Rc , _Rd , _Rg , and _Rh are independently selected from -H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl. In certain embodiments _, each of Ra, _Rb , _Ri , and _Rj is -H; and _Rc , _Rd , _Rg , and _Rh are independently selected from -H, alkyl, hydroxyalkyl, amine Alkyl and alkoxyalkyl.

。 In certain embodiments, _R has the structure:

.

。在某些實施例中，R ₁係選自：

。 In certain embodiments, _R is selected from:

. In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

In certain embodiments, each of R _a , R _b , R _g , Rh , _{R i and} R _j is -H; and R _c and R _d together with the carbon atom to which they are bonded form an unsubstituted or substituted Substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl.

In certain embodiments, _Rc and _Rd together with the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperolyl, oxetanyl , tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, _-CF3 , alkyl, and acetyl.

。 In certain embodiments, _R is selected from:

.

In certain embodiments, R _d and _Rh are each -H; and R _c and R _g together with the carbon atom to which they are bonded form a substituted C ₃ -C ₆ cycloalkyl.

In certain embodiments, R _c and R _g are each -H; and R _d and _Rh and the carbon atom to which they are bonded together form a substituted C ₃ -C ₆ cycloalkyl.

In certain embodiments, the substituted C ₃ -C ₆ cycloalkyl is substituted with halo (eg, fluorine) or hydroxy.

。 In certain embodiments, _R is selected from:

.

； R _a、R _b、R _e及R _f獨立地選自-H、鹵素、-CN、-CF ₃及烷基； R _c及R _d獨立地選自-H、鹵素、-CN、-CF ₃、-OH、-CO ₂H、-NH ₂、烷基、鹵烷基、羥烷基、胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜烷基、芳基、雜芳基、-C(O)NR ₅R ₆、-NR ₅C(O)R ₆、C(O)R ₇、-NR ₅C(O)NR ₅R ₆、-SO ₂R ₇、-SO ₂NR ₅R ₆、烷基-C(O)NR ₅R ₆、烷基-NR ₅C(O)R ₆、烷基-C(O)R ₇、烷基-NR ₅C(O)NR ₅R ₆、烷基-SO ₂R ₇及烷基-SO ₂NR ₅R ₆，或 R _c與R _d以及其所鍵結之碳原子一起形成未經取代或經取代之C ₃-C ₆環烷基或C ₄-C ₆雜環基； R ₅及R ₆在每次出現時獨立地選自-H、烷基、雜烷基、鹵烷基、芳基及雜芳基，或其限制條件為在-C(O)NR ₅R ₆、-NR ₅C(O)NR ₅R ₆、烷基-C(O)NR ₅R ₆及烷基-NR ₅C(O)NR ₅R ₆之情況下，該R ₅與R ₆以及其所鍵結之氮原子一起可形成未經取代或經取代之C ₄-C ₆雜環基；及 R ₇在每次出現時選自烷基、雜烷基、鹵烷基、芳基及雜芳基， 其限制條件為R _a、R _b、R _c、R _d、R _e及R _f中之一者不為-H。 In certain embodiments, wherein R ₁ is

; R _a , R _b , _Re and R _f are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c and R _d are independently selected from -H, halogen, -CN, -CF _3. -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, Aryl, Heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R ₆ , -SO ₂ R _7. -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C (O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ and Alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d together with the carbon atom to which it is bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl group, or its restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O ) In the case of NR ₅ R ₆ , said R ₅ and R ₆ together with the nitrogen atom to which it is bonded may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ at each occurrence selected from alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl, with the limitation that one of R _a , R _b , R _c , R _d , _Re and R _f is not -H.

In certain embodiments, each of Ra, _Rb , _Re , _{and Rf} is -H; and _Rc and _Rd are independently selected from -H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxy base alkyl.

In certain embodiments, R _a , R _b , Re and R _f are each -H; and R _c and _{R d together} with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl.

In certain embodiments, _Rc and _Rd together with the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperolyl, oxetanyl , tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, _-CF3 , alkyl, and acetyl.

。 In certain embodiments, _R is selected from:

.

。 In certain embodiments, _R is selected from:

.

In certain embodiments, R ₁ is unsubstituted heteroaryl.

In certain embodiments, _R is selected from unsubstituted oxazolyl, unsubstituted pyrazolyl, and unsubstituted triazolyl.

。在某些實施例中，其中X ₁不存在，或選自-O-、-SO ₂-、-C(O)-、-N(X ₂)-及-C(X ₃) ₂-。 In certain embodiments, _R is selected from

. In some embodiments, wherein X ₁ is absent, or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -.

In certain embodiments, wherein _X is absent.

。 In certain embodiments, R ₁ is unsubstituted cycloalkyl, for example R ₁ is

.

In certain embodiments, R ₁ is substituted cycloalkyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, -CF _{3 ,} and alkyl.

。 In certain embodiments, _R is

.

。 In certain embodiments, _R is selected from

.

In certain embodiments, X ₁ is -N(X ₂ )-, wherein X ₂ is -H or -CH ₃ .

In certain embodiments, _R is selected from optionally substituted alkylaminoalkyl, alkoxyalkyl, and cycloalkyl.

In certain embodiments, each substituent is independently selected from halogen, -OH, -CN, -CF _{3 ,} and alkyl.

In certain embodiments, R ₁ is -NH-(alkyl)-N(CH ₃ ) ₂ , -N(CH ₃ )-(alkyl)-N(CH ₃ ) ₂ , -NH-(alkyl )-OCH ₃ and N(CH ₃ )-(alkyl)-OCH ₃ .

。 In certain embodiments, _R is

.

In certain embodiments, R ₂ is halogen or alkyl, eg, R ₂ is -CH ₃ , -Cl or -F.

In certain embodiments, _R is selected from -Br and -CN.

In certain embodiments, R ₂ is -Cl. In other embodiments, _R2 is -Br. In other embodiments, _R2 is -F.

In other embodiments, _R2 is _-CH3 .

In other embodiments, R ₂ is -CN.

In certain embodiments, R ₂ ' is alkyl, for example R ₂ ' is -CH ₃ .

In certain embodiments, R ₂ ' is hydroxyalkyl, eg, R ₂ ' is -CH ₂ -OH.

In certain embodiments, _R2 '' is -H.

In some embodiments, R ₂ ″ is alkyl, for example, R ₂ ″ is —CH ₃ .

In some embodiments, R ₂ ″ is an acyl group, for example, R ₂ ″ is -C(O)CH ₃ .

In certain embodiments, R ₂ ″ is —H, —CH ₃ , or —C(O)CH ₃ .

。 In certain embodiments, the compound has Formula (Ia):

.

。 In certain embodiments, the compound has Formula (Ib):

.

。 In certain embodiments, the compound has Formula (Ic):

.

。 In certain embodiments, the compound has the formula (Id):

.

。 In certain embodiments, the compound has Formula (Ie):

.

In certain embodiments, the compound is selected from Table 1 below: Table 1

In certain embodiments, compounds are selected from Table 1A disclosed herein. In certain embodiments, compounds are selected from Table 2 disclosed herein. In some embodiments, the compounds are metaisomers. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds resulting from the replacement of hydrogen with deuterium or tritium or the replacement of carbon with ¹³ C or ¹⁴ C enriched carbon are within the scope of the invention. Such compounds are suitable as, for example, analytical tools, probes in biological assays or therapeutic agents according to the invention. For example, in the case of the variable R ¹ , (C ₁ -C ₄ )alkyl or -O-(C ₁ -C ₄ )alkyl may be suitably deuterated (eg, -CD ₃ , -OCD ₃ ) .

Any of the compounds of the invention may also be radiolabeled to prepare a radiopharmaceutical.

Methods of Treatment One aspect of the present invention provides compounds, compositions and methods useful for inhibiting the function of SLC34A1 in mammals.

Another aspect of the invention provides compounds, compositions and methods useful for treating or preventing diseases or conditions associated with elevated phosphate levels in a subject in need thereof, comprising administering to the subject an effective amount of formula (I ) compounds.

Another aspect of the present invention provides compounds, compositions and methods suitable for treating or preventing diseases or conditions associated with elevated levels of FGF-23 in an individual in need thereof, comprising administering to the individual an effective amount of the formula ( I) Compounds.

Another aspect of the present invention relates to a method of treating or preventing chronic kidney disease (CKD), the method comprising administering to an individual an effective amount of a compound of formula (I).

In certain embodiments, the chronic kidney disease is selected from the group consisting of Alport syndrome, C3-glomerulopathy, tubulointerstitial nephritis, diabetic nephropathy, idiopathic nephrosclerosis, hemolytic uremic syndrome, focal segmental glomerulosclerosis, ApoL1 nephropathy, hypertensive nephrosclerosis, IgA nephropathy, membranous nephropathy, and acute phosphate nephropathy.

Another aspect of the present invention relates to a method of treating or preventing medial calcification, the method comprising administering to an individual an effective amount of a compound of formula (I).

Another aspect of the present invention relates to a method of treating or preventing vascular calcification, the method comprising administering to an individual an effective amount of a compound of formula (I).

In certain embodiments, medial calcification or vascular calcification is associated with chronic kidney disease in an individual. In other embodiments, medial calcification or vascular calcification is associated with heart disease in the individual.

In certain embodiments, medial calcification or vascular calcification is associated with chronic kidney disease. In other embodiments, medial calcification or vascular calcification is associated with: Moenckeberg's medial sclerosis, atherosclerosis, intimal calcification, postmenopausal osteoporosis, type II diabetes, aging, Hypophosphaturia, hyperparathyroidism, vitamin D disorders, vitamin K deficiency, Kawasaki disease, arterial calcification due to CD73 deficiency (ACDC), generalized arterial calcification of infancy (GACI), idiopathic Basal ganglia calcification (IBGC), pseudoxanthoma elasticum (PXE), morbus fahr ferrocalcinosis, Singleton-Merten syndrome, P-thalassemia, Calcium hypersensitivity, heterotopic ossification, preterm placental calcification, uterine calcification, calcified uterine fibroids, idiopathic basal ganglia calcification (FIBGC), Fareck's ferrocalcification, idiopathic basal ganglia calcification, primary Arterial valve calcification, brain calcification, tumor calcification, or tumor lysis syndrome.

Another aspect of the invention relates to a method of treating or preventing acromegaly, rhabdomyolysis, hemolysis, hyperphosphatemia, familial hyperphosphatemia, hypoparathyroidism, pseudoparathyroidism Hypoenergy, secondary hyperparathyroidism, osteodystrophy, CKD-mineral and bone disorders, diabetic ketoacidosis, metabolic acidosis, respiratory acidosis, fulminant hepatitis, hepatic osteodystrophy, fever , malignant fever, sarcoid disease, arterial hypertension, peripheral arterial disease, rheumatoid arthritis, calcium phosphate mediated inflammatory disease, alveolar microlithiasis, or heart disease, the method comprising administering to a subject an effective amount of Compounds of formula (I).

In certain embodiments, the hyperphosphatemia or familial hyperphosphatemia is associated with a GALNT3 , CaSR , Klotho , or FGF23 mutation.

In certain embodiments, the heart disease is associated with chronic kidney disease. In other embodiments, heart disease is associated with elevated levels of FGF-23 in the individual. In other embodiments, the heart disease is heart failure with a normal ejection fraction. In other embodiments, the heart disease is CKD-related cardiac hypertrophy, CKD-related renal dystrophy, congestive heart failure, left ventricular hypertrophy, or atrial fibrillation.

Another aspect of the invention relates to a method of treating or preventing elevated magnesium deficiency in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I).

Another aspect of the present invention relates to a method of treating or preventing elevated plasma FGF-23 levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I).

Another aspect of the present invention relates to a method of treating or preventing a disease or condition associated with elevated FGF-23 levels, the method comprising administering an effective amount of a compound of formula (I) to an individual in need thereof.

In certain embodiments, the disease or condition associated with elevated FGF-23 levels is heart disease.

X ₁不存在或選自-O-、-SO ₂-、-C(O)-、-N(X ₂)-及-C(X ₃) ₂-； X ₂係選自-H、烷基及-SO ₂-X ₂''； X ₂''為烷基； 各X ₃獨立地選自-H及烷基； R ₁係選自視情況經取代之胺基烷基、烷胺基烷基、烷氧基烷基、環烷基、雜環基、芳基及雜芳基；及 R ₂係選自-H、鹵素(例如氯)及烷基； R ₂'係選自烷基、烯基、炔基、環烷基及芳基；及 R ₂''係選自H、烷基及醯基； 其限制條件為當X ₁為-O-或-N(X ₂)-且R ₁為含氮雜環基時，則該-O-或-N(X ₂)-不直接鍵結於該雜環基上之氮； 或其醫藥學上可接受之鹽。 In some embodiments of any of the disclosed methods, the compound of formula (I) is defined as:

X ₁ does not exist or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -; X ₂ is selected from -H, alkyl And -SO ₂ -X ₂ ''; X ₂ '' is an alkyl group; each X ₃ is independently selected from -H and an alkyl group; R ₁ is selected from optionally substituted aminoalkyl, alkylaminoalkane radical, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R ₂ is selected from -H, halogen (such as chlorine) and alkyl; R ₂ ' is selected from alkyl, Alkenyl, alkynyl, cycloalkyl and aryl; and R ₂ '' is selected from H, alkyl and acyl; the restriction is that when X ₁ is -O- or -N(X ₂ )- and R When ₁ is a nitrogen-containing heterocyclic group, the -O- or -N(X ₂ )- is not directly bonded to the nitrogen of the heterocyclic group; or a pharmaceutically acceptable salt thereof.

。 In some embodiments of any of the disclosed methods, the compound is represented by Formula (I), as defined immediately above, with the proviso that when X ₁ is absent, R ₂ is —Cl, R ₂ ′ is -CH ₃ and R ₂ '' is -H, then R ₁ is not

.

Pharmaceutical Compositions, Routes of Administration, and Administration In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, pharmaceutical compositions comprise various compounds of the invention and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one other pharmaceutically active agent in addition to the compounds of the present invention. The at least one other pharmaceutically active agent may be an agent useful in the treatment of ischemia-reperfusion injury.

The pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and optionally one or more other pharmaceutically active agents.

As noted above, an "effective amount" refers to any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, by selecting among various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side effects, and mode of administration, it is possible to formulate compounds that do not cause substantial adverse effects. Effective prophylactic or therapeutic treatment regimens that are as toxic as desired and yet effective in treating a particular individual. The effective amount for any particular application may vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art can determine empirically, without undue experimentation, the effective amount of a particular compound of the invention and/or other therapeutic agent. The maximum dose that can be used is the highest safe dose based on certain medical judgments. Multiple daily doses may be considered to achieve adequate systemic levels of the compound. Appropriate systemic levels can be determined by, for example, measuring peak or sustained plasma levels of the drug in the patient. The terms "dose" and "dosage" are used interchangeably herein.

In certain embodiments, intravenous administration of the compound may generally be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of the compound may generally be in the range of 0.1 mg/kg/day to 2 mg/kg/day. In one embodiment, intravenous administration of the compound may generally be in the range of 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of the compound may generally be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of the compound may generally be from 1 mg/kg/day to 10 mg/kg/day.

Generally, the daily oral dosage of the compound will be from about 0.01 mg/kg to 1000 mg/kg per day for human subjects. Oral dosages in the range of 0.5 to 50 mg/kg administered one or more times daily are expected to produce therapeutic results. Depending on the mode of administration, dosage may be adjusted appropriately to achieve the desired level of drug (local or systemic). For example, it is expected that intravenous administration will be at doses that are an order of magnitude lower than daily doses by several orders of magnitude. Where the response in an individual is insufficient at such doses, even higher doses (or effectively higher doses utilizing a different more local route of delivery) may be employed as patient tolerance permits. Multiple daily doses are considered to achieve adequate systemic levels of the compound.

For any compound described herein, the therapeutically effective amount can be determined initially from animal models. A therapeutically effective dose can also be determined from human data on compounds that have been tested in humans and on compounds known to exhibit similar pharmacological activity, such as other related active agents. Parenteral administration may require higher doses. The dose administered can be adjusted based on the relative bioavailability and potency of the compound being administered. Adjustment of dosage for maximum efficacy based on the methods described above and others well known in the art is well within the ability of an ordinarily skilled artisan.

The formulations of the present invention can be administered in the form of pharmaceutically acceptable solutions, which can routinely contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants and, optionally, other therapeutic ingredients.

For use in therapy, an effective amount of a compound may be administered to a subject by any mode of delivery of the compound to the desired surface. Administration of pharmaceutical compositions can be accomplished by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (eg, into a tumor or abscess), mucosal (eg, topical administration to the eye) , inhalation and topical.

For intravenous and other parenteral routes of administration, the compounds of the invention can be formulated as lyophilized preparations; lyophilized preparations of the active compound as liposomal dosing or encapsulates; lipoplexes in aqueous suspensions; or salt complexes . Lyophilized formulations are typically reconstituted in a suitable aqueous solution, such as sterile water or saline, shortly before administration.

For oral administration, the compounds can be formulated readily by combining one or more active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained in the form of a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if necessary, to obtain dragees or dragee cores. Suitable excipients are especially fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl Cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). If desired, a disintegrant such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added. Optionally, oral formulations can also be formulated in saline or buffers such as EDTA to neutralize internal acid conditions or can be administered without any carrier.

Oral dosage forms of one or more of the above components are also specifically contemplated. The component(s) may be chemically modified to render the oral delivery of the derivative effective. In general, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, wherein the moiety permits (a) inhibition of acid hydrolysis; and (b) absorption in the bloodstream from the stomach or intestine. There is also a need to increase the overall stability of one or more components and increase circulation time in vivo. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", Enzymes as Drugs, eds. Hocenberg and Roberts, Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185- 9 (1982). Other polymers that may be used are poly-1,3-dioxolane and poly-1,3,6-trioxocane. For pharmaceutical use, polyethylene glycol moieties are suitable, as indicated above.

For components (or derivatives), the site of release may be the stomach, the small intestine (duodenum, jejunum or ileum) or the large intestine. Those skilled in the art have available formulations that will not dissolve in the stomach but will release the substance in the duodenum or elsewhere in the intestinal tract. Preferably, the release will avoid the deleterious effects of the gastric environment by protecting the compound (or derivative) of the invention or by releasing the biologically active substance outside the gastric environment, such as in the intestinal tract.

To ensure complete gastroresistance, a coating impermeable to at least pH 5.0 is essential. Examples of more common inert ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate Phthalate (PVAP), Eudragit L30D, Aquateric, Cellulose Acetate Phthalate (CAP), Eudragit L, Eudragit S, and Shellac. Such coatings may be applied in the form of mixed films.

Coatings or mixtures of coatings can also be used on lozenges, which are not intended for gastric protection. This may include sugar coatings or coatings to make the tablet easier to swallow. Capsules can consist of a hard shell, such as gelatin, for delivery of dry therapeutic agent (eg, powder); for liquid forms, a soft gelatin shell can be used. The shell material of cachets may be thick starch or other edible paper. For pills, lozenges, molded lozenges or tablet grinds, wet massing techniques may be used.

The therapeutic agent can be included in the formulation as finely multiparticulate particles or pellets having a particle size of about 1 mm. The formulation of the material for capsule administration may also be presented as a powder, lightly compressed plug or even as a lozenge. Therapeutic agents can be prepared by compression.

Both coloring and flavoring agents may be included. For example, compounds (or derivatives) of the invention may be formulated (such as by encapsulation by liposomes or microspheres) and then further contained in edible products (such as refrigerated beverages containing coloring and flavoring agents).

Inert substances can be used to dilute or increase the volume of the therapeutic agent. Such diluents may include carbohydrates, especially mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose, modified dextran and starch. Certain inorganic salts can also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

Disintegrants can be included in the process of formulating therapeutic agents into solid dosage forms. Substances useful as disintegrants include, but are not limited to, starch, including the commercial starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, natural sponge, and bentonite can be used. Another form of disintegrant is an insoluble cation exchange resin. Powdered jellies can be used as disintegrants and binders, and these can include powdered jellies such as agar-agar, gala gum, or tragacanth. Alginic acid and its sodium salt are also suitable as disintegrants.

Binders may be used to hold the therapeutic agents together to form hard tablets and include substances derived from natural products such as acacia, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Both polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can be used in alcoholic solutions to granulate the therapeutic agent.

Anti-friction agents can be included in the formulation of therapeutic agents to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic agent and the mold wall, and such lubricants may include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid Paraffin, vegetable oils and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and 6000 may also be used.

Glidants can be added that can improve the flow characteristics of the drug during dispensing and aid rearrangement during compression. Glidants may include starch, talc, fumed silica, and hydrated aluminosilicates.

To aid dissolution of the therapeutic agent in an aqueous environment, surfactants may be added as wetting agents. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may be used and may include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, macrogol 40 stearate, polyethylene oxide hydrogenated castor oil 10, 50 and 60, glycerol Monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. These surfactants may be present alone or in mixtures in different ratios in the formulations of the compounds or derivatives of the present invention.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration can also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

For buccal administration, the compositions may be in the form of lozenges or lozenges formulated in conventional manner.

For topical administration, the compounds can be formulated as solutions, gels, ointments, creams, suspensions, and the like, as is well known in the art. Systemic formulations include those designed for administration by injection, eg, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

For administration by inhalation, the compounds for use according to the invention may conveniently be presented as an aerosol spray from pressurized packs or nebulizers, using a suitable propellant (e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, Fluoroethane, carbon dioxide or other suitable gas) delivery. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of eg gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Pulmonary delivery of a compound (or salt thereof) disclosed herein is also contemplated herein. Compounds are delivered to the lungs of mammals upon inhalation and pass through the epithelial lining of the lungs to the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceuticals 63:135-144 (1990) (leuprolide acetate); Braquet et al. Al, J Cardiovasc Pharmacol 13(Suppl 5):143-146 (1989) (endothelin-1); Hubbard et al, Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al , 1989, J Clin Invest 84:1145-1146 (a-1-Protease); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (Recombinant Human Growth hormones); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony-stimulating factor; incorporated by reference ). Methods and compositions for pulmonary delivery of drugs for systemic effects are described in US Patent No. 5,451,569, issued September 19, 1995 to Wong et al. (incorporated by reference).

A wide range of mechanical devices are contemplated for the practice of the present invention, which are designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers and powder inhalers, those skilled in the art are familiar with these devices.

Some specific examples of commercially available devices suitable for use in the practice of the present invention are the Ultravent nebulizer manufactured by Mallinckrodt Company (St. Louis, Mo.); the Acorn II nebulizer manufactured by Marquest Medical Products (Englewood, Colo.); the Acorn II nebulizer manufactured by Glaxo Corporation; (Research Triangle Park, North Carolina); and the Spinhaler powder inhaler, manufactured by Fisons, Inc. (Bedford, Mass).

All such devices require the use of formulations suitable for administering the compounds of the invention. In general, each formulation is specific to the type of device used and may also involve the use of suitable propellant substances, in addition to usual diluents, adjuvants and/or carriers used in therapy. In addition, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Depending on the type of chemical modification or the type of equipment used, the chemically modified compounds of the invention can also be prepared in different formulations.

Formulations suitable for use with a nebulizer (spray or ultrasound) will generally contain the compound of the invention (or derivative) dissolved in water at a concentration of from about 0.1 to 25 mg of the biologically active compound of the invention per milliliter of solution. The formulations can also include buffers and monosaccharides (eg, for inhibitor stabilization and regulation of osmotic pressure). Nebulizer formulations may also contain surfactants to reduce or prevent surface-induced aggregation of the compounds of the invention caused by atomization of solutions when forming an aerosol.

Formulations for use with metered dose inhalers will generally comprise a finely divided powder containing the compound (or derivative) of the invention suspended in a propellant by means of a surfactant. The propellant can be any known material for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane or combinations thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid is also suitable as a surfactant.

Formulations for administration from a powder inhaler device will comprise a finely divided dry powder comprising a compound (or derivative) of the invention, and may also include bulking agents such as lactose, sorbitol, sucrose or mannitol, which The amount facilitates dispersion of the powder from the device, for example 50 to 90% by weight of the formulation. The compound (or derivative) of the present invention should preferably be prepared in the form of microparticles with an average particle size of less than 10 microns (μm), preferably 0.5 to 5 μm, so as to be most effectively delivered to the deep lung.

Nasal delivery of the pharmaceutical compositions of the invention is also contemplated. Nasal delivery allows the pharmaceutical compositions of the invention to pass through the bloodstream directly after nasal administration of the therapeutic product without depositing the product in the lungs. Formulations for nasal delivery include those with dextran or cyclodextran.

For nasal administration, a suitable device is the vial to which a metered dose nebulizer is attached. In one embodiment, the metered dose is delivered by pumping a solution of the pharmaceutical composition of the invention into a chamber of defined volume having a volume sized to form when the liquid in the chamber is compressed. Spray to aerosolize the orifice of the aerosol formulation. The chamber is compressed to administer the pharmaceutical composition of the invention. In a particular embodiment, the chamber is a piston configuration. Such devices are commercially available.

Alternatively, a plastic squeeze bottle is used that has an orifice or opening sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is usually found at the top of the bottle, and the top is usually tapered to fit partially in the nasal cavity for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered aerosol formulation for administering a measured dose of drug.

When systemic delivery of the compounds is desired, the compounds can be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil; or synthetic fatty acid esters, such as ethyl oleate or triglycerides; or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, eg sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may also be formulated as depot preparations. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials, eg as emulsions in acceptable oils, or with ion exchange resins, or as sparingly soluble derivatives, eg, sparingly soluble salts.

The pharmaceutical composition may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycol.

Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation; microencapsulation; lipid encochleate; coating onto microscopic gold particles; ; in the form of pellets implanted in the skin; or dried on a sharp object to scrape into the skin. Pharmaceutical compositions also include granules, powders, lozenges, coated lozenges, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with prolonged release of the active compound, in which Excipients and additives and/or auxiliary agents (such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners or solubilizers) are usually used as described above in the preparation. These pharmaceutical compositions are suitable for various drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249:1527-33 (1990).

Compounds of the invention and optionally other therapeutic agents may be administered as such (pure) or as pharmaceutically acceptable salts or co-crystals. When used in medicine, the salt or co-crystal should be pharmaceutically acceptable, but a non-pharmaceutically acceptable salt or co-crystal can be suitably used to prepare a pharmaceutically acceptable salt or co-crystal thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, Methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Furthermore, such salts may be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

Suitable buffers include: acetic acid and salts (1-2% w/v); citric acid and salts (1-3% w/v); boric acid and salts (0.5-2.5% w/v); and phosphoric acid and salts ( 0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v); and thimerosal ( 0.004-0.02% w/v).

The pharmaceutical compositions of the present invention contain an effective amount of a compound as described herein and optionally a therapeutic agent included in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" means an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to aid application. The components of the pharmaceutical compositions can also be blended with the compounds of the invention and with each other in such a manner that there are no interactions that would materially impair the desired pharmaceutical efficacy.

Therapeutic agents, including, in particular but not limited to, compounds of the invention, can be provided in particles. Particle, as used herein, means nanoparticles or microparticles (or in some cases larger particles), which may consist in whole or in part of a compound of the invention or other therapeutic agent as described herein. Particles may contain a therapeutic agent in a core surrounded by a coating, including but not limited to an enteric coating. The therapeutic agent can also be dispersed throughout the particle. Therapeutic agents can also be adsorbed on the particles. The particles can have release kinetics of any order, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, any combination thereof, and the like. In addition to therapeutic agents, particles may comprise any of those materials conventionally used in the fields of pharmacy and medicine, including but not limited to erodible, non-erodible, biodegradable or non-biodegradable materials or combinations thereof . Particles may be microcapsules containing the compound of the invention in solution or in semi-solid state. The particles can be in almost any shape.

Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivery of therapeutic agents. Such polymers may be natural or synthetic polymers. The polymer is chosen based on the time period of release desired. Bioadhesive polymers of interest include bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acid, casein, gelatin, gluten, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(methyl butyl acrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(methacrylate phenyl ester), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

The therapeutic agent can be contained in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation that controls the manner and profile of drug release from the formulation. This refers to immediate as well as non-immediate release formulations, where non-immediate release formulations include, but are not limited to, sustained-release and delayed-release formulations. The term "sustained release" (also known as "extended release") is used in its conventional sense to refer to a drug that provides gradual release of a drug over an extended period of time, and preferably, though not necessarily, occurs over an extended period of time. A drug formulation of a substantially constant blood level of a drug. The term "delayed release" is used in its conventional sense to refer to pharmaceutical formulations in which there is a time delay between administration of the formulation and release of the drug therefrom. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and thus may or may not be "sustained release".

The use of long-term sustained-release implants may be particularly useful in the treatment of chronic conditions. As used herein, "long-term" release means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30 to 60 days. Long term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above.

Those of ordinary skill in the relevant art will appreciate that other suitable changes and modifications to the compositions and methods described herein will be apparent from and can be made from the description of the invention contained herein, given the information known to those of ordinary skill in the art. made without departing from the scope of the invention or any embodiment thereof. Now that the present invention has been described in detail, it will be more clearly understood by reference to the following examples, which are included for the purpose of illustration only and are not intended to limit the invention.

EXAMPLES The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

Example 1 : SLC34A1 Transport Assay SLC34A1 transport activity was measured via the use of a phosphate transport radiometric assay. A cell line with stable expression was made by transfecting human SLC34A1 into Flp-In T-REx 293 cells (Invitrogen). Grow Flp-In SLC34A1 cell line in DMEM + Glutamax-I (1X), Gibco #A41920-01 supplemented with 10% FBS (Gibco #16140-071), 1X at 37° _C , 5% CO 2 Penicillin/Streptomycin, 0.250 mg/mL Hygromycin B (Thermo #10687010), 0.01 mg/mL Blasticidin S HCl (Gibco #A11139-03).

Two days prior to the transport assay, cells were dissociated and plated at a density of 30k cells/well (96 wells, 100 µL total volume) or 18k cells/well (384 wells, 40 µL total volume) on poly-D-isolated Amino acid-coated Isoplate-96 TC or Viewplate-384 TC pans (Perkin Elmer, #6005070 or #6007480). Plating medium was DMEM + Glutamax-I (1X), Gibco #A41920-01 supplemented with 10% FBS (Gibco #16140-071), 1X Penicillin/Streptomycin. Cells were replaced in the incubator and induced with 1 µg/mL tetracycline 1 day before transfer.

Cell culture medium was removed by manual medium removal and mechanical washing. The wash solution was manually removed, followed by the mechanical addition of 20 µL of live cell imaging solution with compound (DMSO 0.5% final). Cells were incubated at room temperature for 20 minutes before mechanical addition of 10 µL of radioactive phosphate solution (240 µM sodium phosphate in live cell imaging solution, pH 7.4, 33 µCi/mL ³³ P as phosphate). Cells were incubated at room temperature followed by a mechanical wash once with live cell imaging solution. Cells were lysed by mechanical addition of 30 µL of Ultima Gold XR scintillation fluid (Perkin Elmer), sealed and scanned for radioactive signal on a scintillation counter.

Relative phosphate uptake by SLC34A1 was determined by normalizing the measured radioactive signal using signals from 0.5% DMSO without compound (negative control) and 10 µM positive control.

IC ₅₀= 380 nM (Filipski等人)；278 nM (如本文分析中所量測)。 The positive control is disclosed in Filipski, KJ et al. ACS Med. Chem. Lett. 2018, 9, 440−445 and has the structure:

_IC50 = 380 nM (Filipski et al.); 278 nM (as measured in the assay herein).

步驟 1 ：合成 2在室溫下向第三丁醇鉀(70.1 g，624.76 mmol)於無水甲苯(700 mL)中之懸浮液中逐滴添加三氟乙酸甲酯(80.0 g，624.756 mmol)於乙腈(25.02 g，624.756 mmol)中之溶液。在添加之後，所得混合物在80℃下攪拌6小時。隨後將混合物冷卻至室溫且過濾，得到呈黃色固體狀之粗 2(80.1 g，73.1%產率)，其不經任何進一步純化即用於下一步驟。 ¹H NMR (400 MHz, D ₂O) δ 4.55 (s, 1H)。 Example 2 : Synthesis of Exemplary Compounds Synthesis of the Azaindole Nucleus ( Nucleosynthetic Procedure 1)

Step 1 : Synthesis 2 To a suspension of potassium tert-butoxide (70.1 g, 624.76 mmol) in dry toluene (700 mL) was added dropwise methyl trifluoroacetate (80.0 g, 624.756 mmol) at room temperature in Solution in acetonitrile (25.02 g, 624.756 mmol). After the addition, the resulting mixture was stirred at 80°C for 6 hours. The mixture was then cooled to room temperature and filtered to afford crude 2 (80.1 g, 73.1% yield) as a yellow solid, which was used in the next step without any further purification. ¹ H NMR (400 MHz, D ₂ O) δ 4.55 (s, 1H).

Step 2 : Synthesis of 3 To a suspension of 2 (80.0 g, 456.75 mmol) in acetonitrile (800 mL) was added portionwise tosyl chloride (223.6 g, 1172.83 mmol) at room temperature and stirred at room temperature The resulting mixture was left overnight. The mixture was then concentrated in vacuo and the residue was diluted with water (800 mL) and extracted twice with EtOAc (400 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was then purified by silica gel flash column chromatography (eluted with PE/EtOAc = 100:0 to 10:1) to give compound 3 (80.0 g, 60.1% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) Main peaks: δ 7.96 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 5.9 Hz, 2H), 6.02 (s, 1H), 2.50 (s, 3H) . Secondary peaks: δ 7.84 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 5.9 Hz, 2H), 6.14 (s, 1H), 2.51 (s, 3H).

Step 3 : Synthesis of 6 To a solution of compound 4 (25.0 g, 304.47 mmol) in MeOH (500 mL) was added 5 (53.34 g, 304.47 mmol) at room temperature and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated in vacuo to remove most of the solvent, and the residue was diluted with EtOAc (400 mL) and washed with water (200 mL x 2) and brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was then purified by silica gel flash column chromatography (eluted with PE/EtOAc = 100:0 to 10:1) to afford 6 (50.0 g, 68.3% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.31 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 6.3 Hz, 1H), 4.34 - 4.26 (m, 4H), 3.86 (s, 1H) , 2.19 (s, 3H), 1.31 (t, J = 7.1 Hz, 6H).

Step 4 : Synthesis of 7 To a solution of 6 (50.0 g, 208.11 mmol) in _EtOH (300 mL) was added dropwise sodium ethoxide in ethanol (21% w/w, 15.58 g, 228.92 mmol). The mixture was then stirred at room temperature for 16 hours. Most of the solvent was removed in vacuo and the residue was diluted with ice water (500 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (eluted with PE/EtOAc = 100:0 to 2:1) to afford 7 (27.0 g, 77.1% yield) as an off-white solid. LC/MS (ESI) m/z : 169 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 5.29 (d, J = 2.4 Hz, 1H), 4.93 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H) , 2.06 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

Step 5 : Synthesis of 8 To a mixture of 7 (27.0 g, 160.52 mmol) and DIEA (62.24 g, 481.57 mmol) in DCM (300 mL) was added 3 (74.8 g, 256.84 mmol) at room temperature. The resulting mixture was then stirred at room temperature for 8 hours. The mixture was then washed with water (300 mL) and brine (300 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (eluted with PE/EtOAc = 100:0 to 5:1) to afford 8 (27.0 g, 58.5% yield) as a brown solid. LC/MS (ESI) m/z : 288 (M+H) ⁺ .

Step 6 : Synthesis of 9 To a solution of 8 (26.0 g, 90.52 mmol) in acetonitrile (200 mL) was added DBU (13.78 g, 90.52 mmol) at room temperature and the resulting mixture was refluxed overnight. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was then purified by silica gel flash column chromatography (eluted with DCM/MeOH=100:0 to 10:1) to afford 9 (14.0 g, 64.1% yield) as a brown solid. LC/MS (ESI) m/z : 242 (M+H) ⁺ .

Step 7 : Synthesis of 10 To a solution of 9 (14.0 g, 58.05 mmol) in acetonitrile (70 mL) was added _POCl3 (26.7 g, 174.151 mmol) dropwise at 0 °C, and the resulting mixture was refluxed for 3 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (200 mL) and washed with saturated NaHCO ₃ solution (200 mL) and brine (200 mL). The organic layer was then dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by silica gel flash column chromatography (eluted with PE/EtOAc = 100:0 to 3:1) to afford 10 (14.0 g, 92.8% yield) as a brown solid. LC/MS (ESI) m/z : 260 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 6.77 (d, J = 0.7 Hz, 1H), 2.58 (d, J = 0.6 Hz, 3H).

Step 8 : Synthesis of 11 To a solution of 10 (10.0 g, 38.52 mmol) in DMF (50 mL) was added NCS (5.4 g, 40.44 mmol) portionwise at room temperature, and the resulting mixture was stirred at 50 °C for 2 hours . The mixture was then cooled to room temperature, diluted with water (300 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (eluted with PE/EtOAc = 100:0 to 3:1) to afford 11 (10.0 g, 88.2% yield) as a brown solid. LC/MS (ESI) m/z : 294 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.34 (s, 1H), 2.57 (s, 3H).

步驟 1 ：合成 13向 11(1.0 eq.)及對應胺 12(2.0 eq.)於乙腈中之混合物中添加DIPEA (3.0 eq.)且將所得混合物加熱至80℃隔夜。隨後將混合物冷卻至室溫且真空濃縮。殘餘物用水稀釋且用EtOAc萃取兩次。合併之有機層經無水Na ₂SO ₄乾燥，過濾且真空濃縮。經由製備型HPLC純化殘餘物，得到 13。 General procedure for SnAr ( general procedure 1) :

Step 1 : Synthesis of 13 To a mixture of 11 (1.0 eq.) and the corresponding amine 12 (2.0 eq.) in acetonitrile was added DIPEA (3.0 eq.) and the resulting mixture was heated to 80 °C overnight. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified via preparative HPLC to afford 13 .

將 11(200 mg，0.681 mmol)、反-4-哌啶醇-3-甲基-鹽酸鹽(1:1) (206 mg，1.36 mmol)及DIEA (355 μL，2.04 mmol)於MeCN (5 mL)中之混合物在80℃下攪拌2小時。隨後將混合物冷卻至室溫且真空濃縮。將殘餘物用水(40 mL)稀釋且用EtOAc (20 mL×3)萃取。合併之有機層用鹽水洗滌，經無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由矽膠急驟管柱層析(用PE/EtOAc=100:0至3:1溶離)純化殘餘物，得到呈黃色固體狀及鏡像異構體之混合物的 1A / 1B(231 mg，91.2%產率)。隨後藉由對掌性管柱純化混合物且分離兩種鏡像異構體。 Synthesis 1A/1B

11 (200 mg, 0.681 mmol), trans-4-piperidinol-3-methyl-hydrochloride (1:1) (206 mg, 1.36 mmol) and DIEA (355 μL, 2.04 mmol) were dissolved in MeCN ( 5 mL) was stirred at 80°C for 2 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with water (40 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc=100:0 to 3:1) to afford 1A / 1B (231 mg, 91.2% yield) as a yellow solid and a mixture of mirror-image isomers. Rate). The mixture was then purified by pairing a chiral column and the two mirror-image isomers were separated.

向 化合物 14(1.0 eq.)於MeOH/H ₂O (3:1，V/V)中之溶液中添加LiOH-H ₂O (2.0 eq.)，且在室溫下攪拌所得混合物2小時。用HCl水溶液(1M)將反應混合物調節至pH=3且用EtOAc萃取兩次。合併之有機層用鹽水洗滌，經Na ₂SO ₄乾燥，過濾且真空濃縮。藉由矽膠管柱層析(用PE/EtOAc溶離)純化殘餘物，得到 化合物 15。 General Procedure for Esters Hydrolysis ( General Procedure 2)

To a solution of compound 14 (1.0 eq.) in MeOH/ _H2O (3:1, V/V) was added LiOH- _H2O (2.0 eq.), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH=3 with aqueous HCl (1M) and extracted twice with EtOAc. The combined organic _layers were washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (elution with PE/EtOAc) to afford compound 15 .

向 2A(230 mg，0.571 mmol)於MeOH/H ₂O (12 mL，3:1)中之溶液中添加LiOH-H ₂O (48 mg，1.142 mmol)，且在室溫下攪拌所得混合物2小時。反應混合物用HCl水溶液(1M)調節至pH=3，用EtOAc (50 mL×3)萃取。合併之有機層用鹽水洗滌，經Na ₂SO ₄乾燥，過濾且真空濃縮。藉由矽膠管柱層析(用DCM/MeOH=100:1至10:1溶離)純化殘餘物，得到呈白色固體狀之 2B(180 mg，81.1%產率)。LC/MS (ESI) m/z: 387 (M+H) ⁺。1H NMR (400 MHz, MeOD) δ 3.91 (dt, J = 12.5, 3.2 Hz, 2H), 3.58 - 3.46 (m, 2H), 2.63 (tt, J = 10.7, 4.1 Hz, 1H), 2.53 (s, 3H), 2.18 - 2.08 (m, 2H), 2.05 - 1.97 (m, 2H)。 Synthesis 2B

To a solution of 2A (230 mg, 0.571 mmol) in MeOH/H ₂ O (12 mL, 3:1 ) was added LiOH—H ₂ O (48 mg, 1.142 mmol) and the resulting mixture was stirred at room temperature 2 Hour. The reaction mixture was adjusted to pH=3 with aqueous HCl (1M), extracted with EtOAc (50 mL×3). The combined organic _layers were washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with DCM/MeOH=100:1 to 10:1) to afford 2B (180 mg, 81.1% yield) as a white solid. LC/MS (ESI) m/z: 387 (M+H) ⁺ . 1H NMR (400 MHz, MeOD) δ 3.91 (dt, J = 12.5, 3.2 Hz, 2H), 3.58 - 3.46 (m, 2H), 2.63 (tt, J = 10.7, 4.1 Hz, 1H), 2.53 (s, 3H), 2.18 - 2.08 (m, 2H), 2.05 - 1.97 (m, 2H).

向 酸 16(1.0 eq.)及適當胺(1.5 eq.)於DCM中之混合物中添加HATU (1.5 eq.)及DIEA (3.0 eq.)且在室溫下攪拌反應混合物12小時。反應混合物隨後用冰水淬滅且用DCM萃取兩次。合併之有機層用鹽水洗滌，經Na ₂SO ₄乾燥，過濾且真空濃縮。經由製備型HPLC純化殘餘物，得到 17。 General Procedure for Amide Couplings ( General Procedure 3)

To a mixture of acid 16 (1.0 eq.) and the appropriate amine (1.5 eq.) in DCM was added HATU (1.5 eq.) and DIEA (3.0 eq.) and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched with ice water and extracted twice with DCM. The combined organic _layers were washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified via preparative HPLC to afford 17 .

在0℃下向 3A(50 mg，0.131 mmol)及二甲胺鹽酸鹽(16 mg，0.159 mmol)於DCM(5 mL)中之混合物中添加HATU (74 mg，0.159 mmol)及DIEA (51 mg，0.393 mmol)，且在室溫下攪拌反應混合物12小時。隨後用冰水(20 mL)淬滅反應混合物且用DCM (10 mL×3)萃取。使合併之有機層經Na ₂SO ₄乾燥，過濾且真空濃縮。經由製備型HPLC純化殘餘物，得到呈白色固體狀之 3B(20 mg，37.3%產率)。LC/MS (ESI) m/z: 415.9 (M+H) ⁺。1H NMR (400 MHz, MeOD) δ 4.67 (dd, J = 7.1, 3.1 Hz, 1H), 3.87 (dddd, J = 29.9, 14.8, 9.2, 2.5 Hz, 5H), 3.63 (td, J = 11.0, 5.0 Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H)。 Synthetic 3B

To a mixture of 3A (50 mg, 0.131 mmol) and dimethylamine hydrochloride (16 mg, 0.159 mmol) in DCM (5 mL) was added HATU (74 mg, 0.159 mmol) and DIEA (51 mg, 0.393 mmol), and the reaction mixture was stirred at room temperature for 12 hours. Then the reaction mixture was quenched with ice water (20 mL) and extracted with DCM (10 mL×3). _The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified via preparative HPLC to afford 3B (20 mg, 37.3% yield) as a white solid. LC/MS (ESI) m/z: 415.9 (M+H) ⁺ . 1H NMR (400 MHz, MeOD) δ 4.67 (dd, J = 7.1, 3.1 Hz, 1H), 3.87 (dddd, J = 29.9, 14.8, 9.2, 2.5 Hz, 5H), 3.63 (td, J = 11.0, 5.0 Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H).

在0℃下將 化合物 18(1.0 eq.)溶解於TFA/DCM (1:4，V/V)之混合物中且在室溫下攪拌所得混合物2小時。隨後真空濃縮反應混合物，得到粗產物，藉由製備型HPLC純化，得到胺 19。 General procedure for removal of Boc protecting groups ( general procedure 4)

Compound 18 (1.0 eq.) was dissolved in a mixture of TFA/DCM (1:4, V/V) at 0 °C and the resulting mixture was stirred at room temperature for 2 h. Subsequent concentration of the reaction mixture in vacuo afforded a crude product, which was purified by preparative HPLC to afford amine 19 .

在0℃下將 4A(30 mg，0.061 mmol)溶解於DCM (3 mL)及TFA (1 mL)之混合物中，且在室溫下攪拌所得混合物2小時。隨後真空濃縮反應混合物，且藉由製備型HPLC純化殘餘物，得到呈白色固體狀之 4B(15.3 mg，63.9%產率)。LC/MS (ESI) m/z: 398 (M+H) ⁺。1H NMR (400 MHz, CD3OD) δ 3.72 (q, J = 12.5 Hz, 3H), 3.43 - 3.34 (m, 3H), 2.57 (s, 3H), 2.07 (ddd, J = 16.0, 12.3, 6.1 Hz, 5H), 2.02 - 1.91 (m, 3H)。 Synthetic 4B

4A (30 mg, 0.061 mmol) was dissolved in a mixture of DCM (3 mL) and TFA (1 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo, and the residue was purified by preparative HPLC to afford 4B (15.3 mg, 63.9% yield) as a white solid. LC/MS (ESI) m/z: 398 (M+H) ⁺ . 1H NMR (400 MHz, CD3OD) δ 3.72 (q, J = 12.5 Hz, 3H), 3.43 - 3.34 (m, 3H), 2.57 (s, 3H), 2.07 (ddd, J = 16.0, 12.3, 6.1 Hz, 5H), 2.02 - 1.91 (m, 3H).

在0℃下向 20(1.0 eq.)及TEA(3.0 eq.)於DCM中之混合物中逐滴添加Ac ₂O (1.0 eq.)且在室溫下攪拌所得混合物12小時。隨後真空濃縮反應混合物，且經由製備型HPLC純化殘餘物，得到 21。 General procedure for acetylation ( general procedure 5)

To a mixture of 20 (1.0 eq.) and TEA (3.0 eq.) in DCM was added _Ac2O (1.0 eq.) dropwise at 0 °C and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated in vacuo, and the residue was purified via preparative HPLC to afford 21 .

在0℃下向 4B(10 mg，0.025 mmol)及TEA (8 mg，0.075 mmol)於DCM (3 mL)中之混合物中逐滴添加Ac ₂O (3 mg，0.025 mmol)，且在室溫下攪拌所得混合物12小時。隨後真空濃縮反應混合物，且經由製備型HPLC純化殘餘物，得到呈白色固體狀之 4C(8 mg，72.2%產率)。LC/MS (ESI) m/z: 440 (M+H) ⁺。 ¹H NMR (400 MHz, CD3OD) δ 4.50 (d, J = 10.2 Hz, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.60 (ddd, J = 15.3, 10.5, 5.8 Hz, 2H), 3.37 - 3.33 (m, 2H), 3.07 (td, J = 13.3, 4.6 Hz, 1H), 2.53 (s, 3H), 2.40 - 2.30 (m, 1H), 2.25 - 2.11 (m, 1H), 2.09 (s, 3H), 2.01 - 1.91 (m, 1H), 1.90 - 1.78 (m, 3H), 1.63 (d, J = 14.1 Hz, 1H)。 Synthetic 4C

To a mixture of 4B (10 mg, 0.025 mmol) and TEA (8 mg, 0.075 mmol) in DCM (3 mL) was added Ac ₂ O (3 mg, 0.025 mmol) dropwise at 0 °C and heated at room temperature. The resulting mixture was stirred for 12 hours. The reaction mixture was then concentrated in vacuo, and the residue was purified via preparative HPLC to afford 4C (8 mg, 72.2% yield) as a white solid. LC/MS (ESI) m/z: 440 (M+H) ⁺ . ¹ H NMR (400 MHz, CD3OD) δ 4.50 (d, J = 10.2 Hz, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.60 (ddd, J = 15.3, 10.5, 5.8 Hz, 2H), 3.37 - 3.33 (m, 2H), 3.07 (td, J = 13.3, 4.6 Hz, 1H), 2.53 (s, 3H), 2.40 - 2.30 (m, 1H), 2.25 - 2.11 (m, 1H), 2.09 ( s, 3H), 2.01 - 1.91 (m, 1H), 1.90 - 1.78 (m, 3H), 1.63 (d, J = 14.1 Hz, 1H).

3-氯-2-甲基-7-{[(1r,4r)-4-羥基環己基]胺基}-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈9280 LC-MS:m/z 373.1 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.94 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.62 (d, J = 4.8 Hz, 1H), 4.22 (dd, J = 11.5, 7.2 Hz, 1H), 3.47 (dt, J = 14.3, 5.1 Hz, 1H), 2.45 (s, 3H), 2.06 (d, J = 13.5 Hz, 2H), 1.89 (d, J = 11.6 Hz, 2H), 1.44 - 1.25 (m, 4H)。 相對立體化學反式    2B

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-甲酸 LC-MS:m/z 387 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 3.91 (dt, J = 12.5, 3.2 Hz, 2H), 3.58 - 3.46 (m, 2H), 2.63 (tt, J = 10.7, 4.1 Hz, 1H), 2.53 (s, 3H), 2.18 - 2.08 (m, 2H), 2.05 - 1.97 (m, 2H)。    7A

7-(氮雜環丁烷-1-基)-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 314.9 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.80 - 4.74 (m, 4H), 2.54 (d, J = 7.7 Hz, 2H), 2.46 (s, 3H)。    8A

3-氯-7-(3-羥基氮雜環丁烷-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 330.9 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 5.05 - 4.97 (m, 2H), 4.77 - 4.69 (m, 1H), 4.53 - 4.45 (m, 2H), 2.47 (s, 3H)。    9A

3-氯-7-{2,6-二氮雜螺[3.5]壬-6-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 384 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 3.81 (s, 1H), 3.55 (d, J = 3.4 Hz, 2H), 3.51 (dd, J = 9.5, 4.3 Hz, 2H), 3.30 (m, 4H), 2.56 (s, 3H), 1.99 - 1.81 (m, 4H)。    10A

3-氯-7-{2,7-二氮雜螺[4.5]癸-7-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 398 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 3.69 - 3.33 (m, 8H), 3.18 (d, J = 12.2 Hz, 1H), 2.56 (s, 3H), 2.19 - 2.09 (m, 1H), 2.00 - 1.93 (m, 3H), 1.92 - 1.75 (m, 2H)。 鏡像異構體之混合物 11A

3-氯-2-甲基-7-(2,8-二氮雜螺[4.5]癸-8-基)-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈甲酸酯 LC-MS:m/z 398 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 3.71 (t, J = 5.5 Hz, 4H), 3.44 (t, J = 7.5 Hz, 2H), 3.22 (s, 2H), 2.54 (s, 3H), 2.09 (t, J = 7.5 Hz, 2H), 2.01 - 1.86 (m, 4H)。       4B

3-氯-7-{1,7-二氮雜螺[4.5]癸-7-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 398 (M+H)。 ¹H NMR (400 MHz, CD3OD) δ 3.72 (q, J = 12.5 Hz, 3H), 3.43 - 3.34 (m, 3H), 2.57 (s, 3H), 2.07 (ddd, J = 16.0, 12.3, 6.1 Hz, 5H), 2.02 - 1.91 (m, 3H)。 鏡像異構體之混合物 13A

3-氯-7-((2-(二甲胺基)乙基)胺基)-2-甲基-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈甲酸酯 LC-MS:m/z 346 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.02 (t, J = 6.0 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 2.63 (s, 6H), 2.50 (s, 3H)。    14A

3-氯-2-甲基-7-(3-側氧基哌𠯤-1-基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 358 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 8.19 (s, 1H), 4.28 (s, 2H), 3.84 (t, J = 5.1 Hz, 2H), 3.45 (s, 2H), 2.51 (s, 3H)。       15A

3-氯-2-甲基-7-(4-甲基-3-側氧基哌𠯤-1-基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 372 (M+H)。 ¹H NMR (400 MHz, CD3OD) δ 4.35 (s, 2H), 4.00 - 3.93 (m, 2H), 3.69 - 3.63 (m, 2H), 3.07 (s, 3H), 2.55 (s, 3H)。       16A

3-氯-7-(1,1-二側氧基-1λ ⁶-硫代嗎啉-4-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 393 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 4.07 - 3.95 (m, 4H), 3.44 - 3.39 (m, 4H), 2.53 (s, 3H)。    17A

7-{2-乙醯基-2,8-二氮雜螺[4.5]癸-8-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 440 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 8.00 (d, J = 4.6 Hz, 1H), 4.04 (dd, J = 14.2, 6.8 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.87 (d, J = 12.9 Hz, 1H), 3.71 (dt, J = 11.2, 7.7 Hz, 2H), 3.57 (dd, J = 15.6, 7.5 Hz, 1H), 3.35 (s, 2H), 2.61 (d, J = 4.6 Hz, 3H), 2.53 (s, 3H), 2.53-2.49 (m, 4H), 2.43 - 2.31 (m, 2H)。    18A

2-{4-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]嗎啉-2-基}-N-甲基乙醯胺 LC-MS:m/z 416 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.19 - 4.10 (m, 1H), 3.99 (dd, J = 19.9, 7.4 Hz, 2H), 3.84 (ddd, J = 18.6, 13.6, 7.8 Hz, 2H), 3.69 - 3.62 (m, 1H), 3.37 (dd, J = 12.9, 9.9 Hz, 1H), 2.76 (s, 3H), 2.56 (s, 3H), 2.55 - 2.44 (m, 2H)。 鏡像異構體之混合物 19A

2-{4-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]嗎啉-2-基}-N,N-二甲基乙醯胺 LC-MS:m/z 430 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 12.26 (s, 1H), 4.08 (t, J = 13.4 Hz, 2H), 3.89 (dd, J = 24.4, 10.6 Hz, 2H), 3.72 - 3.59 (m, 2H), 3.30 - 3.25 (m, 1H), 3.01 (s, 3H), 2.90 (s, 3H), 2.77 (dd, J = 16.6, 4.5 Hz, 1H), 2.62 (dd, J = 16.6, 8.6 Hz, 1H), 2.55 (s, 3H)。 鏡像異構體之混合物 20A

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}乙醯胺 LC-MS:m/z 400 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.09 - 3.84 (m, 3H), 3.63 - 3.50 (m, 2H), 2.11 - 2.00 (m, 6H), 1.96 (s, 3H), 1.78 (dd, J = 12.2, 3.7 Hz, 2H)。    21A

3-氯-2-甲基-7-{6-氧雜-2-氮雜螺[3.4]辛-2-基}-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 4.70 (s, 4H), 3.87 (s, 2H), 3.76 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.24 (t, J = 7.0 Hz, 2H)。    22A

3-氯-2-甲基-7-{8-氧雜-2-氮雜螺[4.5]癸-2-基}-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 399 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.17 (t, J = 7.0 Hz, 2H), 3.98 (s, 2H), 3.76 (dd, J = 10.7, 5.7 Hz, 4H), 2.49 (s, 3H), 2.04 (dd, J = 9.1, 4.9 Hz, 2H), 1.72 (dd, J = 11.3, 6.8 Hz, 4H)。    23A

3-氯-7-{2,5-二氧雜-8-氮雜螺[3.5]壬-8-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 426 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 4.59 - 4.45 (m, 4H), 3.88 (s, 2H), 3.87 - 3.83 (m, 2H), 3.63 - 3.52 (m, 2H), 2.54 (s, 3H)。 24A

7-{2-乙醯基-2,6-二氮雜螺[3.5]壬-6-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 426 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 3.90 (d, J = 8.2 Hz, 1H), 3.81 (dd, J = 18.1, 9.8 Hz, 2H), 3.69 (d, J = 11.4 Hz, 1H), 3.62 - 3.50 (m, 3H), 3.39 (dd, J = 11.5, 5.3 Hz, 1H), 2.53 (s, 3H), 1.93 - 1.85 (m, 1H), 1.83 - 1.75 (m, 3H), 1.71 (s, 3H)。    25A

7-{2-乙醯基-2,7-二氮雜螺[4.5]癸-7-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 440.2 (M+H)。 ¹H NMR (400 MHz,CD3OD) δ 3.74 (d, J = 10.7 Hz, 1H), 3.63 - 3.50 (m, 6H), 3.45 - 3.38 (m, 1H), 3.24 (d, J = 12.3 Hz, 1H), 2.54 (d, J = 2.5 Hz, 3H), 2.21 - 2.14 (m, 1H), 2.02 - 1.75 (m, 8H)。 鏡像異構體之混合物    4C

7-{1-乙醯基-1,7-二氮雜螺[4.5]癸-7-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 440 (M+H)。 ¹H NMR (400 MHz, CD3OD) δ 4.50 (d, J = 10.2 Hz, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.60 (ddd, J = 15.3, 10.5, 5.8 Hz, 2H), 3.37 - 3.33 (m, 2H), 3.07 (td, J = 13.3, 4.6 Hz, 1H), 2.53 (s, 3H), 2.40 - 2.30 (m, 1H), 2.25 - 2.11 (m, 1H), 2.09 (s, 3H), 2.01 - 1.91 (m, 1H), 1.90 - 1.78 (m, 3H), 1.63 (d, J = 14.1 Hz, 1H)。 鏡像異構體之混合物    27A

4-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]嗎啉-2-甲醯胺 LC-MS:m/z 387.9 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.36 (dd, J = 6.1, 4.2 Hz, 1H), 4.09 - 4.02 (m, 1H), 4.01 - 3.94 (m, 1H), 3.92 - 3.77 (m, 3H), 3.64 (ddd, J = 12.4, 7.6, 3.1 Hz, 1H), 2.54 (s, 3H)。 鏡像異構體之混合物    28A

4-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-甲基嗎啉-2-甲醯胺 LC-MS:m/z 402 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.42 - 4.27 (m, 1H), 4.07 - 3.93 (m, 2H), 3.91 - 3.77 (m, 3H), 3.62 (ddd, J = 12.4, 7.6, 3.2 Hz, 1H), 2.83 (s, 3H), 2.55 (s, 3H)。 鏡像異構體之混合物    3B

4-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,N-二甲基嗎啉-2-甲醯胺 LC-MS:m/z 415.9 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.67 (dd, J = 7.1, 3.1 Hz, 1H), 3.87 (dddd, J = 29.9, 14.8, 9.2, 2.5 Hz, 5H), 3.63 (td, J = 11.0, 5.0 Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H)。 鏡像異構體之混合物    30A

7-(2-(胺甲基)N-嗎啉基)-3-氯-2-甲基-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈鹽酸鹽 LC-MS:m/z 374 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.15 (s, 1H), 8.13 (s, 3H), 4.10 (d, J = 11.1 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.81 (ddd, J = 27.2, 22.8, 12.9 Hz, 3H), 3.61 - 3.47 (m, 2H), 3.09 (dd, J = 9.6, 3.5 Hz, 1H), 2.99 - 2.88 (m, 1H), 2.57 (s, 3H)。 鏡像異構體之混合物    31A

N-({4-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]嗎啉-2-基}甲基)乙醯胺 LC-MS:m/z 416.1 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.00 (t, J = 5.7 Hz, 1H), 4.02 (d, J = 11.4 Hz, 1H), 3.80 (d, J = 12.3 Hz, 1H), 3.75 - 3.65 (m, 3H), 3.63 - 3.55 (m, 1H), 3.22 (ddd, J = 16.3, 10.5, 6.3 Hz, 3H), 2.52 (s, 3H), 1.82 (s, 3H)。 鏡像異構體之混合物    32A

3-氯-7-{2,2-二側氧基-2λ ⁶-硫雜-7-氮雜螺[4.4]壬-7-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 433.1 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 4.20 - 4.04 (m, 4H), 3.35 (d, J = 13.5 Hz, 2H), 3.28 (t, J = 8.9 Hz, 2H), 2.48 (s, 3H), 2.34 - 2.20 (m, 3H), 2.15 - 2.07 (m, 1H)。 鏡像異構體之混合物    33A

3-氯-2-甲基-7-{2-氧雜-6-氮雜螺[3.5]壬-6-基}-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 385.1 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 4.34 (q, J = 5.9 Hz, 4H), 3.83 (s, 2H), 3.49 - 3.41 (m, 2H), 2.54 (s, 3H), 1.97 - 1.87 (m, 2H), 1.80 - 1.69 (m, 2H)。    34A

3-氯-7-{2,2-二側氧基-2λ ⁶-硫雜-7-氮雜螺[4.5]癸-7-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 447 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 3.70 - 3.57 (m, 2H), 3.46 (dd, J = 43.7, 13.3 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 3.11 (q, J = 13.7 Hz, 2H), 2.54 (s, 3H), 2.16 (dt, J = 14.0, 7.0 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.95 - 1.79 (m, 3H), 1.73 (dd, J = 13.1, 6.7 Hz, 1H)。 鏡像異構體之混合物    35A

3-氯-7-{2,6-二氧雜-9-氮雜螺[4.5]癸-9-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 400.9 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 3.98 - 3.86 (m, 2H), 3.86 - 3.72 (m, 4H), 3.72 - 3.63 (m, 2H), 3.63 - 3.50 (m, 2H), 2.53 (s, 3H), 2.08 - 2.04 (m, 2H)。 鏡像異構體之混合物 36A

3-氯-7-{2,2-二側氧基-6-氧雜-2λ ⁶-硫雜-9-氮雜螺[4.5]癸-9-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 449 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 4.00 (t, J = 4.7 Hz, 2H), 3.75 (dd, J = 32.1, 11.9 Hz, 2H), 3.56 (dd, J = 9.7, 4.4 Hz, 3H), 3.40 (s, 1H), 3.30 - 3.21 (m, 2H), 2.54 (s, 3H), 2.28 (ddd, J = 13.8, 10.7, 8.2 Hz, 1H), 2.07 (s, 1H)。 鏡像異構體之混合物    37A

3-氯-2-甲基-7-(2,7-二氮雜螺[3.5]壬-7-基)-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈鹽酸鹽 LC-MS:m/z 384 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 3.74 (s, 4H), 3.58 (s, 4H), 2.48 (s, 3H), 1.99 (s, 4H)。    38A

7-{2-乙醯基-2,7-二氮雜螺[3.5]壬-7-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 426.1 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 3.91 (s, 2H), 3.64 (s, 2H), 3.62 - 3.55 (m, 4H), 2.51 (s, 3H), 1.98 - 1.89 (m, 4H), 1.79 (s, 3H)。    39A

3-氯-2-甲基-7-(2,6-二氮雜螺[4.5]癸-2-基)-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈鹽酸鹽 LC-MS:m/z 398 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 4.28 (q, J = 7.8 Hz, 1H), 4.07 - 3.92 (m, 3H), 2.83 (s, 2H), 2.47 (s, 3H), 2.20 (s, 1H), 2.02 - 1.86 (m, 1H), 1.65 (d, J = 28.6 Hz, 4H), 1.48 (s, 2H)。 鏡像異構體之混合物 40A

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}-N-甲基乙醯胺 LC-MS:m/z 414.2 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.73 (s, 1H), 4.56 (dd, J = 14.1, 10.2 Hz, 1H), 3.91 (d, J = 10.5 Hz, 2H), 3.55 (dd, J = 26.2, 12.9 Hz, 2H), 2.87 (s, 2H), 2.73 (s, 1H), 2.50 (s, 3H), 2.12 (s, 1H), 2.03 (s, 2H), 1.90 (ddd, J = 29.9, 26.2, 13.5 Hz, 3H), 1.66 (d, J = 10.2 Hz, 1H)。    41A

7-{6-乙醯基-2,6-二氮雜螺[4.5]癸-2-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 440 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 4.53 (d, J = 10.8 Hz, 1H), 4.14 (dd, J = 15.7, 9.6 Hz, 2H), 4.00 (td, J = 9.2, 2.6 Hz, 1H), 3.57 - 3.50 (m, 1H), 3.46 - 3.39 (m, 1H), 2.46 (s, 3H), 2.35 (dd, J = 12.6, 8.6 Hz, 1H), 2.05 (s, 3H), 1.81 - 1.39 (m, 7H)。 鏡像異構體之混合物    42A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-甲醯胺 LC-MS:m/z 385.9 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 7.38 (s, 1H), 6.88 (s, 1H), 3.88 (d, J = 12.6 Hz, 2H), 3.50 - 3.39 (m, 2H), 2.50 - 2.48 (m, 3H), 2.46 - 2.37 (m, 1H), 1.93 - 1.76 (m, 4H)。    43A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-甲基哌啶-4-甲醯胺 LC-MS:m/z 400 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 7.83 (q, J = 4.2 Hz, 1H), 3.88 (d, J = 12.5 Hz, 2H), 3.51 - 3.37 (m, 2H), 2.61 (d, J = 4.6 Hz, 3H), 2.50 (s, 3H), 2.40 (dd, J = 14.7, 6.7 Hz, 1H), 1.89 - 1.79 (m, 4H)。    44A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,N-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 3.89 (d, J = 12.6 Hz, 2H), 3.59 - 3.45 (m, 2H), 3.09 (s, 3H), 2.97 (dt, J = 14.8, 7.9 Hz, 1H), 2.85 (s, 3H), 2.50 (s, 3H), 1.84 (dt, J = 9.0, 6.7 Hz, 4H)。       45A

3-氯-7-[(3S,4S)-3-羥基-4-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 5.58 (s, 1H), 3.95 - 3.85 (m, 2H), 3.77 (s, 1H), 3.58 (s, 2H), 2.48 (s, 3H), 1.76 (dd, J = 23.1, 11.8 Hz, 2H), 1.51 (d, J = 9.4 Hz, 1H), 0.97 (d, J = 6.4 Hz, 3H)。 相對立體化學順式-鏡像異構體之混合物 46A

3-氯-7-[(3R,4S)-3-羥基-4-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 ¹H  NMR (400 MHz, CD3OD) δ 3.92 (ddd, J = 12.0, 4.4, 1.9 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.52 - 3.43 (m, 2H), 3.23 (dd, J = 12.0, 9.4 Hz, 1H), 2.52 (s, 3H), 1.95 - 1.87 (m, 1H), 1.62 - 1.54 (m, 2H), 1.16 (dd, J = 6.1, 2.4 Hz, 3H)。 相對立體化學反式-經任意指配之絕對立體化學(99% ee)    47A

3-氯-7-[(3S,4R)-3-羥基-4-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 ¹H NMR (400 MHz, CD3OD) δ 3.92 (ddd, J = 12.0, 4.4, 1.9 Hz, 1H), 3.81 (d, J = 10.1 Hz, 1H), 3.49 (d, J = 20.5, 12.5, 8.2 Hz, 2H), 3.23 (dd, J = 12.0, 9.4 Hz, 1H), 2.52 (s, 3H), 1.96 - 1.88 (m, 1H), 1.58 (dd, J = 14.1, 7.1 Hz, 2H), 1.15 (d, J = 6.0 Hz, 3H)。 相對立體化學反式-經任意指配之絕對立體化學(91% ee)       48A

3-氯-7-[(3S,4S)-3-羥基-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 3.98 - 3.84 (m, 3H), 3.82 - 3.72 (m, 1H), 3.66 (dd, J = 10.8, 5.9 Hz, 1H), 3.48 (t, J = 11.6 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.53 (s, 3H), 2.04 (d, J = 5.7 Hz, 1H), 1.76 - 1.62 (m, 2H)。 相對立體化學反式-鏡像異構體之混合物 49A

3-氯-7-[(3S,4R)-3-羥基-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.09 (s, 1H), 4.00 (dt, J = 14.3, 2.5 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.59 (dd, J = 10.7, 6.9 Hz, 1H), 3.48 (ddd, J = 14.2, 11.0, 3.5 Hz, 3H), 2.40 (s, 3H), 1.76 (ddd, J = 16.6, 9.6, 3.9 Hz, 2H), 1.53 (dd, J = 12.1, 2.5 Hz, 1H)。 相對立體化學順式-經任意指配之絕對立體化學(97% ee)    50A

3-氯-7-[(3R,4S)-3-羥基-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389 (M+H)。 ¹H NMR (400 MHz, MeOD) δ 4.18 (s, 1H), 4.10 (dt, J = 14.2, 2.4 Hz, 1H), 3.98 (dd, J = 8.5, 6.5 Hz, 1H), 3.68 (dd, J = 10.7, 6.9 Hz, 1H), 3.62 - 3.53 (m, 3H), 2.50 (s, 3H), 1.95 - 1.76 (m, 2H), 1.67 - 1.57 (m, 1H)。 相對立體化學順式-經任意指配之絕對立體化學(93% ee)    51A

3-氯-2-甲基-7-(2-氧雜-7-氮雜螺[4.5]癸-7-基)-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈 LC-MS:m/z 399 (M+H)。 ¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 4.34 (q, J= 5.9 Hz, 4H), 3.83 (s, 2H), 3.49-3.41 (m, 2H), 2.54 (s, 3H), 1.97-1.87 (m, 2H), 1.80-1.69 (m, 2H) 鏡像異構體之混合物 52A

3-氯-7-(4-環丙基哌𠯤-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 383.9 (M+H)。    53A

3-氯-2-甲基-7-[4-(2-甲基丙基)哌𠯤-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 400 (M+H)。    54A

3-氯-2-甲基-7-[4-(丙-2-基)哌𠯤-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 385.9 (M+H)。    55A

3-氯-2-甲基-7-(4-甲基哌𠯤-1-基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 358 (M+H)。    56A

3-氯-7-[(3S,4R)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 相對立體化學順式-經任意指配之絕對立體化學(97% ee)    57A

3-氯-7-[(3R,4S)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 相對立體化學順式-經任意指配之絕對立體化學(99% ee)    1B

3-氯-7-[(3R,4R)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 ¹H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.81 (t, J = 12.5 Hz, 2H), 3.47 (dd, J = 17.1, 7.0 Hz, 1H), 3.25 (dq, J = 14.1, 4.8 Hz, 1H), 3.10 (dd, J = 12.4, 10.5 Hz, 1H), 2.51 (s, 3H), 2.00 (dd, J = 12.8, 3.5 Hz, 1H), 1.78 - 1.59 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-經任意指配之絕對立體化學(90% ee)    1A

3-氯-7-[(3S,4S)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 ¹H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.81 (t, J = 12.5 Hz, 2H), 3.47 (dd, J = 17.1, 7.0 Hz, 1H), 3.25 (dq, J = 14.1, 4.8 Hz, 1H), 3.10 (dd, J = 12.4, 10.5 Hz, 1H), 2.51 (s, 3H), 2.00 (dd, J = 12.8, 3.5 Hz, 1H), 1.78 - 1.59 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H)。 相對立體化學反式- 經任意指配之絕對立體化學(99% ee) 60A

3-氯-7-[(3R,5R)-3-羥基-5-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 相對立體化學反式- 經任意指配之絕對立體化學(99% ee)    61A

3-氯-7-[(3S,5S)-3-羥基-5-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 相對立體化學反式- 經任意指配之絕對立體化學(99% ee)    62A

3-氯-7-[(3R)-3-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359 (M+H)。 絕對立體化學-單一鏡像異構體 63A

3-氯-7-[(3S)-3-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359 (M+H)。 絕對立體化學-單一鏡像異構體 64A

3-氯-2-甲基-7-[(2R)-2-甲基嗎啉-4-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359.1 (M+H)。 絕對立體化學-單一鏡像異構體 65A

3-氯-7-[(2S)-2-(甲氧基甲基)嗎啉-4-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 絕對立體化學-單一鏡像異構體 66A

3-氯-7-[(3S)-3-(羥甲基)吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359.1 (M+H)。 絕對立體化學-單一鏡像異構體 67A

3-氯-2-甲基-7-(吡咯啶-1-基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 329 (M+H)。    68A

3-氯-7-[(2R,6S)-2,6-二甲基嗎啉-4-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。    69A

3-氯-7-(4,4-二氟哌啶-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 379.1 (M+H)。    70A

3-氯-2-甲基-7-(哌啶-1-基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 343.1 (M+H)。    71A

3-氯-2-甲基-7-(嗎啉-4-基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 345 (M+H)。    The compounds in the table below were prepared using the above procedures from appropriate starting materials either previously described or commercially available. Table 1A Compound number structure ¹ H-NMR 5A

3-Chloro-2-methyl-7-{[(1r,4r)-4-hydroxycyclohexyl]amino}-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine -6-carbonitrile 9280 LC-MS: m/z 373.1 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.94 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.62 (d, J = 4.8 Hz, 1H), 4.22 (dd, J = 11.5, 7.2 Hz, 1H), 3.47 (dt, J = 14.3, 5.1 Hz, 1H), 2.45 (s, 3H), 2.06 (d, J = 13.5 Hz, 2H), 1.89 (d, J = 11.6 Hz, 2H), 1.44 - 1.25 (m, 4H). relative stereochemistry trans 2B

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4-carboxylic acid LC-MS: m/z 387 (M+H). ¹ H NMR (400 MHz, MeOD) δ 3.91 (dt, J = 12.5, 3.2 Hz, 2H), 3.58 - 3.46 (m, 2H), 2.63 (tt, J = 10.7, 4.1 Hz, 1H), 2.53 (s , 3H), 2.18 - 2.08 (m, 2H), 2.05 - 1.97 (m, 2H). 7A

7-(azetidin-1-yl)-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 314.9 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.80 - 4.74 (m, 4H), 2.54 (d, J = 7.7 Hz, 2H), 2.46 (s, 3H). 8A

3-Chloro-7-(3-hydroxyazetidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6- Formaldehyde LC-MS: m/z 330.9 (M+H). ¹ H NMR (400 MHz, MeOD) δ 5.05 - 4.97 (m, 2H), 4.77 - 4.69 (m, 1H), 4.53 - 4.45 (m, 2H), 2.47 (s, 3H). 9A

3-Chloro-7-{2,6-diazaspiro[3.5]non-6-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 384 (M+H). ¹ H NMR (400 MHz, MeOD) δ 3.81 (s, 1H), 3.55 (d, J = 3.4 Hz, 2H), 3.51 (dd, J = 9.5, 4.3 Hz, 2H), 3.30 (m, 4H), 2.56 (s, 3H), 1.99 - 1.81 (m, 4H). 10A

3-Chloro-7-{2,7-diazaspiro[4.5]dec-7-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 398 (M+H). ¹ H NMR (400 MHz, MeOD) δ 3.69 - 3.33 (m, 8H), 3.18 (d, J = 12.2 Hz, 1H), 2.56 (s, 3H), 2.19 - 2.09 (m, 1H), 2.00 - 1.93 (m, 3H), 1.92 - 1.75 (m, 2H). mixture of mirror isomers 11A

3-Chloro-2-methyl-7-(2,8-diazaspiro[4.5]dec-8-yl)-5-(trifluoromethyl)-1 H -pyrrolo[3,2- b ]pyridine-6-carbonitrile formate LC-MS: m/z 398 (M+H). ¹ H NMR (400 MHz, MeOD) δ 3.71 (t, J = 5.5 Hz, 4H), 3.44 (t, J = 7.5 Hz, 2H), 3.22 (s, 2H), 2.54 (s, 3H), 2.09 ( t, J = 7.5 Hz, 2H), 2.01 - 1.86 (m, 4H). 4B

3-Chloro-7-{1,7-diazaspiro[4.5]dec-7-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 398 (M+H). ¹ H NMR (400 MHz, CD3OD) δ 3.72 (q, J = 12.5 Hz, 3H), 3.43 - 3.34 (m, 3H), 2.57 (s, 3H), 2.07 (ddd, J = 16.0, 12.3, 6.1 Hz , 5H), 2.02 - 1.91 (m, 3H). mixture of mirror isomers 13A

3-Chloro-7-((2-(dimethylamino)ethyl)amino)-2-methyl-5-(trifluoromethyl)-1 H -pyrrolo[3,2- b ]pyridine -6-carbonitrile formate LC-MS: m/z 346 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.02 (t, J = 6.0 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 2.63 (s, 6H), 2.50 (s, 3H). 14A

3-Chloro-2-methyl-7-(3-oxopiper-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-methyl Nitrile LC-MS: m/z 358 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 8.19 (s, 1H), 4.28 (s, 2H), 3.84 (t, J = 5.1 Hz, 2H), 3.45 (s, 2H), 2.51 (s, 3H). 15A

3-Chloro-2-methyl-7-(4-methyl-3-oxopiper-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 372 (M+H). ¹ H NMR (400 MHz, CD3OD) δ 4.35 (s, 2H), 4.00 - 3.93 (m, 2H), 3.69 - 3.63 (m, 2H), 3.07 (s, 3H), 2.55 (s, 3H). 16A

3-Chloro-7-(1,1-dioxo-1λ ⁶ -thiomorpholin-4-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 393 (M+H). ¹ H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 4.07 - 3.95 (m, 4H), 3.44 - 3.39 (m, 4H), 2.53 (s, 3H). 17A

7-{2-acetyl-2,8-diazaspiro[4.5]dec-8-yl}-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 440 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 8.00 (d, J = 4.6 Hz, 1H), 4.04 (dd, J = 14.2, 6.8 Hz, 1H), 3.98 - 3.91 (m, 1H ), 3.87 (d, J = 12.9 Hz, 1H), 3.71 (dt, J = 11.2, 7.7 Hz, 2H), 3.57 (dd, J = 15.6, 7.5 Hz, 1H), 3.35 (s, 2H), 2.61 (d, J = 4.6 Hz, 3H), 2.53 (s, 3H), 2.53-2.49 (m, 4H), 2.43 - 2.31 (m, 2H). 18A

2-{4-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]morpholine-2 -yl}-N-methylacetamide LC-MS: m/z 416 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.19 - 4.10 (m, 1H), 3.99 (dd, J = 19.9, 7.4 Hz, 2H), 3.84 (ddd, J = 18.6, 13.6, 7.8 Hz, 2H), 3.69 - 3.62 (m, 1H), 3.37 (dd, J = 12.9, 9.9 Hz, 1H), 2.76 (s, 3H), 2.56 (s, 3H), 2.55 - 2.44 (m, 2H). mixture of mirror isomers 19A

2-{4-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]morpholine-2 -yl}-N,N-Dimethylacetamide LC-MS: m/z 430 (M+H). ¹ H NMR (400 MHz, DMSO) δ 12.26 (s, 1H), 4.08 (t, J = 13.4 Hz, 2H), 3.89 (dd, J = 24.4, 10.6 Hz, 2H), 3.72 - 3.59 (m, 2H ), 3.30 - 3.25 (m, 1H), 3.01 (s, 3H), 2.90 (s, 3H), 2.77 (dd, J = 16.6, 4.5 Hz, 1H), 2.62 (dd, J = 16.6, 8.6 Hz, 1H), 2.55 (s, 3H). mixture of mirror isomers 20A

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}acetamide LC-MS: m/z 400 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.09 - 3.84 (m, 3H), 3.63 - 3.50 (m, 2H), 2.11 - 2.00 (m, 6H), 1.96 (s, 3H), 1.78 (dd, J = 12.2, 3.7 Hz, 2H). 21A

3-Chloro-2-methyl-7-{6-oxa-2-azaspiro[3.4]oct-2-yl}-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 371 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 4.70 (s, 4H), 3.87 (s, 2H), 3.76 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.24 (t, J = 7.0 Hz, 2H). 22A

3-Chloro-2-methyl-7-{8-oxa-2-azaspiro[4.5]dec-2-yl}-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 399 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.17 (t, J = 7.0 Hz, 2H), 3.98 (s, 2H), 3.76 (dd, J = 10.7, 5.7 Hz, 4H), 2.49 (s, 3H), 2.04 (dd, J = 9.1, 4.9 Hz, 2H), 1.72 (dd, J = 11.3, 6.8 Hz, 4H). 23A

3-Chloro-7-{2,5-dioxa-8-azaspiro[3.5]non-8-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 426 (M+H). ¹ H NMR (400 MHz, DMSO) δ 4.59 - 4.45 (m, 4H), 3.88 (s, 2H), 3.87 - 3.83 (m, 2H), 3.63 - 3.52 (m, 2H), 2.54 (s, 3H) . 24A

7-{2-acetyl-2,6-diazaspiro[3.5]non-6-yl}-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 426 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 3.90 (d, J = 8.2 Hz, 1H), 3.81 (dd, J = 18.1, 9.8 Hz, 2H), 3.69 (d, J = 11.4 Hz, 1H), 3.62 - 3.50 (m, 3H), 3.39 (dd, J = 11.5, 5.3 Hz, 1H), 2.53 (s, 3H), 1.93 - 1.85 (m, 1H), 1.83 - 1.75 (m, 3H), 1.71 (s, 3H). 25A

7-{2-Acetyl-2,7-diazaspiro[4.5]dec-7-yl}-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 440.2 (M+H). ¹ H NMR (400 MHz, CD3OD) δ 3.74 (d, J = 10.7 Hz, 1H), 3.63 - 3.50 (m, 6H), 3.45 - 3.38 (m, 1H), 3.24 (d, J = 12.3 Hz, 1H ), 2.54 (d, J = 2.5 Hz, 3H), 2.21 - 2.14 (m, 1H), 2.02 - 1.75 (m, 8H). mixture of mirror isomers 4C

7-{1-acetyl-1,7-diazaspiro[4.5]dec-7-yl}-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 440 (M+H). ¹ H NMR (400 MHz, CD3OD) δ 4.50 (d, J = 10.2 Hz, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.60 (ddd, J = 15.3, 10.5, 5.8 Hz, 2H), 3.37 - 3.33 (m, 2H), 3.07 (td, J = 13.3, 4.6 Hz, 1H), 2.53 (s, 3H), 2.40 - 2.30 (m, 1H), 2.25 - 2.11 (m, 1H), 2.09 ( s, 3H), 2.01 - 1.91 (m, 1H), 1.90 - 1.78 (m, 3H), 1.63 (d, J = 14.1 Hz, 1H). mixture of mirror isomers 27A

4-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]morpholine-2-formyl amine LC-MS: m/z 387.9 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.36 (dd, J = 6.1, 4.2 Hz, 1H), 4.09 - 4.02 (m, 1H), 4.01 - 3.94 (m, 1H), 3.92 - 3.77 (m, 3H) , 3.64 (ddd, J = 12.4, 7.6, 3.1 Hz, 1H), 2.54 (s, 3H). mixture of mirror isomers 28A

4-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-methylmorpholine -2-Formamide LC-MS: m/z 402 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.42 - 4.27 (m, 1H), 4.07 - 3.93 (m, 2H), 3.91 - 3.77 (m, 3H), 3.62 (ddd, J = 12.4, 7.6, 3.2 Hz, 1H), 2.83 (s, 3H), 2.55 (s, 3H). mixture of mirror isomers 3B

4-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N,N-dimethyl Morpholine-2-carboxamide LC-MS: m/z 415.9 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.67 (dd, J = 7.1, 3.1 Hz, 1H), 3.87 (dddd, J = 29.9, 14.8, 9.2, 2.5 Hz, 5H), 3.63 (td, J = 11.0, 5.0 Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H). mixture of mirror isomers 30A

7-(2-(aminomethyl)N-morpholinyl)-3-chloro-2-methyl-5-(trifluoromethyl)-1 H -pyrrolo[3,2- b ]pyridine-6 -Formonitrile hydrochloride LC-MS: m/z 374 (M+H). 1H NMR (400 MHz, DMSO) δ 12.15 (s, 1H), 8.13 (s, 3H), 4.10 (d, J = 11.1 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.81 (ddd, J = 27.2, 22.8, 12.9 Hz, 3H), 3.61 - 3.47 (m, 2H), 3.09 (dd, J = 9.6, 3.5 Hz, 1H), 2.99 - 2.88 (m, 1H), 2.57 (s, 3H). mixture of mirror isomers 31A

N-({4-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]morpholine- 2-yl}methyl)acetamide LC-MS: m/z 416.1 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.00 (t, J = 5.7 Hz, 1H), 4.02 (d, J = 11.4 Hz, 1H), 3.80 (d, J = 12.3 Hz, 1H), 3.75 - 3.65 (m, 3H), 3.63 - 3.55 (m, 1H), 3.22 (ddd, J = 16.3, 10.5, 6.3 Hz, 3H), 2.52 (s, 3H), 1.82 (s, 3H) . mixture of mirror isomers 32A

3-Chloro-7-{2,2-dioxo-2λ ⁶ -thia-7-azaspiro[4.4]non-7-yl}-2-methyl-5-(trifluoromethyl) -1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 433.1 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 4.20 - 4.04 (m, 4H), 3.35 (d, J = 13.5 Hz, 2H), 3.28 (t, J = 8.9 Hz, 2H), 2.48 (s, 3H), 2.34 - 2.20 (m, 3H), 2.15 - 2.07 (m, 1H). mixture of mirror isomers 33A

3-Chloro-2-methyl-7-{2-oxa-6-azaspiro[3.5]non-6-yl}-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 385.1 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 4.34 (q, J = 5.9 Hz, 4H), 3.83 (s, 2H), 3.49 - 3.41 (m, 2H), 2.54 (s, 3H ), 1.97 - 1.87 (m, 2H), 1.80 - 1.69 (m, 2H). 34A

3-Chloro-7-{2,2-dioxo-2λ ⁶ -thia-7-azaspiro[4.5]dec-7-yl}-2-methyl-5-(trifluoromethyl) -1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 447 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 3.70 - 3.57 (m, 2H), 3.46 (dd, J = 43.7, 13.3 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H ), 3.11 (q, J = 13.7 Hz, 2H), 2.54 (s, 3H), 2.16 (dt, J = 14.0, 7.0 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.95 - 1.79 (m, 3H), 1.73 (dd, J = 13.1, 6.7 Hz, 1H). mixture of mirror isomers 35A

3-Chloro-7-{2,6-dioxa-9-azaspiro[4.5]dec-9-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 400.9 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 3.98 - 3.86 (m, 2H), 3.86 - 3.72 (m, 4H), 3.72 - 3.63 (m, 2H), 3.63 - 3.50 (m, 2H), 2.53 (s, 3H), 2.08 - 2.04 (m, 2H). mixture of mirror isomers 36A

3-chloro-7-{2,2-two side oxy-6-oxa-2λ ⁶ -thia-9-azaspiro[4.5]dec-9-yl}-2-methyl-5-( Trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 449 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 4.00 (t, J = 4.7 Hz, 2H), 3.75 (dd, J = 32.1, 11.9 Hz, 2H), 3.56 (dd, J = 9.7 , 4.4 Hz, 3H), 3.40 (s, 1H), 3.30 - 3.21 (m, 2H), 2.54 (s, 3H), 2.28 (ddd, J = 13.8, 10.7, 8.2 Hz, 1H), 2.07 (s, 1H). mixture of mirror isomers 37A

3-Chloro-2-methyl-7-(2,7-diazaspiro[3.5]non-7-yl)-5-(trifluoromethyl)-1 H -pyrrolo[3,2- b ]pyridine-6-carbonitrile hydrochloride LC-MS: m/z 384 (M+H). ¹ H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 3.74 (s, 4H), 3.58 (s, 4H), 2.48 (s, 3H), 1.99 (s, 4H). 38A

7-{2-acetyl-2,7-diazaspiro[3.5]non-7-yl}-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 426.1 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 3.91 (s, 2H), 3.64 (s, 2H), 3.62 - 3.55 (m, 4H), 2.51 (s, 3H), 1.98 - 1.89 (m, 4H), 1.79 (s, 3H). 39A

3-Chloro-2-methyl-7-(2,6-diazaspiro[4.5]dec-2-yl)-5-(trifluoromethyl)-1 H -pyrrolo[3,2- b ]pyridine-6-carbonitrile hydrochloride LC-MS: m/z 398 (M+H). ¹ H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 4.28 (q, J = 7.8 Hz, 1H), 4.07 - 3.92 (m, 3H), 2.83 (s, 2H), 2.47 (s, 3H ), 2.20 (s, 1H), 2.02 - 1.86 (m, 1H), 1.65 (d, J = 28.6 Hz, 4H), 1.48 (s, 2H). mixture of mirror isomers 40A

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}-N-methylacetamide LC-MS: m/z 414.2 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.73 (s, 1H), 4.56 (dd, J = 14.1, 10.2 Hz, 1H), 3.91 (d, J = 10.5 Hz, 2H), 3.55 (dd, J = 26.2 , 12.9 Hz, 2H), 2.87 (s, 2H), 2.73 (s, 1H), 2.50 (s, 3H), 2.12 (s, 1H), 2.03 (s, 2H), 1.90 (ddd, J = 29.9, 26.2, 13.5 Hz, 3H), 1.66 (d, J = 10.2 Hz, 1H). 41A

7-{6-acetyl-2,6-diazaspiro[4.5]dec-2-yl}-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 440 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 4.53 (d, J = 10.8 Hz, 1H), 4.14 (dd, J = 15.7, 9.6 Hz, 2H), 4.00 (td, J = 9.2 , 2.6 Hz, 1H), 3.57 - 3.50 (m, 1H), 3.46 - 3.39 (m, 1H), 2.46 (s, 3H), 2.35 (dd, J = 12.6, 8.6 Hz, 1H), 2.05 (s, 3H), 1.81 - 1.39 (m, 7H). mixture of mirror isomers 42A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4-formyl amine LC-MS: m/z 385.9 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 7.38 (s, 1H), 6.88 (s, 1H), 3.88 (d, J = 12.6 Hz, 2H), 3.50 - 3.39 (m, 2H ), 2.50 - 2.48 (m, 3H), 2.46 - 2.37 (m, 1H), 1.93 - 1.76 (m, 4H). 43A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-methylpiperidine -4-formamide LC-MS: m/z 400 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 7.83 (q, J = 4.2 Hz, 1H), 3.88 (d, J = 12.5 Hz, 2H), 3.51 - 3.37 (m, 2H), 2.61 (d, J = 4.6 Hz, 3H), 2.50 (s, 3H), 2.40 (dd, J = 14.7, 6.7 Hz, 1H), 1.89 - 1.79 (m, 4H). 44A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N,N-dimethyl Piperidine-4-carboxamide LC-MS: m/z 414 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 3.89 (d, J = 12.6 Hz, 2H), 3.59 - 3.45 (m, 2H), 3.09 (s, 3H), 2.97 (dt, J = 14.8, 7.9 Hz, 1H), 2.85 (s, 3H), 2.50 (s, 3H), 1.84 (dt, J = 9.0, 6.7 Hz, 4H). 45A

3-chloro-7-[(3S,4S)-3-hydroxyl-4-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 5.58 (s, 1H), 3.95 - 3.85 (m, 2H), 3.77 (s, 1H), 3.58 (s, 2H), 2.48 (s , 3H), 1.76 (dd, J = 23.1, 11.8 Hz, 2H), 1.51 (d, J = 9.4 Hz, 1H), 0.97 (d, J = 6.4 Hz, 3H). Relative Stereochemistry cis-Mixture of Enantiomers 46A

3-chloro-7-[(3R,4S)-3-hydroxyl-4-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). ¹ H NMR (400 MHz, CD3OD) δ 3.92 (ddd, J = 12.0, 4.4, 1.9 Hz, 1H), 3.84 - 3.78 (m, 1H), 3.52 - 3.43 (m, 2H), 3.23 (dd, J = 12.0, 9.4 Hz, 1H), 2.52 (s, 3H), 1.95 - 1.87 (m, 1H), 1.62 - 1.54 (m, 2H), 1.16 (dd, J = 6.1, 2.4 Hz, 3H). Relative Stereochemistry Trans - Arbitrarily Assigned Absolute Stereochemistry (99% ee) 47A

3-chloro-7-[(3S,4R)-3-hydroxyl-4-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). ¹ H NMR (400 MHz, CD3OD) δ 3.92 (ddd, J = 12.0, 4.4, 1.9 Hz, 1H), 3.81 (d, J = 10.1 Hz, 1H), 3.49 (d, J = 20.5, 12.5, 8.2 Hz , 2H), 3.23 (dd, J = 12.0, 9.4 Hz, 1H), 2.52 (s, 3H), 1.96 - 1.88 (m, 1H), 1.58 (dd, J = 14.1, 7.1 Hz, 2H), 1.15 ( d, J = 6.0 Hz, 3H). Relative Stereochemistry Trans - Arbitrarily Assigned Absolute Stereochemistry (91% ee) 48A

3-Chloro-7-[(3S,4S)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389 (M+H). ¹ H NMR (400 MHz, MeOD) δ 3.98 - 3.84 (m, 3H), 3.82 - 3.72 (m, 1H), 3.66 (dd, J = 10.8, 5.9 Hz, 1H), 3.48 (t, J = 11.6 Hz , 1H), 3.28 - 3.22 (m, 1H), 2.53 (s, 3H), 2.04 (d, J = 5.7 Hz, 1H), 1.76 - 1.62 (m, 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers 49A

3-Chloro-7-[(3S,4R)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.09 (s, 1H), 4.00 (dt, J = 14.3, 2.5 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.59 (dd, J = 10.7, 6.9 Hz , 1H), 3.48 (ddd, J = 14.2, 11.0, 3.5 Hz, 3H), 2.40 (s, 3H), 1.76 (ddd, J = 16.6, 9.6, 3.9 Hz, 2H), 1.53 (dd, J = 12.1 , 2.5 Hz, 1H). Relative stereochemistry cis-Absolute stereochemistry with random assignment (97% ee) 50A

3-Chloro-7-[(3R,4S)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.18 (s, 1H), 4.10 (dt, J = 14.2, 2.4 Hz, 1H), 3.98 (dd, J = 8.5, 6.5 Hz, 1H), 3.68 (dd, J = 10.7, 6.9 Hz, 1H), 3.62 - 3.53 (m, 3H), 2.50 (s, 3H), 1.95 - 1.76 (m, 2H), 1.67 - 1.57 (m, 1H). Relative stereochemistry cis-Absolute stereochemistry with random assignment (93% ee) 51A

3-Chloro-2-methyl-7-(2-oxa-7-azaspiro[4.5]dec-7-yl)-5-(trifluoromethyl)-1 H -pyrrolo[3,2 -b ]pyridine-6-carbonitrile LC-MS: m/z 399 (M+H). ¹ H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 4.34 (q, J = 5.9 Hz, 4H), 3.83 (s, 2H), 3.49-3.41 (m, 2H), 2.54 (s, 3H ), 1.97-1.87 (m, 2H), 1.80-1.69 (m, 2H) mixture of enantiomers 52A

3-Chloro-7-(4-cyclopropylpiper-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-methyl Nitrile LC-MS: m/z 383.9 (M+H). 53A

3-Chloro-2-methyl-7-[4-(2-methylpropyl)piper-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 400 (M+H). 54A

3-Chloro-2-methyl-7-[4-(propan-2-yl)piper-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine -6-carbonitrile LC-MS: m/z 385.9 (M+H). 55A

3-Chloro-2-methyl-7-(4-methylpiper-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 358 (M+H). 56A

3-Chloro-7-[(3S,4R)-4-hydroxyl-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). Relative stereochemistry cis-Absolute stereochemistry with random assignment (97% ee) 57A

3-Chloro-7-[(3R,4S)-4-hydroxyl-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). Relative Stereochemistry cis-Absolute Stereochemistry with Arbitrary Assignment (99% ee) 1B

3-Chloro-7-[(3R,4R)-4-hydroxy-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). ¹ H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.81 (t, J = 12.5 Hz, 2H), 3.47 (dd, J = 17.1 , 7.0 Hz, 1H), 3.25 (dq, J = 14.1, 4.8 Hz, 1H), 3.10 (dd, J = 12.4, 10.5 Hz, 1H), 2.51 (s, 3H), 2.00 (dd, J = 12.8, 3.5 Hz, 1H), 1.78 - 1.59 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans - Arbitrarily Assigned Absolute Stereochemistry (90% ee) 1A

3-Chloro-7-[(3S,4S)-4-hydroxy-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). ¹ H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.81 (t, J = 12.5 Hz, 2H), 3.47 (dd, J = 17.1 , 7.0 Hz, 1H), 3.25 (dq, J = 14.1, 4.8 Hz, 1H), 3.10 (dd, J = 12.4, 10.5 Hz, 1H), 2.51 (s, 3H), 2.00 (dd, J = 12.8, 3.5 Hz, 1H), 1.78 - 1.59 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans- Arbitrarily Assigned Absolute Stereochemistry (99% ee) 60A

3-chloro-7-[(3R,5R)-3-hydroxy-5-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). Relative Stereochemistry Trans- Arbitrarily Assigned Absolute Stereochemistry (99% ee) 61A

3-chloro-7-[(3S,5S)-3-hydroxyl-5-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). Relative Stereochemistry Trans- Arbitrarily Assigned Absolute Stereochemistry (99% ee) 62A

3-Chloro-7-[(3R)-3-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 359 (M+H). Absolute Stereochemistry - Single Mirror Isomer 63A

3-Chloro-7-[(3S)-3-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 359 (M+H). Absolute Stereochemistry - Single Mirror Isomer 64A

3-Chloro-2-methyl-7-[(2R)-2-methylmorpholin-4-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine- 6-carbonitrile LC-MS: m/z 359.1 (M+H). Absolute Stereochemistry - Single Mirror Isomer 65A

3-Chloro-7-[(2S)-2-(methoxymethyl)morpholin-4-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). Absolute Stereochemistry - Single Mirror Isomer 66A

3-Chloro-7-[(3S)-3-(hydroxymethyl)pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b ]pyridine-6-carbonitrile LC-MS: m/z 359.1 (M+H). Absolute Stereochemistry - Single Mirror Isomer 67A

3-Chloro-2-methyl-7-(pyrrolidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 329 (M+H). 68A

3-chloro-7-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). 69A

3-Chloro-7-(4,4-difluoropiperidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6- Formaldehyde LC-MS: m/z 379.1 (M+H). 70A

3-Chloro-2-methyl-7-(piperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 343.1 (M+H). 71A

3-Chloro-2-methyl-7-(morpholin-4-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 345 (M+H).

步驟 1 ：合成 72A在0℃下在N ₂氛圍下，向 11(200 mg，0.683 mmol)於THF (20 mL)中之混合物中添加NaH (41 mg，1.025 mmol，60%於礦物油中)。在0℃下攪拌30分鐘之後，逐滴添加CH ₃I (97 mg，0.683 mmol)且在室溫下在氮氣氛圍下攪拌所得混合物2小時。隨後混合物用冰水(20 mL)淬滅且用EtOAc (20 mL×3)萃取。合併之有機層用鹽水洗滌，經Na ₂SO ₄乾燥，過濾且真空濃縮。藉由矽膠管柱層析(用PE:EtOAc=100:0至3:1溶離)純化殘餘物，得到呈白色固體狀之 72AB(42 mg，20.1%產率)。 Synthetic 72B

Step 1 : Synthesis of 72A To a mixture of 11 (200 mg, 0.683 mmol) in THF (20 mL) was added NaH (41 mg, 1.025 mmol, 60% in mineral oil) at 0 °C under _N2 atmosphere . After stirring at 0 °C for 30 min, _CH3I (97 mg, 0.683 mmol) was added dropwise and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. Then the mixture was quenched with ice water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic _layers were washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE:EtOAc=100:0 to 3:1) to afford 72AB (42 mg, 20.1% yield) as a white solid.

Step 2 : Synthesis of 72B A mixture of 72A (42 mg, 0.137 mmol), piperidin-4-ol (28 mg, 0.274 mmol) and DIEA (53 mg, 0.411 mmol) in MeCN (10 mL) was stirred at 80 °C 2 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified via preparative HPLC to afford 72B (18 mg, 35.2% yield) as a white solid. LC/MS (ESI) m/z: 373 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 4.84 (d, J = 3.9 Hz, 1H), 4.09 (s, 3H), 3.73 (s, 1H), 3.51 (s, 2H), 3.40 - 3.32 (m, 2H ), 2.52 (s, 3H), 1.98 - 1.87 (m, 2H), 1.71 - 1.60 (m, 2H).

步驟 1 ：合成 73A向 11(24 mg，0.204 mmol)及( S)-嗎啉-2-基甲醇(50 mg，0.170 mmol)於CH ₃CN (8 mL)中之混合物中添加DIEA (44 mg，0.340 mmol)，且在80℃下攪拌所得混合物2小時。隨後將反應混合物冷卻至室溫且真空濃縮。經由製備型HPLC純化殘餘物，得到呈白色固體狀之 73A(30 mg，39.2%產率)。 Synthetic 73B

Step 1 : Synthesis of 73A DIEA ( 44 _mg , 0.340 mmol), and the resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified via preparative HPLC to afford 73A (30 mg, 39.2% yield) as a white solid.

Step 2 : Synthesis of 73B To a solution of 73A (25 mg, 0.067 mmol) in DCM (5 mL) was added TEA (21 mg, 0.200 mmol) and acetyl chloride (9 mg, 0.080 mmol) at 0 °C, and The resulting mixture was stirred at 25°C for 12 hours. The mixture was then concentrated in vacuo and the residue was purified via preparative HPLC to afford 73B (10 mg, 36.0% yield) as a white solid. LC-MS : m/z 417 (M+H). ¹ H NMR (400 MHz, MeOD) δ 4.24 (dd, J = 11.6, 5.7 Hz, 1H), 4.16 - 3.99 (m, 3H), 3.96 - 3.82 (m, 2H), 3.76 - 3.62 (m, 2H) , 3.42 (dd, J = 12.3, 10.1 Hz, 1H), 2.54 (s, 3H), 2.08 (s, 3H).

步驟 1 ：合成 11-F向 10(50 mg，0.193 mmol)於MeCN (5 mL)中之溶液中添加Selectflour (137 mg，0.385 mmol)，且在室溫下攪拌所得混合物16小時。隨後真空濃縮混合物，且藉由製備型TLC (DCM:EA=10:1)純化殘餘物，得到呈白色固體狀之 11 - F(20.0 mg，42.8%產率，60.2%純度)。LC/MS (ESI) m/z: 278 (M+H) ⁺。 Synthetic 74B

Step 1 : Synthesis of 11-F To a solution of 10 (50 mg, 0.193 mmol) in MeCN (5 mL) was added Selectflour (137 mg, 0.385 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then concentrated in vacuo, and the residue was purified by prep-TLC (DCM:EA=10:1) to afford 11 - F (20.0 mg, 42.8% yield, 60.2% purity) as a white solid. LC/MS (ESI) m/z: 278 (M+H) ⁺ .

Step 2 : Synthesis of 74B To a solution of 11 - F (20 mg, 0.042 mmol, 60.2% purity) in MeCN (5 mL) was added TEA (13 mg, 0.126 mmol) and ( S )-morpholin-2-yl Methanol (8 mg, 0.063 mmol). The resulting mixture was stirred at 80°C for 12 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by prep-TLC (PE:EA=2:1) to give compound 74B (5.9 mg, 19.3% yield) as a white solid. LC/MS (ESI) m/z: 359 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 4.86 (s, 1H), 4.01 (d, J = 12.3 Hz, 1H), 3.83 - 3.63 (m, 4H), 3.60 - 3.44 (m , 3H), 3.39 - 3.35 (m, 1H), 2.48 (d, J = 1.3 Hz, 3H).

步驟 1 ：合成 75A在室溫下在N ₂氛圍下向 10(170 mg，0.578 mmol)、2-(3,6-二氫-2H-哌喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦(122 mg，0.578 mmol)及K ₂CO ₃(160 mg，1.156 mmol)於1,4-二㗁烷/H ₂O (13 mL，10:3)中之混合物中添加Pd(dppf)Cl ₂(21 mg，0.029 mmol)。隨後在85℃下在N ₂氛圍下攪拌所得混合物12小時。隨後使混合物冷卻至室溫，用EtOAc(20 mL)稀釋且過濾。用鹽水(20 mL)洗滌濾液，經無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由急驟管柱層析(用PE/EtOAc=100:0至3:1溶離)純化殘餘物，得到呈白色固體狀之 75A(110 mg，55.6%產率)。LC/MS (ESI) m/z: 308 (M+H) ⁺。 Synthetic 75C

Step 1 : Synthesis of 75A at room temperature under N ₂ atmosphere to 10 (170 mg, 0.578 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaboroxine (122 mg, 0.578 mmol) and K ₂ CO ₃ (160 mg, 1.156 mmol) in 1,4-dioxane/H ₂ O (13 mL , 10:3) was added Pd(dppf) _Cl2 (21 mg, 0.029 mmol). The resulting mixture was then stirred at 85 °C for 12 h under _N2 atmosphere. The mixture was then cooled to room temperature, diluted with EtOAc (20 mL) and filtered. The filtrate was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluted with PE/EtOAc = 100:0 to 3:1) to afford 75A (110 mg, 55.6% yield) as a white solid. LC/MS (ESI) m/z: 308 (M+H) ⁺ .

Step 2 : Synthesis of 75B A mixture of 75A (80 mg, 0.234 mmol) and _PtO2 (25 mg) in methanol (10 mL) was stirred at room temperature under _H2 atmosphere overnight. The mixture was then filtered and concentrated in vacuo to give crude product 75B (70 mg, 96.6% yield) as a white solid, which was used in the next step without any further purification. LC/MS (ESI) m/z: 310 (M+H) ⁺ .

Step 3 : Synthesis of 75C To a solution of 75B (30 mg, 0.097 mmol) in DMF (5 mL) was added NCS (19 mg, 0.146 mmol) portionwise at 0 °C, and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with saturated NH ₄ Cl solution (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (eluted with PE/EtOAc = 100:0 to 5:1) to afford 75C (6 mg, 18.0% yield) as a white solid. LC/MS (ESI) m/z: 344 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.63 (s, 1H), 4.09 - 4.05 (m, 2H), 3.72 - 3.60 (m, 1H), 3.52 (t, J = 11.0 Hz, 2H), 2.57 (s, 3H), 2.45 - 2.29 (m, 2H), 1.71 (d, J = 10.7 Hz, 2H).

步驟 1 ：合成 76A在氮氣氛圍下向 10(200 mg，0.772 mmol)及 1(250 mg，0.927 mmol)於1,4-二㗁烷/H ₂O (48 mL，7:1)中之混合物中添加Pd(dppf)Cl ₂(58 mg，0.080 mmol)及Na ₂CO ₃(250 mg，2.320 mmol)，且在100℃下攪拌混合物12小時。隨後使混合物冷卻至室溫，用EtOAc (50 mL)稀釋且過濾。用鹽水(30 mL)洗滌濾液，經無水Na ₂SO ₄乾燥且真空濃縮。藉由矽膠管柱層析(用PE/EtOAc=100:0至10:1溶離)純化殘餘物，得到呈灰色固體狀之 76A(200 mg，71.4%產率)。LC/MS (ESI) m/z: 364 (M+H) ⁺。 Synthetic 76E

Step 1 : Synthesis of 76A to a mixture of 10 (200 mg, 0.772 mmol) and 1 (250 mg, 0.927 mmol) in 1,4-dioxane/H ₂ O (48 mL, 7:1) under nitrogen atmosphere Pd(dppf)Cl ₂ (58 mg, 0.080 mmol) and Na ₂ CO ₃ (250 mg, 2.320 mmol) were added to , and the mixture was stirred at 100° C. for 12 hours. The mixture was then cooled to room temperature, diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE/EtOAc = 100:0 to 10:1) to afford 76A (200 mg, 71.4% yield) as a gray solid. LC/MS (ESI) m/z: 364 (M+H) ⁺ .

Step 2 : Synthesis of 76B To a solution of 76A (160 mg, 0.402 mmol) in DCM (12 mL) was added TFA (3 mL) dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 12 hours. The mixture was then concentrated in vacuo to afford crude 76B (120 mg, 84.3% yield) as a white solid, which was used in the next step without any further purification. LC/MS (ESI) m/z: 320 (M+H) ⁺ .

Step 3 : Synthesis of 76C On day 0 To a solution of 76B (120 mg, 0.376 mmol) in methanol (5 mL) was added _NaBH4 (13 mg, 0.376 mmol) and the resulting mixture was stirred at room temperature for 1 h. Then the mixture was quenched with ice water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (eluted with PE/EtOAc = 100:0 to 10:1) to afford 76C (100 mg, 82.8% yield) as a white solid. LC/MS (ESI) m/z: 322 (M+H) ⁺ .

Step 4 : Synthesis of 76D A mixture of 76C (50 mg, 0.156 mmol) and _PtO2 (8 mg) in methanol (12 mL) was stirred at room temperature under _H2 atmosphere overnight. The mixture was then filtered and concentrated in vacuo to afford 76D (50 mg, 99.3% yield) as a white solid, which was used in the next step without any further purification. LC/MS (ESI) m/z: 324 (M+H) ⁺ .

Step 5 : Synthesis of 76E To a solution of 76D (50 mg, 0.155 mmol) in DMF (6 mL) was added dropwise a solution of NCS (31 mg, 0.232 mmol) in DMF (2 mL) at 0 °C, and The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (eluted with DCM/MeOH = 100:0 to 5:1) to afford 76E (1.4 mg, 2.5% yield) as a white solid. LC/MS (ESI) m/z: 358 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 4.20 - 4.12 (m, 1H), 3.48 - 3.42 (m, 1H), 2.60 (s, 3H), 2.48 - 2.29 (m, 2H), 2.03 - 1.99 ( m, 2H), 1.83 - 1.76 (m, 2H), 1.75 - 1.66 (m, 2H).

將Pd/C (10% w/w)添加至相應胺(1.0 eq.)於 i-PrOH (0.02 M)中之溶液中。在室溫下在H ₂氛圍下攪拌所得混合物隔夜。隨後用DCM稀釋混合物，過濾且減壓濃縮濾液，得到所需胺。 Example 3. General procedure for other experimental debenzylation ( general procedure 6)

Pd/C (10% w/w) was added to a solution of the corresponding amine (1.0 eq.) in i -PrOH (0.02 M). The resulting mixture was stirred overnight at room temperature under an atmosphere of _H2 . The mixture was then diluted with DCM, filtered and the filtrate concentrated under reduced pressure to afford the desired amine.

步驟 1 - 合成 77B將Pd/C (8 mg，10% w/w)添加至 77A(75 mg，0.23 mmol-遵循醯胺偶合之通用程序製備)於 i-PrOH (10 mL)中之溶液中，且在H ₂氛圍下在室溫下攪拌所得混合物隔夜。隨後用DCM (20 mL)稀釋混合物，過濾且減壓濃縮濾液，得到呈黃色油狀之 JN - 17072 - 2(40 mg，73.17%產率)，其不經任何進一步純化即用於下一步驟。 Synthetic 77C

Step 1 - Synthesis of 77B Pd/C (8 mg, 10% w/w) was added to a solution of 77A (75 mg, 0.23 mmol - prepared following the general procedure for amide coupling) in i -PrOH (10 mL) , and the resulting mixture was stirred overnight at room temperature under _H2 atmosphere. The mixture was then diluted with DCM (20 mL), filtered and the filtrate was concentrated under reduced pressure to give JN - 17072-2 (40 mg, 73.17% yield ) as a yellow oil which was used in the next step without any further purification .

Step 2 - Synthesis of 77C 77C was prepared using the general procedure for SnAr. Azaindole 11 (20 mg, 0.068 mmol) was added to a mixture of 77B (40 mg, 0.10 mmol) and DIEA (39 mg, 0.30 mmol) in MeCN (5 mL) and heated at 80 °C under nitrogen. The resulting mixture was stirred overnight under atmosphere. After cooling, the reaction mixture was concentrated and the residue was purified by preparative HPLC to afford 77C (13.1 mg, 38.46% yield) as a white solid. LC/MS (ESI) m/z: 500 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (s, 1H), 3.95 (d, J = 11.8 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H), 3.61-3.48 (m, 1H ), 3.48-3.40 (m, 1H), 3.36 (d, J = 4.6 Hz, 4H), 3.27-3.05 (m, 3H), 2.52 (s, 3H), 2.01-1.88 (m, 1H), 1.85- 1.69 (m, 1H), 1.69-1.46 (m, 2H), 1.16 (s, 6H), 1.07 (d, J = 4.4 Hz, 3H).

步驟 1在-50℃下在氮氣氛圍下將三光氣(0.5 eq.)添加至相應胺(1.0 eq.)於甲苯(0.03 M)中之溶液中，且在110℃下攪拌所得混合物3小時。冷卻至室溫後，隨後減壓濃縮混合物，得到粗相應異氰酸酯，其不經任何進一步純化即用於下一步驟。 General Procedure for Urea Synthesis ( General Procedure 7)

Step 1 Triphosgene (0.5 eq.) was added to a solution of the corresponding amine (1.0 eq.) in toluene (0.03 M) at -50°C under nitrogen atmosphere, and the resulting mixture was stirred at 110°C for 3 hours. After cooling to room temperature, the mixture was then concentrated under reduced pressure to afford the crude corresponding isocyanate, which was used in the next step without any further purification.

Step 2 A solution of the corresponding isocyanate (1 eq.) in dry DCM (0.05 M) was added dropwise to the appropriate amine (2 eq.) and DIEA (4 eq.) in dry DCM (0.1 M) at 0 °C in the mixture, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated aqueous NaHCO ₃ and extracted twice with DCM. _The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated to dryness. The crude product was then purified by preparative HPLC.

使用用於SnAr之通用程序，繼之以亦在上文所述之脫除Boc保護基來製備 78A。 Synthetic 78C

78A was prepared using the general procedure for SnAr followed by removal of the Boc protecting group also described above.

Step 1 - Synthesis of 78B Triphosgene (17 mg, 0.056 mmol) was added to a solution of 78A (40 mg, 0.11 mmol) in toluene (3 mL) at -50 °C under nitrogen atmosphere and the mixture was heated at 110 °C. The resulting mixture was stirred for 3 hours. After cooling to room temperature, the mixture was then concentrated under reduced pressure to afford crude 78B (40 mg, 93.10% yield) as a colorless oil, which was used in the next step without any further purification.

Step 2 - Synthesis of 78C DIEA (54 mg, 0.42 mmol) was added to a mixture of methylamine hydrochloride (14 mg, 0.21 mmol) in anhydrous DCM (2 mL) and the mixture was stirred at 0 °C for 10 min. A solution of 78B (40 mg, 0.104 mmol) in anhydrous DCM (2 mL) was then added dropwise to the above mixture at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The mixture was then quenched with saturated aqueous NaHCO ₃ (10 mL) and extracted twice with DCM (10 mL). _The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated to dryness. The crude product was purified by preparative HPLC to afford 78C (17 mg, 39.41% yield) as a white solid. LC/MS (ESI) m/z: 415 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 11.70 (s, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 4.7 Hz, 1H), 3.83 (d, J = 12.3 Hz, 2H), 3.67 (d, J = 7.3 Hz, 1H), 3.50 (t, J = 10.9 Hz, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.51 (s, 3H), 1.95 ( d, J = 10.4 Hz, 2H), 1.62-1.54(m, 2H).

將DIEA (22 mg，0.17 mmol)及適當磺醯氯(1.2 eq.)添加至對應胺(2 eq.)於DCM (0.03 M)中之溶液中，且在0℃下攪拌所得混合物1小時。混合物隨後用水(5 mL)稀釋且用DCM (10 mL)萃取兩次。合併之有機層用鹽水洗滌，經無水Na ₂SO ₄乾燥且濃縮至乾燥。藉由製備型HPLC純化粗產物。 General procedure for the synthesis of sulfonamides ( general procedure 8)

DIEA (22 mg, 0.17 mmol) and the appropriate sulfonyl chloride (1.2 eq.) were added to a solution of the corresponding amine (2 eq.) in DCM (0.03 M), and the resulting mixture was stirred at 0 °C for 1 h. The mixture was then diluted with water (5 mL) and extracted twice with DCM (10 mL). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated to _dryness . The crude product was purified by preparative HPLC.

將DIEA (22 mg，0.17 mmol)及 79A(12.94 mg，0.101 mmol)添加至乙磺醯氯(30 mg，0.084 mmol)於DCM (3 mL)中之溶液中，且在0℃下攪拌所得混合物1小時。混合物隨後用水(5 mL)稀釋且用DCM (10 mL)萃取兩次。合併之有機層用鹽水洗滌，經無水Na ₂SO ₄乾燥且濃縮至乾燥。隨後藉由製備型HPLC純化粗產物，得到呈白色固體狀之 79B(6.0 mg，15.90%產率)。LC/MS (ESI) m/z: 450 (M+H) ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.71 (s, 1H), 7.31 (d, J= 7.5 Hz, 1H), 3.86 (d, J= 12.5 Hz, 2H), 3.55 - 3.47 (m, 2H), 3.46 - 3.38 (m, 1H), 3.12 - 3.02 (m, 2H), 2.48 (s, 3H), 2.04 - 1.94 (m, 2H), 1.77-1.69 (m, 2H), 1.23 (t, J= 7.3 Hz, 3H)。 Synthetic 79B

DIEA (22 mg, 0.17 mmol) and 79A (12.94 mg, 0.101 mmol) were added to a solution of ethanesulfonyl chloride (30 mg, 0.084 mmol) in DCM (3 mL), and the resulting mixture was stirred at 0 °C 1 hour. The mixture was then diluted with water (5 mL) and extracted twice with DCM (10 mL). The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated to _dryness . The crude product was then purified by preparative HPLC to afford 79B (6.0 mg, 15.90% yield) as a white solid. LC/MS (ESI) m/z: 450 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.71 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 12.5 Hz, 2H), 3.55 - 3.47 (m, 2H), 3.46 - 3.38 (m, 1H), 3.12 - 3.02 (m, 2H), 2.48 (s, 3H), 2.04 - 1.94 (m, 2H), 1.77-1.69 (m, 2H), 1.23 (t, J = 7.3 Hz, 3H).

步驟 1 - 合成 11-Br將NBS (206 mg，1.16 mmol)添加至 10(300 mg，1.16 mmol)於MeCN (10 mL)中之溶液中，且在50℃下攪拌所得混合物1小時。隨後將混合物減壓濃縮至乾燥，且將殘餘物溶解於EtOAc (20 mL)中且用NaHCO ₃(20 mL)及鹽水(20 mL)洗滌。有機層經無水Na ₂SO ₄乾燥且濃縮至乾燥。藉由矽膠管柱層析(用PE:EtOAc=100:0至1:1溶離)純化粗產物，得到呈棕色固體狀之 11 - Br(305 mg，78.1%產率)。LC/MS (ESI) m/z: 338/340 (M+H) ⁺。 Synthesis of 11-Br ( Nucleosynthesis Procedure 2)

Step 1 - Synthesis of 11-Br NBS (206 mg, 1.16 mmol) was added to a solution of 10 (300 mg, 1.16 mmol) in MeCN (10 mL), and the resulting mixture was stirred at 50 °C for 1 h. The mixture was then concentrated to dryness under reduced pressure, and the residue was dissolved in EtOAc (20 mL) and washed with NaHCO ₃ (20 mL) and brine (20 mL). The organic layer was dried over _{anhydrous Na2SO4} and concentrated to dryness. The crude product was purified by silica gel column chromatography (eluted with PE:EtOAc=100:0 to 1:1) to afford 11 -Br (305 mg , 78.1% yield) as a brown solid. LC/MS (ESI) m/z: 338/340 (M+H) ⁺ .

Step 2 - Synthesis of 80A DIEA (86 mg, 0.67 mmol) was added to ( 3S , 4S )-3-methylpiperidin-4-ol (16 mg, 0.13 mmol) and 11 - Br (30 mg, 0.089 mmol) in a mixture of MeCN (10 mL), and the resulting mixture was stirred at 80 °C overnight. The mixture was then filtered and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to afford 80A (23 mg, 62.14% yield) as a white solid. LC/MS (ESI) m/z: 417 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.77 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.89-3.72 (m, 2H), 3.51-3.44 (m, 1H), 3.28-3.21 (m, 1H), 3.13-3.08 (m, 1H), 2.50 (s, 3H), 2.20-1.98 (m, 1H), 1.79-1.58 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H).

Synthesis of 81D and 81E 81D and 81E were synthesized using the general procedures described above for amide coupling (general procedure 3), removal of Boc protecting groups (general procedure 4) and SnAr (general procedure 1), where the core was synthesized from Procedure 1 preparation.

Step 1 HATU (164 mg, 0.43 mmol) and DIEA (112 mg, 0.86 mmol) were added to a solution of JN - 81A (70 mg, 0.29 mmol) in DMF (2 mL), followed by 1-(methoxy (44 mg, 0.43 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with water (5 mL) and extracted with DCM (10 mL*3). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with DCM:MeOH=100:0 to 95:5) to obtain 81B (70 mg, 74.54% yield) as a yellow oil. LC/MS (ESI) m/z: 327 (M+H) ⁺ .

Step 2 TFA (1 mL) was added dropwise to a solution of 81B (70 mg, 0.22 mmol) in DCM (5 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give crude 81C (38 mg, 78.23% yield) as a yellow oil, which was used in the next step without any further purification.

Step 3 Azaindole 11 (35 mg, 0.12 mmol) was added to a mixture of 81C (38 mg, 0.18 mmol) and DIEA (69 mg, 0.54 mmol) in MeCN (2 mL) and heated at 80 °C The resulting mixture was stirred under nitrogen atmosphere for 12 hours. The mixture was then concentrated to dryness under reduced pressure, and the crude product was purified by preparative HPLC to afford the enantiomer mixture (48 mg, 83.19% yield) as a white solid. The mixture was then further purified by SFC (Waters Thar 80 preparative SFC; ChiralCel OD, 250×4.6 mm 5 µm; OD_MeOH_DEA_40) to obtain 81E (21.6 mg, 45.12% yield) as a white solid and 81D 22.3 as a white solid. mg, 46.45% yield). LC/MS (ESI) m/z: 484 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.43 (s, 1H), 4.37 - 4.33 (m, 1H), 4.24 - 4.20(m, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.49 (d, J = 10.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.35 (s, 3H), 2.77-2.74 (m, 1H) , 2.48 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 0.78 (d, J =5.6 Hz, 4H).

向 10(50 mg，0.193 mmol)於MeCN (5 mL)中之溶液中添加Selectflour (137 mg，0.385 mmol)，且在室溫下攪拌所得混合物16小時。隨後真空濃縮混合物，且藉由製備型TLC (DCM:EA=10:1)純化殘餘物，得到呈白色固體狀之 11 - F(20.0 mg，42.8%產率，60.2%純度)。LC/MS (ESI) m/z: 278 (M+H) ⁺。 Synthesis of 11-F ( Nucleosynthesis Procedure 3)

To a solution of 10 (50 mg, 0.193 mmol) in MeCN (5 mL) was added Selectflour (137 mg, 0.385 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then concentrated in vacuo, and the residue was purified by prep-TLC (DCM:EA=10:1) to afford 11 - F (20.0 mg, 42.8% yield, 60.2% purity) as a white solid. LC/MS (ESI) m/z: 278 (M+H) ⁺ .

步驟 1在0℃下在氮氣下將NaH (136 mg，3.40 mmol)添加至 11(500 mg，1.70 mmol)於無水THF (8 mL)中之溶液中，且所得混合物在0℃下攪拌30分鐘。隨後緩慢添加SEMCl (340 mg，2.04 mmol)且在0℃下攪拌反應混合物30分鐘。完成後，反應混合物用水(30 mL)淬滅且用EtOAc (20 mL×2)萃取。合併之有機層用鹽水(10 mL)洗滌，經無水Na ₂SO ₄乾燥，過濾且濃縮至乾燥。藉由矽膠急驟管柱層析(用PE/EtOAc=100:0至10:1溶離)純化殘餘物，得到呈灰色固體狀之 XX - 1(470 mg，65%產率)。 LC/MS (ESI) m/z: 424 (M+H) ⁺。 Synthesis of 11-HM ( Nucleosynthesis Procedure 4)

Step 1 NaH (136 mg, 3.40 mmol) was added to a solution of 11 (500 mg, 1.70 mmol) in anhydrous THF (8 mL) at 0 °C under nitrogen, and the resulting mixture was stirred at 0 °C for 30 min . Then SEMCl (340 mg, 2.04 mmol) was added slowly and the reaction mixture was stirred at 0 °C for 30 minutes. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (eluted with PE/EtOAc=100:0 to 10:1) to give XX - 1 (470 mg, 65% yield) as gray solid. LC/MS (ESI) m/z : 424 (M+H) ⁺ .

Step 2 AIBN (165 mg, 1.00 mmol) was added to a solution of XX - 1 (470 mg, 1.11 mmol) in CCl ₄ (8 mL) at 0°C, followed by NBS (296 mg, 1.37 mmol). The resulting mixture was heated to 80 °C and stirred under _N2 for 6 h. The mixture was then filtered and the filtrate was concentrated to afford XX - 2 (520 mg, containing some de-SEM adduct) as a yellow solid, which was used in the next step without any further purification. LC/MS (ESI) m/z : 502, 504 (M+H) ⁺ .

Step 3 Cu ₂ O (635 mg, 4.44 mmol) was added to a solution of XX - 2 (520 mg, 1.03 mmol) in DMSO (15 mL) and H ₂ O (3 mL) at room temperature, and The reaction mixture was stirred overnight at room temperature. The mixture was then diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was then washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (eluted with DCM/MeOH=100:0 to 10:1) to afford 11 - HM (85 mg, 26% yield) as a yellow solid. LC/MS (ESI) m/z : 310 (M+H) ⁺ .

步驟 1將HMTA (271.0 mg，1.93 mmol)添加至 10(500.0 mg，1.93 mmol)於AcOH (10 mL)及H ₂O (5 mL)中之溶液中，且在N ₂氛圍下在80℃下攪拌所得混合物隔夜。隨後減壓濃縮混合物，得到呈黃色固體狀之 YY - 1(512.0 mg，92%產率)，其不經任何進一步純化即用於下一步驟中。 LC/MS (ESI) m/z: 288 (M+H) ⁺。 Synthesis of 11-CN ( Nucleosynthesis Procedure 5)

Step 1 HMTA (271.0 mg, 1.93 mmol) was added to a solution of 10 (500.0 mg, 1.93 mmol) in AcOH (10 mL) and H ₂ O (5 mL) and heated at 80 °C under _N atmosphere The resulting mixture was stirred overnight. The mixture was then concentrated under reduced pressure to afford YY - 1 (512.0 mg, 92% yield) as a yellow solid, which was used in the next step without any further purification. LC/MS (ESI) m/z : 288 (M+H) ⁺ .

Step 2 NH ₂ OH ^. HCl (29.0 mg, 0.42 mmol) and TEA (0.29 mL, 2.08 mmol) were added to YY - 1 (100.0 mg, 0.35 mmol) in THF (10 mL) and DMF (2 mL) solution, and the resulting mixture was stirred overnight at 80 °C under _N2 atmosphere. The mixture was then concentrated under reduced pressure to afford YY - 2 (126 mg, crude) as a yellow solid, which was used in the next step without any further purification. LC/MS (ESI) m/z : 303 (M+H) ⁺ .

Step 3 A solution of YY - 2 (126.0 mg) in Ac ₂ O (10 mL) was stirred at 130°C for 3 hours. The reaction mixture was then poured into ice water (30 mL), and the resulting suspension was filtered and the filter cake was washed with H ₂ O (5 mL×5). The filter cake was then dried in vacuo to afford 11 -CN (56.8 mg, 57% yield over two steps) as a yellow solid. LC/MS (ESI) m/z : 285 (M+H) ⁺ .

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基-N-(1-甲基環丙基)吡咯啶-3-甲醯胺 LC-MS:m/z 454.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.41 (s, 1H), 8.32 (s, 1H), 4.25 (dd,J = 10.4, 7.4 Hz, 1H), 4.11 (dd,J = 10.4, 4.8 Hz, 1H), 3.96 (d,J = 9.4 Hz, 1H), 3.80 (d,J = 9.3 Hz, 1H), 2.65 (dd,J = 7.1, 4.9 Hz, 1H), 2.46 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.65 - 0.58 (m, 2H), 0.57 - 0.50 (m, 2H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)及SnAr (GP1) 82B

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基-N-(1-甲基環丙基)吡咯啶-3-甲醯胺 LC-MS:m/z 454.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.41 (s, 1H), 8.32 (s, 1H), 4.25 (dd,J = 10.3, 7.3 Hz, 1H), 4.12 (dd,J = 10.4, 4.9 Hz, 1H), 3.96 (d,J = 9.4 Hz, 1H), 3.80 (d,J = 9.3 Hz, 1H), 2.65 (dd,J = 7.2, 5.0 Hz, 1H), 2.46 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.67 - 0.57 (m, 2H), 0.57 - 0.50 (m, 2H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)及SnAr (GP1) 83A

1-(胺甲基)-N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}環丙烷-1-甲醯胺 LC-MS:m/z 481.2 (M-H)。 1H NMR(400 MHz, MeOD) δ 8.52 (s, 1H), 3.93 (d,J = 12.1 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.51 (dd,J = 13.5, 3.8 Hz, 1H), 3.46 - 3.35 (m, 1H), 3.23 - 3.09 (m, 2H), 3.08 - 3.02 (m, 2H), 2.52 (s, 3H), 1.95 - 1.82 (m, 1H), 1.80 - 1.66 (m, 1H), 1.65 - 1.41 (m, 2H), 1.32 (dd,J = 6.9, 5.3 Hz, 2H), 1.07 (d,J = 6.5 Hz, 3H), 1.04 (dd, J = 10.4, 4.9 Hz, 2H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3)，脫除Boc保護基(GP4) 84A

2-胺基-N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}-2-甲基丙醯胺 LC-MS:m/z 469.2 (M-H)。 1H NMR(400 MHz, CD3OD) δ 8.47 (s, 1H), 3.95 (d,J = 12.3 Hz, 1H), 3.89 - 3.77 (m, 1H), 3.59 - 3.50 (m, 1H), 3.49 - 3.40 (m, 1H), 3.28 (s, 1H), 3.16 - 3.08 (m, 1H), 2.53 (s, 3H), 1.98 - 1.83 (m, 1H), 1.81 - 1.71 (m, 1H), 1.70 - 1.62 (m, 1H), 1.58 (d,J = 4.0 Hz, 6H), 1.54 (d,J = 11.3 Hz, 1H), 1.09 (t,J = 9.1 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3)，脫除Boc保護基(GP4) 85A

2-胺基-N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}乙醯胺 LC-MS:m/z 443.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 8.44 (s, 1H), 3.95 (d,J = 12.4 Hz, 1H), 3.84 (d,J = 10.7 Hz, 1H), 3.67 (s, 2H), 3.60 - 3.53 (m, 1H), 3.50 - 3.41 (m, 1H), 3.34 (d,J = 7.1 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.52 (s, 3H), 1.98 - 1.88 (m, 1H), 1.85 - 1.73 (m, 1H), 1.72 - 1.60 (m, 1H), 1.55 - 1.44 (m, 1H), 1.07 (t,J = 7.3 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物    SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3)，脫除Boc保護基(GP4) 86A

N-{[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 456.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.83 (s, 1H), 3.89 - 3.61 (m, 4H), 3.45 (dd,J = 12.6, 10.1 Hz, 1H), 3.03 (d,J = 13.7 Hz, 1H), 2.53 (s, 3H), 2.28 (q,J = 7.6 Hz, 2H), 1.94 (ddd,J = 10.7, 7.1, 3.9 Hz, 1H), 1.80 (dt,J = 7.0, 3.0Hz, 1H), 1.59 - 1.47 (m, 1H), 1.16 (t,J = 7.6 Hz, 3H), 1.09 (s, 3H), 1.02 (d,J = 7.1 Hz, 3H)。 相對立體化學順式-鏡像異構體之混合物    醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 81D

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[1-(甲氧基甲基)環丙基]-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 484.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (s, 1H), 4.35 (dd, J = 10.4, 7.3 Hz, 1H), 4.22 (dd, J = 10.4, 4.9 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.49 (d, J = 10.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.35(s, 3H), 2.75 (dd, J = 7.1, 5.1 Hz, 1H), 2.48 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 0.78 (d, J = 5.6 Hz, 4H)。 單一鏡像異構體-未知絕對組態(97% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 81E

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[1-(甲氧基甲基)環丙基]-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 484.2 (M+H)。 1H NMR1HNMR(400 MHz, MeOD) δ 4.35 (dd, J = 10.4, 7.3 Hz, 1H), 4.22 (dd, J = 10.4, 5.0 Hz, 1H), 4.05 (d,J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.49 (d, J = 10.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.35 (s, 3H), 2.75 (dd, J = 7.2, 5.1 Hz, 1H), 2.48 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 0.78 (d, J = 5.4 Hz, 4H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 87A

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基-2-甲基丙基)-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 486.2 (M+H)。 1H NMR1HNMR(400 MHz, MeOD) δ 7.95 (s, 1H), 4.39 (dd, J = 10.4, 7.3 Hz, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 9.1 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.22 (s, 3H), 3.22 - 3.17 (m, 1H), 2.94 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.31 (s, 3H), 1.18 (s, 6H), 1.17 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 87B

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基-2-甲基丙基)-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 486.2 (M+H)。 1H NMR1HNMR(400 MHz, MeOD) δ 4.39 (dd, J = 10.4, 7.3 Hz, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 9.2 Hz, 1H), 3.36 (d, J = 13.8 Hz, 1H), 3.22 (s, 3H), 3.20 (d, J = 13.9 Hz, 1H), 2.94 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.31 (s, 3H), 1.18 (d, J = 2.8 Hz, 9H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 88A

3-氯-7-[(3S,4S)-3-(羥甲基)-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.21 (d, J = 9.6 Hz, 1H), 4.13 (dd, J = 9.7, 7.8 Hz, 1H), 3.96 (t, J = 9.8 Hz, 1H), 3.74 (d, J = 9.6 Hz, 1H), 3.55 (q, J = 11.2 Hz, 2H), 2.48 (s, 3H), 2.41 - 2.33 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H)。 單一非鏡像異構體-未知絕對組態(99% de) SnAr (GP1) 88B

3-氯-7-[(3R,4S)-3-(羥甲基)-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.21 (d, J = 9.6 Hz, 1H), 4.13 (dd, J = 9.7, 7.8 Hz, 1H), 3.96 (t, J = 9.8 Hz, 1H), 3.75 (d, J = 9.6 Hz, 1H), 3.55 (q, J = 11.2 Hz, 2H), 2.48 (s, 3H), 2.43 - 2.31 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H) 單一非鏡像異構體-未知絕對組態(99% de) SnAr (GP1) 88C

3-氯-7-[(3S,4R)-3-(羥甲基)-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR1HNMR(400 MHz, MeOD) δ 4.19 (d, J = 10.0 Hz, 1H), 4.16 - 4.10 (m, 1H), 4.04 (t, J = 9.7 Hz, 1H), 3.87 (d, J = 10.0 Hz, 1H), 3.58 - 3.46 (m, 2H), 2.48 (s, 3H), 2.32 - 2.21 (m, 1H), 1.19 (s, 3H), 1.12 (d, J = 7.0 Hz, 3H)。 單一非鏡像異構體-未知絕對組態(85% de) SnAr (GP1) 88D

3-氯-7-[(3R,4R)-3-(羥甲基)-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.19 (d, J = 10.0 Hz, 1H), 4.16 - 4.10 (m, 1H), 4.05 (t, J = 9.7 Hz, 1H), 3.87 (d, J = 10.0 Hz, 1H), 3.58 - 3.46 (m, 2H), 2.48 (s, 3H), 2.31 - 2.21 (m, 1H), 1.19 (s, 3H), 1.12 (d, J = 7.0 Hz, 3H) 單一非鏡像異構體-未知絕對組態(99% de) SnAr (GP1) 89A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-羥基-4-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 6.12 (s, 1H), 3.82 - 3.71 (m, 2H), 3.66 - 3.50 (m, 3H), 2.48 (s, 2H), 2.35 (d, J = 14.9 Hz, 1H), 1.52 - 1.44 (m, 1H), 1.25 (d, J = 9.0 Hz, 4H)。 相對立體化學反式-未知絕對組態(99% ee)    醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 89B

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-羥基-4-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.97 - 3.91 (m, 1H), 3.88 - 3.82 (m, 1H), 3.76 - 3.57 (m, 3H), 2.51 (s, 3H), 2.48 - 2.41 (m, 1H), 1.68 - 1.61 (m, 1H), 1.39 (s, 3H)。 相對立體化學反式-未知絕對組態(99% ee)    醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 90A

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基-2-甲基丙基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 472.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 8.13 (s, 1H), 4.35 (t, J = 9.5 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.45 - 3.39 (m, 1H), 3.27 - 3.20 (m, 4H), 2.89 - 2.80 (m, 1H), 2.67 - 2.58 (m, 1H), 2.48 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H), 1.19 (s, 6H)。 相對立體化學反式-未知絕對組態(96% ee)    醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 90B

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基-2-甲基丙基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 472.2 (M+H)。 H NMR(400 MHz, CD3OD) δ 8.13 (s, 1H), 4.35 (t, J = 9.5 Hz, 1H), 4.25 - 4.15 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.26 - 3.21 (m, 4H), 2.88 - 2.80 (m, 1H), 2.68 - 2.57 (m, 1H), 2.48 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H), 1.19 (s, 6H)。 相對立體化學反式-未知絕對組態(99% ee)    醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 91A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N-[1-(甲氧基甲基)環丙基]-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 500.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.84 - 3.71 (m, 2H), 3.61 (d, J = 2.8 Hz, 1H), 3.51 (t, J = 11.7 Hz, 2H), 3.41 (d, J = 10.3 Hz, 1H), 3.36 (s, 3H), 2.52 (s, 3H), 2.49 - 2.38 (m, 2H), 1.76 - 1.70 (m, 1H), 0.89 - 0.80 (m, 7H)。 相對立體化學順式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 77C

N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}-3-甲氧基-2,2-二甲基丙醯胺 LC-MS:m/z 500.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.61 (s, 1H), 3.95 (d, J = 11.8 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.48 - 3.40 (m, 1H), 3.36 (d, J = 4.6 Hz, 4H), 3.27 - 3.05 (m, 3H), 2.52 (s, 3H), 2.01 - 1.88 (m, 1H), 1.85 - 1.69 (m, 1H), 1.69 - 1.46 (m, 2H), 1.16 (s, 6H), 1.06 (dd, J = 15.3, 6.7 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 92A

1-胺基-N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}環丙烷-1-甲醯胺 LC-MS:m/z 469.2 (M+H)。 1H NMR400 MHz, MeOD) δ 8.19 (s,0.3H), 3.94 (d, J = 12.6 Hz, 1H), 3.83 (d, J = 10.7 Hz, 1H), 3.56 (dd, J = 13.7, 3.5 Hz, 1H), 3.47 - 3.41 (m, 1H), 3.19 - 3.07 (m, 2H), 2.52 (s, 3H), 1.92 (dd, J = 12.6, 2.5 Hz, 1H), 1.83 - 1.70 (m, 1H), 1.67 - 1.49 (m, 2H), 1.43 - 1.33 (m, 2H), 1.15 - 1.02 (m, 5H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除BOC保護基，及SnAr (GP1) 93A

N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}-2-甲氧基-2-甲基丙醯胺 LC-MS:m/z 486.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.94 (s, 1H), 3.94 (d, J = 11.9 Hz, 1H), 3.83 (d, J = 11.6 Hz, 1H), 3.58 - 3.49 (m, 1H), 3.49 - 3.41 (m, 1H), 3.30 (s, 3H), 3.24 - 3.15 (m, 1H), 3.14 - 3.06 (m, 1H), 2.52 (s, 3H), 1.92 (dd, J = 12.9, 2.5 Hz, 1H), 1.82 - 1.70 (m, 1H), 1.67 - 1.49 (m, 2H), 1.37 (s, 6H), 1.07 (dd, J = 15.8, 7.0 Hz, 3H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除BOC保護基，及SnAr (GP1) 94A

N-{[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-羥基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 442.2 (M-H)。 1H NMR(400 MHz, CD3OD) δ 3.98 - 3.91 (m, 1H), 3.86 (d, J = 12.2 Hz, 1H), 3.69 - 3.61 (m, 1H), 3.53 - 3.44 (m, 2H), 3.41 - 3.36 (m, 1H), 3.29 - 3.25 (m, 1H), 2.53 (s, 3H), 2.25 (q, J = 7.6 Hz, 2H), 2.01 - 1.90 (m, 1H), 1.77 - 1.58 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(95% ee)    醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 94B

N-{[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-羥基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 442.2 (M-H)。 1H NMR1HNMR(400 MHz, CD3OD) δ 3.98 - 3.91 (m, 1H), 3.86 (d, J = 12.1 Hz, 1H), 3.68 - 3.61 (m, 1H), 3.53 - 3.44 (m, 2H), 3.41 - 3.36 (m, 1H), 3.29 - 3.24 (m, 1H), 2.53 (s, 3H), 2.25 (q, J = 7.6 Hz, 2H), 2.03 - 1.91 (m, 1H), 1.79 - 1.58 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(98% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 95A

3-氯-7-[(3R,4R)-4-羥基-3-甲基環己基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 372.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.57 - 3.44 (m, 1H), 3.44 - 3.35 (m, 1H), 2.60 (d, J = 12.2 Hz, 3H), 2.40 - 2.25 (m, 1H), 2.22 - 2.12 (m, 1H), 2.10 - 1.97 (m, 1H), 1.95 - 1.80 (m, 2H), 1.67 - 1.50 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H)。 相對立體化學反式    與化合物 75C相同之程序 95B

3-氯-7-[(3S,4S)-4-羥基-3-甲基環己基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 372.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.55 - 3.44 (m, 1H), 3.44 - 3.35 (m, 1H), 2.59 (s, 3H), 2.40 - 2.26 (m, 1H), 2.21 - 2.12 (m, 1H), 2.09 - 1.97 (m, 1H), 1.94 - 1.80 (m, 2H), 1.67 - 1.51 (m, 2H), 1.12 (d, J = 6.5 Hz, 3H)。 相對立體化學反式    與化合物 75C相同之程序 96A

2-[(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-基]乙醯胺 LC-MS:m/z 412.1 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.18 - 4.00 (m, 3H), 3.81 (d, J = 9.6 Hz, 1H), 2.54 - 2.49 (m, 1H), 2.49 (s, 3H), 2.46 - 2.38 (m, 1H), 2.22 (dd, J = 14.2, 10.2 Hz, 1H), 1.23 (s, 3H), 1.04 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 96B

2-[(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-基]乙醯胺 LC-MS:m/z 412.1 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.18 - 4.00 (m, 3H), 3.81 (d, J = 9.5 Hz, 1H), 2.53 (d, J = 4.0 Hz, 1H), 2.49 (s, 3H), 2.46 - 2.37 (m, 1H), 2.22 (dd, J = 14.2, 10.2 Hz, 1H), 1.23 (s, 3H), 1.04 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 97A

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-乙基-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 426.1 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.42 - 4.34 (m, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.28 - 3.13 (m, 2H), 2.78 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.29 (s, 3H), 1.15 (dd, J = 9.5, 4.9 Hz, 6H)。 單一鏡像異構體-未知絕對組態(94% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 97B

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-乙基-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 426.1 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.38 (dd, J = 10.4, 7.4 Hz, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.28 - 3.12 (m, 2H), 2.78 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.29 (s, 3H), 1.15 (dd, J = 9.4, 5.0 Hz, 6H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 98A

(3R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 382.1 (M-H)。 1H NMR(400 MHz, CD3OD) δ 4.41 - 4.34 (m, 1H), 4.31 - 4.25 (m, 1H), 4.04 (d, J = 9.3 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.45 (s, 3H), 1.32 (s, 3H), 1.19 (s, 3H)。 單一鏡像異構體-未知絕對組態(95% ee) 核合成程序3，醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 98B

(3S)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 382.1 (M-H)。 1H NMR(400 MHz, CD3OD) δ 4.40 - 4.34 (m, 1H), 4.32 - 4.25 (m, 1H), 4.04 (d, J = 9.3 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H), 2.92 - 2.85 (m, 1H), 2.45 (d, J = 1.5 Hz, 3H), 1.31 (s, 3H), 1.19 (s, 3H)。 單一鏡像異構體-未知絕對組態(98% ee) 核合成程序3，醯胺偶合(GP3)，脫除Boc保護基，SnAr (GP1) 99A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 398 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.56 (d, J = 9.8 Hz, 1H), 4.16 (dd,J = 9.7, 7.4 Hz, 1H), 3.98 - 3.89 (m, 2H), 2.85 - 2.75 (m, 1H), 2.48 (s, 3H), 1.33 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1) 100A

N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}-2-羥乙醯胺 LC-MS:m/z 442.1 (M-H)。 1H NMR(400 MHz, MeOD) δ 7.96 (s, 1H), 4.00 (s, 2H), 3.97 - 3.92 (m, 1H), 3.88 - 3.77 (m, 1H), 3.65 - 3.56 (m, 1H), 3.45 (td, J = 11.8, 2.3 Hz, 1H), 3.25 - 3.18 (m, 1H), 3.11 (dd, J = 12.2, 10.8 Hz, 1H), 2.52 (s, 3H), 2.00 - 1.91 (m, 1H), 1.83 - 1.71 (m, 1H), 1.68 - 1.48 (m, 2H), 1.07 (dd, J = 14.9, 6.7 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 101A

N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 456.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.92 (t, J = 6.1 Hz, 1H), 3.81 - 3.60 (m, 3H), 3.40 - 3.33 (m, 1H), 3.28 (s, 1H), 3.22 - 3.15 (m, 1H), 2.52 (s, 3H), 2.27 (q, J = 7.6 Hz, 2H), 2.02 - 1.92 (m, 1H), 1.89 - 1.78 (m, 1H), 1.63 - 1.54 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 1.01 (s, 3H), 0.96 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 102A

N-{[(3R,4S)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 426.3 (M+H)。 1H NMR(400 MHz, CD3OD) δ 7.97 (s, 1H), 3.96 (d, J = 12.8 Hz, 1H), 3.85 (d, J = 12.6 Hz, 1H), 3.59 - 3.51 (m, 1H), 3.49 - 3.42 (m, 1H), 3.14 - 3.06 (m, 2H), 2.48 (d, J = 1.5 Hz, 3H), 2.23 (q, J = 7.6 Hz, 2H), 1.97 - 1.90 (m, 1H), 1.80 - 1.70 (m, 1H), 1.66 - 1.55 (m, 1H), 1.49 (d, J = 17.8 Hz, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序3，SnAr (GP1)，脫除Boc保護基(GP4)及醯胺偶合(GP3) 103A

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 440.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.38 (dd, J = 10.4, 7.3 Hz, 1H), 4.21 (dd, J = 10.4, 4.8 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.88 (d, J = 9.1 Hz, 1H), 2.73 (dd, J = 7.2, 4.8 Hz, 1H), 2.71 - 2.64 (m, 1H), 2.49 (s, 3H), 1.27 (s, 3H), 1.15 (s, 3H), 0.77 - 0.69 (m, 2H), 0.55 - 0.45 (m, 2H)。 單一鏡像異構體-未知絕對立體化學(98% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 103B

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 440.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.38 (dd, J = 10.4, 7.3 Hz, 1H), 4.21 (dd, J = 10.4, 4.7 Hz, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.88 (d, J = 9.1 Hz, 1H), 2.73 (dd, J = 7.2, 4.8 Hz, 1H), 2.71 - 2.64 (m, 1H), 2.49 (s, 3H), 1.27 (s, 3H), 1.15 (s, 3H), 0.74 (dt, J = 7.2, 3.4 Hz, 2H), 0.56 - 0.45 (m, 2H)。 單一鏡像異構體-未知絕對立體化學(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 104A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-羥乙基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 430.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.36 (t, J = 9.5 Hz, 1H), 4.20 (dt, J = 9.7, 7.0 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.64 (t, J = 5.9 Hz, 2H), 3.38 (t, J = 5.7 Hz, 2H), 2.76 (td ,J = 9.5, 7.7 Hz, 1H), 2.61 (tt, J = 9.8, 6.9 Hz, 1H), 2.48 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 105A

3-氯-7-[(3S,4S)-3-(2-羥基丙-2-基)-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 399.2 (M-H)。 1H NMR(400 MHz, CD3OD) δ 4.27 - 4.20 (m, 1H), 4.17 - 4.05 (m, 2H), 3.78 (t, J = 9.1 Hz, 1H), 2.49 (s, 3H), 2.46 - 2.34 (m, 1H), 2.09 (q, J = 8.4 Hz, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.25 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee)    SnAr (GP1) 105B

3-氯-7-[(3R,4R)-3-(2-羥基丙-2-基)-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 399.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.26 - 4.19 (m, 1H), 4.16 - 4.06 (m, 2H), 3.78 (t, J = 9.1 Hz, 1H), 2.49 (s, 3H), 2.46 - 2.34 (m, 1H), 2.09 (q, J = 8.4 Hz, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.25 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee)    SnAr (GP1) 106A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[(1-羥基環丙基)甲基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 454.2 (M-H)。 1H NMR(400 MHz, CD3OD) δ 8.38 (s, 1H), 4.37 (t, J = 9.5 Hz, 1H), 4.26 - 4.17 (m, 2H), 3.87 (t, J = 9.6 Hz, 1H), 3.42 (d, J = 4.3 Hz, 2H), 2.86 - 2.76 (m, 1H), 2.69 - 2.57 (m, 1H), 2.48 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H), 0.77 - 0.69 (m, 2H), 0.68 - 0.59 (m, 2H)。 相對立體化學反式- 鏡像異構體之混合物       醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 107A

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-羥基-4-甲基哌啶-4-甲醯胺 LC-MS:m/z 414.2 (M-H)。 1H NMR(400 MHz, DMSO) δ 11.74 (s, 1H), 7.29 (s, 1H), 7.08 (s, 1H), 5.41 (s, 1H), 4.08 (s, 1H), 3.67 (s, 3H), 3.50 (s, 1H), 2.48 (s, 3H), 1.91 (d, J = 52.0 Hz, 2H), 1.19 (s, 3H)。 相對立體化學順式- 鏡像異構體之混合物          醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 108A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 456.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.84 - 3.71 (m, 2H), 3.66 - 3.59 (m, 1H), 3.51 (t, J = 11.9 Hz, 1H), 2.76 - 2.67 (m, 1H), 2.53 (s, 3H), 2.51 - 2.41 (m, 2H), 1.79 - 1.69 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H), 0.81 - 0.74 (m, 2H), 0.59 - 0.53 (m, 2H)。 相對立體化學順式- 未知絕對組態(98% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 108B

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 456.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.86 - 3.70 (m, 2H), 3.67 - 3.59 (m, 1H), 3.51 (t, J = 11.9 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.53 (s, 3H), 2.50 - 2.41 (m, 2H), 1.78 - 1.71 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H), 0.81 - 0.74 (m, 2H), 0.60 - 0.53 (m, 2H)。 相對立體化學順式- 未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 109A

N-{[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}環丙烷甲醯胺 LC-MS:m/z 454.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.95 (d, J = 13.2 Hz, 1H), 3.75 (dd, J = 11.6, 3.0 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.37 - 3.32 (m, 1H), 3.23 (d, J = 6.8 Hz, 2H), 2.52 (s, 3H), 2.18 - 2.08 (m, 1H), 2.05 - 1.91 (m, 2H), 1.69 (dd, J = 12.5, 3.0 Hz, 1H), 1.63 - 1.56 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.88 - 0.82 (m, 2H), 0.80 - 0.69 (m, 2H)。 相對立體化學順式- 未知絕對組態(97% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 109B

N-{[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}環丙烷甲醯胺 LC-MS:m/z 454.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.95 (d, J = 13.2 Hz, 1H), 3.75 (dd, J = 11.6, 2.9 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.38 - 3.32 (m, 1H), 3.23 (d, J = 6.9 Hz, 2H), 2.51 (s, 3H), 2.19 - 2.08 (m, 1H), 2.05 - 1.91 (m, 2H), 1.69 (dd, J = 12.5, 2.9 Hz, 1H), 1.64 - 1.54 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.90 - 0.83 (m, 2H), 0.81 - 0.68 (m, 2H)。 相對立體化學順式- 未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 110A

N-{[(3R,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 424.2 (M-H)。 1H NMR(400 MHz, CD3OD) δ 7.98 (s, 1H), 3.97 (d, J = 12.7 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.59 - 3.51 (m, 1H), 3.49 - 3.40 (m, 1H), 3.17 - 3.06 (m, 2H), 2.49 (d, J = 1.5 Hz, 3H), 2.24 (q, J = 7.6 Hz, 2H), 2.00 - 1.90 (m, 1H), 1.81 - 1.70 (m, 1H), 1.65 - 1.55 (m, 1H), 1.53 - 1.43 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H)。 相對立體化學順式- 未知絕對組態(99% ee) 核合成程序3，SnAr (GP1)，脫除Boc保護基(GP4)及醯胺偶合(GP3) 111A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基乙基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 444.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.49 (s, 0.3H), 4.36 (t, J = 9.5 Hz, 1H), 4.19 (dd, J = 17.6, 10.0 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.52 - 3.48 (m, 2H), 3.48 - 3.38 (m, 2H), 3.37 (s, 3H), 2.76 (dd, J = 17.4, 9.5 Hz, 1H), 2.60 (dt, J = 23.5, 8.3 Hz, 1H), 2.47 (s, 3H), 1.20 (d, J = 6.5 Hz, 3H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 112A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[1-(羥甲基)環丙基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 456.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.49 (s, 0.3H), 4.35 (t, J = 9.4 Hz, 1H), 4.23 - 4.13 (m, 2H), 3.85 (t, J = 9.6 Hz, 1H), 3.64 (d, J = 11.6 Hz, 1H), 3.57 (d, J = 11.6 Hz, 1H), 2.69 (dd, J = 17.1, 9.3 Hz, 1H), 2.58 (ddd, J = 19.0, 9.7, 6.6 Hz, 1H), 2.48 (s, 3H), 1.19 (d, J = 6.5 Hz, 3H), 0.86 - 0.80 (m, 2H), 0.77 (dt, J = 9.1, 3.8 Hz, 2H)。 相對立體化學順式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 113A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N-(1-羥基-2-甲基丙-2-基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 488.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.52 (s, 1H), 3.88 - 3.67 (m, 2H), 3.67 - 3.47 (m, 4H), 2.52 (s, 3H), 2.45 (dd, J = 13.3, 5.1 Hz, 2H), 1.76 (d, J = 13.9 Hz, 1H), 1.35 (s, 6H), 0.89 (d, J = 6.9 Hz, 3H)。 相對立體化學順式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 114A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,3-二氟-4-甲基哌啶-4-甲醯胺 LC-MS:m/z 436.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.89 (s, 1H), 7.37 (d, J = 7.3 Hz, 2H), 4.37 (dd, J = 25.1, 12.1 Hz, 1H), 3.99 (dd, J = 21.2, 12.2 Hz, 1H), 3.69 (dt, J = 13.7, 12.3 Hz, 2H), 2.51 (s, 3H), 2.38 - 2.26 (m, 1H), 2.01 - 1.87 (m, 1H), 1.41 (s, 3H)。 外消旋混合物 SnAr (GP1) 115A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N-(2-甲氧基乙基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 474.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.84 - 3.71 (m, 2H), 3.66 - 3.60 (m, 1H), 3.53 (t, J = 7.9 Hz, 1H), 3.51 - 3.39 (m, 4H), 3.37 (s, 3H), 2.52 (s, 3H), 2.51 - 2.39 (m, 2H), 1.81 - 1.73 (m, 1H), 0.87 (d, J = 6.9 Hz, 3H)。 相對立體化學順式- 未知絕對組態(98% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 115B

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N-(2-甲氧基乙基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 474.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.00 (s, 1H), 3.84 - 3.71 (m, 2H), 3.66 - 3.60 (m, 1H), 3.53 (t, J = 7.8 Hz, 1H), 3.51 - 3.40 (m, 4H), 3.37 (s, 3H), 2.53 (s, 3H), 2.51 - 2.39 (m, 2H), 1.77 (dt, J = 13.7, 2.3 Hz, 1H), 0.87 (d, J = 6.9 Hz, 3H)。 相對立體化學順式- 未知絕對組態(98% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 116A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.40 (s, 1H), 7.56 (s, 1H), 7.10 (s, 1H), 4.23 - 4.03 (m, 3H), 3.85 (t, J = 8.5 Hz, 1H), 3.10 (dd, J = 11.0, 6.7 Hz, 1H), 2.67 (dt, J = 13.7, 6.8 Hz, 1H), 2.46 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H)。 相對立體化學順式- 未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 116B

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.41 (s, 1H), 7.55 (s, 1H), 7.09 (s, 1H), 4.26 - 4.02 (m, 3H), 3.90 - 3.79 (m, 1H), 3.10 (dd, J = 11.1, 6.7 Hz, 1H), 2.67 (dt, J = 14.2, 7.0 Hz, 1H), 2.46 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee)    醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 117A

(3R,4R)-N-[(1-胺基環丙基)甲基]-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 455.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (s, 1H), 4.40 (t, J = 9.4 Hz, 1H), 4.31 - 4.15 (m, 2H), 3.87 (t, J = 9.3 Hz, 1H), 3.64 (d, J = 14.9 Hz, 1H), 3.36 - 3.32 (m, 1H), 2.86 - 2.73 (m, 1H), 2.71 - 2.58 (m, 1H), 2.48 (s, 3H), 1.24 (d, J = 6.5 Hz, 3H), 1.01 - 0.86 (m, 4H)。 相對立體化學反式- 鏡像異構體之混合物 SnAr (GP1)，醯胺偶合(GP3)，脫除Boc保護基(GP4) 118A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(1-羥基-2-甲基丙-2-基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 458.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.32 (t, J = 9.5 Hz, 1H), 4.17 (dd, J = 16.8, 8.5 Hz, 2H), 3.84 (t, J = 9.7 Hz, 1H), 3.68 (d, J = 11.0 Hz, 1H), 3.59 (d, J = 11.0 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.55 (ddd, J = 16.8, 8.3, 4.9 Hz, 1H), 2.48 (s, 3H), 1.33 (d, J = 5.1 Hz, 6H), 1.21 (d, J = 6.5 Hz, 3H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 119A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基-N-(1-甲基環丙基)吡咯啶-3-甲醯胺 LC-MS:m/z 440.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.33 (t,J = 9.3 Hz, 1H), 4.16 (ddd, J = 19.3, 9.7, 7.1 Hz, 2H), 3.84 (t, J = 9.5 Hz, 1H), 2.59 (tt, J = 9.6, 8.3 Hz, 2H), 2.47 (s, 3H), 1.38 (s, 3H), 1.17 (d, J = 6.2 Hz, 3H), 0.79 - 0.71 (m, 2H), 0.68 - 0.61 (m, 2H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 120A

(3R,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 370.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.37 (t, J = 9.5 Hz, 1H), 4.28 - 4.15 (m, 2H), 3.87 (t, J = 9.6 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.67 - 2.55 (m, 1H), 2.44 (d, J = 1.4 Hz, 3H), 1.23 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序3，醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 121A

N-{[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-氟哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 444.2 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.92 (s, 0.5H), 4.79 (s, 0.5H), 4.16 (t, J = 11.9 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.76 (dd, J = 36.2, 13.3 Hz, 1H), 3.50 - 3.32 (m, 2H), 3.27 (d, J = 7.2 Hz, 1H), 2.53 (s, 3H), 2.24 (q, J = 7.6 Hz, 2H), 2.14 - 1.95 (m, 2H), 1.77 (d, J = 8.8 Hz, 1H), 1.15 (t, J = 7.6 Hz, 3H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 122A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[(1-甲氧基環丙基)甲基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 470.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.38 (t, J = 9.5 Hz, 1H), 4.21 (dd, J = 16.9, 9.4 Hz, 2H), 3.87 (t, J = 9.6 Hz, 1H), 3.56 (d, J = 14.5 Hz, 1H), 3.41 (d, J = 14.5 Hz, 1H), 3.33 (d, J = 4.6 Hz, 3H), 2.81 (dd, J = 17.4, 9.4 Hz, 1H), 2.63 (dd, J = 15.2, 8.1 Hz, 1H), 2.48 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H), 0.81 (t, J = 5.3 Hz, 2H), 0.64 (t, J = 3.5 Hz, 2H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 123A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[1-(甲氧基甲基)環丙基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 470.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.18 (ddd, J = 17.2, 9.6, 7.4 Hz, 2H), 3.84 (t, J = 9.6 Hz, 1H), 3.47 (dd, J = 27.9, 10.5 Hz, 2H), 3.37 (s, 3H), 2.72 - 2.63 (m, 1H), 2.61 - 2.50 (m, 1H), 2.48 (s, 3H), 1.19 (d, J = 6.5 Hz, 3H), 0.85 - 0.76 (m, 4H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基，SnAr (GP1) 124A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 428.1 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.04 - 3.79 (m, 2H), 3.76 - 3.62 (m, 1H), 3.47 (d, J = 11.1 Hz, 1H), 2.74 (s, 1H), 2.53 (s, 3H), 1.85 (d, J = 14.6 Hz, 1H), 1.10 (d, J = 20.0 Hz, 6H)。 外消旋混合物    SnAr (GP1) 125A

(3S,4S)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 400.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.18 - 4.08 (m, 1H), 3.92 - 3.76 (m, 3H), 2.48 (d, J = 1.5 Hz, 3H), 2.32 (dd, J = 9.8, 4.3 Hz, 1H), 2.11 (dd, J = 13.9, 6.9 Hz, 1H), 2.01 - 1.91 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序3，醯胺偶合(GP3)，脫苯甲基化(GP6)及SnAr (GP1) 125B

(3S,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR (400 MHz, MeOD) δ 3.87 - 3.81 (m, 1H), 3.81 - 3.72 (m, 1H), 3.70 - 3.63 (m, 1H), 3.52 (t, J = 11.9 Hz, 1H), 2.49 (d, J = 1.4 Hz, 3H), 2.48 - 2.38 (m, 2H), 1.81 (d, J = 13.7 Hz, 1H), 0.92 (d, J = 6.8 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 核合成程序3，醯胺偶合(GP3)，脫苯甲基化(GP6)及SnAr (GP1) 126A

7-{4-[(1S)-1-胺基-2,2,2-三氟乙基]哌啶-1-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 438.2 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.06 - 3.88 (m, 2H), 3.49 (dt, J = 12.1, 6.5 Hz, 2H), 3.22 (dd, J = 8.4, 4.2 Hz, 1H), 2.53 (s, 3H), 2.08 - 1.75 (m, 5H)。 單一鏡像異構體-未知絕對組態(99% ee)    SnAr (GP1)之通用程序 126B

7-{4-[(1R)-1-胺基-2,2,2-三氟乙基]哌啶-1-基}-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 438.2 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.08 - 3.92 (m, 2H), 3.49 (dt, J = 12.2, 6.6 Hz, 2H), 3.26 - 3.19 (m, 1H), 2.53 (s, 3H), 2.04 - 1.74 (m, 5H)。 單一鏡像異構體-未知絕對組態(99% ee)    SnAr (GP1)之通用程序 127A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-羥基-2-甲基丙基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 456.2 (M-H)。 1H NMR(400 MHz, CD3OD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.20 (dd, J = 17.2, 7.7 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.34 (d, J = 13.5 Hz, 1H), 3.20 (d, J = 13.5 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.67 (s, 1H), 2.47 (s, 3H), 1.22 (d, J = 7.6 Hz, 9H)。 相對立體化學反式-鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 128A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(1-甲氧基-2-甲基丙-2-基)-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 470.2 (M-H)。 1H NMR(400 MHz, MeOD) δ 7.71 (s, 1H), 4.31 (t, J = 9.5 Hz, 1H), 4.17 (dt, J = 23.1, 8.6 Hz, 2H), 3.83 (t, J = 9.7 Hz, 1H), 3.50 (dd, J = 24.9, 9.0 Hz, 2H), 3.36 (s, 3H), 2.75 (dd, J = 17.3, 9.4 Hz, 1H), 2.63 - 2.50 (m, 1H), 2.49 (d, J = 10.4 Hz, 3H), 1.34 (d, J = 3.6 Hz, 6H), 1.20 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 129A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 424.2 (M-H)。 1H NMR(400 MHz, MeOD) δ 4.35 (t, J = 9.2 Hz, 1H), 4.24 - 4.07 (m, 2H), 3.84 (t, J = 9.5 Hz, 1H), 2.80 - 2.54 (m, 3H), 2.47 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.76 (dd, J = 7.2, 3.6 Hz, 2H), 0.53 (d, J = 4.2 Hz, 2H)。 相對立體化學反式- 鏡像異構體之混合物 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 130A

(3S,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 398.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.78 - 3.67 (m, 3H), 3.43 (dd, J = 12.4, 9.9 Hz, 1H), 2.60 - 2.51 (m, 1H), 2.49 (s, 3H), 2.33 - 2.21 (m, 1H), 1.87 - 1.75 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(98% ee) 核合成程序3，醯胺偶合(GP3)，脫苯甲基化(GP6)及SnAr (GP1) 131A

(3R,4S)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 398.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.71 (dd ,J = 8.6, 4.9 Hz, 3H), 3.43 (dd, J = 12.5, 9.8 Hz, 1H), 2.54 (ddd, J = 10.3, 6.7, 3.7 Hz, 1H), 2.48 (d, J = 1.2 Hz, 3H), 2.32 - 2.22 (m, 1H), 1.85 - 1.77 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序3，醯胺偶合(GP3)，脫苯甲基化(GP6)及SnAr (GP1) 132A

3-氯-7-[(3R,4R)-3-羥基-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.25 (d, J = 10.7 Hz, 1H), 4.07 (d, J = 9.7 Hz, 2H), 3.88 (d, J = 10.6 Hz, 1H), 2.48 (s, 3H), 2.21 (dd, J = 16.2, 9.2 Hz, 1H), 1.42 (s, 3H), 1.13 (d, J = 6.7 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1) 132B

3-氯-7-[(3S,4S)-3-羥基-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.25 (d, J = 10.7 Hz, 1H), 4.07 (d, J = 9.3 Hz, 2H), 3.88 (d, J = 10.6 Hz, 1H), 2.48 (s, 3H), 2.22 (dd, J = 15.9, 9.2 Hz, 1H), 1.42 (s, 3H), 1.13 (d, J = 6.7 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1) 133A

3-氯-7-[(3S,4R)-3-(羥甲基)-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.21 (dd, J = 9.5, 6.8 Hz, 1H), 4.18 - 4.11 (m, 1H), 4.09 (d, J = 6.1 Hz, 1H), 3.85 (dd, J = 9.6, 5.8 Hz, 1H), 3.77 (dd, J = 10.9, 6.2 Hz, 1H), 3.63 (dd, J = 10.9, 7.8 Hz, 1H), 2.67 - 2.58 (m, 1H), 2.57 - 2.49 (m, 1H), 2.47 (s, 3H), 1.13 (d, J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(95% ee) SnAr (GP1) 133B

3-氯-7-[(3R,4S)-3-(羥甲基)-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.22 (dd, J = 9.5, 6.8 Hz, 1H), 4.15 (dd, J = 9.9, 7.0 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.86 (dd, J = 9.5, 5.8 Hz, 1H), 3.77 (dd, J = 10.9, 6.2 Hz, 1H), 3.63 (dd, J = 10.9, 7.8 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.58 - 2.50 (m, 1H), 2.47 (s, 3H), 1.13 (d,J = 7.0 Hz, 3H) 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1) 134A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 456.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.20 - 4.11 (m, 1H), 3.89 - 3.78 (m, 3H), 2.73 - 2.63 (m, 1H), 2.52 (s, 3H), 2.28 (d, J = 13.6 Hz, 1H), 2.09 (dd, J = 13.9, 7.0 Hz, 1H), 1.97 - 1.86 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H), 0.79 - 0.70 (m, 2H), 0.58 - 0.47 (m, 2H)。 相對立體化學反式-未知絕對組態(98% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 134B

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 456.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.22 - 4.10 (m, 1H), 3.90 - 3.76 (m, 3H), 2.72 - 2.64 (m, 1H), 2.52 (s, 3H), 2.28 (d, J = 13.7 Hz, 1H), 2.09 (dd, J = 13.8, 6.9 Hz, 1H), 1.98 - 1.89 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H), 0.79 - 0.69 (m, 2H), 0.60 - 0.49 (m, 2H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 135A

3-氯-7-[3-(氟甲基)-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.68 (dd, J = 9.1, 6.2 Hz, 1H), 4.63 - 4.52 (m, 1H), 4.47 (t, J = 8.6 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.90 - 3.80 (m, 1H), 3.70 (d, J = 7.2 Hz, 2H), 3.63 (dt, J = 12.3, 4.3 Hz, 1H), 2.53 (s, 3H), 2.42 (s, 1H), 2.13 - 2.02 (m, 1H), 2.00 - 1.90 (m, 1H)。 外消旋混合物 SnAr (GP1) 136A

3-氯-7-[(3S)-3-[(1S)-1-羥乙基]吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.39 (s, 1H), 4.76 (d, J = 4.9 Hz, 1H), 4.07 (dd, J = 8.1, 5.2 Hz, 2H), 3.99 (d, J = 7.7 Hz, 2H), 3.63 (dd, J = 12.0, 6.2 Hz, 1H), 2.45 (s, 3H), 2.23 (dd, J = 15.9, 7.4 Hz, 1H), 2.09 - 1.96 (m, 1H), 1.78 (dd, J = 11.8, 9.5 Hz, 1H), 1.17 (d,J = 6.2 Hz, 3H)。 單一非鏡像異構體-未知絕對組態(97% de) SnAr (GP1) 137A

3-氯-7-[(3R)-3-[(1S)-1-羥乙基]吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.40 (s, 1H), 4.76 (d, J = 4.7 Hz, 1H), 4.07 (dd, J = 7.9, 4.9 Hz, 2H), 3.99 (d, J = 7.7 Hz, 2H), 3.63 (d, J = 4.0 Hz, 1H), 2.46 (s, 3H), 2.23 (dd, J = 16.0, 7.5 Hz, 1H), 2.02 (dd, J = 11.0, 5.9 Hz, 1H), 1.78 (dd, J = 11.9, 9.5 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H)。 單一非鏡像異構體-未知絕對組態(98% de) SnAr (GP1) 137B

3-氯-7-[(3R)-3-[(1R)-1-羥乙基]吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.39 (s, 1H), 4.76 (d, J = 5.0 Hz, 1H), 4.06 (dd, J = 8.7, 4.8 Hz, 2H), 3.98 - 3.89 (m, 1H), 3.84 (t, J = 9.3 Hz, 1H), 3.66 (dd, J = 11.6, 6.2 Hz, 1H), 2.46 (s, 3H), 2.24 (d, J = 7.6 Hz, 1H), 2.12 (dd, J = 11.5, 5.9 Hz, 1H), 1.93 - 1.80 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H)。 單一非鏡像異構體-未知絕對組態(96% de) SnAr (GP1) 137C

3-氯-7-[(3S)-3-[(1R)-1-羥乙基]吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.39 (s, 1H), 4.76 (d, J = 5.0 Hz, 1H), 4.06 (dd, J = 8.6, 4.8 Hz, 2H), 3.93 (t, J = 8.7 Hz, 1H), 3.84 (t, J = 9.3 Hz, 1H), 3.66 (dd, J = 11.6, 6.2 Hz, 1H), 2.46 (s, 3H), 2.24 (d, J = 7.3 Hz, 1H), 2.17 - 2.04 (m, 1H), 1.93 - 1.82 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H)。 單一非鏡像異構體-未知絕對組態(99% de) SnAr (GP1) 138A

3-氯-7-[(1R,6R)-6-羥基-3-氮雜雙環[4.1.0]庚-3-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.64 (s, 1H), 5.54 (s, 1H), 4.14 (dd, J = 11.8, 6.3 Hz, 1H), 3.66 (d, J = 11.6 Hz, 1H), 3.63 - 3.53 (m, 1H), 3.29 - 3.20 (m, 1H), 2.49 (s, 3H), 2.40 - 2.31 (m, 1H), 2.30 - 2.20 (m, 1H), 1.40 - 1.30 (m, 1H), 0.89 (dd, J = 9.9, 5.2 Hz, 1H), 0.64 (t, J = 5.6 Hz, 1H)。 單一鏡像異構體-未知絕對組態(94% ee) SnAr (GP1)之通用程序 138B

3-氯-7-[(1S,6S)-6-羥基-3-氮雜雙環[4.1.0]庚-3-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.60 (s, 1H), 5.54 (s, 1H), 4.14 (dd, J = 11.9, 6.1 Hz, 1H), 3.67 (d, J = 10.7 Hz, 1H), 3.64 - 3.54 (m, 1H), 3.29 - 3.22 (m, 1H), 2.49 (s, 3H), 2.39 - 2.32 (m, 1H), 2.29 - 2.19 (m, 1H), 1.40 - 1.28 (m, 1H), 0.88 (dd, J = 9.7, 5.2 Hz, 1H), 0.64 (t, J = 5.6 Hz, 1H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1)之通用程序 139A

3-氯-7-[(3S,4R)-3-氟-4-(三氟甲氧基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 445.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.10 - 4.88 (m, 2H), 4.12 - 3.82 (m, 3H), 3.67 - 3.54 (m, 1H), 2.54 (s, 3H), 2.40 (ddd, J = 14.1, 7.1, 3.6 Hz, 1H), 2.30 - 2.16 (m, 1H) 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)之通用程序 140A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N-(2-甲氧基乙基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 474.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.20 - 4.11 (m, 1H), 3.89 - 3.78 (m, 3H), 3.51 - 3.47 (m, 2H), 3.47 - 3.37 (m, 2H), 3.37 (s, 3H), 2.52 (s, 3H), 2.29 (d, J = 13.5 Hz, 1H), 2.11 (dd, J = 13.9, 6.9 Hz, 1H), 2.00 - 1.90 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(95% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 140B

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N-(2-甲氧基乙基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 474.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.20 - 4.11 (m, 1H), 3.88 - 3.78 (m, 3H), 3.52 - 3.47 (m, 2H), 3.45 - 3.37 (m, 2H), 3.36 (d, J = 8.8 Hz, 3H), 2.52 (s, 3H), 2.29 (d, J = 14.0 Hz, 1H), 2.15 - 2.08 (m, 1H), 1.95 (ddd, J = 14.7, 10.4, 4.5 Hz, 1H), 1.01 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 141A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 430.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.20 - 4.12 (m, 1H), 3.83 (dd, J = 13.2, 4.5 Hz, 3H), 2.77 (s, 3H), 2.52 (s, 3H), 2.32 - 2.24 (m, 1H), 2.10 (dd, J = 13.9, 7.0 Hz, 1H), 1.99 - 1.89 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 141B

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 430.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.21 - 4.12 (m, 1H), 3.82 (dt, J = 12.0, 6.0 Hz, 3H), 2.77 (s, 3H), 2.52 (s, 3H), 2.28 (d, J = 14.1 Hz, 1H), 2.10 (dd, J = 13.8, 6.9 Hz, 1H), 1.99 - 1.89 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 142A

(3R,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 398.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.03 - 3.93 (m, 1H), 3.88 (dd, J = 12.0, 3.6 Hz, 1H), 3.78 - 3.61 (m, 2H), 2.48 (d, J = 1.4 Hz, 3H), 2.38 - 2.28 (m, 1H), 2.08 - 1.94 (m, 1H), 1.79 - 1.65 (m, 1H), 1.41 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 核合成程序3，醯胺偶合(GP3)，脫苯甲基化(GP6)及SnAr (GP1) 142B

(3S,4S)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 398.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.01 - 3.93 (m, 1H), 3.88 (dd, J = 12.2, 3.5 Hz, 1H), 3.78 - 3.61 (m, 2H), 2.48 (d, J = 1.4 Hz, 3H), 2.39 - 2.29 (m, 1H), 2.05 - 1.97 (m, 1H), 1.76 - 1.67 (m, 1H), 1.41 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 核合成程序3，醯胺偶合(GP3)，脫苯甲基化(GP6)及SnAr (GP1) 143A

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,4,4-三甲基吡咯啶-3-甲醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.41 - 4.32 (m, 1H), 4.28 - 4.21 (m, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 2.83 - 2.70 (m, 4H), 2.49 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H)。 單一鏡像異構體-未知絕對組態(98% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 143B

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,4,4-三甲基吡咯啶-3-甲醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.41 - 4.32 (m, 1H), 4.29 - 4.20 (m, 1H), 4.08 - 3.99 (m, 1H), 3.94 - 3.85 (m, 1H), 2.86 - 2.70 (m, 4H), 2.48 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 144A

3-氯-7-[(8S)-8-羥基-5-氮雜螺[2.5]辛-5-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 385.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.98 (m, 1H), 3.92 - 3.83 (m, 1H), 3.78 - 3.67 (m, 1H), 3.46 - 3.40 (m, 1H), 3.13 (m, 1H), 2.52 (s, 3H), 2.33 - 2.24 (m, 1H), 2.00 - 1.91 (m, 1H), 0.73 - 0.44 (m, 4H) 單一鏡像異構體-未知絕對組態(97% ee) SnAr (GP1)之通用程序 144B

3-氯-7-[(8S)-8-羥基-5-氮雜螺[2.5]辛-5-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 385.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.04 - 3.94 (m, 1H), 3.92 - 3.82 (m, 1H), 3.77 - 3.68 (m, 1H), 3.45 - 3.40 (m, 1H), 3.17 - 3.06 (m, 1H), 2.51 (s, 3H), 2.35 - 2.22 (m, 1H), 2.03 - 1.91 (m, 1H), 0.75 - 0.42 (m, 4H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1)之通用程序 145A

2-[(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-基]-N-甲基乙醯胺 LC-MS:m/z 428.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.95 - 3.88 (m, 2H), 3.77 (d, J = 9.6 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.46 (s, 3H), 2.37 - 2.28 (m, 2H), 2.13 - 2.03 (m, 1H), 1.12 (s, 3H), 0.96 (s, 3H)。 單一鏡像異構體-未知絕對組態(97% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 145B

2-[(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-基]-N-甲基乙醯胺 LC-MS:m/z 428.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.95 - 3.88 (m, 2H), 3.77 (d, J = 9.7 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.47 (s, 3H), 2.38 - 2.28 (m, 2H), 2.13 - 2.04 (m, 1H), 1.12 (s, 3H), 0.96 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 146A

3-氯-7-[(4S)-4-(羥甲基)-3,3-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.37 (s, 1H), 4.70 (s, 1H), 4.14 - 4.07 (m, 1H), 4.07 - 3.99 (m, 1H), 3.88 (d, J = 9.7 Hz, 1H), 3.80 (d, J = 9.7 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.49 - 3.41 (m, 1H), 2.46 (s, 3H), 2.17 - 2.07 (m, 1H), 1.19 (s, 3H), 1.01 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 146B

3-氯-7-[(4R)-4-(羥甲基)-3,3-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.37 (s, 1H), 4.70 (s, 1H), 4.16 - 4.07 (m, 1H), 4.06 - 3.98 (m, 1H), 3.88 (d, J = 9.6 Hz, 1H), 3.80 (d, J = 9.6 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.50 - 3.40 (m, 1H), 2.46 (s, 3H), 2.20 - 2.06 (m, 1H), 1.19 (s, 3H), 1.01 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 147A

3-氯-7-[(3R,4S)-4-羥基-3-甲基環己基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 372.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.84 (d, J = 2.5 Hz, 1H), 3.76 - 3.65 (m, 1H), 2.60 (s, 3H), 2.59 - 2.52 (m, 1H), 2.43 - 2.30 (m, 1H), 2.16 (s, 1H), 2.02 - 1.93 (m, 1H), 1.85 (d, J = 11.5 Hz, 1H), 1.66 (d, J = 13.1 Hz, 1H), 1.51 (d, J = 12.7 Hz, 1H), 1.20 (d, J = 7.4 Hz, 3H)。 相對立體化學順式-非鏡像異構體之混合物 與化合物75C相同之程序 148A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基氮雜環丁烷-3-甲醯胺 LC-MS:m/z 372 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.40 (s, 1H), 7.59 (s, 1H), 7.20 (s, 1H), 4.92 - 4.88 (m, 2H), 4.45 - 4.42 (m, 2H), 2.44 (s, 3H), 1.57 (s, 3H)。 SnAr (GP1)之通用程序 149A

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.39 - 4.31 (m, 1H), 4.31 - 4.24 (m, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H), 2.91 - 2.85 (m, 1H), 2.48 (d, J = 2.8 Hz, 3H), 1.30 (s, 3H), 1.19 (s, 3H)。 單一鏡像異構體-未知絕對組態(92% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 149B

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.40 - 4.32 (m, 1H), 4.31 - 4.24 (m, 1H), 4.03 (d, J = 9.3 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.48 (d, J = 1.3 Hz, 3H), 1.32 (s, 3H), 1.19 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 150A

3-氯-7-[(4S)-4-(羥甲基)-3,3-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 401.1 (M+H)。 1H NMR (400 MHz, MeOD) δ 4.02-3.99 (m, 1H), 3.92 - 3.79 (m, 1H), 3.45 - 3.33 (m, 3H), 3.29 - 3.22 (m, 1H), 2.53 (s, 3H), 2.05 - 1.87 (m, 2H), 1.62 - 1.49 (m, 1H), 1.10 (s, 3H), 0.96 (s, 3H)。 單一鏡像異構體-未知絕對組態(94% ee) SnAr (GP1) 150B

3-氯-7-[(4R)-4-(羥甲基)-3,3-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 401.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.06 - 3.96 (m, 1H), 3.91 - 3.82 (m, 1H), 3.44 - 3.33 (m, 3H), 3.30 - 3.24 (m, 1H), 2.53 (s, 3H), 2.02 - 1.87 (m, 2H), 1.63 - 1.50 (m, 1H), 1.10 (s, 3H), 0.97 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 151A

7-[(4R)-3,3-二氟-4-羥基哌啶-1-基]-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 379 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.23 - 4.12 (m, 1H), 4.09 - 4.00 (m, 1H), 3.90 - 3.75 (m, 2H), 3.67 - 3.56 (m, 1H), 2.50 (d, J = 1.6 Hz, 3H), 2.37 - 2.28 (m, 1H), 2.15 - 2.05 (m, 1H)。 單一鏡像異構體-未知絕對組態(95% ee) 核合成程序3，SnAr (GP1) 151B

7-[(4S)-3,3-二氟-4-羥基哌啶-1-基]-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 379 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.25 - 4.12 (m, 1H), 4.10 - 3.98 (m, 1H), 3.91 - 3.77 (m, 2H), 3.66 - 3.57 (m, 1H), 2.50 (d, J = 1.6 Hz, 3H), 2.38 - 2.26 (m, 1H), 2.15 - 2.04 (m, 1H)。 單一鏡像異構體-未知絕對組態(99% ee) 核合成程序3，SnAr (GP1) 152A

3-氯-7-[(3R,4S)-3-羥基-3,4-二甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.54 - 4.46 (m, 1H), 4.14 (d, J = 10.4 Hz, 1H), 3.90 (d, J = 10.4 Hz, 1H), 3.79 (dd, J = 9.4, 4.5 Hz, 1H), 2.48 (s, 3H), 2.32 (dd, J = 11.6, 6.6 Hz, 1H), 1.37 (s, 3H), 1.09 (d, J = 7.1 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1) 153A

N-{[(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}環丙烷甲醯胺 LC-MS:m/z 454.3 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 8.08 (t, J = 5.7 Hz, 1H), 3.89 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 10.7 Hz, 1H), 3.41 (dd, J = 21.6, 11.8 Hz, 2H), 3.08 (t, J = 11.6 Hz, 1H), 2.97 (dt, J = 13.6, 6.9 Hz, 1H), 2.50 (s, 3H), 1.86 (d, J = 10.5 Hz, 1H), 1.70 - 1.55 (m, 2H), 1.55 - 1.33 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H), 0.71 - 0.60 (m, 4H)。 相對立體化學反式-未知絕對組態(96% ee) SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 153B

N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}環丙烷甲醯胺 LC-MS:m/z 454.3 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.69 (s, 1H), 8.09 (t, J = 5.8 Hz, 1H), 3.90 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 10.3 Hz, 1H), 3.42 (ddd, J = 16.5, 10.8, 6.9 Hz, 2H), 3.11 - 3.03 (m, 1H), 3.02 - 2.92 (m, 1H), 2.51 - 2.50 (m, 3H), 1.86 (d, J = 10.2 Hz, 1H), 1.60 (ddt, J = 12.6, 7.7, 6.4 Hz, 2H), 1.52 - 1.33 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H), 0.69 - 0.59 (m, 4H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 154A

3-氯-7-[(4S)-4-羥基-3,3-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.92 - 3.83 (m, 1H), 3.57 - 3.50 (m, 2H), 3.49 - 3.41 (m, 1H), 3.35 (s, 1H), 2.53 (s, 3H), 2.10 - 2.02 (m, 2H), 1.07 (s, 3H), 1.02 (s, 3H)。 單一鏡像異構體-未知絕對組態(97% ee) SnAr (GP1) 154B

3-氯-7-[(4R)-4-羥基-3,3-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.92 - 3.84 (m, 1H), 3.57 - 3.50 (m, 2H), 3.49 - 3.41 (m, 1H), 3.35 (s, 1H), 2.53 (s, 3H), 2.09 - 2.02 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 155A

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.49 (d, J = 9.7 Hz, 1H), 4.25 - 4.10 (m, 2H), 3.90 (d, J = 9.8 Hz, 1H), 2.48 (s, 4H), 2.12 - 2.02 (m, 1H), 1.49 (s, 3H)。 單一鏡像異構體-未知絕對組態(94% ee) SnAr (GP1) 155B

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.49 (d, J = 9.7 Hz, 1H), 4.25 - 4.10 (m, 2H), 3.90 (d, J = 9.7 Hz, 1H), 2.53 - 2.45 (m, 4H), 2.12 - 2.03 (m, 1H), 1.49 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 156A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 430.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.77 (qd, J = 12.4, 4.9 Hz, 2H), 3.69 - 3.59 (m, 1H), 3.52 (t, J = 11.9 Hz, 1H), 2.81 (d, J = 3.8 Hz, 3H), 2.52 (s, 3H), 2.51 - 2.36 (m, 2H), 1.80 - 1.70 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee)    醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 156B

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-N,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 430.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.77 (qd, J = 12.4, 4.8 Hz, 2H), 3.63 (dd, J = 13.0, 3.7 Hz, 1H), 3.52 (t, J = 11.9 Hz, 1H), 2.80 (s, 3H), 2.52 (s, 3H), 2.45 (ddd, J = 11.6, 10.2, 6.3 Hz, 2H), 1.76 (dd, J = 11.4, 2.4 Hz, 1H), 0.85 (d, J = 6.9 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 157A

3-氯-7-[(4R)-3,3-二氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 409.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.06 - 3.81 (m, 4H), 3.62 (dd, J = 11.1, 8.0 Hz, 1H), 3.45 (dd, J = 19.6, 7.7 Hz, 1H), 2.33 - 2.14 (m, 2H), 2.11 - 1.97 (m, 1H)。 單一鏡像異構體-未知絕對組態(95% ee) SnAr (GP1) 157B

3-氯-7-[(4S)-3,3-二氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 409.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.07 - 3.81 (m, 4H), 3.62 (dd, J = 11.0, 8.0 Hz, 1H), 3.44 (t, J = 12.4 Hz, 1H), 2.35 - 2.16 (m, 2H), 2.10 - 1.97 (m, 1H)。 單一鏡像異構體-未知絕對組態(95% ee) SnAr (GP1) 158A

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.36 (t, J = 9.5 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.66 - 2.55 (m, 1H), 2.48 (s, 3H), 1.26 - 1.20 (m, 3H) 相對立體化學反式-未知絕對組態(96% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 158B

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386.1 (M+H)。 1H NMR (400 MHz, MeOD) δ 4.36 (t, J = 9.5 Hz, 1H), 4.21 (t, J = 8.2 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 2.83 - 2.74 (m, 1H), 2.65 - 2.56 (m, 1H), 2.48 (s, 3H), 1.25 - 1.20 (m, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 159A

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.23 - 4.14 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 2.80 (s, 3H), 2.75 - 2.67 (m, 1H), 2.65 - 2.56 (m, 1H), 2.48 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H)。 相對立體化學反式-未知絕對組態(94% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 159B

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,4-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.23 - 4.14 (m, 2H), 3.85 (t, J = 9.6 Hz, 1H), 2.80 (s, 3H), 2.71 (td, J = 9.5, 7.6 Hz, 1H), 2.65 - 2.54 (m, 1H), 2.47 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H)。 相對立體化學反式-未知絕對組態(94% ee) 醯胺偶合(GP3)，脫除Boc保護基(GP4)，SnAr (GP1) 160A

3-氟-7-[(4R)-4-羥基-3,3-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.31 (s, 1H), 4.80 (d, J = 4.6 Hz, 1H), 3.77 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 11.6 Hz, 1H), 3.39 (d, J = 4.3 Hz, 2H), 3.26 (s, 1H), 2.46 (d, J = 1.1 Hz, 3H), 1.94 - 1.81 (m, 2H), 0.97 (s, 3H), 0.90 (s, 3H)。 單一鏡像異構體-未知絕對組態(98% ee) 核合成程序3，SnAr (GP1) 160B

3-氟-7-[(4S)-4-羥基-3,3-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371.1 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.31 (s, 1H), 4.81 (d, J = 4.6 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 3.54 (d, J = 11.1 Hz, 1H), 3.39 (d, J = 4.4 Hz, 2H), 3.26 (s, 1H), 2.47 (s, 3H), 2.01 - 1.77 (m, 2H), 0.98 (s, 3H), 0.91 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) 核合成程序3，SnAr (GP1) 161A

3-氯-2-甲基-5-(三氟甲基)-7-[(3S)-3-(三氟甲基)吡咯啶-1-基]-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 397.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.24 (dt, J = 12.9, 7.3 Hz, 4H), 3.35 (d, J = 6.3 Hz, 1H), 2.47 (d, J = 18.7 Hz, 3H), 2.40 (td, J = 12.4, 6.7 Hz, 1H), 2.32 - 2.21 (m, 1H) 單一鏡像異構體-未知絕對組態(81% ee) SnAr (GP1) 161B

3-氯-2-甲基-5-(三氟甲基)-7-[(3R)-3-(三氟甲基)吡咯啶-1-基]-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 397.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.32 - 4.15 (m, 4H), 3.39 - 3.32 (m, 1H), 2.47 (d, J = 19.0 Hz, 3H), 2.40 (dt, J = 12.3, 6.2 Hz, 1H), 2.33 - 2.18 (m, 1H) 單一鏡像異構體-未知絕對組態(96% ee) SnAr (GP1) 162A

N-{[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.95 (d,J = 13.3 Hz, 1H), 3.78 - 3.72 (m, 1H), 3.67 - 3.61 (m, 1H), 3.36 (d,J = 3.3 Hz, 1H), 3.21 (d,J = 7.1 Hz, 2H), 2.53 (s, 3H), 2.23 (q,J = 7.6 Hz, 2H), 2.16 - 2.08 (m, 1H), 2.06 - 1.93 (m, 2H), 1.72 - 1.64 (m, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.04 (d,J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 162B

N-{[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz,CD3OD) δ 3.95 (d, J = 13.2 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.67 - 3.61 (m, 1H), 3.35 (d, J = 3.5 Hz, 1H), 3.21 (d, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.23 (q, J = 7.6 Hz, 2H), 2.15 - 2.08 (m, 1H), 2.06 - 1.91 (m, 2H), 1.71 - 1.63 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 162C

N-{[(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 7.80 (t, J = 5.9 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 10.6 Hz, 1H), 3.40 (dd, J = 16.8, 6.7 Hz, 2H), 3.14 - 3.04 (m, 1H), 3.01 - 2.90 (m, 1H), 2.51 (s, 3H), 2.10 (q, J = 7.6 Hz, 2H), 1.88 - 1.77 (m, 1H), 1.69 - 1.55 (m, 1H), 1.52 - 1.30 (m, 2H), 1.00 (dd, J = 14.9, 7.1 Hz, 6H)。 相對立體化學反式-未知絕對組態(93% ee) SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 162D

N-{[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 7.80 (t, J = 5.7 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 10.6 Hz, 1H), 3.44 - 3.36 (m, 2H), 3.14 - 3.03 (m, 1H), 3.01 - 2.89 (m, 1H), 2.51 (s, 3H), 2.14 - 2.03 (m, 2H), 1.84 (d, J = 10.4 Hz, 1H), 1.70 - 1.55 (m, 1H), 1.54 - 1.30 (m, 2H), 1.00 (dd, J = 14.9, 7.2 Hz, 6H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 163A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.85 - 3.72 (m, 2H), 3.63 (d, J = 4.3 Hz, 1H), 3.54 (dd, J = 25.7, 14.0 Hz, 1H), 2.53 (s, 3H), 2.45 (ddd, J = 11.3, 10.4, 4.9 Hz, 2H), 1.81 (d, J = 13.7 Hz, 1H), 0.92 (d, J = 6.8 Hz, 3H)。 相對立體化學順式-未知絕對組態(92% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 163B

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.86 - 3.72 (m, 2H), 3.64 (dd, J = 11.6, 3.6 Hz, 1H), 3.54 (dd, J = 25.7, 13.9 Hz, 1H), 2.53 (s, 3H), 2.45 (ddd, J = 11.3, 10.4, 4.9 Hz, 2H), 1.84 - 1.77 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 163C

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR (400 MHz, CD3OD) δ 4.19 - 4.07 (m, 1H), 3.84 (qd, J = 12.0, 6.6 Hz, 3H), 2.52 (s, 3H), 2.32 (d, J = 14.3 Hz, 1H), 2.11 (dd, J = 13.7, 6.8 Hz, 1H), 1.99 - 1.89 (m, 1H), 1.06 (d,J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(93% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 163D

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.19 - 4.08 (m, 1H), 3.90 - 3.78 (m, 3H), 2.52 (s, 3H), 2.36 - 2.27 (m, 1H), 2.11 (ddd, J = 8.9, 6.9, 4.6 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 164A

(3R,5S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,5-二甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.90 (dd, J = 12.3, 3.0 Hz, 2H), 3.12 (t, J = 11.9 Hz, 2H), 2.54 (s, 3H), 2.21 (dt, J = 10.9, 6.7 Hz, 2H), 1.80 (t, J = 10.9 Hz, 1H), 1.00 (d, J = 6.6 Hz, 6H)。 SnAr (GP1) 164B

(3R,5R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,5-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR (400 MHz, CD3OD) δ 4.03 (d, J = 13.5 Hz, 1H), 3.99 - 3.93 (m, 1H), 3.84 - 3.68 (m, 1H), 3.58 (d, J = 11.4 Hz, 1H), 3.45 - 3.32 (m, 2H), 2.96 (dd, J = 12.9, 10.5 Hz, 1H), 2.61 (d, J = 5.9 Hz, 1H), 2.53 (t, J = 2.0 Hz, 3H), 2.42 (dd, J = 10.5, 3.9 Hz, 1H), 2.35 (t, J = 6.6 Hz, 1H), 1.88 (d, J = 9.4 Hz, 1H), 1.13 (s, 4H), 1.10 (d ,J = 6.8 Hz, 1H), 0.98 (d, J = 6.4 Hz, 1H)。 鏡像異構體之混合物 SnAr (GP1) 165A

3-氯-7-[4-氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.84 - 3.73 (m, 4H), 3.66 (s, 1H), 3.61 (s, 1H), 2.53 (s, 3H), 2.06 (dd, J = 15.0, 5.4 Hz, 3H), 2.01 - 1.92 (m, 1H)。 SnAr (GP1) 166A

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基吡咯啶-3-甲醯胺 LC-MS:m/z 391.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.48 (s, 1H), 8.23 (d, J = 4.2 Hz, 1H), 4.09 (t, J = 9.2 Hz, 4H), 3.12 - 2.98 (m, 1H), 2.67 (td, J = 7.3, 3.9 Hz, 1H), 2.45 (s, 3H), 2.26 - 2.01 (m, 2H), 0.64 (td, J = 6.7, 4.5 Hz, 2H), 0.49 - 0.28 (m, 2H)。 絕對組態 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 167A

3-氯-2-甲基-7-[4-(4H-1,2,4-三唑-3-基)哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 410.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 13.78 (s, 1H), 11.75 (s, 1H), 8.16 (d, J = 219.1 Hz, 1H), 3.93 (d, J = 12.7 Hz, 2H), 3.60 (t, J = 10.6 Hz, 2H), 3.11 (s, 1H), 2.50 (d, J = 1.8 Hz, 3H), 2.14 (d, J = 10.4 Hz, 2H), 2.06 - 1.92 (m, 2H)。 SnAr (GP1)之通用程序 168A

3-氯-7-(4-環丙氧基哌啶-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 399.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.91 - 3.79 (m, 3H), 3.60 - 3.53 (m, 2H), 3.49 - 3.42 (m, 1H), 2.52 (s, 3H), 2.19 - 2.10 (m, 2H), 1.94 - 1.84 (m, 2H), 0.63 - 0.56 (m, 2H), 0.56 - 0.50 (m, 2H)。 SnAr (GP1)之通用程序 169A

3-氯-7-(3-甲磺醯基吡咯啶-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 407 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.57 (s, 1H), 4.42 (d, J = 7.6 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.26 (dd, J = 16.5, 7.1 Hz, 1H), 4.19 (dd, J = 12.2, 6.7 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.15 (s, 3H), 2.48 (s, 5H)。 鏡像異構體之混合物 SnAr (GP1) 170A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.75 - 3.66 (m, 3H), 3.42 (m, 1H), 2.61 - 2.48 (m, 4H), 2.27 (m, 1H), 1.81 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(98% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 170B

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.76 - 3.66 (m, 3H), 3.42 (m, 9.8 Hz, 1H), 2.60 - 2.48 (m, 4H), 2.27 (m, 1H), 1.81 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 171A

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(丙-2-基)吡咯啶-3-甲醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.48 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 4.18 - 4.03 (m, 4H), 3.87 (d, J = 7.2 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.45 (s, 3H), 2.22 (dd, J = 11.7, 5.5 Hz, 1H), 2.15 - 2.05 (m, 1H), 1.08 (d, J = 6.6 Hz, 6H)。 絕對組態 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 172A

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基乙基)吡咯啶-3-甲醯胺 LC-MS:m/z 430.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.48 (s, 1H), 8.26 (t, J = 5.5 Hz, 1H), 4.10 (dd, J = 12.3, 7.5 Hz, 4H), 3.37 (t, J = 5.7 Hz, 2H), 3.29 - 3.23 (m, 5H), 3.18 - 3.11 (m, 1H), 2.45 (s, 3H), 2.27 - 2.18 (m, 1H), 2.16 - 2.07 (m, 1H)。 絕對組態 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 173A

3-氟-7-[4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 357.3 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.98 (d, J = 12.3 Hz, 2H), 3.53 - 3.43 (m, 4H), 2.49 (d, J = 1.6 Hz, 3H), 1.95 (d, J = 12.8 Hz, 2H), 1.84 - 1.74 (m, 1H), 1.59 - 1.48 (m, 2H) 核合成程序3，SnAr (GP1) 174A

3-氯-2-甲基-7-[4-(1,3-㗁唑-2-基)哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 410.1 (M+H)。 1H NMR (400 MHz, MeOD) δ 7.88 (d, J = 0.8 Hz, 1H), 7.14 (d,J = 0.8 Hz, 1H), 3.97 (dt, J = 6.3, 2.9 Hz, 2H), 3.66 - 3.57 (m, 2H), 3.22 (tt, J = 11.1, 4.1 Hz, 1H), 2.53 (s, 3H), 2.27 (dd, J = 13.2, 3.5 Hz, 2H), 2.15 (ddd, J = 24.4, 11.1, 3.8 Hz, 2H)。 SnAr (GP1) 175A

3-氯-7-[(3S,4S)-3-(羥甲基)-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.42 (s, 1H), 4.79 (s, 1H), 4.15 (dd, J = 9.5, 7.3 Hz, 1H), 4.01 (dd, J = 17.2, 8.2 Hz, 2H), 3.73 (t, J = 9.3 Hz, 1H), 3.61 (d, J = 7.6 Hz, 1H), 3.53 - 3.45 (m, 1H), 2.46 (s, 3H), 2.17 (dd, J = 14.8, 7.9 Hz, 1H), 2.06 - 1.95 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(95% ee) SnAr (GP1) 175B

3-氯-7-[(3R,4R)-3-(羥甲基)-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.43 (s, 1H), 4.78 (s, 1H), 4.16 (dd, J = 9.6, 7.3 Hz, 1H), 4.02 (dd, J = 17.0, 8.1 Hz, 2H), 3.73 (t,J = 9.3 Hz, 1H), 3.61 (dd, J = 10.9, 4.3 Hz, 1H), 3.49 (dd, J = 10.8, 6.4 Hz, 1H), 2.46 (s, 3H), 2.23 - 2.12 (m, 1H), 2.02 (s, 1H), 1.11 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1) 176A

3-氯-7-[(3R)-3-羥基-3-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.45 (dd, J = 17.1, 9.5 Hz, 1H), 4.15 (d, J = 10.4 Hz, 1H), 4.12 - 4.04 (m, 1H), 3.85 (d, J = 10.6 Hz, 1H), 2.48 (s, 3H), 2.07 (dd, J = 10.1, 7.5 Hz, 2H), 1.52 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 176B

3-氯-7-[(3S)-3-羥基-3-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.45 (dd, J = 17.2, 9.5 Hz, 1H), 4.15 (d, J = 10.5 Hz, 1H), 4.08 (dd, J = 11.8, 5.1 Hz, 1H), 3.85 (d, J = 10.4 Hz, 1H), 2.48 (s, 3H), 2.07 (dd, J = 10.1, 7.4 Hz, 2H), 1.52 (s, 3H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 177A

3-氯-7-[(1S,4S,5S)-5-羥基-2-氮雜雙環[2.2.1]庚-2-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.32 (s, 1H), 5.02 (s, 1H), 4.91 (s, 1H), 4.28 (d, J = 6.3 Hz, 1H), 4.15 (dd, J = 8.8, 3.1 Hz, 1H), 4.00 (d, J = 8.8 Hz, 1H), 2.68 (s, 1H), 2.46 (s, 3H), 2.24 - 2.13 (m, 1H), 1.90 (d, J = 10.4 Hz, 1H), 1.76 (d, J = 10.2 Hz, 1H), 1.40 (d, J = 13.4 Hz, 1H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 177B

3-氯-7-[(1R,4R,5R)-5-羥基-2-氮雜雙環[2.2.1]庚-2-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.31 (s, 1H), 5.02 (s, 1H), 4.91 (s, 1H), 4.26 (s, 1H), 4.15 (dd, J = 8.8, 3.1 Hz, 1H), 4.00 (d, J = 9.0 Hz, 1H), 2.68 (s, 1H), 2.46 (s, 3H), 2.19 (ddd, J = 12.7, 9.8, 2.5 Hz, 1H), 1.90 (d, J = 10.3 Hz, 1H), 1.76 (d, J = 10.0 Hz, 1H), 1.40 (d, J = 13.4 Hz, 1H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 178A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基乙基)-4-甲基哌啶-4-甲醯胺 LC-MS:m/z 458.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 7.82 (t, J = 5.5 Hz, 1H), 3.83 - 3.76 (m, 2H), 3.63 - 3.55 (m, 2H), 3.51 (dd, J = 8.5, 3.0 Hz, 2H), 3.47 - 3.41 (m, 2H), 3.35 (d, J = 3.1 Hz, 3H), 2.52 (s, 3H), 2.32 (d, J = 13.9 Hz, 2H), 1.78 (ddd, J = 13.8, 10.0, 3.7 Hz, 2H), 1.30 (s, 3H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 179A

3-氯-7-[(4S)-3,3-二氟-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 395 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.25 - 4.10 (m, 1H), 4.05 (s, 1H), 3.91 - 3.76 (m, 2H), 3.66 - 3.55 (m, 1H), 2.54 (s, 3H), 2.33 (s, 1H), 2.11 (s, 1H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 179B

3-氯-7-[(4R)-3,3-二氟-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 395 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.23 - 4.12 (m, 1H), 4.05 (d, J = 5.8 Hz, 1H), 3.90 - 3.74 (m, 2H), 3.61 (d, J = 14.4 Hz, 1H), 2.55 (s, 3H), 2.39 - 2.27 (m, 1H), 2.16 - 2.05 (m, 1H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1) 180A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-甲基氮雜環丁烷-3-甲醯胺 LC-MS:m/z 372.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.41 (s, 1H), 8.07 (d, J = 4.6 Hz, 1H), 4.82 (t, J = 8.8 Hz, 2H), 4.71 (dd, J = 8.6, 5.9 Hz, 2H), 3.53 (dq, J = 9.1, 5.7 Hz, 1H), 2.65 (d, J = 4.6 Hz, 3H), 2.44 (s, 3H)。 SnAr (GP1)之通用程序，酯水解(GP2)及醯胺偶合(GP3) 181A

3-氯-7-[(3R,4R)-3-羥基-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.42 (s, 1H), 5.15 (d, J = 4.2 Hz, 1H), 4.29 (dd, J = 10.7, 3.7 Hz, 1H), 4.20 (d, J = 3.6 Hz, 1H), 3.98 (t,J = 8.4 Hz, 1H), 3.87 (t, J = 9.8 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.46 (s, 3H), 2.35 - 2.28 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H)。 相對立體化學順式-未知絕對組態(97% ee) SnAr (GP1) 181B

3-氯-7-[(3S,4S)-3-羥基-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.42 (s, 1H), 5.15 (d, J = 4.2 Hz, 1H), 4.29 (dd, J = 10.8, 3.7 Hz, 1H), 4.20 (d, J = 3.6 Hz, 1H), 3.98 (t, J = 8.4 Hz, 1H), 3.87 (t, J = 9.9 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.46 (s, 3H), 2.32 (dd, J = 7.0, 3.6 Hz, 1H), 1.09 (d,J = 6.7 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1) 182A

7-[(3R,4R)-3-胺基-4-氟吡咯啶-1-基]-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 362.1 (M+H)。 1H NMR (400 MHz, MeOD) δ 5.10 (d, J = 51.5 Hz, 1H), 4.68 (ddd, J = 38.3, 12.2, 3.6 Hz, 1H), 4.50 (dd, J = 9.3, 5.1 Hz, 1H), 4.15 (dd, J = 23.8, 12.2 Hz, 1H), 3.88 (d, J = 10.5 Hz, 1H), 3.79 (dd, J = 11.0, 5.1 Hz, 1H), 2.50 (s, 3H)。 相對立體化學反式-未知絕對組態(88% ee) SnAr (GP1)，脫除Boc保護基(GP4) 182B

7-[(3S,4S)-3-胺基-4-氟吡咯啶-1-基]-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 362.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.10 (d, J = 51.4 Hz, 1H), 4.68 (ddd, J = 38.1, 12.2, 3.6 Hz, 1H), 4.50 (dd, J = 9.8, 4.5 Hz, 1H), 4.15 (dd, J = 23.8, 12.2 Hz, 1H), 3.89 (d, J = 10.5 Hz, 1H), 3.80 (dd, J = 10.8, 4.8 Hz, 1H), 2.50 (s, 3H)。 相對立體化學反式-未知絕對組態(95% ee) SnAr (GP1)，脫除Boc保護基(GP4) 183A

2-[(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]吡咯啶-3-基]乙醯胺 LC-MS:m/z 386 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.45 (s, 1H), 7.39 (s, 1H), 6.87 (s, 1H), 4.08 (dd, J = 14.9, 8.0 Hz, 3H), 3.74 (dd, J = 9.8, 7.3 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.46 (s, 3H), 2.24 (tdd, J = 17.9, 13.3, 6.6 Hz, 3H), 1.74 (dq, J = 16.0, 7.9 Hz, 1H)。 單一鏡像異構體-未知絕對組態(95% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 183B

2-[(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]吡咯啶-3-基]乙醯胺 LC-MS:m/z 386 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.45 (s, 1H), 7.39 (s, 1H), 6.87 (s, 1H), 4.13 - 3.99 (m, 3H), 3.74 (dd, J = 9.9, 7.3 Hz, 1H), 2.69 - 2.60 (m, 1H), 2.46 (s, 3H), 2.24 (tdd, J = 18.0, 13.3, 6.7 Hz, 3H), 1.80 - 1.68 (m, 1H)。 單一鏡像異構體-未知絕對組態(95% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 184A

3-氯-7-(3,3-二甲基吡咯啶-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 357.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.39 (s, 1H), 4.12 (t, J = 6.9 Hz, 2H), 3.77 (s, 2H), 2.46 (s, 3H), 1.83 (s, 2H), 1.15 (s, 6H)。 SnAr (GP1) 185A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,3-二甲基吡咯啶-3-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.47 (d, J = 9.7 Hz, 1H), 4.27 - 4.15 (m, 1H), 4.14 - 4.06 (m, 1H), 3.90 (d, J = 9.8 Hz, 1H), 2.76 (s, 3H), 2.50 - 2.42 (m, 4H), 2.09 - 1.98 (m, 1H), 1.45 (s, 3H)。 外消旋混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 80A

3-溴-7-((3 S,4 S)-4-羥基-3-甲基哌啶-1-基)-2-甲基-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈 LC-MS:m/z 417.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.77 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.89 - 3.72 (m, 2H),3.51- 3.44 (m, 1H), 3.28-3.21 (m, 1H), 3.13-3.08 (m, 1H), 2.50 (s, 3H), 2.2-1.98 (m, 1H), 1.79 - 1.58 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H)。 絕對組態(99% ee) 核合成程序2，隨後SnAr (GP1) 80B

3-溴-7-((3 R,4 R)-4-羥基-3-甲基哌啶-1-基)-2-甲基-5-(三氟甲基)-1 H-吡咯并[3,2- b]吡啶-6-甲腈 LC-MS:m/z 417.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.76 (s, 1H), 4.84 (d, J = 5.5 Hz, 1H), 3.93 - 3.69 (m, 2H), 3.55 - 3.44 (m, 1H), 3.26 - 3.20 (m, 1H), 3.13-3.08 (m, 1H), 2.51 (s, 3H), 2.04 - 1.94 (m, 1H), 1.80 - 1.57 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H)。 絕對組態(98% ee) 核合成程序2，隨後SnAr (GP1) 186A

3-氯-7-[(3S,4R)-3-羥基-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.42 - 4.29 (m, 2H), 4.13 - 4.05 (m, 1H), 3.92 - 3.84 (m, 1H), 3.82 - 3.75 (m, 1H), 2.48 (s, 3H), 2.39 - 2.28 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(94% ee) SnAr (GP1) 186B

3-氯-7-[(3R,4S)-3-羥基-4-甲基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.41 - 4.30 (m, 2H), 4.13 - 4.04 (m, 1H), 3.92 - 3.85 (m, 1H), 3.82 - 3.75 (m, 1H), 2.48 (s, 3H), 2.40 - 2.29 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H) 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1) 187A

7-[(3aR,5R,6aS)-5-羥基-八氫環戊并[c]吡咯-2-基]-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 385.2 (M+H)。 1H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 4.78 (s, 1H), 4.19 (dd, J = 9.9, 7.6 Hz, 3H), 4.01 (dd, J = 10.3, 3.8 Hz, 2H), 2.75 (d, J = 10.5 Hz, 2H), 2.47 (s, 3H), 2.10 (dt, J = 14.2, 7.1 Hz, 2H), 1.57 - 1.44 (m, 2H)。 SnAr (GP1) 188A

7-[(3aR,5S,6aS)-5-羥基-八氫環戊并[c]吡咯-2-基]-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 385.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.45 (s, 1H), 4.58 (d, J = 3.7 Hz, 1H), 4.33 (d,J = 3.3 Hz, 1H), 4.14 (dd, J = 10.3, 7.6 Hz, 2H), 3.83 (dd, J = 10.2, 3.5 Hz, 2H), 2.93 (s, 2H), 2.47 (s, 3H), 1.83 - 1.69 (m, 4H)。 SnAr (GP1) 189A

7-[(3R,4S)-3-胺基-4-氟吡咯啶-1-基]-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 362.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.32 (d, J = 52.9 Hz, 1H), 4.70 - 4.53 (m, 1H), 4.39 - 4.17 (m, 3H), 4.00 - 3.81 (m, 1H), 2.51 (s, 3H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)，脫除Boc保護基(GP4) 190A

3-氯-2-甲基-7-[(3S)-3-甲基吡咯啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 343.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.24 - 4.03 (m, 3H), 3.72 (t, J = 9.0 Hz, 1H), 2.47 (s, 3H), 2.43 (d, J = 8.7 Hz, 1H), 2.29 - 2.15 (m, 1H), 1.79 - 1.63 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H)。 絕對組態(99% ee) SnAr (GP1) 190B

3-氯-2-甲基-7-[(3R)-3-甲基吡咯啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 343.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.23 - 4.03 (m, 3H), 3.72 (t, J = 9.0 Hz, 1H), 2.53 - 2.38 (m, 4H), 2.26 - 2.16 (m, 1H), 1.71 (ddd, J = 21.4, 12.1, 9.4 Hz, 1H), 1.21 (d, J = 6.6 Hz, 3H)。 絕對組態(99% ee) SnAr (GP1) 191A

3-氯-7-[(3S)-3-氟吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 347.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.46 (d, J = 52.3 Hz, 1H), 4.57 - 4.32 (m, 2H), 4.18 - 4.06 (m, 2H), 2.49 (s, 3H), 2.46 - 2.12 (m, 2H)。 絕對組態(97% ee) SnAr (GP1) 192A

3-氯-7-[(1S,4S,5R)-5-羥基-2-氮雜雙環[2.2.1]庚-2-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.02 (s, 1H), 4.35 - 4.23 (m, 1H), 4.02 (d, J = 6.6 Hz, 1H), 3.36 - 3.32 (m, 1H), 2.64 (d, J = 8.1 Hz, 1H), 2.47 (s, 3H), 2.35 - 2.28 (m, 1H), 2.10 (d, J = 10.3 Hz, 1H), 1.86 (d, J = 10.3 Hz, 1H), 1.73 (d, J = 13.7 Hz, 1H)。 相對立體化學順式-未知絕對組態(97% ee) SnAr (GP1) 193A

3-氯-7-[(1R,4R,5S)-5-羥基-2-氮雜雙環[2.2.1]庚-2-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.02 (s, 1H), 4.32 - 4.25 (m, 1H), 4.02 (d, J = 6.6 Hz, 1H), 3.34 (d, J = 10.3 Hz, 1H), 2.66 (s, 1H), 2.47 (s, 3H), 2.31 (d, J = 2.4 Hz, 1H), 2.10 (d, J = 10.1 Hz, 1H), 1.86 (d, J = 10.4 Hz, 1H), 1.73 (d, J = 13.5 Hz, 1H)。 相對立體化學順式-未知絕對組態(98% ee) SnAr (GP1) 194A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.01 - 3.92 (m, 1H), 3.92 - 3.83 (m, 1H), 3.75 - 3.64 (m, 2H), 2.52 (s, 3H), 2.41 - 2.29 (m, 1H), 2.09 - 1.97 (m, 1H), 1.78 - 1.66 (m, 1H), 1.41 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 194B

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.02 - 3.92 (m, 1H), 3.91 - 3.83 (m, 1H), 3.75 - 3.60 (m, 2H), 2.52 (s, 3H), 2.40 - 2.29 (m, 1H), 2.07 - 1.94 (m, 1H), 1.78 - 1.66 (m, 1H), 1.41 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，及SnAr (GP1) 195A

3-氯-7-[3-(甲氧基甲基)氮雜環丁烷-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.80 (t, J = 8.8 Hz, 2H), 4.55 - 4.48 (m, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.41 (s, 3H), 3.14 - 3.04 (m, 1H), 2.45 (s, 3H) SnAr (GP1)之通用程序 196A

3-氯-7-[3-(羥甲基)氮雜環丁烷-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 345.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.35 (s, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.72 (t, J = 8.7 Hz, 2H), 4.45 (dd, J = 8.8, 5.5 Hz, 2H), 3.63 (t, J = 5.6 Hz, 2H), 2.97-2.82 (m, 1H), 2.44 (s, 3H)。 SnAr (GP1)之通用程序 197A

3-氯-7-(3-氟氮雜環丁烷-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 333.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.56 (tt, J = 6.0, 3.0 Hz, 1H), 5.41 (tt,J = 6.0, 3.0 Hz, 1H), 5.05 (dddd, J = 21.6, 10.5, 6.0, 1.7 Hz, 2H), 4.84 - 4.71 (m, 2H), 2.47 (s, 3H)。 SnAr (GP1)之通用程序 198A

3-氯-7-{6,6-二氟-3-氮雜雙環[3.1.0]己-3-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 377.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.49 - 4.44 (m, 2H), 4.43 - 4.38 (m, 2H), 2.69 - 2.67 (m, 1H), 2.66 - 2.64 (m, 1H), 2.49 (s, 3H)。 SnAr (GP1) 199A

3-氯-7-[(3S)-3-(2-羥基丙-2-基)吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.24 - 4.15 (m, 1H), 4.15 - 4.06 (m, 2H), 4.02 - 3.92 (m, 1H), 2.47 (s, 3H), 2.46 - 2.39 (m, 1H), 2.18 - 2.09 (m, 1H), 2.04 - 1.94 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H)。 絕對組態(99% ee) SnAr (GP1) 199B

3-氯-7-[(3R)-3-(2-羥基丙-2-基)吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.24 - 4.06 (m, 3H), 4.01 - 3.90 (m, 1H), 2.51 - 2.37 (m, 4H), 2.19 - 2.08 (m, 1H), 2.03 - 1.90 (m, 1H), 1.31 (d, J = 6.7 Hz, 6H)。 絕對組態(99% ee) SnAr (GP1) 200A

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.28 - 4.11 (m, 4H), 3.22 - 3.12 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 2.36 - 2.32 (m, 1H), 2.30 - 2.20 (m, 1H)。 絕對組態(85% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 200B

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-甲基吡咯啶-3-甲醯胺 LC-MS:m/z 386.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.47 (s, 1H), 8.11-8.08 (m, 1H), 4.23 - 4.00 (m, 4H), 3.14 - 3.04 (m, 1H), 2.63 (d, J = 4.6 Hz, 3H), 2.45 (s, 3H), 2.26-2.17 (m, 1H), 2.15-2.10 (m, 1H)。 絕對組態(94% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 201A

(3S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]吡咯啶-3-甲醯胺 LC-MS:m/z 372.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.26-4.15 (m, 4H), 3.27 - 3.21 (m, 1H), 2.48 (s, 3H), 2.40-2.35 (m, 1H), 2.29-2.24 (m, 1H)。 絕對組態(99% ee) SnAr (GP1) 201B

(3R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]吡咯啶-3-甲醯胺 LC-MS:m/z 372.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.48 (s, 1H), 7.61 (s, 1H), 7.12 (s, 1H), 4.19 - 3.99 (m, 4H), 3.14 - 3.07 (m, 1H), 2.45 (s, 3H), 2.30 - 2.19 (m, 1H), 2.20 - 2.09 (m, 1H) 絕對組態(99% ee) SnAr (GP1) 202A

3-氯-7-[(3R)-3-(羥甲基)吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 359.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.19 - 4.06 (m, 3H), 3.94 (dd, J = 9.7, 7.4 Hz, 1H), 3.67 (qd, J = 10.9, 6.7 Hz, 2H), 2.58 (dt, J = 13.7, 6.6 Hz, 1H), 2.47 (s, 3H), 2.21 (td, J = 11.9, 6.3 Hz, 1H), 1.90 (dq, J = 12.3, 8.1 Hz, 1H)。 絕對組態 SnAr (GP1) 203A

3-氯-7-[(3S)-3-羥基吡咯啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 345.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.58 (d, J = 3.7 Hz, 1H), 4.33 (ddd, J = 15.0, 10.2, 5.7 Hz, 2H), 4.12 - 4.03 (m, 1H), 3.85 (d, J = 10.8 Hz, 1H), 2.47 (s, 3H), 2.22 - 2.08 (m, 2H)。 絕對組態(99% ee) SnAr (GP1) 204A

3-氯-7-[(3S,4R)-4-(羥甲基)-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.67 (s, 1H), 4.50 (t, J = 5.1 Hz, 1H), 3.91 (d, J = 12.2 Hz, 1H), 3.77 (d, J = 10.5 Hz, 1H), 3.62 - 3.55 (m, 1H), 3.47 - 3.39 (m, 2H), 3.12 - 3.01 (m, 1H), 2.51 (s, 3H), 1.88 (d, J = 10.4 Hz, 1H), 1.79 - 1.69 (m, 1H), 1.63 - 1.53 (m, 1H), 1.28 (s, 1H), 0.95 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(97% ee) 通用程序SnAr (GP1) 204B

3-氯-7-[(3R,4S)-4-(羥甲基)-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.68 (s, 1H), 4.51 (t, J = 5.1 Hz, 1H), 3.90 (d, J = 13.0 Hz, 1H), 3.77 (d, J = 10.7 Hz, 1H), 3.63 - 3.54 (m, 1H), 3.48 - 3.39 (m, 2H), 3.13 - 3.02 (m, 1H), 2.50 (s, 3H), 1.89 (d, J = 10.4 Hz, 1H), 1.79 - 1.70 (m, 1H), 1.65 - 1.55 (m, 1H), 1.28 (s, 1H), 0.95 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(96% ee) 通用程序SnAr (GP1) 205A

3-氯-7-(3-羥基-3-甲基氮雜環丁烷-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 345.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.68 (d, J = 12 Hz, 2H), 4.57 (d, J = 9.0 Hz, 2H), 2.46 (s, 3H), 1.60 (s, 3H)。 SnAr (GP1)之通用程序 206A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基-N-(丙-2-基)哌啶-4-甲醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 8.00 (d, J = 7.4 Hz, 1H), 4.07 - 3.94 (m, 2H), 3.92 - 3.84 (m, 1H), 3.50 - 3.42 (m, 1H), 3.17 - 3.07 (m, 1H), 2.53 (s, 3H), 2.26 - 2.15 (m, 1H), 2.17 - 2.04 (m, 2H), 1.93 - 1.84 (m, 1H), 1.21 - 1.14 (m, 6H), 0.96 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 207A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 440.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.70 (s, 1H), 8.04 (d, J = 4.1 Hz, 1H), 3.88 (d, J = 12.3 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.37 (dd, J = 12.0, 9.7 Hz, 1H), 3.09 - 3.00 (m, 1H), 2.65 (tq, J = 7.8, 3.9 Hz, 1H), 2.50 (s, 3H), 2.07 - 1.83 (m, 3H), 1.77 (dd, J = 12.6, 2.9 Hz, 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.66 - 0.61 (m, 2H), 0.43 - 0.38 (m, 2H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 208A

3-氯-2-甲基-7-[(3R,4S)-3-甲基-4-(嗎啉-4-羰基)哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 470.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.97 (d, J = 12.5 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.71 (d, J = 7.9 Hz, 4H), 3.67 (d, J = 3.3 Hz, 4H), 3.55 - 3.46 (m, 1H), 3.21 (t, J = 11.8 Hz, 1H), 2.77 - 2.67 (m, 1H), 2.53 (s, 3H), 2.40 - 2.27 (m, 1H), 2.09 - 1.96 (m, 1H), 1.95 - 1.85 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 209A

N-[(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]乙醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.20 - 4.12 (m, 1H), 3.93 - 3.83 (m, 1H), 3.83 - 3.76 (m, 1H), 3.61 - 3.46 (m, 2H), 2.53 (s, 3H), 2.36 - 2.26 (m, 1H), 2.22 - 2.10 (m, 1H), 2.01 (s, 3H), 1.88 - 1.80 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 210A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-氟-N-(丙-2-基)哌啶-4-甲醯胺 LC-MS:m/z 446.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 5.07 (s, 1H), 4.24 - 4.14 (m, 1H), 4.07 (s, 2H), 3.89 - 3.77 (m, 1H), 3.48 (t, J = 12.0 Hz, 1H), 2.81 - 2.68 (m, 1H), 2.54 (s, 3H), 2.46 (d, J = 15.6 Hz, 1H), 1.93 (d, J = 11.8 Hz, 1H), 1.18 (d, J = 4.5 Hz, 6H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 211A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基-3-氟哌啶-4-甲醯胺 LC-MS:m/z 444.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 8.04 (s, 1H), 5.12 (d, J = 47.3 Hz, 1H), 4.22 - 4.05 (m, 2H), 3.90 - 3.77 (m, 1H), 3.47 (t, J = 11.8 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.54 (s, 3H), 2.50 - 2.40 (m, 1H), 1.94 (d, J = 12.9 Hz, 1H), 0.75 (d, J = 5.7 Hz, 2H), 0.54 (s, 2H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 212A

3-氯-7-[(3S,4R)-3-氟-4-(嗎啉-4-羰基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 472.2 (M-H)。 1H NMR(400 MHz, DMSO-d6) δ 11.71 (s, 1H), 5.03 (d, J = 47.4 Hz, 1H), 4.11 - 3.87 (m, 3H), 3.62 - 3.36 (m, 10H), 2.50 (s, 3H), 2.46 (s, 1H), 1.71 (d, J = 12.0 Hz, 1H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 213A

3-氯-7-[(3S,5S)-4-羥基-3,5-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.70 (s, 1H), 3.56 - 3.50 (m, 2H), 3.43 (t, J = 11.9 Hz, 2H), 2.52 (s, 3H), 2.14 - 2.03 (m, 2H), 1.05 (d, J = 6.9 Hz, 6H)。 未知絕對組態 SnAr (GP1) 214A

3-氯-7-[(3R,5R)-4-羥基-3,5-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.86 (d, J = 14.6 Hz, 2H), 3.17 (t, J = 12.0 Hz, 2H), 2.87 (t, J = 9.9 Hz, 1H), 2.53 (s, 3H), 1.99 - 1.85 (m, 2H), 1.09 (d, J = 6.5 Hz, 6H)。 未知絕對組態 SnAr (GP1) 215A

3-氯-2-甲基-7-[(3R,4s,5S)-4-羥基-3,5-二甲基哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.00 - 3.91 (m, 1H), 3.74 - 3.66 (m, 1H), 3.57 - 3.50 (m, 2H), 3.16 - 3.08 (m, 1H), 2.52 (s, 3H), 2.33 - 2.17 (m, 2H), 1.06 (t, J = 6.2 Hz, 6H)。 SnAr (GP1) 216A

3-氯-7-[(3R,4S)-3-氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.05 (s, 0.5H), 4.93 (s, 0.5H), 4.18 (t, J = 11.9 Hz, 1H), 4.05 (d, J = 12.4 Hz, 1H), 3.86 - 3.66 (m, 2H), 3.57 (m, 1H), 3.46 (t, J = 11.1 Hz, 1H), 2.53 (s, 3H), 1.99 (m, 2H), 1.74 (d, J = 8.9 Hz, 1H)。 相對立體化學順式-未知絕對組態(97% ee) SnAr (GP1)之通用程序 216B

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,3-二氟哌啶-4-甲醯胺 LC-MS:m/z 422.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.91 (s, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 4.33 (dd, J = 21.4, 8.9 Hz, 1H), 3.98 - 3.82 (m, 2H), 3.58 (s, 1H), 3.10 (d, J = 6.6 Hz, 1H), 2.52 (s, 3H), 2.18 (d, J = 12.5 Hz, 2H)。 外消旋混合物 SnAr (GP1) 217A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-氟哌啶-4-甲醯胺 LC-MS:m/z 404.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.14 - 4.95 (m, 1H), 4.24 - 4.13 (m, 1H), 3.83 (d, J = 12.1 Hz, 1H), 3.54 - 3.43 (m, 2H), 2.76 - 2.65 (m, 1H), 2.54 (s, 3H), 2.15 - 2.02 (m, 2H)。 相對立體化學反式-未知絕對組態(97% ee) SnAr (GP1)之通用程序 217B

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-氟哌啶-4-甲醯胺 LC-MS:m/z 404.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.20 (d, J = 47.9 Hz, 1H), 4.20 (t, J = 10.7 Hz, 1H), 4.08 (d, J = 13.4 Hz, 1H), 3.85 (m, 1H), 3.48 (t, J = 12.0 Hz, 1H), 2.79 (m, 1H), 2.53 (d, J = 9.1 Hz, 3H), 2.50 - 2.37 (m, 1H), 1.99 (d, J = 13.5 Hz, 1H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 218A

3-氯-7-[(3R,4S)-4-羥基-3,4-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.69 (s, 1H), 4.39 (s, 1H), 3.84 - 3.72 (m, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.49 - 3.38 (m, 2H), 2.49 (s, 3H), 1.82 - 1.68 (m, 3H), 1.20 (s, 3H), 0.89 (d, J = 6.7 Hz, 3H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1) 218B

3-氯-7-[(3S,4S)-4-羥基-3,4-二甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.93 (d, J = 8.8 Hz, 1H), 3.77 (s, 1H), 3.64 (t, J = 11.1 Hz, 1H), 3.28 - 3.26 (m, 1H), 2.52 (s, 3H), 2.01 (s, 2H), 1.86 (d, J = 9.0 Hz, 1H), 1.26 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1) 219A

3-氯-7-[(3R,4R)-3-氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.77 - 4.58 (m, 1H), 4.24 - 4.08 (m, 1H), 3.82 (m, 2H), 3.71 (m, 1H), 3.52 - 3.41 (m, 2H), 2.54 (s, 3H), 2.07 (d, J = 11.1 Hz, 1H), 1.96 - 1.73 (m, 2H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 219B

3-氯-7-[(3S,4S)-3-氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.67 (m, 1H), 4.21 - 4.11 (m, 1H), 3.89 - 3.79 (m, 2H), 3.71 (m, 1H), 3.47 (m, 2H), 2.54 (s, 3H), 2.11 - 2.02 (m, 1H), 1.95 - 1.73 (m, 2H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 220A

3-氯-7-[(3S,4R)-3-氟-4-甲氧基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.06 - 4.92 (m, 1H), 4.10 - 4.01 (m, 1H), 3.90 - 3.70 (m, 3H), 3.55 - 3.46 (m, 4H), 2.53 (s, 3H), 2.27 - 2.17 (m, 1H), 2.07 - 1.97 (m, 1H) 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 220B

3-氯-7-[(3R,4S)-3-氟-4-甲氧基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 5.05 - 4.92 (m, 1H), 4.11 - 3.99 (m, 1H), 3.90 - 3.70 (m, 3H), 3.55 - 3.46 (m, 4H), 2.53 (s, 3H), 2.27 - 2.16 (m, 1H), 2.04 - 1.98 (m, 1H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 221A

(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-(三氟甲基)哌啶-4-甲醯胺 LC-MS:m/z 454.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.45 - 4.35 (m, 1H), 4.27 - 4.15 (m, 1H), 3.86 (d, J = 12.4 Hz, 1H), 3.64 (d, J = 12.7 Hz, 1H), 3.06 (t, J = 9.8 Hz, 2H), 2.54 (s, 3H), 2.24 - 2.11 (m, 2H)。 相對立體化學順式-未知絕對組態(95% ee) SnAr (GP1)之通用程序 221B

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-(三氟甲基)哌啶-4-甲醯胺 LC-MS:m/z 454.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.44 - 4.35 (m, 1H), 4.25 - 4.16 (m, 1H), 3.86 (d, J = 9.5 Hz, 1H), 3.64 (d, J = 12.4 Hz, 1H), 3.11 - 2.98 (m, 2H), 2.54 (s, 3H), 2.21 - 2.12 (m, 2H)。 相對立體化學順式-未知絕對組態(95% ee) SnAr (GP1)之通用程序 222A

3-氯-7-[(3S,4S)-3-羥基-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.98 - 3.92 (m, 1H), 3.91 - 3.84 (m, 2H), 3.82 - 3.74 (m, 1H), 3.70 - 3.63 (m, 1H), 3.53 - 3.44 (m, 1H), 3.28 - 3.23 (m, 1H), 2.53 (s, 3H), 2.05 - 2.02 (m, 1H), 1.75 - 1.65 (m, 2H)。 相對立體化學反式-未知絕對組態(98% ee) SnAr (GP1)之通用程序 222B

3-氯-7-[(3R,4R)-3-羥基-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.98 - 3.91 (m, 1H), 3.91 - 3.83 (m, 2H), 3.81 - 3.74 (m, 1H), 3.69 - 3.63 (m, 1H), 3.48 (t, J = 11.4 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.53 (s, 3H), 2.05 - 2.00 (m, 1H), 1.75 - 1.65 (m, 2H)。 相對立體化學反式-未知絕對組態(98% ee) SnAr (GP1)之通用程序 223A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.03 (d, J = 13.4 Hz, 1H), 3.58 (d, J = 11.3 Hz, 1H), 3.39 (dd, J = 13.0, 7.3 Hz, 2H), 2.53 (s, 3H), 2.44 - 2.31 (m, 2H), 1.88 (d, J = 8.7 Hz, 1H), 1.13 (s, 6H)。 外消旋混合物 SnAr (GP1)之通用程序 224A

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-(羥甲基)哌啶-4-甲醯胺 LC-MS:m/z 416.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.96 (d, J = 6.9 Hz, 2H), 3.69 (dd, J = 10.9, 3.4 Hz, 1H), 3.61 - 3.47 (m, 3H), 2.63 (td, J = 10.7, 3.7 Hz, 1H), 2.53 (s, 3H), 2.07 (d, J = 10.9 Hz, 2H), 1.75 (dd, J = 22.2, 12.7 Hz, 1H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)之通用程序 225A

3-氯-7-[(3S,4R)-4-羥基-3-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.84 (s, 1H), 4.86 (d, J = 4.8 Hz, 2H), 3.90 (d, J = 10.0 Hz, 1H), 3.80 (d, J = 12.5 Hz, 1H), 3.69 (m, 1H), 3.63 - 3.54 (m, 1H), 3.45 (m, 3H), 2.50 (s, 3H), 2.04 - 1.92 (m, 1H), 1.83 - 1.74 (m, 1H), 1.73 - 1.61 (m, 1H)。 相對立體化學反式-未知絕對組態 SnAr (GP1)之通用程序 225B

3-氯-7-[(3R,4S)-4-羥基-3-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.84 (s, 1H), 4.86 (d, J = 4.8 Hz, 2H), 3.90 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 12.7 Hz, 1H), 3.69 (m, 1H), 3.62 - 3.36 (m, 4H), 2.50 (s, 3H), 2.04 - 1.92 (m, 1H), 1.85 - 1.74 (m, 1H), 1.74 - 1.60 (m, 1H)。 相對立體化學反式-未知絕對組態 SnAr (GP1)之通用程序 226A

3-氯-7-[(3S,4R)-3-氟-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 392.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 4.96 (m, 1H), 4.76 (t, J = 5.1 Hz, 1H), 4.09 (t, J = 11.9 Hz, 1H), 3.98 (m, 1H), 3.83 (m, 1H), 3.50 (m, 1H), 3.40 (m, 2H), 2.51 - 2.45 (m, 3H), 1.87m, 2H), 1.69 (m, 1H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 227A

3-氯-7-[(3S,4S)-3-氟-4-甲氧基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 391.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.79 - 4.61 (m, 1H), 4.09 (t, J = 11.7 Hz, 1H), 3.81 - 3.73 (m, 1H), 3.67 - 3.49 (m, 6H), 2.54 (s, 3H), 2.32 (d, J = 9.0 Hz, 1H), 1.91 - 1.80 (m, 1H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)之通用程序 228A

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-氟哌啶-4-甲醯胺 LC-MS:m/z 404.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.85 (s, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 5.14 - 4.81 (m, 1H), 4.30 - 4.02 (m, 1H), 3.76 (m, 1H), 3.45 (m, 2H), 2.60 (m, 1H), 2.52 (s, 3H), 2.08 - 1.75 (m, 2H)。 相對立體化學反式-未知絕對組態(98% ee) SnAr (GP1)之通用程序 228B

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-氟哌啶-4-甲醯胺 LC-MS:m/z 404.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.71 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 5.21 (m, 1H), 4.32 - 3.61 (m, 3H), 3.40 (m, 1H), 2.73 (m, 1H), 2.51 - 2.47 (m, 3H), 2.28 (m, 1H), 1.85 (d, J = 10.5 Hz, 1H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 229A

3-氯-7-[(3R,4R)-3-氟-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 377.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.67 - 4.48 (m, 1H), 4.12 (t, J = 10.1 Hz, 1H), 3.92 - 3.75 (m, 2H), 3.55 (t, J = 10.6 Hz, 2H), 2.54 (s, 3H), 2.21 (d, J = 8.3 Hz, 1H), 1.87 (d, J = 10.0 Hz, 1H)。 相對立體化學反式-未知絕對組態(98% ee) SnAr (GP1)之通用程序 229B

3-氯-7-[(3S,4S)-3-氟-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 377.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.69 - 4.50 (m, 1H), 4.13 (t, J = 9.8 Hz, 1H), 3.93 - 3.76 (m, 2H), 3.62 - 3.52 (m, 2H), 2.55 (s, 3H), 2.27 - 2.17 (m, 1H), 1.95 - 1.80 (m, 1H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 229C

3-氯-7-[(3S,4R)-3-氟-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 377.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.77 (d, J = 6.8 Hz, 1H), 4.15 - 4.00 (m, 2H), 3.94 - 3.75 (m, 2H), 3.51 (s, 1H), 2.53 (s, 3H), 2.23 - 2.14 (m, 1H), 2.06 - 1.97 (m, 1H) 相對立體化學順式-未知絕對組態(97% ee) SnAr (GP1)之通用程序 229D

3-氯-7-[(3R,4S)-3-氟-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 377.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.82 - 4.75 (m, 1H), 4.15 - 4.01 (m, 2H), 3.93 - 3.76 (m, 2H), 3.55 - 3.46 (m, 1H), 2.54 (s, 3H), 2.23 - 2.13 (m, 1H), 2.06 - 1.97 (m, 1H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1)之通用程序 230A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基哌啶-3-甲醯胺 LC-MS:m/z 402.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.02 (s, 1H), 7.35 (s, 1H), 7.06 (s, 1H), 5.07 (d, J = 5.0 Hz, 1H), 3.98 - 3.72 (m, 3H), 3.68 - 3.56 (m, 1H), 3.39 - 3.33 (m, 1H), 2.50 (s, 3H), 2.47 - 2.40 (m, 1H), 2.03 - 1.92 (m, 1H), 1.81 -1.71 (m, 1H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)之通用程序 230B

(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基哌啶-3-甲醯胺 LC-MS:m/z 402.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.24 (s, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 5.38 (s, 1H), 4.34 - 4.21 (m, 1H), 4.04 - 3.99 (m, 1H), 3.77 (t, J = 9.6 Hz, 1H), 3.58 (t, J = 11.3 Hz, 2H), 2.77 - 2.67 (m, 1H), 2.50 (s, 3H), 1.96 - 1.85 (m, 1H), 1.84 - 1.72 (m, 1H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)之通用程序 231A

3-氯-7-[(3S,4S)-4-羥基-3-(三氟甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 427.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.88 (s, 1H), 5.33 (s, 1H), 4.35 (s, 1H), 3.94 - 3.80 (m, 2H), 3.71 (d, J = 10.7 Hz, 1H), 3.58 (d, J = 11.8 Hz, 1H), 2.82 (s, 1H), 2.51 (s, 3H), 1.95 (t, J = 11.1 Hz, 1H), 1.83 (d, J = 12.9 Hz, 1H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)之通用程序 232A

2-[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]乙醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.68 (s, 1H), 7.36 (s, 1H), 6.81 (s, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 11.6 Hz, 1H), 3.42 (t, J = 11.6 Hz, 1H), 3.12 - 3.05 (m, 1H), 2.51 (s, 3H), 2.43 - 2.37 (m, 1H), 1.93 - 1.81 (m, 2H), 1.62 (s, 2H), 1.46 (d, J = 9.2 Hz, 1H), 0.94 (d, J = 5.8 Hz, 3H)。 相對立體化學反式-未知絕對組態(97% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 232B

2-[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]乙醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.71 (s, 1H), 7.37 (s, 1H), 6.82 (s, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.73 (dd, J = 11.7, 2.8 Hz, 1H), 3.55 (d, J = 9.5 Hz, 1H), 3.29 (s, 1H), 2.51 (s, 3H), 2.18 (d, J = 4.0 Hz, 1H), 2.12 - 2.07 (m, 2H), 2.03 - 1.94 (m, 1H), 1.82 (dd, J = 20.2, 10.8 Hz, 1H), 1.59 (dd, J = 13.1, 3.3 Hz, 1H), 0.92 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 233A

3-氯-7-{6-羥基-3-氮雜雙環[3.1.1]庚-3-基}-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 371.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.28 - 4.18 (m, 3H), 4.11 (d, J = 10.5 Hz, 2H), 2.65 (s, 2H), 2.50 (s, 3H), 1.79 - 1.69 (m, 2H)。 外消旋混合物 SnAr (GP1)之通用程序 234A

2-[(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]-N-甲基乙醯胺 LC-MS:m/z 428.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.69 (d, J = 10.8 Hz, 1H), 7.83 (s, 1H), 3.77 (dd, J = 37.8, 12.1 Hz, 2H), 3.59 - 3.36 (m, 2H), 3.10 (t, J = 11.3 Hz, 1H), 2.59 (d, J = 4.2 Hz, 3H), 2.50 - 2.48 (m, 3H), 2.43 (d, J = 19.5 Hz, 1H), 2.19 (s, 1H), 2.00 - 1.39 (m, 4H), 0.96 - 0.88 (m, 3H)。 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 234B

2-[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]-N-甲基乙醯胺 LC-MS:m/z 428.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.68 (s, 1H), 7.84 (s, 1H), 3.84 (d, J = 10.5 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.17 (s, 1H), 3.08 (d, J = 12.1 Hz, 1H), 2.59 (d, J = 4.5 Hz, 3H), 2.51 (s, 3H), 2.40 (d, J = 3.8 Hz, 1H), 1.88 (dd, J = 13.9, 8.7 Hz, 1H), 1.78 (d, J = 12.5 Hz, 1H), 1.60 (s, 2H), 1.46 (s, 1H), 0.93 (d, J = 6.1 Hz, 3H)。 相對立體化學反式-未知絕對組態 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 234C

2-[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]-N-甲基乙醯胺 LC-MS:m/z 428.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.70 (s, 1H), 7.84 (d, J = 4.6 Hz, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.55 (d, J = 9.2 Hz, 1H), 3.29 (d, J = 6.5 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.50 - 2.49 (m, 3H), 2.19 (s, 1H), 2.10 (d, J = 6.4 Hz, 2H), 1.95 (s, 1H), 1.87 - 1.74 (m, 1H), 1.56 (d, J = 10.1 Hz, 1H), 0.91 (d, J = 6.9 Hz, 3H)。 相對立體化學反式-未知絕對組態 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 234D

(3S,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 384.3 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.99 (d, J = 12.8 Hz, 1H), 3.91 (d, J = 12.7 Hz, 1H), 3.47 (t, J = 11.1 Hz, 1H), 3.12 (t, J = 11.4 Hz, 1H), 2.49 (s, 3H), 2.21 - 1.94 (m, 4H), 1.00 (d, J = 5.4 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序3，SnAr (GP1) 235A

N-[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基哌啶-3-基]乙醯胺 LC-MS:m/z 416.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.45 (s, 1H), 8.66 (d, J = 5.4 Hz, 1H), 5.02 (d, J = 5.7 Hz, 1H), 4.16 - 3.94 (m, 2H), 3.74 - 3.65 (m, 1H), 3.65 - 3.50 (m, 2H), 3.12 - 3.06 (m, 1H), 2.56 (s, 3H), 2.08 - 1.92 (m, 4H), 1.62 - 1.49 (m, 1H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 236A

3-氯-7-[4-羥基-4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.71 (s, 1H), 4.73 (t, J = 5.6 Hz, 1H), 4.40 (s, 1H), 3.82 - 3.61 (m, 4H), 3.34 - 3.29 (m, 2H), 2.49 (s, 3H), 1.89 - 1.82 (m, 2H), 1.57 - 1.54 (m, 2H)。 SnAr (GP1) 237A

3-氯-7-[(3R,4S)-3-乙基-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.72 (s, 1H), 4.74 (d, J = 3.5 Hz, 1H), 3.96 (s, 1H), 3.79 (s, 1H), 3.58 - 3.43 (m, 3H), 2.51 (s, 3H), 1.84 (s, 2H), 1.70 (s, 1H), 1.43 (dt, J = 14.5, 7.4 Hz, 1H), 1.29 (dd, J = 14.2, 7.0 Hz, 1H), 0.90 (t, J = 7.4 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) SnAr (GP1) 238A

(3S,4R)-1-[6-氰基-3-氟-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,3-二甲基哌啶-4-甲醯胺 LC-MS:m/z 398.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.98 (d, J = 11.7 Hz, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.47 (t, J = 11.9 Hz, 1H), 3.12 (t, J = 11.7 Hz, 1H), 2.76 (s, 3H), 2.49 (s, 3H), 2.26 - 2.16 (m, 1H), 2.13 - 2.04 (m, 2H), 1.94 - 1.85 (m, 1H), 0.94 (d, J = 6.4 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 核合成程序3，SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 239A  

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基乙基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 458.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.96 (d, J = 12.3 Hz, 1H), 3.88 (d, J = 11.4 Hz, 1H), 3.51 - 3.45 (m, 3H), 3.40 (dd, J = 13.5, 5.2 Hz, 2H), 3.36 (s, 3H), 3.12 (t, J = 11.5 Hz, 1H), 2.53 (s, 3H), 2.23 - 2.04 (m, 3H), 1.91 (d, J = 10.2 Hz, 1H), 0.96 (d, J = 6.2 Hz, 3H)。 相對立體化學反式-未知絕對組態(94% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 239B

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(2-甲氧基乙基)-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 458.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.96 (d, J = 12.9 Hz, 1H), 3.88 (d, J = 12.2 Hz, 1H), 3.51 - 3.45 (m, 3H), 3.45 - 3.37 (m, 2H), 3.36 (s, 3H), 3.12 (t, J = 11.5 Hz, 1H), 2.53 (s, 3H), 2.23 - 2.04 (m, 3H), 1.91 (d, J = 10.0 Hz, 1H), 0.96 (d, J = 6.2 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 240A

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR (400 MHz, MeOD) δ 3.97 (d, J = 12.5 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.12 (t, J = 11.3 Hz, 1H), 2.53 (s, 3H), 2.24 - 2.03 (m, 3H), 1.96 (dd, J = 12.5, 1.9 Hz, 1H), 1.00 (d, J = 5.7 Hz, 3H)。 相對立體化學反式-未知絕對組態(98% ee) SnAr (GP1) 240B

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.97 (d, J = 12.5 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.47 (t, J = 11.3 Hz, 1H), 3.12 (t, J = 11.2 Hz, 1H), 2.53 (s, 3H), 2.22 - 2.02 (m, 3H), 2.00 - 1.93 (m, 1H), 1.00 (d, J = 5.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) SnAr (GP1) 241A

N-[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]乙醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.72 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 3.85 (t, J = 11.9 Hz, 2H), 3.54 (dd, J = 22.2, 11.3 Hz, 2H), 3.17 (t, J = 11.8 Hz, 1H), 2.51 (s, 3H), 1.91 (d, J = 13.4 Hz, 1H), 1.83 (d, J = 17.9 Hz, 4H), 1.70 - 1.53 (m, 1H), 0.89 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 242A

N-[(3S,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲磺醯胺 LC-MS:m/z 450.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.73 (s, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.87 (d, J = 12.3 Hz, 2H), 3.51 (t, J = 11.8 Hz, 1H), 3.21 - 3.14 (m, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.98 (s, 3H), 2.52 (s, 3H), 2.11 (d, J = 9.7 Hz, 1H), 1.85 - 1.71 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態 SnAr (GP1)，脫除Boc保護基(GP4)，磺醯胺合成(GP8) 242B

N-[(3R,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲磺醯胺 LC-MS:m/z 450.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.73 (s, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.87 (d, J = 12.8 Hz, 2H), 3.51 (t, J = 11.8 Hz, 1H), 3.21 - 3.13 (m, 1H), 3.06 (d, J = 12.2 Hz, 1H), 2.98 (s, 3H), 2.52 (s, 3H), 2.11 (d, J = 9.7 Hz, 1H), 1.77 (d, J = 11.8 Hz, 2H), 1.01 (d, J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態 SnAr (GP1)，脫除Boc保護基(GP4)，磺醯胺合成(GP8) 243A

3-氯-7-[(3R,4R)-4-(羥甲基)-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.96 (d, J = 12.7 Hz, 1H), 3.80 - 3.74 (m, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.60 - 3.52 (m, 2H), 3.38 - 3.32 (m, 1H), 2.52 (s, 3H), 2.24 - 2.17 (m, 1H), 2.01 - 1.90 (m, 2H), 1.69 (t, J = 10.5 Hz, 1H), 1.01 (d, J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(95% ee) SnAr (GP1) 243B

3-氯-7-[(3S,4S)-4-(羥甲基)-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.96 (d, J = 12.7 Hz, 1H), 3.82 - 3.73 (m, 1H), 3.66 (d, J = 11.5 Hz, 1H), 3.60 - 3.50 (m, 2H), 3.40 - 3.32 (m, 1H), 2.51 (s, 3H), 2.27 - 2.15 (m, 1H), 2.03 - 1.90 (m, 2H), 1.69 (t, J = 10.4 Hz, 1H), 1.01 (d, J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(98% ee) SnAr (GP1) 244A

3-氯-7-[(3R,4R)-4-甲氧基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.93 - 3.85 (m, 2H), 3.56 - 3.47 (m, 1H), 3.44 (s, 3H), 3.24 - 3.15 (m, 1H), 3.09 (td, J = 9.1, 4.1 Hz, 1H), 2.53 (s, 3H), 2.37 - 2.29 (m, 1H), 2.02 - 1.93 (m, 1H), 1.76 - 1.66 (m, 1H), 1.12 - 1.05 (d, J = 8 Hz, 3H)。 相對立體化學反式-未知絕對組態(94% ee) SnAr (GP1) 244B

3-氯-7-[(3S,4S)-4-甲氧基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.95 - 3.84 (m, 2H), 3.56 - 3.48 (m, 1H), 3.44 (s, 3H), 3.23 - 3.15 (m, 1H), 3.09 (td, J = 9.5, 4.2 Hz, 1H), 2.53 (s, 3H), 2.37 - 2.28 (m, 1H), 2.02 - 1.93 (m, 1H), 1.77 - 1.65 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(98% ee) SnAr (GP1) 245A

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基哌啶-4-基}甲磺醯胺 LC-MS:m/z 450.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.83 (t, J = 10.1 Hz, 2H), 3.71 (d, J = 13.0 Hz, 2H), 3.08 (s, 3H), 2.52 (s, 3H), 2.24 (d, J = 13.9 Hz, 2H), 1.95 - 1.84 (m, 2H), 1.56 (s, 3H) SnAr (GP1)，脫除Boc保護基(GP4)及磺醯胺合成(GP8) 246A

2-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基哌啶-4-基}乙醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 7.32 (s, 1H), 6.79 (s, 1H), 3.73 - 3.58 (m, 4H), 2.52 (s, 3H), 2.15 (s, 2H), 1.84 - 1.75 (m, 2H), 1.63 - 1.54 (m, 2H), 1.14 (s, 3H) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 247A

3-氯-7-[(3S,4S)-4-羥基-3-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.96 (s, 1H), 4.85 (d, J = 3.2 Hz, 1H), 4.02 (d, J = 2.6 Hz, 1H), 3.78 (m, 2H), 3.65 (m, 1H), 3.61 - 3.45 (m, 3H), 2.48 (s, 3H), 1.99 (d, J = 4.3 Hz, 1H), 1.91 - 1.68 (m, 2H) 相對立體化學順式-鏡像異構體之混合物 SnAr (GP1) 248A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-甲基哌啶-4-甲醯胺 LC-MS:m/z 400.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.71 (s, 1H), 7.33 (s, 1H), 7.04 (s, 1H), 3.72 (d, J = 12.9 Hz, 2H), 3.53 (t, J = 10.3 Hz, 2H), 2.48 (s, 3H), 2.21 (d, J = 13.9 Hz, 2H), 1.63 - 1.51 (m, 2H), 1.20 (s, 3H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 249A

3-氯-7-[4-(羥甲基)-4-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.78 - 3.64 (m, 4H), 3.42 (s, 2H), 2.52 (s, 3H), 1.86 - 1.78 (m, 2H), 1.60 - 1.53 (m, 2H), 1.11 (s, 3H)。 SnAr (GP1) 250A

3-氯-7-[(3S,4S)-3-乙基-4-羥基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.69 (s, 1H), 4.81 (d, J = 5.5 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.80 (d, J = 12.3 Hz, 1H), 3.49 (t, J = 10.7 Hz, 1H), 3.36 (d, J = 4.4 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.50 - 2.48 (m, 3H), 2.01 (d, J = 9.8 Hz, 1H), 1.80 (ddd, J = 13.4, 7.6, 3.5 Hz, 1H), 1.72 - 1.47 (m, 2H), 1.17 (tt, J = 15.3, 7.5 Hz, 1H), 0.91 (t, J = 7.5 Hz, 3H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1) 251A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N,4-二甲基哌啶-4-甲醯胺 LC-MS:m/z 414.1(M+H)。 1H NMR(400 MHz, MeOD) δ 3.82 - 3.75 (m, 2H), 3.61 - 3.54 (m, 2H), 2.79 (d, J = 3.8 Hz, 3H), 2.51 (s, 3H), 2.33 - 2.26 (m, 2H), 1.77 (ddd, J = 13.5, 9.8, 3.6 Hz, 2H), 1.28 (s, 3H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 252A

3-氯-7-(4-羥基-4-甲基哌啶-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.1(M+H)。 1H NMR(400 MHz, DMSO) δ 11.70 (s, 1H), 4.51 (s, 1H), 3.75 (t, J = 9.7 Hz, 2H), 3.61 (d, J = 12.2 Hz, 2H), 2.52 (s, 3H), 1.69 (t, J = 13.8 Hz, 4H), 1.24 (s, 3H)。 SnAr (GP1) 253A

N-({1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}甲基)環丙烷甲醯胺 LC-MS:m/z 440.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 3.94 (d, J = 12.3 Hz, 2H), 3.44 (t, J = 11.4 Hz, 2H), 3.20 (d, J = 6.7 Hz, 2H), 2.50 (s, 3H), 1.92 (d, J = 12.8 Hz, 2H), 1.87 - 1.76 (m, 1H), 1.64 - 1.45 (m, 3H), 0.90 - 0.82 (m, 2H), 0.81 - 0.70 (m, 2H)。 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 254A

N-({1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}甲基)丙醯胺 LC-MS:m/z 428.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 3.94 (d, J = 12.4 Hz, 2H), 3.48 - 3.40 (m, 2H), 3.18 (d, J = 6.6 Hz, 2H), 2.52 (s, 3H), 2.23 (q, J = 7.6 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.87 - 1.76 (m, 1H), 1.59 - 1.47 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H)。 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 255A

N-({1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}甲基)乙醯胺 LC-MS:m/z 414.1(M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.95 (t, J = 5.4 Hz, 1H), 3.87 (d, J = 12.3 Hz, 2H), 3.42 (s, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.48 (s, 3H), 1.82 (d, J = 11.8 Hz, 5H), 1.68 (d, J = 7.2 Hz, 1H), 1.43 - 1.29 (m, 2H)。 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 256A

3-氯-7-[4-(2-羥乙基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1(M+H)。 1H NMR(400 MHz, DMSO) δ 11.65 (s, 1H), 4.42 (s, 1H), 3.86 (d, J = 12.2 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.42 (t, J = 11.6 Hz, 2H), 2.50 (s, 3H), 1.85 (d, J = 12.2 Hz, 2H), 1.71 (s, 1H), 1.47 (m, 2H), 1.44 - 1.31 (m, 2H)。 SnAr (GP1)之通用程序 257A

2-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}-N-乙基乙醯胺 LC-MS:m/z 428.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 3.92 (d, J = 12.5 Hz, 2H), 3.47 (t, J = 11.5 Hz, 2H), 3.22 (q, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.21 (d, J = 7.2 Hz, 2H), 2.07 (s, 1H), 1.89 (d, J = 12.7 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 258A

3-氯-7-[4-(甲氧基甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 387.1(M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 3.88 (d, 2H), 3.43 (t, 2H), 3.32 (s, 3H), 3.29 (s, 2H), 2.50 - 2.49 (s, 3H), 1.83 (d, 3H), 1.45 (m, 2H) SnAr (GP1)之通用程序 79B

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}乙烷-1-磺醯胺 LC-MS:m/z 450.1(M+H)。 1H NMR(400 MHz, DMSO) δ 11.71 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 12.5 Hz, 2H), 3.49 (t, J = 11.3 Hz, 2H), 3.42 (d, J = 7.3 Hz, 1H), 3.06 (q, J = 7.3 Hz, 2H), 2.49 - 2.48 (m, 3H), 2.00 (d, J = 10.7 Hz, 2H), 1.73 (dd, J = 20.5, 10.4 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H)。 SnAr (GP1)，脫除Boc保護基(GP4)，磺醯胺合成(GP8) 259A

2-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}-N,N-二甲基乙醯胺 LC-MS:m/z 428.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 3.93 (d, J = 11.9 Hz, 2H), 3.48 (t, J = 11.4 Hz, 2H), 3.10 (s, 3H), 2.96 (s, 3H), 2.52 (s, 3H), 2.44 (d, J = 6.9 Hz, 2H), 2.12 (s, 1H), 1.94 (d, J = 12.5 Hz, 2H), 1.65 - 1.52 (m, 2H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 260A

2-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}-N-甲基乙醯胺 LC-MS:m/z 414.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 3.92 (d, J = 12.3 Hz, 2H), 3.47 (t, J = 11.7 Hz, 2H), 2.74 (s, 3H), 2.52 (s, 3H), 2.22 (d, J = 7.2 Hz, 2H), 2.07 (s, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.63 - 1.50 (m, 2H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 261A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-羥基-N-甲基哌啶-4-甲醯胺 LC-MS:m/z 416.1(M+H)。 1H NMR(400 MHz, DMSO) δ 11.78 (s, 1H), 7.85 (d, J = 4.5 Hz, 1H), 5.29 (d, J = 4.4 Hz, 1H), 3.97 - 3.73 (m, 3H), 3.36 (d, J = 12.0 Hz, 1H), 3.19 (t, J = 10.5 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H), 2.50 - 2.49 (m, 3H), 2.24 (td, J = 10.8, 4.7 Hz, 1H), 1.87 (dt, J = 20.6, 11.2 Hz, 2H)。 相對立體化學反式-鏡像異構體之混合物 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 262A

3-氟-7-[(3S,4S)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 357.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 3.99 - 3.83 (m, 2H), 3.58 - 3.48 (m, 1H), 3.41 - 3.34 (m, 1H), 3.19 - 3.11 (m, 1H), 2.49 (d, J = 1.3 Hz, 3H), 2.17 - 2.08 (m, 1H), 1.92 - 1.76 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序3，SnAr (GP1) 263A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[(3S)- 氧雜環戊烷-3-基]哌啶-4-甲醯胺 LC-MS:m/z 456.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 4.39 (s, 1H), 4.00 - 3.85 (m, 4H), 3.84 - 3.77 (m, 1H), 3.64 - 3.58 (m, 1H), 3.50 (t, J = 10.8 Hz, 2H), 2.57 - 2.47 (m, 4H), 2.28 - 2.18 (m, 1H), 2.08 - 1.91 (m, 4H), 1.89 - 1.81 (m, 1H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 263B

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-[(3R)-氧雜環戊烷-3-基]哌啶-4-甲醯胺 LC-MS:m/z 456.1(M+H)。 1H NMR(400 MHz, CD3OD) δ 4.39 (s, 1H), 4.00 - 3.85 (m, 4H), 3.83 - 3.77 (m, 1H), 3.65 - 3.59 (m, 1H), 3.50 (t, J = 10.8 Hz, 2H), 2.58 - 2.48 (m, 4H), 2.28 - 2.18 (m, 1H), 2.08 - 1.91 (m, 4H), 1.89 - 1.78 (m, 1H)。 單一鏡像異構體-未知絕對組態(99% ee) SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 264A

3-氯-2-甲基-7-[4-(吡咯啶-1-羰基)哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 440.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.98 (d, J = 12.5 Hz, 2H), 3.64 (t, J = 6.7 Hz, 2H), 3.54 (t, J = 11.0 Hz, 2H), 3.44 (t, J = 6.9 Hz, 2H), 2.89 - 2.80 (m, 1H), 2.53 (s, 3H), 2.08 - 1.99 (m, 4H), 1.97 - 1.89 (m, 4H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 265A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(氧雜環丁烷-3-基)哌啶-4-甲醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.65 (d, J = 6.5 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.73 (t, J = 6.7 Hz, 2H), 4.44 (t, J = 6.2 Hz, 2H), 3.89 (d, J = 12.3 Hz, 2H), 3.45 (t, J = 10.1 Hz, 2H), 2.50 - 2.49 (m, 4H), 1.92 - 1.78 (m, 4H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 266A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-(氧雜環己烷-4-基)哌啶-4-甲醯胺 LC-MS:m/z 442.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.02 - 3.86 (m, 5H), 3.54 - 3.44 (m, 4H), 2.58 - 2.42 (m, 4H), 2.09 - 1.91 (m, 4H), 1.83 (d, J = 12.6 Hz, 2H), 1.61 - 1.48 (m, 2H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 267A

7-[4-(氮雜環丁烷-1-羰基)哌啶-1-基]-3-氯-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 426.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.34 (t, J = 7.7 Hz, 2H), 4.03 (t, J = 7.8 Hz, 2H), 3.95 (d, J = 12.6 Hz, 2H), 3.55 - 3.47 (m, 2H), 2.64 - 2.56 (m, 1H), 2.53 (s, 3H), 2.38 - 2.29 (m, 2H), 2.04 - 1.95 (m, 2H), 1.89 (d, J = 10.3 Hz, 2H)。    SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 268A

3-氯-2-甲基-7-[4-(嗎啉-4-羰基)哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 456.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.97 (d, J = 12.6 Hz, 2H), 3.72 - 3.51 (m, 10H), 3.00 (t, J = 11.2 Hz, 1H), 2.53 (s, 3H), 2.10 - 1.99 (m, 2H), 1.92 (d, J = 10.9 Hz, 2H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 78C

1-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}-3-甲基脲 LC-MS:m/z 415.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.70 (s, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 4.7 Hz, 1H), 3.83 (d, J = 12.3 Hz, 2H), 3.67 (d, J = 7.3 Hz, 1H), 3.50 (t, J = 10.9 Hz, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.51 (s, 3H), 1.95 (d, J = 10.4 Hz, 2H), 1.58 (dd, J = 20.1, 10.3 Hz, 2H)。 SnAr (GP1)，脫除Boc保護基(GP4)，脲合成(GP7) 269A

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}甲磺醯胺 LC-MS:m/z 436.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.93 (d, J = 13.0 Hz, 2H), 3.55 (t, J = 10.9 Hz, 3H), 3.01 (s, 3H), 2.53 (s, 3H), 2.17 (d, J = 10.3 Hz, 2H), 1.87 (td, J = 14.8, 3.7 Hz, 2H)。 SnAr (GP1)，脫除Boc保護基，磺醯胺合成(GP8) 270A

3-氯-7-[4-(羥甲基)哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.67 (s, 1H), 4.58 (t, J = 5.2 Hz, 1H), 3.89 (d, J = 12.4 Hz, 2H), 3.47 - 3.34 (m, 4H), 2.51 (s, 3H), 1.84 (d, J = 11.5 Hz, 2H), 1.67 (s, 1H), 1.48 - 1.31 (m, 2H)。 通用程序SnAr (GP1) 271A

3-氯-7-(4-甲氧基哌啶-1-基)-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 373.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.91 - 3.83 (m, 2H), 3.61 - 3.55 (m, 2H), 3.55 - 3.51 (m, 1H), 3.43 (s, 3H), 2.52 (s, 3H), 2.18 - 2.08 (m, 2H), 1.92 - 1.80 (m, 2H)。 通用程序SnAr (GP1) 272A

3-氯-2-甲基-7-[4-(1H-吡唑-4-基)哌啶-1-基]-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 409.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.62 (s, 1H), 11.64 (brs, 1H), 7.53 (s, 2H), 3.92 (d, J = 12.7 Hz, 2H), 3.55 (t, J = 11.2 Hz, 2H), 2.87 - 2.76 (m, 1H), 2.51 (s, 3H), 2.12 - 2.02 (m, 2H), 1.82 - 1.72 (m, 2H)。 通用程序SnAr (GP1) 273A

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}-3-甲氧基丙醯胺 LC-MS:m/z 444 (M+H)。 1H NMR(400 MHz, CD3OD) δ 4.00 - 3.90 (m, 3H), 3.66 (t, J = 6.2 Hz, 2H), 3.55 (t, J = 11.0 Hz, 2H), 3.34 (s, 3H), 2.53 (s, 3H), 2.45 (t, J = 6.2 Hz, 2H), 2.07 (d, J = 9.3 Hz, 2H), 1.84 - 1.74 (m, 2H)。 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 274A

N-{1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]哌啶-4-基}丙醯胺 LC-MS:m/z 414.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 3.95 (dd, J = 15.1, 11.7 Hz, 3H), 3.60 - 3.47 (m, 2H), 2.53 (s, 3H), 2.22 (q, J = 7.6 Hz, 2H), 2.06 (d, J = 9.8 Hz, 2H), 1.79 (qd, J = 12.0, 4.0 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H)。 SnAr (GP1)，脫除Boc保護基(GP4)，醯胺偶合(GP3) 275A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-環丙基哌啶-4-甲醯胺 LC-MS:m/z 426.1 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.94 (d, J = 4.0 Hz, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.45 - 3.40 (m, 2H), 2.64 (d, J = 7.2, 3.8 Hz, 1H), 2.49 (s, 3H), 2.34 (dd, J = 14.8, 7.6 Hz, 1H), 1.82 (d, J = 3.5 Hz, 4H), 0.65 - 0.58 (m, 2H), 0.45 - 0.37 (m, 2H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 276A

1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-N-乙基哌啶-4-甲醯胺 LC-MS:m/z 414.1 (M+H)。 1H NMR(400 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.88 (t, J = 5.4 Hz, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.43 (dd, J = 12.7, 6.7 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.50 (s, 3H), 2.39 (dd, J = 14.9, 7.3 Hz, 1H), 1.84 (dd, J = 10.1, 6.6 Hz, 4H), 1.04 (t, J = 7.2 Hz, 3H)。 SnAr (GP1)，酯水解(GP2)，醯胺偶合(GP3) 277A

(3S,4R)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基-N-(1-甲基環丙基)哌啶-4-甲醯胺 LC-MS:m/z 470.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 3.83 - 3.70 (m, 2H), 3.65 - 3.59 (m, 1H), 3.51 (t,J = 11.8 Hz, 1H), 2.51 (d,J = 9.9 Hz, 3H), 2.48 - 2.39 (m, 2H), 1.71 (d,J = 13.8 Hz, 1H), 1.37 (s, 3H), 0.85 (d,J = 6.8 Hz, 3H), 0.75 (s, 2H), 0.66 (d,J = 2.9 Hz, 2H)。 單一鏡像異構體-未知絕對組態(94% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，隨後SnAr (GP1) 277B

(3R,4S)-1-[3-氯-6-氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-4-羥基-3-甲基-N-(1-甲基環丙基)哌啶-4-甲醯胺 LC-MS:m/z 470.2 (M+H)。 1H NMR(400 MHz, CD3OD) δ 8.19 (s, 1H), 3.84 - 3.70 (m, 2H), 3.65 - 3.58 (m, 1H), 3.51 (t,J = 11.8 Hz, 1H), 2.53 (s, 3H), 2.49 - 2.38 (m, 2H), 1.71 (d,J = 13.6 Hz, 1H), 1.37 (s, 3H), 0.85 (d,J = 6.8 Hz, 3H), 0.75 (s, 2H), 0.66 (d,J = 2.9 Hz, 2H)。 單一鏡像異構體-未知絕對組態(99% ee) 醯胺偶合(GP3)，脫苯甲基化(GP6)，隨後SnAr (GP1) 278A

N-{[(3R,4R)-1-[3-氯-6-氰基-2-(羥甲基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 458.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.83 (d,J = 5.3 Hz, 2H), 4.00 (d,J = 13.4 Hz, 1H), 3.79 (dd,J = 11.7, 3.0 Hz, 1H), 3.70 (dd,J = 11.7, 2.0 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.21 (d,J = 7.1 Hz, 2H), 2.23 (q,J = 7.6 Hz, 2H), 2.12 (dd,J = 6.9, 3.4 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.69 (dd,J = 12.5, 3.1 Hz, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.03 (d,J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(95% ee) 核合成程序4， 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 278B

N-{[(3S,4S)-1-[3-氯-6-氰基-2-(羥甲基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 458.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.83 (d,J = 5.4 Hz, 2H), 4.00 (d,J = 13.3 Hz, 1H), 3.79 (dd,J = 11.7, 2.9 Hz, 1H), 3.70 (d,J = 11.4 Hz, 1H), 3.41 - 3.34 (m, 1H), 3.21 (d,J = 7.1 Hz, 2H), 2.23 (q,J = 7.7 Hz, 2H), 2.12 (d,J = 3.0 Hz, 1H), 2.00 (dd,J = 20.4, 9.1 Hz, 2H), 1.69 (d,J = 12.9 Hz, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.03 (d,J = 7.0 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 核合成程序4， 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 278C

N-{[(3S,4R)-1-[3-氯-6-氰基-2-(羥甲基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 458.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.97 (s, 1H), 4.83 (s, 2H), 4.00 (d,J = 12.3 Hz, 1H), 3.89 (d,J = 10.8 Hz, 1H), 3.59 - 3.44 (m, 2H), 3.13 (dd,J = 19.7, 8.4 Hz, 2H), 2.23 (q,J = 7.6 Hz, 2H), 1.94 (dd,J = 13.0, 2.9 Hz, 1H), 1.84 - 1.70  (m, 1H), 1.68 - 1.45 (m, 2H), 1.15 (t,J = 7.6 Hz, 3H), 1.08 (d,J = 6.5 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序4， 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 278D

N-{[(3R,4S)-1-[3-氯-6-氰基-2-(羥甲基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 458.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.97 (s, 1H), 4.83 (s, 2H), 4.00 (d,J = 12.3 Hz, 1H), 3.88 (dd,J = 9.4, 3.0 Hz, 1H), 3.58 - 3.44 (m, 2H), 3.18 - 3.08 (m, 2H), 2.23 (q,J = 7.6 Hz, 2H), 1.94 (dd,J = 13.1, 3.0 Hz, 1H), 1.77 (dt, J = 10.4, 6.5 Hz, 1H), 1.66 - 1.55 (m, 1H), 1.54 - 1.45 (m, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.08 (d,J = 6.5 Hz, 3H)。 相對立體化學反式- 未知絕對組態(96% ee) 核合成程序4， 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 279A        

N-{[(3R,4R)-1-[3,6-二氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 433.3 (M+H)。 1H NMR(400 MHz, CD3OD) δ 7.98 (s, 1H), 3.98 (d,J = 12.4 Hz, 1H), 3.87 (d,J = 10.8 Hz, 1H), 3.58 - 3.51 (m, 1H), 3.50 - 3.42 (m, 1H), 3.16 - 3.07 (m, 2H), 2.68 (s, 3H), 2.24 (q,J = 7.6 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.83 - 1.71 (m, 1H), 1.67 - 1.56 (m, 1H), 1.48 (s, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.08 (d,J = 6.5 Hz, 3H)。 相對立體化學順式-未知絕對組態(99% ee) 核合成程序5， 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 279B

N-{[(3R,4S)-1-[3,6-二氰基-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-7-基]-3-甲基哌啶-4-基]甲基}丙醯胺 LC-MS:m/z 433.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.20 (s, 1H), 7.79 (t,J = 5.6 Hz, 1H), 3.92 (d,J = 12.3 Hz, 1H), 3.79 (d,J = 11.7 Hz, 1H), 3.48 - 3.33 (m, 2H), 3.13 - 3.04 (m, 1H), 3.00 - 2.88 (m, 1H), 2.65 (s, 3H), 2.15 - 2.04 (m,2H), 1.84 (d,J = 10.4 Hz, 1H), 1.68 - 1.53 (m, 1H), 1.51 - 1.32 (m, 2H), 1.07 - 0.87 (m, 6H)。 相對立體化學反式-鏡像異構體之混合物 核合成程序5， 醯胺偶合(GP3)，脫除Boc保護基(GP4)，及SnAr (GP1) 280A

3-氯-7-[(3R,4R)-4-羥基-3-甲基哌啶-1-基]-2-(羥甲基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.83 (s, 2H), 4.01 - 3.87 (m, 2H), 3.57 (td,J = 12.2, 2.6 Hz, 1H), 3.38 (td,J = 10.1, 4.5 Hz, 1H), 3.18 (dd,J = 12.5, 10.6 Hz, 1H), 2.19 - 2.08 (m, 1H), 1.95 - 1.76 (m, 2H), 1.09 (d,J = 6.6 Hz,3H)。 相對立體化學反式-未知絕對組態(98% ee) 核合成程序4，SnAr (GP1) 280B

3-氯-7-[(3S,4S)-4-羥基-3-甲基哌啶-1-基]-2-(羥甲基)-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-6-甲腈 LC-MS:m/z 389.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 4.83 (s, 2H), 4.02 - 3.87 (m, 2H), 3.57 (td,J = 12.2, 2.6 Hz, 1H), 3.38 (td,J = 10.0, 4.5 Hz, 1H), 3.18 (dd,J = 12.4, 10.6 Hz, 1H), 2.13 (dd,J = 12.7, 3.9 Hz, 1H), 1.93 - 1.75 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H)。 相對立體化學反式-未知絕對組態(99% ee) 核合成程序4，SnAr (GP1) 281A

7-[(3S,4S)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-3,6-二甲腈 LC-MS:m/z 364.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.21 (s, 1H), 4.84 (d,J = 5.5 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.56 - 3.44 (m, 1H), 3.29 - 3.21 (m, 1H), 3.17 - 3.07 (m, 1H), 2.65 (s, 3H), 2.05 - 1.94 (m, 1H), 1.78 - 1.58 (m, 2H), 0.99 (d,J = 6.6 Hz, 3H)。 絕對組態(99% de) 核合成程序5，SnAr (GP1) 281B

7-[(3R,4R)-4-羥基-3-甲基哌啶-1-基]-2-甲基-5-(三氟甲基)-1H-吡咯并[3,2-b]吡啶-3,6-二甲腈 LC-MS:m/z 364.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 12.21 (s, 1H), 4.84 (d,J = 5.5 Hz, 1H), 3.94 - 3.73 (m, 2H), 3.57 - 3.43 (m, 1H), 3.30 - 3.22 (m, 1H), 3.16 - 3.05 (m, 1H), 2.65 (s, 3H), 2.05 - 1.95 (m, 1H), 1.78 - 1.58 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H)。 絕對組態(94% de) 核合成程序5，SnAr (GP1) example 4. Other Exemplary Compounds The compounds exemplified in the table below were prepared using one or more of general procedures 1 to 8, starting from nuclei prepared by one of nucleosynthetic procedures 1 to 5. Compound number structure ¹ H-NMR Procedure ( nucleosynthesis procedure 1 was used unless otherwise indicated ) 82A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4, 4-Dimethyl-N-(1-methylcyclopropyl)pyrrolidine-3-carboxamide LC-MS: m/z 454.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.32 (s, 1H), 4.25 (dd,J = 10.4, 7.4 Hz, 1H), 4.11 (dd,J = 10.4, 4.8 Hz, 1H) , 3.96 (d,J = 9.4 Hz, 1H), 3.80 (d,J = 9.3 Hz, 1H), 2.65 (dd,J = 7.1, 4.9 Hz, 1H), 2.46 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.65 - 0.58 (m, 2H), 0.57 - 0.50 (m, 2H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4) and SnAr (GP1) 82B

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4, 4-Dimethyl-N-(1-methylcyclopropyl)pyrrolidine-3-carboxamide LC-MS: m/z 454.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.32 (s, 1H), 4.25 (dd,J = 10.3, 7.3 Hz, 1H), 4.12 (dd,J = 10.4, 4.9 Hz, 1H) , 3.96 (d,J = 9.4 Hz, 1H), 3.80 (d,J = 9.3 Hz, 1H), 2.65 (dd,J = 7.2, 5.0 Hz, 1H), 2.46 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.67 - 0.57 (m, 2H), 0.57 - 0.50 (m, 2H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4) and SnAr (GP1) 83A

1-(aminomethyl)-N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}cyclopropane-1-formamide LC-MS: m/z 481.2 (MH). 1H NMR (400 MHz, MeOD) δ 8.52 (s, 1H), 3.93 (d,J = 12.1 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.51 (dd,J = 13.5, 3.8 Hz, 1H) , 3.46 - 3.35 (m, 1H), 3.23 - 3.09 (m, 2H), 3.08 - 3.02 (m, 2H), 2.52 (s, 3H), 1.95 - 1.82 (m, 1H), 1.80 - 1.66 (m, 1H), 1.65 - 1.41 (m, 2H), 1.32 (dd, J = 6.9, 5.3 Hz, 2H), 1.07 (d, J = 6.5 Hz, 3H), 1.04 (dd, J = 10.4, 4.9 Hz, 2H ). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3), removal of Boc protecting group (GP4) 84A

2-amino-N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}-2-methylpropionamide LC-MS: m/z 469.2 (MH). 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 3.95 (d, J = 12.3 Hz, 1H), 3.89 - 3.77 (m, 1H), 3.59 - 3.50 (m, 1H), 3.49 - 3.40 ( m, 1H), 3.28 (s, 1H), 3.16 - 3.08 (m, 1H), 2.53 (s, 3H), 1.98 - 1.83 (m, 1H), 1.81 - 1.71 (m, 1H), 1.70 - 1.62 ( m, 1H), 1.58 (d,J = 4.0 Hz, 6H), 1.54 (d,J = 11.3 Hz, 1H), 1.09 (t,J = 9.1 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3), removal of Boc protecting group (GP4) 85A

2-amino-N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}acetamide LC-MS: m/z 443.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 3.95 (d,J = 12.4 Hz, 1H), 3.84 (d,J = 10.7 Hz, 1H), 3.67 (s, 2H), 3.60 - 3.53 (m, 1H), 3.50 - 3.41 (m, 1H), 3.34 (d,J = 7.1 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.52 (s, 3H), 1.98 - 1.88 (m, 1H ), 1.85 - 1.73 (m, 1H), 1.72 - 1.60 (m, 1H), 1.55 - 1.44 (m, 1H), 1.07 (t,J = 7.3 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3), removal of Boc protecting group (GP4) 86A

N-{[(3S,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3,4-dimethylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 456.3 (M+H). 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 3.89 - 3.61 (m, 4H), 3.45 (dd,J = 12.6, 10.1 Hz, 1H), 3.03 (d,J = 13.7 Hz, 1H) , 2.53 (s, 3H), 2.28 (q,J = 7.6 Hz, 2H), 1.94 (ddd,J = 10.7, 7.1, 3.9 Hz, 1H), 1.80 (dt,J = 7.0, 3.0Hz, 1H), 1.59 - 1.47 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 1.09 (s, 3H), 1.02 (d, J = 7.1 Hz, 3H). Relative Stereochemistry cis-Mixture of Enantiomers Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 81D

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- [1-(methoxymethyl)cyclopropyl]-4,4-dimethylpyrrolidine-3-carboxamide LC-MS: m/z 484.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 4.35 (dd, J = 10.4, 7.3 Hz, 1H), 4.22 (dd, J = 10.4, 4.9 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.49 (d, J = 10.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.35(s, 3H), 2.75 (dd, J = 7.1, 5.1 Hz, 1H), 2.48 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 0.78 (d, J = 5.6 Hz, 4H). Single Spiegelmer - unknown absolute configuration (97% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 81E

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- [1-(methoxymethyl)cyclopropyl]-4,4-dimethylpyrrolidine-3-carboxamide LC-MS: m/z 484.2 (M+H). 1H NMR 1HNMR(400 MHz, MeOD) δ 4.35 (dd, J = 10.4, 7.3 Hz, 1H), 4.22 (dd, J = 10.4, 5.0 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.49 (d, J = 10.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.35 (s, 3H), 2.75 (dd, J = 7.2 , 5.1 Hz, 1H), 2.48 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 0.78 (d, J = 5.4 Hz, 4H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 87A

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- (2-Methoxy-2-methylpropyl)-4,4-dimethylpyrrolidine-3-carboxamide LC-MS: m/z 486.2 (M+H). 1H NMR 1HNMR(400 MHz, MeOD) δ 7.95 (s, 1H), 4.39 (dd, J = 10.4, 7.3 Hz, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 9.1 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.22 (s, 3H), 3.22 - 3.17 (m, 1H), 2.94 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.31 (s, 3H), 1.18 (s, 6H), 1.17 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 87B

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- (2-Methoxy-2-methylpropyl)-4,4-dimethylpyrrolidine-3-carboxamide LC-MS: m/z 486.2 (M+H). 1H NMR 1HNMR(400 MHz, MeOD) δ 4.39 (dd, J = 10.4, 7.3 Hz, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.90 (d, J = 9.2 Hz, 1H), 3.36 (d, J = 13.8 Hz, 1H), 3.22 (s, 3H), 3.20 (d, J = 13.9 Hz, 1H), 2.94 (dd, J = 7.2 , 5.0 Hz, 1H), 2.48 (s, 3H), 1.31 (s, 3H), 1.18 (d, J = 2.8 Hz, 9H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 88A

3-Chloro-7-[(3S,4S)-3-(hydroxymethyl)-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.21 (d, J = 9.6 Hz, 1H), 4.13 (dd, J = 9.7, 7.8 Hz, 1H), 3.96 (t, J = 9.8 Hz, 1H), 3.74 (d , J = 9.6 Hz, 1H), 3.55 (q, J = 11.2 Hz, 2H), 2.48 (s, 3H), 2.41 - 2.33 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H). Single diastereomer - unknown absolute configuration (99% de) SnAr (GP1) 88B

3-Chloro-7-[(3R,4S)-3-(hydroxymethyl)-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387 (M+H). 1H NMR (400 MHz, MeOD) δ 4.21 (d, J = 9.6 Hz, 1H), 4.13 (dd, J = 9.7, 7.8 Hz, 1H), 3.96 (t, J = 9.8 Hz, 1H), 3.75 (d , J = 9.6 Hz, 1H), 3.55 (q, J = 11.2 Hz, 2H), 2.48 (s, 3H), 2.43 - 2.31 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H) single diastereomer - absolute configuration unknown (99% de) SnAr (GP1) 88C

3-Chloro-7-[(3S,4R)-3-(hydroxymethyl)-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR 1HNMR(400 MHz, MeOD) δ 4.19 (d, J = 10.0 Hz, 1H), 4.16 - 4.10 (m, 1H), 4.04 (t, J = 9.7 Hz, 1H), 3.87 (d, J = 10.0 Hz, 1H), 3.58 - 3.46 (m, 2H), 2.48 (s, 3H), 2.32 - 2.21 (m, 1H), 1.19 (s, 3H), 1.12 (d, J = 7.0 Hz, 3H). Single diastereomer - unknown absolute configuration (85% de) SnAr (GP1) 88D

3-Chloro-7-[(3R,4R)-3-(hydroxymethyl)-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387 (M+H). 1H NMR (400 MHz, MeOD) δ 4.19 (d, J = 10.0 Hz, 1H), 4.16 - 4.10 (m, 1H), 4.05 (t, J = 9.7 Hz, 1H), 3.87 (d, J = 10.0 Hz , 1H), 3.58 - 3.46 (m, 2H), 2.48 (s, 3H), 2.31 - 2.21 (m, 1H), 1.19 (s, 3H), 1.12 (d, J = 7.0 Hz, 3H) single non-mirror Isomer - unknown absolute configuration (99% de) SnAr (GP1) 89A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Hydroxy-4-methylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 6.12 (s, 1H), 3.82 - 3.71 (m, 2H), 3.66 - 3.50 (m, 3H), 2.48 (s, 2H), 2.35 (d, J = 14.9 Hz, 1H), 1.52 - 1.44 (m, 1H), 1.25 (d, J = 9.0 Hz, 4H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 89B

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Hydroxy-4-methylpiperidine-4-carboxamide LC-MS: m/z 416.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.97 - 3.91 (m, 1H), 3.88 - 3.82 (m, 1H), 3.76 - 3.57 (m, 3H), 2.51 (s, 3H), 2.48 - 2.41 (m, 1H ), 1.68 - 1.61 (m, 1H), 1.39 (s, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 90A

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-methoxy-2-methylpropyl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 472.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 4.35 (t, J = 9.5 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.45 - 3.39 (m, 1H), 3.27 - 3.20 (m, 4H), 2.89 - 2.80 (m, 1H), 2.67 - 2.58 (m, 1H), 2.48 (s, 3H), 1.22 (d, J = 6.5 Hz , 3H), 1.19 (s, 6H). Relative stereochemistry trans-unknown absolute configuration (96% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 90B

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-methoxy-2-methylpropyl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 472.2 (M+H). H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 4.35 (t, J = 9.5 Hz, 1H), 4.25 - 4.15 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.26 - 3.21 (m, 4H), 2.88 - 2.80 (m, 1H), 2.68 - 2.57 (m, 1H), 2.48 (s, 3H), 1.22 (d, J = 6.5 Hz , 3H), 1.19 (s, 6H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 91A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N-[1-(methoxymethyl)cyclopropyl]-3-methylpiperidine-4-carboxamide LC-MS: m/z 500.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.84 - 3.71 (m, 2H), 3.61 (d, J = 2.8 Hz, 1H), 3.51 (t, J = 11.7 Hz, 2H), 3.41 (d, J = 10.3 Hz , 1H), 3.36 (s, 3H), 2.52 (s, 3H), 2.49 - 2.38 (m, 2H), 1.76 - 1.70 (m, 1H), 0.89 - 0.80 (m, 7H). Relative Stereochemistry cis-Mixture of Mirror Isomers Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 77C

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}-3-methoxy-2,2-dimethylpropionamide LC-MS: m/z 500.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 3.95 (d, J = 11.8 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.48 - 3.40 (m, 1H), 3.36 (d, J = 4.6 Hz, 4H), 3.27 - 3.05 (m, 3H), 2.52 (s, 3H), 2.01 - 1.88 (m, 1H), 1.85 - 1.69 (m , 1H), 1.69 - 1.46 (m, 2H), 1.16 (s, 6H), 1.06 (dd, J = 15.3, 6.7 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 92A

1-amino-N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}cyclopropane-1-formamide LC-MS: m/z 469.2 (M+H). 1H NMR 400 MHz, MeOD) δ 8.19 (s,0.3H), 3.94 (d, J = 12.6 Hz, 1H), 3.83 (d, J = 10.7 Hz, 1H), 3.56 (dd, J = 13.7, 3.5 Hz , 1H), 3.47 - 3.41 (m, 1H), 3.19 - 3.07 (m, 2H), 2.52 (s, 3H), 1.92 (dd, J = 12.6, 2.5 Hz, 1H), 1.83 - 1.70 (m, 1H ), 1.67 - 1.49 (m, 2H), 1.43 - 1.33 (m, 2H), 1.15 - 1.02 (m, 5H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of BOC protecting group, and SnAr (GP1) 93A

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}-2-methoxy-2-methylpropionamide LC-MS: m/z 486.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.94 (s, 1H), 3.94 (d, J = 11.9 Hz, 1H), 3.83 (d, J = 11.6 Hz, 1H), 3.58 - 3.49 (m, 1H), 3.49 - 3.41 (m, 1H), 3.30 (s, 3H), 3.24 - 3.15 (m, 1H), 3.14 - 3.06 (m, 1H), 2.52 (s, 3H), 1.92 (dd, J = 12.9, 2.5 Hz , 1H), 1.82 - 1.70 (m, 1H), 1.67 - 1.49 (m, 2H), 1.37 (s, 6H), 1.07 (dd, J = 15.8, 7.0 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of BOC protecting group, and SnAr (GP1) 94A

N-{[(3S,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-hydroxypiperidin-4-yl]methyl}propanamide LC-MS: m/z 442.2 (MH). 1H NMR (400 MHz, CD3OD) δ 3.98 - 3.91 (m, 1H), 3.86 (d, J = 12.2 Hz, 1H), 3.69 - 3.61 (m, 1H), 3.53 - 3.44 (m, 2H), 3.41 - 3.36 (m, 1H), 3.29 - 3.25 (m, 1H), 2.53 (s, 3H), 2.25 (q, J = 7.6 Hz, 2H), 2.01 - 1.90 (m, 1H), 1.77 - 1.58 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (95% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 94B

N-{[(3R,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-hydroxypiperidin-4-yl]methyl}propanamide LC-MS: m/z 442.2 (MH). 1H NMR 1HNMR(400 MHz, CD3OD) δ 3.98 - 3.91 (m, 1H), 3.86 (d, J = 12.1 Hz, 1H), 3.68 - 3.61 (m, 1H), 3.53 - 3.44 (m, 2H), 3.41 - 3.36 (m, 1H), 3.29 - 3.24 (m, 1H), 2.53 (s, 3H), 2.25 (q, J = 7.6 Hz, 2H), 2.03 - 1.91 (m, 1H), 1.79 - 1.58 (m , 2H), 1.16 (t, J = 7.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 95A

3-Chloro-7-[(3R,4R)-4-hydroxy-3-methylcyclohexyl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 372.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.57 - 3.44 (m, 1H), 3.44 - 3.35 (m, 1H), 2.60 (d, J = 12.2 Hz, 3H), 2.40 - 2.25 (m, 1H), 2.22 - 2.12 (m, 1H), 2.10 - 1.97 (m, 1H), 1.95 - 1.80 (m, 2H), 1.67 - 1.50 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H). relative stereochemistry trans Same procedure as compound 75C 95B

3-Chloro-7-[(3S,4S)-4-hydroxy-3-methylcyclohexyl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 372.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.55 - 3.44 (m, 1H), 3.44 - 3.35 (m, 1H), 2.59 (s, 3H), 2.40 - 2.26 (m, 1H), 2.21 - 2.12 (m, 1H ), 2.09 - 1.97 (m, 1H), 1.94 - 1.80 (m, 2H), 1.67 - 1.51 (m, 2H), 1.12 (d, J = 6.5 Hz, 3H). relative stereochemistry trans Same procedure as compound 75C 96A

2-[(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl] -4,4-Dimethylpyrrolidin-3-yl]acetamide LC-MS: m/z 412.1 (MH). 1H NMR (400 MHz, MeOD) δ 4.18 - 4.00 (m, 3H), 3.81 (d, J = 9.6 Hz, 1H), 2.54 - 2.49 (m, 1H), 2.49 (s, 3H), 2.46 - 2.38 ( m, 1H), 2.22 (dd, J = 14.2, 10.2 Hz, 1H), 1.23 (s, 3H), 1.04 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 96B

2-[(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl] -4,4-Dimethylpyrrolidin-3-yl]acetamide LC-MS: m/z 412.1 (MH). 1H NMR (400 MHz, MeOD) δ 4.18 - 4.00 (m, 3H), 3.81 (d, J = 9.5 Hz, 1H), 2.53 (d, J = 4.0 Hz, 1H), 2.49 (s, 3H), 2.46 - 2.37 (m, 1H), 2.22 (dd, J = 14.2, 10.2 Hz, 1H), 1.23 (s, 3H), 1.04 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 97A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Ethyl-4,4-dimethylpyrrolidin-3-carboxamide LC-MS: m/z 426.1 (MH). 1H NMR (400 MHz, MeOD) δ 4.42 - 4.34 (m, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.28 - 3.13 (m, 2H), 2.78 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.29 (s, 3H), 1.15 (dd, J = 9.5 , 4.9 Hz, 6H). Single Spiegelmer - unknown absolute configuration (94% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 97B

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Ethyl-4,4-dimethylpyrrolidin-3-carboxamide LC-MS: m/z 426.1 (MH). 1H NMR (400 MHz, MeOD) δ 4.38 (dd, J = 10.4, 7.4 Hz, 1H), 4.23 (dd, J = 10.4, 4.9 Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.28 - 3.12 (m, 2H), 2.78 (dd, J = 7.2, 5.0 Hz, 1H), 2.48 (s, 3H), 1.29 (s, 3H), 1.15 ( dd, J = 9.4, 5.0 Hz, 6H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 98A

(3R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4, 4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 382.1 (MH). 1H NMR (400 MHz, CD3OD) δ 4.41 - 4.34 (m, 1H), 4.31 - 4.25 (m, 1H), 4.04 (d, J = 9.3 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H) , 2.93 - 2.85 (m, 1H), 2.45 (s, 3H), 1.32 (s, 3H), 1.19 (s, 3H). Single Spiegelmer - unknown absolute configuration (95% ee) Nucleosynthesis procedure 3, amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 98B

(3S)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4, 4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 382.1 (MH). 1H NMR (400 MHz, CD3OD) δ 4.40 - 4.34 (m, 1H), 4.32 - 4.25 (m, 1H), 4.04 (d, J = 9.3 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H) , 2.92 - 2.85 (m, 1H), 2.45 (d, J = 1.5 Hz, 3H), 1.31 (s, 3H), 1.19 (s, 3H). Single Spiegelmer - unknown absolute configuration (98% ee) Nucleosynthesis Procedure 3, Amide Coupling (GP3), Boc Deprotection, SnAr (GP1) 99A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 398 (MH). 1H NMR (400 MHz, MeOD) δ 4.56 (d, J = 9.8 Hz, 1H), 4.16 (dd, J = 9.7, 7.4 Hz, 1H), 3.98 - 3.89 (m, 2H), 2.85 - 2.75 (m, 1H), 2.48 (s, 3H), 1.33 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1) 100A

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}-2-hydroxyacetamide LC-MS: m/z 442.1 (MH). 1H NMR (400 MHz, MeOD) δ 7.96 (s, 1H), 4.00 (s, 2H), 3.97 - 3.92 (m, 1H), 3.88 - 3.77 (m, 1H), 3.65 - 3.56 (m, 1H), 3.45 (td, J = 11.8, 2.3 Hz, 1H), 3.25 - 3.18 (m, 1H), 3.11 (dd, J = 12.2, 10.8 Hz, 1H), 2.52 (s, 3H), 2.00 - 1.91 (m, 1H), 1.83 - 1.71 (m, 1H), 1.68 - 1.48 (m, 2H), 1.07 (dd, J = 14.9, 6.7 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 101A

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3,4-dimethylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 456.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.92 (t, J = 6.1 Hz, 1H), 3.81 - 3.60 (m, 3H), 3.40 - 3.33 (m, 1H), 3.28 (s, 1H), 3.22 - 3.15 ( m, 1H), 2.52 (s, 3H), 2.27 (q, J = 7.6 Hz, 2H), 2.02 - 1.92 (m, 1H), 1.89 - 1.78 (m, 1H), 1.63 - 1.54 (m, 1H) , 1.16 (t, J = 7.6 Hz, 3H), 1.01 (s, 3H), 0.96 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 102A

N-{[(3R,4S)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 426.3 (M+H). 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 3.96 (d, J = 12.8 Hz, 1H), 3.85 (d, J = 12.6 Hz, 1H), 3.59 - 3.51 (m, 1H), 3.49 - 3.42 (m, 1H), 3.14 - 3.06 (m, 2H), 2.48 (d, J = 1.5 Hz, 3H), 2.23 (q, J = 7.6 Hz, 2H), 1.97 - 1.90 (m, 1H), 1.80 - 1.70 (m, 1H), 1.66 - 1.55 (m, 1H), 1.49 (d, J = 17.8 Hz, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.07 (d, J = 6.5 Hz , 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthesis procedure 3, SnAr (GP1), removal of Boc protecting group (GP4) and amide coupling (GP3) 103A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Cyclopropyl-4,4-dimethylpyrrolidine-3-carboxamide LC-MS: m/z 440.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.38 (dd, J = 10.4, 7.3 Hz, 1H), 4.21 (dd, J = 10.4, 4.8 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.88 (d, J = 9.1 Hz, 1H), 2.73 (dd, J = 7.2, 4.8 Hz, 1H), 2.71 - 2.64 (m, 1H), 2.49 (s, 3H), 1.27 (s, 3H), 1.15 ( s, 3H), 0.77 - 0.69 (m, 2H), 0.55 - 0.45 (m, 2H). Single enantiomer - unknown absolute stereochemistry (98% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 103B

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Cyclopropyl-4,4-dimethylpyrrolidine-3-carboxamide LC-MS: m/z 440.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.38 (dd, J = 10.4, 7.3 Hz, 1H), 4.21 (dd, J = 10.4, 4.7 Hz, 1H), 4.07 (d, J = 9.1 Hz, 1H), 3.88 (d, J = 9.1 Hz, 1H), 2.73 (dd, J = 7.2, 4.8 Hz, 1H), 2.71 - 2.64 (m, 1H), 2.49 (s, 3H), 1.27 (s, 3H), 1.15 ( s, 3H), 0.74 (dt, J = 7.2, 3.4 Hz, 2H), 0.56 - 0.45 (m, 2H). Single enantiomer - unknown absolute stereochemistry (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 104A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-Hydroxyethyl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 430.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.36 (t, J = 9.5 Hz, 1H), 4.20 (dt, J = 9.7, 7.0 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.64 (t , J = 5.9 Hz, 2H), 3.38 (t, J = 5.7 Hz, 2H), 2.76 (td , J = 9.5, 7.7 Hz, 1H), 2.61 (tt, J = 9.8, 6.9 Hz, 1H), 2.48 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 105A

3-Chloro-7-[(3S,4S)-3-(2-hydroxypropan-2-yl)-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl )-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 399.2 (MH). 1H NMR (400 MHz, CD3OD) δ 4.27 - 4.20 (m, 1H), 4.17 - 4.05 (m, 2H), 3.78 (t, J = 9.1 Hz, 1H), 2.49 (s, 3H), 2.46 - 2.34 ( m, 1H), 2.09 (q, J = 8.4 Hz, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.25 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1) 105B

3-Chloro-7-[(3R,4R)-3-(2-hydroxypropan-2-yl)-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl )-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 399.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.26 - 4.19 (m, 1H), 4.16 - 4.06 (m, 2H), 3.78 (t, J = 9.1 Hz, 1H), 2.49 (s, 3H), 2.46 - 2.34 ( m, 1H), 2.09 (q, J = 8.4 Hz, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.25 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1) 106A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-[(1-Hydroxycyclopropyl)methyl]-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 454.2 (MH). 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 4.37 (t, J = 9.5 Hz, 1H), 4.26 - 4.17 (m, 2H), 3.87 (t, J = 9.6 Hz, 1H), 3.42 (d, J = 4.3 Hz, 2H), 2.86 - 2.76 (m, 1H), 2.69 - 2.57 (m, 1H), 2.48 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H), 0.77 - 0.69 (m, 2H), 0.68 - 0.59 (m, 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 107A

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Hydroxy-4-methylpiperidine-4-carboxamide LC-MS: m/z 414.2 (MH). 1H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 7.29 (s, 1H), 7.08 (s, 1H), 5.41 (s, 1H), 4.08 (s, 1H), 3.67 (s, 3H) , 3.50 (s, 1H), 2.48 (s, 3H), 1.91 (d, J = 52.0 Hz, 2H), 1.19 (s, 3H). Relative Stereochemistry cis-Mixture of Mirror Isomers Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 108A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-4-hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 456.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.84 - 3.71 (m, 2H), 3.66 - 3.59 (m, 1H), 3.51 (t, J = 11.9 Hz, 1H), 2.76 - 2.67 (m, 1H), 2.53 ( s, 3H), 2.51 - 2.41 (m, 2H), 1.79 - 1.69 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H), 0.81 - 0.74 (m, 2H), 0.59 - 0.53 (m, 2H). Relative stereochemistry cis- unknown Absolute configuration (98% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 108B

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-4-hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 456.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.86 - 3.70 (m, 2H), 3.67 - 3.59 (m, 1H), 3.51 (t, J = 11.9 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.53 ( s, 3H), 2.50 - 2.41 (m, 2H), 1.78 - 1.71 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H), 0.81 - 0.74 (m, 2H), 0.60 - 0.53 (m, 2H). Relative Stereochemistry cis- Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 109A

N-{[(3R,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}cyclopropaneformamide LC-MS: m/z 454.3 (M+H). 1H NMR (400 MHz, MeOD) δ 3.95 (d, J = 13.2 Hz, 1H), 3.75 (dd, J = 11.6, 3.0 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.37 - 3.32 (m, 1H), 3.23 (d, J = 6.8 Hz, 2H), 2.52 (s, 3H), 2.18 - 2.08 (m, 1H), 2.05 - 1.91 (m, 2H), 1.69 (dd, J = 12.5, 3.0 Hz , 1H), 1.63 - 1.56 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.88 - 0.82 (m, 2H), 0.80 - 0.69 (m, 2H). Relative Stereochemistry cis- Unknown Absolute Configuration (97% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 109B

N-{[(3S,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}cyclopropaneformamide LC-MS: m/z 454.3 (M+H). 1H NMR (400 MHz, MeOD) δ 3.95 (d, J = 13.2 Hz, 1H), 3.75 (dd, J = 11.6, 2.9 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.38 - 3.32 (m, 1H), 3.23 (d, J = 6.9 Hz, 2H), 2.51 (s, 3H), 2.19 - 2.08 (m, 1H), 2.05 - 1.91 (m, 2H), 1.69 (dd, J = 12.5, 2.9 Hz , 1H), 1.64 - 1.54 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.90 - 0.83 (m, 2H), 0.81 - 0.68 (m, 2H). Relative Stereochemistry cis- Unknown Absolute Configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 110A

N-{[(3R,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 424.2 (MH). 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 3.97 (d, J = 12.7 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.59 - 3.51 (m, 1H), 3.49 - 3.40 ( m, 1H), 3.17 - 3.06 (m, 2H), 2.49 (d, J = 1.5 Hz, 3H), 2.24 (q, J = 7.6 Hz, 2H), 2.00 - 1.90 (m, 1H), 1.81 - 1.70 (m, 1H), 1.65 - 1.55 (m, 1H), 1.53 - 1.43 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H). Relative Stereochemistry cis- Unknown Absolute Configuration (99% ee) Nucleosynthesis procedure 3, SnAr (GP1), removal of Boc protecting group (GP4) and amide coupling (GP3) 111A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-methoxyethyl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 444.1 (M+H). 1H NMR (400 MHz, MeOD) δ 8.49 (s, 0.3H), 4.36 (t, J = 9.5 Hz, 1H), 4.19 (dd, J = 17.6, 10.0 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.52 - 3.48 (m, 2H), 3.48 - 3.38 (m, 2H), 3.37 (s, 3H), 2.76 (dd, J = 17.4, 9.5 Hz, 1H), 2.60 (dt, J = 23.5, 8.3 Hz, 1H), 2.47 (s, 3H), 1.20 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 112A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-[1-(Hydroxymethyl)cyclopropyl]-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 456.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.49 (s, 0.3H), 4.35 (t, J = 9.4 Hz, 1H), 4.23 - 4.13 (m, 2H), 3.85 (t, J = 9.6 Hz, 1H), 3.64 (d, J = 11.6 Hz, 1H), 3.57 (d, J = 11.6 Hz, 1H), 2.69 (dd, J = 17.1, 9.3 Hz, 1H), 2.58 (ddd, J = 19.0, 9.7, 6.6 Hz , 1H), 2.48 (s, 3H), 1.19 (d, J = 6.5 Hz, 3H), 0.86 - 0.80 (m, 2H), 0.77 (dt, J = 9.1, 3.8 Hz, 2H). Relative Stereochemistry cis-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 113A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N-(1-hydroxy-2-methylpropan-2-yl)-3-methylpiperidine-4-formamide LC-MS: m/z 488.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.52 (s, 1H), 3.88 - 3.67 (m, 2H), 3.67 - 3.47 (m, 4H), 2.52 (s, 3H), 2.45 (dd, J = 13.3, 5.1 Hz, 2H), 1.76 (d, J = 13.9 Hz, 1H), 1.35 (s, 6H), 0.89 (d, J = 6.9 Hz, 3H). Relative Stereochemistry cis-Mixture of Mirror Isomers Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 114A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-3,3-difluoro -4-Methylpiperidine-4-carboxamide LC-MS: m/z 436.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 7.37 (d, J = 7.3 Hz, 2H), 4.37 (dd, J = 25.1, 12.1 Hz, 1H), 3.99 (dd, J = 21.2, 12.2 Hz, 1H), 3.69 (dt, J = 13.7, 12.3 Hz, 2H), 2.51 (s, 3H), 2.38 - 2.26 (m, 1H), 2.01 - 1.87 (m, 1H), 1.41 (s, 3H ). racemic mixture SnAr (GP1) 115A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N-(2-methoxyethyl)-3-methylpiperidine-4-carboxamide LC-MS: m/z 474.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.84 - 3.71 (m, 2H), 3.66 - 3.60 (m, 1H), 3.53 (t, J = 7.9 Hz, 1H), 3.51 - 3.39 (m, 4H), 3.37 ( s, 3H), 2.52 (s, 3H), 2.51 - 2.39 (m, 2H), 1.81 - 1.73 (m, 1H), 0.87 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis- unknown Absolute configuration (98% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 115B

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N-(2-methoxyethyl)-3-methylpiperidine-4-carboxamide LC-MS: m/z 474.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.00 (s, 1H), 3.84 - 3.71 (m, 2H), 3.66 - 3.60 (m, 1H), 3.53 (t, J = 7.8 Hz, 1H), 3.51 - 3.40 ( m, 4H), 3.37 (s, 3H), 2.53 (s, 3H), 2.51 - 2.39 (m, 2H), 1.77 (dt, J = 13.7, 2.3 Hz, 1H), 0.87 (d, J = 6.9 Hz , 3H). Relative stereochemistry cis- unknown Absolute configuration (98% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 116A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-methylpyrrolidine-3-carboxamide LC-MS: m/z 386.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 7.56 (s, 1H), 7.10 (s, 1H), 4.23 - 4.03 (m, 3H), 3.85 (t, J = 8.5 Hz, 1H) , 3.10 (dd, J = 11.0, 6.7 Hz, 1H), 2.67 (dt, J = 13.7, 6.8 Hz, 1H), 2.46 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). Relative Stereochemistry cis- Unknown Absolute Configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 116B

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-methylpyrrolidine-3-carboxamide LC-MS: m/z 386.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 7.55 (s, 1H), 7.09 (s, 1H), 4.26 - 4.02 (m, 3H), 3.90 - 3.79 (m, 1H), 3.10 ( dd, J = 11.1, 6.7 Hz, 1H), 2.67 (dt, J = 14.2, 7.0 Hz, 1H), 2.46 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 117A

(3R,4R)-N-[(1-aminocyclopropyl)methyl]-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridin-7-yl]-4-methylpyrrolidin-3-carboxamide LC-MS: m/z 455.1 (M+H). 1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 4.40 (t, J = 9.4 Hz, 1H), 4.31 - 4.15 (m, 2H), 3.87 (t, J = 9.3 Hz, 1H), 3.64 (d, J = 14.9 Hz, 1H), 3.36 - 3.32 (m, 1H), 2.86 - 2.73 (m, 1H), 2.71 - 2.58 (m, 1H), 2.48 (s, 3H), 1.24 (d, J = 6.5 Hz, 3H), 1.01 - 0.86 (m, 4H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), amide coupling (GP3), removal of Boc protecting group (GP4) 118A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(1-Hydroxy-2-methylpropan-2-yl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 458.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.32 (t, J = 9.5 Hz, 1H), 4.17 (dd, J = 16.8, 8.5 Hz, 2H), 3.84 (t, J = 9.7 Hz, 1H), 3.68 (d , J = 11.0 Hz, 1H), 3.59 (d, J = 11.0 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.55 (ddd, J = 16.8, 8.3, 4.9 Hz, 1H), 2.48 (s, 3H), 1.33 (d, J = 5.1 Hz, 6H), 1.21 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 119A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Methyl-N-(1-methylcyclopropyl)pyrrolidine-3-carboxamide LC-MS: m/z 440.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.33 (t, J = 9.3 Hz, 1H), 4.16 (ddd, J = 19.3, 9.7, 7.1 Hz, 2H), 3.84 (t, J = 9.5 Hz, 1H), 2.59 (tt, J = 9.6, 8.3 Hz, 2H), 2.47 (s, 3H), 1.38 (s, 3H), 1.17 (d, J = 6.2 Hz, 3H), 0.79 - 0.71 (m, 2H), 0.68 - 0.61 (m, 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 120A

(3R,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-methylpyrrolidine-3-carboxamide LC-MS: m/z 370.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.37 (t, J = 9.5 Hz, 1H), 4.28 - 4.15 (m, 2H), 3.87 (t, J = 9.6 Hz, 1H), 2.84 - 2.73 (m, 1H) , 2.67 - 2.55 (m, 1H), 2.44 (d, J = 1.4 Hz, 3H), 1.23 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthesis procedure 3, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 121A

N-{[(3R,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-fluoropiperidin-4-yl]methyl}propionamide LC-MS: m/z 444.2 (MH). 1H NMR (400 MHz, MeOD) δ 4.92 (s, 0.5H), 4.79 (s, 0.5H), 4.16 (t, J = 11.9 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.76 (dd, J = 36.2, 13.3 Hz, 1H), 3.50 - 3.32 (m, 2H), 3.27 (d, J = 7.2 Hz, 1H), 2.53 (s, 3H), 2.24 (q, J = 7.6 Hz, 2H), 2.14 - 1.95 (m, 2H), 1.77 (d, J = 8.8 Hz, 1H), 1.15 (t, J = 7.6 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 122A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-[(1-methoxycyclopropyl)methyl]-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 470.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.38 (t, J = 9.5 Hz, 1H), 4.21 (dd, J = 16.9, 9.4 Hz, 2H), 3.87 (t, J = 9.6 Hz, 1H), 3.56 (d , J = 14.5 Hz, 1H), 3.41 (d, J = 14.5 Hz, 1H), 3.33 (d, J = 4.6 Hz, 3H), 2.81 (dd, J = 17.4, 9.4 Hz, 1H), 2.63 (dd , J = 15.2, 8.1 Hz, 1H), 2.48 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H), 0.81 (t, J = 5.3 Hz, 2H), 0.64 (t, J = 3.5 Hz , 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 123A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-[1-(methoxymethyl)cyclopropyl]-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 470.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.18 (ddd, J = 17.2, 9.6, 7.4 Hz, 2H), 3.84 (t, J = 9.6 Hz, 1H), 3.47 (dd, J = 27.9, 10.5 Hz, 2H), 3.37 (s, 3H), 2.72 - 2.63 (m, 1H), 2.61 - 2.50 (m, 1H), 2.48 (s, 3H), 1.19 (d, J = 6.5 Hz, 3H), 0.85 - 0.76 (m, 4H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group, SnAr (GP1) 124A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4-hydroxyl-3, 3-Dimethylpiperidine-4-carboxamide LC-MS: m/z 428.1 (MH). 1H NMR (400 MHz, MeOD) δ 4.04 - 3.79 (m, 2H), 3.76 - 3.62 (m, 1H), 3.47 (d, J = 11.1 Hz, 1H), 2.74 (s, 1H), 2.53 (s, 3H), 1.85 (d, J = 14.6 Hz, 1H), 1.10 (d, J = 20.0 Hz, 6H). racemic mixture SnAr (GP1) 125A

(3S,4S)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 400.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.18 - 4.08 (m, 1H), 3.92 - 3.76 (m, 3H), 2.48 (d, J = 1.5 Hz, 3H), 2.32 (dd, J = 9.8, 4.3 Hz, 1H), 2.11 (dd, J = 13.9, 6.9 Hz, 1H), 2.01 - 1.91 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthesis procedure 3, amide coupling (GP3), debenzylation (GP6) and SnAr (GP1) 125B

(3S,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.87 - 3.81 (m, 1H), 3.81 - 3.72 (m, 1H), 3.70 - 3.63 (m, 1H), 3.52 (t, J = 11.9 Hz, 1H), 2.49 ( d, J = 1.4 Hz, 3H), 2.48 - 2.38 (m, 2H), 1.81 (d, J = 13.7 Hz, 1H), 0.92 (d, J = 6.8 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Nucleosynthesis program 3, amide coupling (GP3), debenzylation (GP6) and SnAr (GP1) 126A

7-{4-[(1S)-1-amino-2,2,2-trifluoroethyl]piperidin-1-yl}-3-chloro-2-methyl-5-(trifluoromethyl )-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 438.2 (MH). 1H NMR (400 MHz, MeOD) δ 4.06 - 3.88 (m, 2H), 3.49 (dt, J = 12.1, 6.5 Hz, 2H), 3.22 (dd, J = 8.4, 4.2 Hz, 1H), 2.53 (s, 3H), 2.08 - 1.75 (m, 5H). Single Spiegelmer - unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 126B

7-{4-[(1R)-1-amino-2,2,2-trifluoroethyl]piperidin-1-yl}-3-chloro-2-methyl-5-(trifluoromethyl )-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 438.2 (MH). 1H NMR (400 MHz, MeOD) δ 4.08 - 3.92 (m, 2H), 3.49 (dt, J = 12.2, 6.6 Hz, 2H), 3.26 - 3.19 (m, 1H), 2.53 (s, 3H), 2.04 - 1.74 (m, 5H). Single Spiegelmer - unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 127A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-Hydroxy-2-methylpropyl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 456.2 (MH). 1H NMR (400 MHz, CD3OD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.20 (dd, J = 17.2, 7.7 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 3.34 (d , J = 13.5 Hz, 1H), 3.20 (d, J = 13.5 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.67 (s, 1H), 2.47 (s, 3H), 1.22 (d, J = 7.6 Hz, 9H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 128A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(1-methoxy-2-methylpropan-2-yl)-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 470.2 (MH). 1H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 4.31 (t, J = 9.5 Hz, 1H), 4.17 (dt, J = 23.1, 8.6 Hz, 2H), 3.83 (t, J = 9.7 Hz , 1H), 3.50 (dd, J = 24.9, 9.0 Hz, 2H), 3.36 (s, 3H), 2.75 (dd, J = 17.3, 9.4 Hz, 1H), 2.63 - 2.50 (m, 1H), 2.49 ( d, J = 10.4 Hz, 3H), 1.34 (d, J = 3.6 Hz, 6H), 1.20 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 129A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-4-methylpyrrolidine-3-carboxamide LC-MS: m/z 424.2 (MH). 1H NMR (400 MHz, MeOD) δ 4.35 (t, J = 9.2 Hz, 1H), 4.24 - 4.07 (m, 2H), 3.84 (t, J = 9.5 Hz, 1H), 2.80 - 2.54 (m, 3H) , 2.47 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.76 (dd, J = 7.2, 3.6 Hz, 2H), 0.53 (d, J = 4.2 Hz, 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 130A

(3S,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 398.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.78 - 3.67 (m, 3H), 3.43 (dd, J = 12.4, 9.9 Hz, 1H), 2.60 - 2.51 (m, 1H), 2.49 (s, 3H), 2.33 - 2.21 (m, 1H), 1.87 - 1.75 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) Nucleosynthesis procedure 3, amide coupling (GP3), debenzylation (GP6) and SnAr (GP1) 131A

(3R,4S)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 398.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.71 (dd , J = 8.6, 4.9 Hz, 3H), 3.43 (dd, J = 12.5, 9.8 Hz, 1H), 2.54 (ddd, J = 10.3, 6.7, 3.7 Hz, 1H), 2.48 (d, J = 1.2 Hz, 3H), 2.32 - 2.22 (m, 1H), 1.85 - 1.77 (m, 1H), 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H ). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthesis program 3, amide coupling (GP3), debenzylation (GP6) and SnAr (GP1) 132A

3-Chloro-7-[(3R,4R)-3-hydroxy-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.25 (d, J = 10.7 Hz, 1H), 4.07 (d, J = 9.7 Hz, 2H), 3.88 (d, J = 10.6 Hz, 1H), 2.48 (s, 3H ), 2.21 (dd, J = 16.2, 9.2 Hz, 1H), 1.42 (s, 3H), 1.13 (d, J = 6.7 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1) 132B

3-Chloro-7-[(3S,4S)-3-hydroxy-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.25 (d, J = 10.7 Hz, 1H), 4.07 (d, J = 9.3 Hz, 2H), 3.88 (d, J = 10.6 Hz, 1H), 2.48 (s, 3H ), 2.22 (dd, J = 15.9, 9.2 Hz, 1H), 1.42 (s, 3H), 1.13 (d, J = 6.7 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1) 133A

3-Chloro-7-[(3S,4R)-3-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.21 (dd, J = 9.5, 6.8 Hz, 1H), 4.18 - 4.11 (m, 1H), 4.09 (d, J = 6.1 Hz, 1H), 3.85 (dd, J = 9.6, 5.8 Hz, 1H), 3.77 (dd, J = 10.9, 6.2 Hz, 1H), 3.63 (dd, J = 10.9, 7.8 Hz, 1H), 2.67 - 2.58 (m, 1H), 2.57 - 2.49 (m , 1H), 2.47 (s, 3H), 1.13 (d, J = 7.0 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (95% ee) SnAr (GP1) 133B

3-Chloro-7-[(3R,4S)-3-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.22 (dd, J = 9.5, 6.8 Hz, 1H), 4.15 (dd, J = 9.9, 7.0 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.86 (dd, J = 9.5, 5.8 Hz, 1H), 3.77 (dd, J = 10.9, 6.2 Hz, 1H), 3.63 (dd, J = 10.9, 7.8 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.58 - 2.50 (m, 1H), 2.47 (s, 3H), 1.13 (d,J = 7.0 Hz, 3H) relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1) 134A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-4-hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 456.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.20 - 4.11 (m, 1H), 3.89 - 3.78 (m, 3H), 2.73 - 2.63 (m, 1H), 2.52 (s, 3H), 2.28 (d, J = 13.6 Hz, 1H), 2.09 (dd, J = 13.9, 7.0 Hz, 1H), 1.97 - 1.86 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H), 0.79 - 0.70 (m, 2H), 0.58 - 0.47 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 134B

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-4-hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 456.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.22 - 4.10 (m, 1H), 3.90 - 3.76 (m, 3H), 2.72 - 2.64 (m, 1H), 2.52 (s, 3H), 2.28 (d, J = 13.7 Hz, 1H), 2.09 (dd, J = 13.8, 6.9 Hz, 1H), 1.98 - 1.89 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H), 0.79 - 0.69 (m, 2H), 0.60 - 0.49 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 135A

3-Chloro-7-[3-(fluoromethyl)-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b ]pyridine-6-carbonitrile LC-MS: m/z 391 (M+H). 1H NMR (400 MHz, MeOD) δ 4.68 (dd, J = 9.1, 6.2 Hz, 1H), 4.63 - 4.52 (m, 1H), 4.47 (t, J = 8.6 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.90 - 3.80 (m, 1H), 3.70 (d, J = 7.2 Hz, 2H), 3.63 (dt, J = 12.3, 4.3 Hz, 1H), 2.53 (s, 3H), 2.42 (s, 1H ), 2.13 - 2.02 (m, 1H), 2.00 - 1.90 (m, 1H). racemic mixture SnAr (GP1) 136A

3-Chloro-7-[(3S)-3-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). 1H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 4.76 (d, J = 4.9 Hz, 1H), 4.07 (dd, J = 8.1, 5.2 Hz, 2H), 3.99 (d, J = 7.7 Hz , 2H), 3.63 (dd, J = 12.0, 6.2 Hz, 1H), 2.45 (s, 3H), 2.23 (dd, J = 15.9, 7.4 Hz, 1H), 2.09 - 1.96 (m, 1H), 1.78 ( dd, J = 11.8, 9.5 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). Single diastereomer - unknown absolute configuration (97% de) SnAr (GP1) 137A

3-Chloro-7-[(3R)-3-[(1S)-1-hydroxyethyl]pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 4.76 (d, J = 4.7 Hz, 1H), 4.07 (dd, J = 7.9, 4.9 Hz, 2H), 3.99 (d, J = 7.7 Hz , 2H), 3.63 (d, J = 4.0 Hz, 1H), 2.46 (s, 3H), 2.23 (dd, J = 16.0, 7.5 Hz, 1H), 2.02 (dd, J = 11.0, 5.9 Hz, 1H) , 1.78 (dd, J = 11.9, 9.5 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H). Single diastereomer - unknown absolute configuration (98% de) SnAr (GP1) 137B

3-Chloro-7-[(3R)-3-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). 1H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 4.76 (d, J = 5.0 Hz, 1H), 4.06 (dd, J = 8.7, 4.8 Hz, 2H), 3.98 - 3.89 (m, 1H) , 3.84 (t, J = 9.3 Hz, 1H), 3.66 (dd, J = 11.6, 6.2 Hz, 1H), 2.46 (s, 3H), 2.24 (d, J = 7.6 Hz, 1H), 2.12 (dd, J = 11.5, 5.9 Hz, 1H), 1.93 - 1.80 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H). Single diastereomer - unknown absolute configuration (96% de) SnAr (GP1) 137C

3-Chloro-7-[(3S)-3-[(1R)-1-hydroxyethyl]pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373 (M+H). 1H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 4.76 (d, J = 5.0 Hz, 1H), 4.06 (dd, J = 8.6, 4.8 Hz, 2H), 3.93 (t, J = 8.7 Hz , 1H), 3.84 (t, J = 9.3 Hz, 1H), 3.66 (dd, J = 11.6, 6.2 Hz, 1H), 2.46 (s, 3H), 2.24 (d, J = 7.3 Hz, 1H), 2.17 - 2.04 (m, 1H), 1.93 - 1.82 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H). Single diastereomer - unknown absolute configuration (99% de) SnAr (GP1) 138A

3-Chloro-7-[(1R,6R)-6-hydroxy-3-azabicyclo[4.1.0]hept-3-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 371.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 5.54 (s, 1H), 4.14 (dd, J = 11.8, 6.3 Hz, 1H), 3.66 (d, J = 11.6 Hz, 1H), 3.63 - 3.53 (m, 1H), 3.29 - 3.20 (m, 1H), 2.49 (s, 3H), 2.40 - 2.31 (m, 1H), 2.30 - 2.20 (m, 1H), 1.40 - 1.30 (m, 1H) , 0.89 (dd, J = 9.9, 5.2 Hz, 1H), 0.64 (t, J = 5.6 Hz, 1H). Single Spiegelmer - unknown absolute configuration (94% ee) General procedure for SnAr (GP1) 138B

3-Chloro-7-[(1S,6S)-6-hydroxy-3-azabicyclo[4.1.0]hept-3-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 371.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 5.54 (s, 1H), 4.14 (dd, J = 11.9, 6.1 Hz, 1H), 3.67 (d, J = 10.7 Hz, 1H), 3.64 - 3.54 (m, 1H), 3.29 - 3.22 (m, 1H), 2.49 (s, 3H), 2.39 - 2.32 (m, 1H), 2.29 - 2.19 (m, 1H), 1.40 - 1.28 (m, 1H) , 0.88 (dd, J = 9.7, 5.2 Hz, 1H), 0.64 (t, J = 5.6 Hz, 1H). Single Spiegelmer - unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 139A

3-Chloro-7-[(3S,4R)-3-fluoro-4-(trifluoromethoxy)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 445.1 (M+H). 1H NMR (400 MHz, MeOD) δ 5.10 - 4.88 (m, 2H), 4.12 - 3.82 (m, 3H), 3.67 - 3.54 (m, 1H), 2.54 (s, 3H), 2.40 (ddd, J = 14.1 , 7.1, 3.6 Hz, 1H), 2.30 - 2.16 (m, 1H) Relative stereochemistry Mixture of cis-mirror isomers General procedure for SnAr (GP1) 140A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N-(2-methoxyethyl)-3-methylpiperidine-4-carboxamide LC-MS: m/z 474.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.20 - 4.11 (m, 1H), 3.89 - 3.78 (m, 3H), 3.51 - 3.47 (m, 2H), 3.47 - 3.37 (m, 2H), 3.37 (s, 3H) ), 2.52 (s, 3H), 2.29 (d, J = 13.5 Hz, 1H), 2.11 (dd, J = 13.9, 6.9 Hz, 1H), 2.00 - 1.90 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (95% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 140B

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N-(2-methoxyethyl)-3-methylpiperidine-4-carboxamide LC-MS: m/z 474.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.20 - 4.11 (m, 1H), 3.88 - 3.78 (m, 3H), 3.52 - 3.47 (m, 2H), 3.45 - 3.37 (m, 2H), 3.36 (d, J = 8.8 Hz, 3H), 2.52 (s, 3H), 2.29 (d, J = 14.0 Hz, 1H), 2.15 - 2.08 (m, 1H), 1.95 (ddd, J = 14.7, 10.4, 4.5 Hz, 1H) , 1.01 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 141A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N,3-dimethylpiperidine-4-carboxamide LC-MS: m/z 430.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.20 - 4.12 (m, 1H), 3.83 (dd, J = 13.2, 4.5 Hz, 3H), 2.77 (s, 3H), 2.52 (s, 3H), 2.32 - 2.24 ( m, 1H), 2.10 (dd, J = 13.9, 7.0 Hz, 1H), 1.99 - 1.89 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 141B

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N,3-dimethylpiperidine-4-carboxamide LC-MS: m/z 430.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.21 - 4.12 (m, 1H), 3.82 (dt, J = 12.0, 6.0 Hz, 3H), 2.77 (s, 3H), 2.52 (s, 3H), 2.28 (d, J = 14.1 Hz, 1H), 2.10 (dd, J = 13.8, 6.9 Hz, 1H), 1.99 - 1.89 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 142A

(3R,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 398.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.03 - 3.93 (m, 1H), 3.88 (dd, J = 12.0, 3.6 Hz, 1H), 3.78 - 3.61 (m, 2H), 2.48 (d, J = 1.4 Hz, 3H), 2.38 - 2.28 (m, 1H), 2.08 - 1.94 (m, 1H), 1.79 - 1.65 (m, 1H), 1.41 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Nucleosynthesis program 3, amide coupling (GP3), debenzylation (GP6) and SnAr (GP1) 142B

(3S,4S)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 398.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.01 - 3.93 (m, 1H), 3.88 (dd, J = 12.2, 3.5 Hz, 1H), 3.78 - 3.61 (m, 2H), 2.48 (d, J = 1.4 Hz, 3H), 2.39 - 2.29 (m, 1H), 2.05 - 1.97 (m, 1H), 1.76 - 1.67 (m, 1H), 1.41 (s, 3H), 1.10 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Nucleosynthesis program 3, amide coupling (GP3), debenzylation (GP6) and SnAr (GP1) 143A

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N, 4,4-Trimethylpyrrolidine-3-carboxamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.41 - 4.32 (m, 1H), 4.28 - 4.21 (m, 1H), 4.05 (d, J = 9.1 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H) , 2.83 - 2.70 (m, 4H), 2.49 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H). Single Spiegelmer - unknown absolute configuration (98% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 143B

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N, 4,4-Trimethylpyrrolidine-3-carboxamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.41 - 4.32 (m, 1H), 4.29 - 4.20 (m, 1H), 4.08 - 3.99 (m, 1H), 3.94 - 3.85 (m, 1H), 2.86 - 2.70 (m , 4H), 2.48 (s, 3H), 1.29 (s, 3H), 1.14 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 144A

3-Chloro-7-[(8S)-8-hydroxyl-5-azaspiro[2.5]oct-5-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 385.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.98 (m, 1H), 3.92 - 3.83 (m, 1H), 3.78 - 3.67 (m, 1H), 3.46 - 3.40 (m, 1H), 3.13 (m, 1H), 2.52 (s, 3H), 2.33 - 2.24 (m, 1H), 2.00 - 1.91 (m, 1H), 0.73 - 0.44 (m, 4H) single enantiomer - unknown absolute configuration (97% ee) General procedure for SnAr (GP1) 144B

3-Chloro-7-[(8S)-8-hydroxyl-5-azaspiro[2.5]oct-5-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 385.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.04 - 3.94 (m, 1H), 3.92 - 3.82 (m, 1H), 3.77 - 3.68 (m, 1H), 3.45 - 3.40 (m, 1H), 3.17 - 3.06 (m , 1H), 2.51 (s, 3H), 2.35 - 2.22 (m, 1H), 2.03 - 1.91 (m, 1H), 0.75 - 0.42 (m, 4H). Single Spiegelmer - unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 145A

2-[(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl] -4,4-Dimethylpyrrolidin-3-yl]-N-methylacetamide LC-MS: m/z 428.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.95 - 3.88 (m, 2H), 3.77 ( d, J = 9.6 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.46 (s, 3H), 2.37 - 2.28 (m, 2H), 2.13 - 2.03 (m, 1H), 1.12 (s , 3H), 0.96 (s, 3H). Single Spiegelmer - unknown absolute configuration (97% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 145B

2-[(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl] -4,4-Dimethylpyrrolidin-3-yl]-N-methylacetamide LC-MS: m/z 428.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.95 - 3.88 (m, 2H), 3.77 ( d, J = 9.7 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.47 (s, 3H), 2.38 - 2.28 (m, 2H), 2.13 - 2.04 (m, 1H), 1.12 (s , 3H), 0.96 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 146A

3-Chloro-7-[(4S)-4-(hydroxymethyl)-3,3-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 4.70 (s, 1H), 4.14 - 4.07 (m, 1H), 4.07 - 3.99 (m, 1H), 3.88 (d, J = 9.7 Hz, 1H), 3.80 (d, J = 9.7 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.49 - 3.41 (m, 1H), 2.46 (s, 3H), 2.17 - 2.07 (m, 1H), 1.19 (s, 3H), 1.01 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 146B

3-Chloro-7-[(4R)-4-(hydroxymethyl)-3,3-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.37 (s, 1H), 4.70 (s, 1H), 4.16 - 4.07 (m, 1H), 4.06 - 3.98 (m, 1H), 3.88 (d, J = 9.6 Hz, 1H), 3.80 (d, J = 9.6 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.50 - 3.40 (m, 1H), 2.46 (s, 3H), 2.20 - 2.06 (m, 1H), 1.19 (s, 3H), 1.01 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 147A

3-Chloro-7-[(3R,4S)-4-hydroxy-3-methylcyclohexyl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 372.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.84 (d, J = 2.5 Hz, 1H), 3.76 - 3.65 (m, 1H), 2.60 (s, 3H), 2.59 - 2.52 (m, 1H), 2.43 - 2.30 ( m, 1H), 2.16 (s, 1H), 2.02 - 1.93 (m, 1H), 1.85 (d, J = 11.5 Hz, 1H), 1.66 (d, J = 13.1 Hz, 1H), 1.51 (d, J = 12.7 Hz, 1H), 1.20 (d, J = 7.4 Hz, 3H). Relative stereochemistry cis-diastereomer mixture Same procedure as compound 75C 148A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-3-methylazepine Cyclobutane-3-carboxamide LC-MS: m/z 372 (M+H). 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 7.59 (s, 1H), 7.20 (s, 1H), 4.92 - 4.88 (m, 2H), 4.45 - 4.42 (m, 2H), 2.44 ( s, 3H), 1.57 (s, 3H). General procedure for SnAr (GP1) 149A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4, 4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.39 - 4.31 (m, 1H), 4.31 - 4.24 (m, 1H), 4.03 (d, J = 9.2 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H) , 2.91 - 2.85 (m, 1H), 2.48 (d, J = 2.8 Hz, 3H), 1.30 (s, 3H), 1.19 (s, 3H). Single Spiegelmer - unknown absolute configuration (92% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 149B

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4, 4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.40 - 4.32 (m, 1H), 4.31 - 4.24 (m, 1H), 4.03 (d, J = 9.3 Hz, 1H), 3.91 (d, J = 9.2 Hz, 1H) , 2.91 - 2.84 (m, 1H), 2.48 (d, J = 1.3 Hz, 3H), 1.32 (s, 3H), 1.19 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 150A

3-Chloro-7-[(4S)-4-(hydroxymethyl)-3,3-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 401.1 (M+H). 1H NMR ( 400 MHz, MeOD) δ 4.02-3.99 (m, 1H), 3.92 - 3.79 (m, 1H), 3.45 - 3.33 (m, 3H), 3.29 - 3.22 (m, 1H), 2.53 (s, 3H) ), 2.05 - 1.87 (m, 2H), 1.62 - 1.49 (m, 1H), 1.10 (s, 3H), 0.96 (s, 3H). Single Spiegelmer - unknown absolute configuration (94% ee) SnAr (GP1) 150B

3-Chloro-7-[(4R)-4-(hydroxymethyl)-3,3-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 401.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.06 - 3.96 (m, 1H), 3.91 - 3.82 (m, 1H), 3.44 - 3.33 (m, 3H), 3.30 - 3.24 (m, 1H), 2.53 (s, 3H) ), 2.02 - 1.87 (m, 2H), 1.63 - 1.50 (m, 1H), 1.10 (s, 3H), 0.97 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 151A

7-[(4R)-3,3-Difluoro-4-hydroxypiperidin-1-yl]-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 379 (M+H). 1H NMR (400 MHz, MeOD) δ 4.23 - 4.12 (m, 1H), 4.09 - 4.00 (m, 1H), 3.90 - 3.75 (m, 2H), 3.67 - 3.56 (m, 1H), 2.50 (d, J = 1.6 Hz, 3H), 2.37 - 2.28 (m, 1H), 2.15 - 2.05 (m, 1H). Single Spiegelmer - unknown absolute configuration (95% ee) Nucleosynthetic Program 3, SnAr (GP1) 151B

7-[(4S)-3,3-Difluoro-4-hydroxypiperidin-1-yl]-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 379 (M+H). 1H NMR (400 MHz, MeOD) δ 4.25 - 4.12 (m, 1H), 4.10 - 3.98 (m, 1H), 3.91 - 3.77 (m, 2H), 3.66 - 3.57 (m, 1H), 2.50 (d, J = 1.6 Hz, 3H), 2.38 - 2.26 (m, 1H), 2.15 - 2.04 (m, 1H). Single Spiegelmer - unknown absolute configuration (99% ee) Nucleosynthetic Program 3, SnAr (GP1) 152A

3-Chloro-7-[(3R,4S)-3-hydroxy-3,4-dimethylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.54 - 4.46 (m, 1H), 4.14 (d, J = 10.4 Hz, 1H), 3.90 (d, J = 10.4 Hz, 1H), 3.79 (dd, J = 9.4, 4.5 Hz, 1H), 2.48 (s, 3H), 2.32 (dd, J = 11.6, 6.6 Hz, 1H), 1.37 (s, 3H), 1.09 (d, J = 7.1 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1) 153A

N-{[(3S,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}cyclopropaneformamide LC-MS: m/z 454.3 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 8.08 (t, J = 5.7 Hz, 1H), 3.89 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 10.7 Hz, 1H ), 3.41 (dd, J = 21.6, 11.8 Hz, 2H), 3.08 (t, J = 11.6 Hz, 1H), 2.97 (dt, J = 13.6, 6.9 Hz, 1H), 2.50 (s, 3H), 1.86 (d, J = 10.5 Hz, 1H), 1.70 - 1.55 (m, 2H), 1.55 - 1.33 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H), 0.71 - 0.60 (m, 4H). Relative stereochemistry trans-unknown absolute configuration (96% ee) SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 153B

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}cyclopropaneformamide LC-MS: m/z 454.3 (M+H). 1H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 8.09 (t, J = 5.8 Hz, 1H), 3.90 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 10.3 Hz, 1H ), 3.42 (ddd, J = 16.5, 10.8, 6.9 Hz, 2H), 3.11 - 3.03 (m, 1H), 3.02 - 2.92 (m, 1H), 2.51 - 2.50 (m, 3H), 1.86 (d, J = 10.2 Hz, 1H), 1.60 (ddt, J = 12.6, 7.7, 6.4 Hz, 2H), 1.52 - 1.33 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H), 0.69 - 0.59 (m, 4H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 154A

3-Chloro-7-[(4S)-4-hydroxyl-3,3-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.92 - 3.83 (m, 1H), 3.57 - 3.50 (m, 2H), 3.49 - 3.41 (m, 1H), 3.35 (s, 1H), 2.53 (s, 3H), 2.10 - 2.02 (m, 2H), 1.07 (s, 3H), 1.02 (s, 3H). Single Spiegelmer - unknown absolute configuration (97% ee) SnAr (GP1) 154B

3-Chloro-7-[(4R)-4-hydroxyl-3,3-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.92 - 3.84 (m, 1H), 3.57 - 3.50 (m, 2H), 3.49 - 3.41 (m, 1H), 3.35 (s, 1H), 2.53 (s, 3H), 2.09 - 2.02 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 155A

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-3- Methylpyrrolidine-3-carboxamide LC-MS: m/z 386 (M+H). 1H NMR (400 MHz, MeOD) δ 4.49 (d, J = 9.7 Hz, 1H), 4.25 - 4.10 (m, 2H), 3.90 (d, J = 9.8 Hz, 1H), 2.48 (s, 4H), 2.12 - 2.02 (m, 1H), 1.49 (s, 3H). Single Spiegelmer - unknown absolute configuration (94% ee) SnAr (GP1) 155B

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-3- Methylpyrrolidine-3-carboxamide LC-MS: m/z 386 (M+H). 1H NMR (400 MHz, MeOD) δ 4.49 (d, J = 9.7 Hz, 1H), 4.25 - 4.10 (m, 2H), 3.90 (d, J = 9.7 Hz, 1H), 2.53 - 2.45 (m, 4H) , 2.12 - 2.03 (m, 1H), 1.49 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 156A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N,3-dimethylpiperidine-4-carboxamide LC-MS: m/z 430.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.77 (qd, J = 12.4, 4.9 Hz, 2H), 3.69 - 3.59 (m, 1H), 3.52 (t, J = 11.9 Hz, 1H), 2.81 (d, J = 3.8 Hz, 3H), 2.52 (s, 3H), 2.51 - 2.36 (m, 2H), 1.80 - 1.70 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 156B

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-N,3-dimethylpiperidine-4-carboxamide LC-MS: m/z 430.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.77 (qd, J = 12.4, 4.8 Hz, 2H), 3.63 (dd, J = 13.0, 3.7 Hz, 1H), 3.52 (t, J = 11.9 Hz, 1H), 2.80 (s, 3H), 2.52 (s, 3H), 2.45 (ddd, J = 11.6, 10.2, 6.3 Hz, 2H), 1.76 (dd, J = 11.4, 2.4 Hz, 1H), 0.85 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 157A

3-Chloro-7-[(4R)-3,3-difluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 409.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.06 - 3.81 (m, 4H), 3.62 (dd, J = 11.1, 8.0 Hz, 1H), 3.45 (dd, J = 19.6, 7.7 Hz, 1H), 2.33 - 2.14 ( m, 2H), 2.11 - 1.97 (m, 1H). Single Spiegelmer - unknown absolute configuration (95% ee) SnAr (GP1) 157B

3-Chloro-7-[(4S)-3,3-difluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 409.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.07 - 3.81 (m, 4H), 3.62 (dd, J = 11.0, 8.0 Hz, 1H), 3.44 (t, J = 12.4 Hz, 1H), 2.35 - 2.16 (m, 2H), 2.10 - 1.97 (m, 1H). Single Spiegelmer - unknown absolute configuration (95% ee) SnAr (GP1) 158A

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-methylpyrrolidine-3-carboxamide LC-MS: m/z 386.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.36 (t, J = 9.5 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 2.84 - 2.74 (m, 1H) , 2.66 - 2.55 (m, 1H), 2.48 (s, 3H), 1.26 - 1.20 (m, 3H) relative stereochemistry trans-unknown absolute configuration (96% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 158B

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-methylpyrrolidine-3-carboxamide LC-MS: m/z 386.1 (M+H). 1H NMR ( 400 MHz, MeOD) δ 4.36 (t, J = 9.5 Hz, 1H), 4.21 (t, J = 8.2 Hz, 2H), 3.86 (t, J = 9.6 Hz, 1H), 2.83 - 2.74 (m , 1H), 2.65 - 2.56 (m, 1H), 2.48 (s, 3H), 1.25 - 1.20 (m, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 159A

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N,4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.23 - 4.14 (m, 2H), 3.86 (t, J = 9.6 Hz, 1H), 2.80 (s, 3H), 2.75 - 2.67 (m, 1H), 2.65 - 2.56 (m, 1H), 2.48 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (94% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 159B

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N,4-Dimethylpyrrolidine-3-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.35 (t, J = 9.5 Hz, 1H), 4.23 - 4.14 (m, 2H), 3.85 (t, J = 9.6 Hz, 1H), 2.80 (s, 3H), 2.71 (td, J = 9.5, 7.6 Hz, 1H), 2.65 - 2.54 (m, 1H), 2.47 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (94% ee) Amide coupling (GP3), removal of Boc protecting group (GP4), SnAr (GP1) 160A

3-fluoro-7-[(4R)-4-hydroxyl-3,3-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 371.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 4.80 (d, J = 4.6 Hz, 1H), 3.77 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 11.6 Hz , 1H), 3.39 (d, J = 4.3 Hz, 2H), 3.26 (s, 1H), 2.46 (d, J = 1.1 Hz, 3H), 1.94 - 1.81 (m, 2H), 0.97 (s, 3H) , 0.90 (s, 3H). Single Spiegelmer - unknown absolute configuration (98% ee) Nucleosynthetic Program 3, SnAr (GP1) 160B

3-fluoro-7-[(4S)-4-hydroxyl-3,3-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 371.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 4.81 (d, J = 4.6 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 3.54 (d, J = 11.1 Hz , 1H), 3.39 (d, J = 4.4 Hz, 2H), 3.26 (s, 1H), 2.47 (s, 3H), 2.01 - 1.77 (m, 2H), 0.98 (s, 3H), 0.91 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) Nucleosynthetic Program 3, SnAr (GP1) 161A

3-Chloro-2-methyl-5-(trifluoromethyl)-7-[(3S)-3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 397.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.24 (dt, J = 12.9, 7.3 Hz, 4H), 3.35 (d, J = 6.3 Hz, 1H), 2.47 (d, J = 18.7 Hz, 3H), 2.40 (td , J = 12.4, 6.7 Hz, 1H), 2.32 - 2.21 (m, 1H) single enantiomer - unknown absolute configuration (81% ee) SnAr (GP1) 161B

3-Chloro-2-methyl-5-(trifluoromethyl)-7-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 397.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.32 - 4.15 (m, 4H), 3.39 - 3.32 (m, 1H), 2.47 (d, J = 19.0 Hz, 3H), 2.40 (dt, J = 12.3, 6.2 Hz, 1H), 2.33 - 2.18 (m, 1H) single enantiomer - absolute configuration unknown (96% ee) SnAr (GP1) 162A

N-{[(3R,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.95 (d,J = 13.3 Hz, 1H), 3.78 - 3.72 (m, 1H), 3.67 - 3.61 (m, 1H), 3.36 (d,J = 3.3 Hz, 1H) , 3.21 (d,J = 7.1 Hz, 2H), 2.53 (s, 3H), 2.23 (q,J = 7.6 Hz, 2H), 2.16 - 2.08 (m, 1H), 2.06 - 1.93 (m, 2H), 1.72 - 1.64 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 162B

N-{[(3S,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.95 (d, J = 13.2 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.67 - 3.61 (m, 1H), 3.35 (d, J = 3.5 Hz, 1H) , 3.21 (d, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.23 (q, J = 7.6 Hz, 2H), 2.15 - 2.08 (m, 1H), 2.06 - 1.91 (m, 2H), 1.71 - 1.63 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 162C

N-{[(3S,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 7.80 (t, J = 5.9 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 10.6 Hz, 1H ), 3.40 (dd, J = 16.8, 6.7 Hz, 2H), 3.14 - 3.04 (m, 1H), 3.01 - 2.90 (m, 1H), 2.51 (s, 3H), 2.10 (q, J = 7.6 Hz, 2H), 1.88 - 1.77 (m, 1H), 1.69 - 1.55 (m, 1H), 1.52 - 1.30 (m, 2H), 1.00 (dd, J = 14.9, 7.1 Hz, 6H). Relative stereochemistry trans-unknown absolute configuration (93% ee) SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 162D

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7 -yl]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 7.80 (t, J = 5.7 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 10.6 Hz, 1H ), 3.44 - 3.36 (m, 2H), 3.14 - 3.03 (m, 1H), 3.01 - 2.89 (m, 1H), 2.51 (s, 3H), 2.14 - 2.03 (m, 2H), 1.84 (d, J = 10.4 Hz, 1H), 1.70 - 1.55 (m, 1H), 1.54 - 1.30 (m, 2H), 1.00 (dd, J = 14.9, 7.2 Hz, 6H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 163A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.85 - 3.72 (m, 2H), 3.63 (d, J = 4.3 Hz, 1H), 3.54 (dd, J = 25.7, 14.0 Hz, 1H), 2.53 (s, 3H) , 2.45 (ddd, J = 11.3, 10.4, 4.9 Hz, 2H), 1.81 (d, J = 13.7 Hz, 1H), 0.92 (d, J = 6.8 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (92% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 163B

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.86 - 3.72 (m, 2H), 3.64 (dd, J = 11.6, 3.6 Hz, 1H), 3.54 (dd, J = 25.7, 13.9 Hz, 1H), 2.53 (s, 3H), 2.45 (ddd, J = 11.3, 10.4, 4.9 Hz, 2H), 1.84 - 1.77 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 163C

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR ( 400 MHz, CD3OD) δ 4.19 - 4.07 (m, 1H), 3.84 (qd, J = 12.0, 6.6 Hz, 3H), 2.52 (s, 3H), 2.32 (d, J = 14.3 Hz, 1H) , 2.11 (dd, J = 13.7, 6.8 Hz, 1H), 1.99 - 1.89 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (93% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 163D

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.19 - 4.08 (m, 1H), 3.90 - 3.78 (m, 3H), 2.52 (s, 3H), 2.36 - 2.27 (m, 1H), 2.11 (ddd, J = 8.9 , 6.9, 4.6 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.06 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 164A

(3R,5S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,5-Dimethylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.90 (dd, J = 12.3, 3.0 Hz, 2H), 3.12 (t, J = 11.9 Hz, 2H), 2.54 (s, 3H), 2.21 (dt, J = 10.9, 6.7 Hz, 2H), 1.80 (t, J = 10.9 Hz, 1H), 1.00 (d, J = 6.6 Hz, 6H). SnAr (GP1) 164B

(3R,5R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,5-Dimethylpiperidine-4-carboxamide LC-MS: m/z 414.2 (M+H). 1H NMR ( 400 MHz, CD3OD) δ 4.03 (d, J = 13.5 Hz, 1H), 3.99 - 3.93 (m, 1H), 3.84 - 3.68 (m, 1H), 3.58 (d, J = 11.4 Hz, 1H) , 3.45 - 3.32 (m, 2H), 2.96 (dd, J = 12.9, 10.5 Hz, 1H), 2.61 (d, J = 5.9 Hz, 1H), 2.53 (t, J = 2.0 Hz, 3H), 2.42 ( dd, J = 10.5, 3.9 Hz, 1H), 2.35 (t, J = 6.6 Hz, 1H), 1.88 (d, J = 9.4 Hz, 1H), 1.13 (s, 4H), 1.10 (d, J = 6.8 Hz, 1H), 0.98 (d, J = 6.4 Hz, 1H). mixture of mirror isomers SnAr (GP1) 165A

3-Chloro-7-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b ]pyridine-6-carbonitrile LC-MS: m/z 391.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.84 - 3.73 (m, 4H), 3.66 (s, 1H), 3.61 (s, 1H), 2.53 (s, 3H), 2.06 (dd, J = 15.0, 5.4 Hz, 3H), 2.01 - 1.92 (m, 1H). SnAr (GP1) 166A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Cyclopropylpyrrolidine-3-carboxamide LC-MS: m/z 391.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 8.23 (d, J = 4.2 Hz, 1H), 4.09 (t, J = 9.2 Hz, 4H), 3.12 - 2.98 (m, 1H), 2.67 (td, J = 7.3, 3.9 Hz, 1H), 2.45 (s, 3H), 2.26 - 2.01 (m, 2H), 0.64 (td, J = 6.7, 4.5 Hz, 2H), 0.49 - 0.28 (m, 2H ). absolute configuration SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 167A

3-Chloro-2-methyl-7-[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 410.1 (M+H). 1H NMR (400 MHz, DMSO) δ 13.78 (s, 1H), 11.75 (s, 1H), 8.16 (d, J = 219.1 Hz, 1H), 3.93 (d, J = 12.7 Hz, 2H), 3.60 (t , J = 10.6 Hz, 2H), 3.11 (s, 1H), 2.50 (d, J = 1.8 Hz, 3H), 2.14 (d, J = 10.4 Hz, 2H), 2.06 - 1.92 (m, 2H). General procedure for SnAr (GP1) 168A

3-Chloro-7-(4-cyclopropoxypiperidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6- Formaldehyde LC-MS: m/z 399.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.91 - 3.79 (m, 3H), 3.60 - 3.53 (m, 2H), 3.49 - 3.42 (m, 1H), 2.52 (s, 3H), 2.19 - 2.10 (m, 2H ), 1.94 - 1.84 (m, 2H), 0.63 - 0.56 (m, 2H), 0.56 - 0.50 (m, 2H). General procedure for SnAr (GP1) 169A

3-Chloro-7-(3-methylsulfonylpyrrolidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6- Formaldehyde LC-MS: m/z 407 (M+H). 1H NMR (400 MHz, DMSO) δ 11.57 (s, 1H), 4.42 (d, J = 7.6 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.26 (dd, J = 16.5, 7.1 Hz, 1H) , 4.19 (dd, J = 12.2, 6.7 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.15 (s, 3H), 2.48 (s, 5H). mixture of mirror isomers SnAr (GP1) 170A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.75 - 3.66 (m, 3H), 3.42 (m, 1H), 2.61 - 2.48 (m, 4H), 2.27 (m, 1H), 1.81 (m, 1H), 1.30 ( s, 3H), 0.94 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 170B

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.76 - 3.66 (m, 3H), 3.42 (m, 9.8 Hz, 1H), 2.60 - 2.48 (m, 4H), 2.27 (m, 1H), 1.81 (m, 1H) , 1.30 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 171A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- (Propan-2-yl)pyrrolidine-3-carboxamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 4.18 - 4.03 (m, 4H), 3.87 (d, J = 7.2 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.45 (s, 3H), 2.22 (dd, J = 11.7, 5.5 Hz, 1H), 2.15 - 2.05 (m, 1H), 1.08 (d, J = 6.6 Hz, 6H). absolute configuration SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 172A

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- (2-methoxyethyl)pyrrolidine-3-carboxamide LC-MS: m/z 430.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 8.26 (t, J = 5.5 Hz, 1H), 4.10 (dd, J = 12.3, 7.5 Hz, 4H), 3.37 (t, J = 5.7 Hz , 2H), 3.29 - 3.23 (m, 5H), 3.18 - 3.11 (m, 1H), 2.45 (s, 3H), 2.27 - 2.18 (m, 1H), 2.16 - 2.07 (m, 1H). absolute configuration SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 173A

3-Fluoro-7-[4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 357.3 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.98 (d, J = 12.3 Hz, 2H), 3.53 - 3.43 (m, 4H), 2.49 (d, J = 1.6 Hz, 3H), 1.95 (d, J = 12.8 Hz , 2H), 1.84 - 1.74 (m, 1H), 1.59 - 1.48 (m, 2H) Nucleosynthetic Program 3, SnAr (GP1) 174A

3-Chloro-2-methyl-7-[4-(1,3-oxazol-2-yl)piperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 410.1 (M+H). 1H NMR ( 400 MHz, MeOD) δ 7.88 (d, J = 0.8 Hz, 1H), 7.14 (d, J = 0.8 Hz, 1H), 3.97 (dt, J = 6.3, 2.9 Hz, 2H), 3.66 - 3.57 (m, 2H), 3.22 (tt, J = 11.1, 4.1 Hz, 1H), 2.53 (s, 3H), 2.27 (dd, J = 13.2, 3.5 Hz, 2H), 2.15 (ddd, J = 24.4, 11.1 , 3.8 Hz, 2H). SnAr (GP1) 175A

3-Chloro-7-[(3S,4S)-3-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 4.79 (s, 1H), 4.15 (dd, J = 9.5, 7.3 Hz, 1H), 4.01 (dd, J = 17.2, 8.2 Hz, 2H) , 3.73 (t, J = 9.3 Hz, 1H), 3.61 (d, J = 7.6 Hz, 1H), 3.53 - 3.45 (m, 1H), 2.46 (s, 3H), 2.17 (dd, J = 14.8, 7.9 Hz, 1H), 2.06 - 1.95 (m, 1H), 1.11 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (95% ee) SnAr (GP1) 175B

3-Chloro-7-[(3R,4R)-3-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.43 (s, 1H), 4.78 (s, 1H), 4.16 (dd, J = 9.6, 7.3 Hz, 1H), 4.02 (dd, J = 17.0, 8.1 Hz, 2H) , 3.73 (t, J = 9.3 Hz, 1H), 3.61 (dd, J = 10.9, 4.3 Hz, 1H), 3.49 (dd, J = 10.8, 6.4 Hz, 1H), 2.46 (s, 3H), 2.23 - 2.12 (m, 1H), 2.02 (s, 1H), 1.11 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1) 176A

3-Chloro-7-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 359.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.45 (dd, J = 17.1, 9.5 Hz, 1H), 4.15 (d, J = 10.4 Hz, 1H), 4.12 - 4.04 (m, 1H), 3.85 (d, J = 10.6 Hz, 1H), 2.48 (s, 3H), 2.07 (dd, J = 10.1, 7.5 Hz, 2H), 1.52 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 176B

3-Chloro-7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 359 (M+H). 1H NMR (400 MHz, MeOD) δ 4.45 (dd, J = 17.2, 9.5 Hz, 1H), 4.15 (d, J = 10.5 Hz, 1H), 4.08 (dd, J = 11.8, 5.1 Hz, 1H), 3.85 (d, J = 10.4 Hz, 1H), 2.48 (s, 3H), 2.07 (dd, J = 10.1, 7.4 Hz, 2H), 1.52 (s, 3H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 177A

3-Chloro-7-[(1S,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]hept-2-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 371 (M+H). 1H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 5.02 (s, 1H), 4.91 (s, 1H), 4.28 (d, J = 6.3 Hz, 1H), 4.15 (dd, J = 8.8, 3.1 Hz, 1H), 4.00 (d, J = 8.8 Hz, 1H), 2.68 (s, 1H), 2.46 (s, 3H), 2.24 - 2.13 (m, 1H), 1.90 (d, J = 10.4 Hz, 1H), 1.76 (d, J = 10.2 Hz, 1H), 1.40 (d, J = 13.4 Hz, 1H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) General procedure for SnAr (GP1) 177B

3-Chloro-7-[(1R,4R,5R)-5-hydroxy-2-azabicyclo[2.2.1]hept-2-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 371 (M+H). 1H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 5.02 (s, 1H), 4.91 (s, 1H), 4.26 (s, 1H), 4.15 (dd, J = 8.8, 3.1 Hz, 1H) , 4.00 (d, J = 9.0 Hz, 1H), 2.68 (s, 1H), 2.46 (s, 3H), 2.19 (ddd, J = 12.7, 9.8, 2.5 Hz, 1H), 1.90 (d, J = 10.3 Hz, 1H), 1.76 (d, J = 10.0 Hz, 1H), 1.40 (d, J = 13.4 Hz, 1H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) General procedure for SnAr (GP1) 178A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-(2-methyl Oxyethyl)-4-methylpiperidine-4-carboxamide LC-MS: m/z 458.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 7.82 (t, J = 5.5 Hz, 1H), 3.83 - 3.76 (m, 2H), 3.63 - 3.55 (m, 2H), 3.51 (dd, J = 8.5, 3.0 Hz, 2H), 3.47 - 3.41 (m, 2H), 3.35 (d, J = 3.1 Hz, 3H), 2.52 (s, 3H), 2.32 (d, J = 13.9 Hz, 2H), 1.78 (ddd, J = 13.8 , 10.0, 3.7 Hz, 2H), 1.30 (s, 3H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 179A

3-chloro-7-[(4S)-3,3-difluoro-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 395 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.25 - 4.10 (m, 1H), 4.05 (s, 1H), 3.91 - 3.76 (m, 2H), 3.66 - 3.55 (m, 1H), 2.54 (s, 3H), 2.33 (s, 1H), 2.11 (s, 1H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 179B

3-chloro-7-[(4R)-3,3-difluoro-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 395 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.23 - 4.12 (m, 1H), 4.05 (d, J = 5.8 Hz, 1H), 3.90 - 3.74 (m, 2H), 3.61 (d, J = 14.4 Hz, 1H) , 2.55 (s, 3H), 2.39 - 2.27 (m, 1H), 2.16 - 2.05 (m, 1H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1) 180A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-methylazepine Cyclobutane-3-carboxamide LC-MS: m/z 372.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.41 (s, 1H), 8.07 (d, J = 4.6 Hz, 1H), 4.82 (t, J = 8.8 Hz, 2H), 4.71 (dd, J = 8.6, 5.9 Hz , 2H), 3.53 (dq, J = 9.1, 5.7 Hz, 1H), 2.65 (d, J = 4.6 Hz, 3H), 2.44 (s, 3H). General Procedures for SnAr (GP1), Ester Hydrolysis (GP2) and Amide Coupling (GP3) 181A

3-Chloro-7-[(3R,4R)-3-hydroxyl-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 359.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 5.15 (d, J = 4.2 Hz, 1H), 4.29 (dd, J = 10.7, 3.7 Hz, 1H), 4.20 (d, J = 3.6 Hz , 1H), 3.98 (t, J = 8.4 Hz, 1H), 3.87 (t, J = 9.8 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.46 (s, 3H), 2.35 - 2.28 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (97% ee) SnAr (GP1) 181B

3-chloro-7-[(3S,4S)-3-hydroxyl-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 359 (M+H). 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 5.15 (d, J = 4.2 Hz, 1H), 4.29 (dd, J = 10.8, 3.7 Hz, 1H), 4.20 (d, J = 3.6 Hz , 1H), 3.98 (t, J = 8.4 Hz, 1H), 3.87 (t, J = 9.9 Hz, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.46 (s, 3H), 2.32 (dd , J = 7.0, 3.6 Hz, 1H), 1.09 (d, J = 6.7 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1) 182A

7-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 362.1 (M+H). 1H NMR ( 400 MHz, MeOD) δ 5.10 (d, J = 51.5 Hz, 1H), 4.68 (ddd, J = 38.3, 12.2, 3.6 Hz, 1H), 4.50 (dd, J = 9.3, 5.1 Hz, 1H) , 4.15 (dd, J = 23.8, 12.2 Hz, 1H), 3.88 (d, J = 10.5 Hz, 1H), 3.79 (dd, J = 11.0, 5.1 Hz, 1H), 2.50 (s, 3H). Relative stereochemistry trans-unknown absolute configuration (88% ee) SnAr (GP1), removal of Boc protecting group (GP4) 182B

7-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 362.1 (M+H). 1H NMR (400 MHz, MeOD) δ 5.10 (d, J = 51.4 Hz, 1H), 4.68 (ddd, J = 38.1, 12.2, 3.6 Hz, 1H), 4.50 (dd, J = 9.8, 4.5 Hz, 1H) , 4.15 (dd, J = 23.8, 12.2 Hz, 1H), 3.89 (d, J = 10.5 Hz, 1H), 3.80 (dd, J = 10.8, 4.8 Hz, 1H), 2.50 (s, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (95% ee) SnAr (GP1), removal of Boc protecting group (GP4) 183A

2-[(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl] Pyrrolidin-3-yl]acetamide LC-MS: m/z 386 (M+H). 1H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 7.39 (s, 1H), 6.87 (s, 1H), 4.08 (dd, J = 14.9, 8.0 Hz, 3H), 3.74 (dd, J = 9.8, 7.3 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.46 (s, 3H), 2.24 (tdd, J = 17.9, 13.3, 6.6 Hz, 3H), 1.74 (dq, J = 16.0, 7.9 Hz , 1H). Single Spiegelmer - unknown absolute configuration (95% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 183B

2-[(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl] Pyrrolidin-3-yl]acetamide LC-MS: m/z 386 (M+H). 1H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 7.39 (s, 1H), 6.87 (s, 1H), 4.13 - 3.99 (m, 3H), 3.74 (dd, J = 9.9, 7.3 Hz, 1H), 2.69 - 2.60 (m, 1H), 2.46 (s, 3H), 2.24 (tdd, J = 18.0, 13.3, 6.7 Hz, 3H), 1.80 - 1.68 (m, 1H). Single Spiegelmer - unknown absolute configuration (95% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 184A

3-Chloro-7-(3,3-dimethylpyrrolidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 357.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 4.12 (t, J = 6.9 Hz, 2H), 3.77 (s, 2H), 2.46 (s, 3H), 1.83 (s, 2H), 1.15 (s, 6H). SnAr (GP1) 185A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N,3-dimethyl Pyrrolidine-3-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.47 (d, J = 9.7 Hz, 1H), 4.27 - 4.15 (m, 1H), 4.14 - 4.06 (m, 1H), 3.90 (d, J = 9.8 Hz, 1H) , 2.76 (s, 3H), 2.50 - 2.42 (m, 4H), 2.09 - 1.98 (m, 1H), 1.45 (s, 3H). racemic mixture SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 80A

3-Bromo-7-((3 S ,4 S )-4-hydroxy-3-methylpiperidin-1-yl)-2-methyl-5-(trifluoromethyl)-1 H -pyrrolo [3,2- b ]pyridine-6-carbonitrile LC-MS: m/z 417.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.89 - 3.72 (m, 2H), 3.51- 3.44 (m, 1H), 3.28-3.21 ( m, 1H), 3.13-3.08 (m, 1H), 2.50 (s, 3H), 2.2-1.98 (m, 1H), 1.79 - 1.58 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H) . Absolute configuration (99% ee) Nucleosynthetic program 2, followed by SnAr (GP1) 80B

3-Bromo-7-((3 R ,4 R )-4-hydroxy-3-methylpiperidin-1-yl)-2-methyl-5-(trifluoromethyl)-1 H -pyrrolo [3,2- b ]pyridine-6-carbonitrile LC-MS: m/z 417.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 4.84 (d, J = 5.5 Hz, 1H), 3.93 - 3.69 (m, 2H), 3.55 - 3.44 (m, 1H), 3.26 - 3.20 ( m, 1H), 3.13-3.08 (m, 1H), 2.51 (s, 3H), 2.04 - 1.94 (m, 1H), 1.80 - 1.57 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H) . Absolute configuration (98% ee) Nucleosynthetic program 2, followed by SnAr (GP1) 186A

3-Chloro-7-[(3S,4R)-3-hydroxyl-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 359 (M+H). 1H NMR (400 MHz, MeOD) δ 4.42 - 4.29 (m, 2H), 4.13 - 4.05 (m, 1H), 3.92 - 3.84 (m, 1H), 3.82 - 3.75 (m, 1H), 2.48 (s, 3H ), 2.39 - 2.28 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (94% ee) SnAr (GP1) 186B

3-chloro-7-[(3R,4S)-3-hydroxyl-4-methylpyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 359 (M+H). 1H NMR (400 MHz, MeOD) δ 4.41 - 4.30 (m, 2H), 4.13 - 4.04 (m, 1H), 3.92 - 3.85 (m, 1H), 3.82 - 3.75 (m, 1H), 2.48 (s, 3H ), 2.40 - 2.29 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H) relative stereochemistry trans-unknown absolute configuration (99% ee) SnAr (GP1) 187A

7-[(3aR,5R,6aS)-5-Hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-3-chloro-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 385.2 (M+H). 1H NMR ( 400 MHz, DMSO) δ 11.47 (s, 1H), 4.78 (s, 1H), 4.19 (dd, J = 9.9, 7.6 Hz, 3H), 4.01 (dd, J = 10.3, 3.8 Hz, 2H) , 2.75 (d, J = 10.5 Hz, 2H), 2.47 (s, 3H), 2.10 (dt, J = 14.2, 7.1 Hz, 2H), 1.57 - 1.44 (m, 2H). SnAr (GP1) 188A

7-[(3aR,5S,6aS)-5-Hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-3-chloro-2-methyl-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 385.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.45 (s, 1H), 4.58 (d, J = 3.7 Hz, 1H), 4.33 (d, J = 3.3 Hz, 1H), 4.14 (dd, J = 10.3, 7.6 Hz , 2H), 3.83 (dd, J = 10.2, 3.5 Hz, 2H), 2.93 (s, 2H), 2.47 (s, 3H), 1.83 - 1.69 (m, 4H). SnAr (GP1) 189A

7-[(3R,4S)-3-amino-4-fluoropyrrolidin-1-yl]-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 362.2 (M+H). 1H NMR (400 MHz, MeOD) δ 5.32 (d, J = 52.9 Hz, 1H), 4.70 - 4.53 (m, 1H), 4.39 - 4.17 (m, 3H), 4.00 - 3.81 (m, 1H), 2.51 ( s, 3H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1), removal of Boc protecting group (GP4) 190A

3-Chloro-2-methyl-7-[(3S)-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine- 6-carbonitrile LC-MS: m/z 343.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.24 - 4.03 (m, 3H), 3.72 (t, J = 9.0 Hz, 1H), 2.47 (s, 3H), 2.43 (d, J = 8.7 Hz, 1H), 2.29 - 2.15 (m, 1H), 1.79 - 1.63 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H). Absolute configuration (99% ee) SnAr (GP1) 190B

3-Chloro-2-methyl-7-[(3R)-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine- 6-carbonitrile LC-MS: m/z 343.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.23 - 4.03 (m, 3H), 3.72 (t, J = 9.0 Hz, 1H), 2.53 - 2.38 (m, 4H), 2.26 - 2.16 (m, 1H), 1.71 ( ddd, J = 21.4, 12.1, 9.4 Hz, 1H), 1.21 (d, J = 6.6 Hz, 3H). Absolute configuration (99% ee) SnAr (GP1) 191A

3-Chloro-7-[(3S)-3-fluoropyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 347.2 (M+H). 1H NMR (400 MHz, MeOD) δ 5.46 (d, J = 52.3 Hz, 1H), 4.57 - 4.32 (m, 2H), 4.18 - 4.06 (m, 2H), 2.49 (s, 3H), 2.46 - 2.12 ( m, 2H). Absolute configuration (97% ee) SnAr (GP1) 192A

3-Chloro-7-[(1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]hept-2-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 371 (M+H). 1H NMR (400 MHz, MeOD) δ 5.02 (s, 1H), 4.35 - 4.23 (m, 1H), 4.02 (d, J = 6.6 Hz, 1H), 3.36 - 3.32 (m, 1H), 2.64 (d, J = 8.1 Hz, 1H), 2.47 (s, 3H), 2.35 - 2.28 (m, 1H), 2.10 (d, J = 10.3 Hz, 1H), 1.86 (d, J = 10.3 Hz, 1H), 1.73 ( d, J = 13.7 Hz, 1H). Relative stereochemistry cis-unknown absolute configuration (97% ee) SnAr (GP1) 193A

3-Chloro-7-[(1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]hept-2-yl]-2-methyl-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 371 (M+H). 1H NMR (400 MHz, MeOD) δ 5.02 (s, 1H), 4.32 - 4.25 (m, 1H), 4.02 (d, J = 6.6 Hz, 1H), 3.34 (d, J = 10.3 Hz, 1H), 2.66 (s, 1H), 2.47 (s, 3H), 2.31 (d, J = 2.4 Hz, 1H), 2.10 (d, J = 10.1 Hz, 1H), 1.86 (d, J = 10.4 Hz, 1H), 1.73 (d, J = 13.5 Hz, 1H). Relative stereochemistry cis-unknown absolute configuration (98% ee) SnAr (GP1) 194A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.01 - 3.92 (m, 1H), 3.92 - 3.83 (m, 1H), 3.75 - 3.64 (m, 2H), 2.52 (s, 3H), 2.41 - 2.29 (m, 1H ), 2.09 - 1.97 (m, 1H), 1.78 - 1.66 (m, 1H), 1.41 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 194B

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3,4-Dimethylpiperidine-4-carboxamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.02 - 3.92 (m, 1H), 3.91 - 3.83 (m, 1H), 3.75 - 3.60 (m, 2H), 2.52 (s, 3H), 2.40 - 2.29 (m, 1H ), 2.07 - 1.94 (m, 1H), 1.78 - 1.66 (m, 1H), 1.41 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Amide Coupling (GP3), Debenzylation (GP6), and SnAr (GP1) 195A

3-Chloro-7-[3-(methoxymethyl)azetidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 359.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.80 (t, J = 8.8 Hz, 2H), 4.55 - 4.48 (m, 2H), 3.64 (d, J = 6.1 Hz, 2H), 3.41 (s, 3H), 3.14 - 3.04 (m, 1H), 2.45 (s, 3H) General procedure for SnAr (GP1) 196A

3-Chloro-7-[3-(hydroxymethyl)azetidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 345.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.72 (t, J = 8.7 Hz, 2H), 4.45 (dd, J = 8.8, 5.5 Hz , 2H), 3.63 (t, J = 5.6 Hz, 2H), 2.97-2.82 (m, 1H), 2.44 (s, 3H). General procedure for SnAr (GP1) 197A

3-Chloro-7-(3-fluoroazetidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6- Formaldehyde LC-MS: m/z 333.1 (M+H). 1H NMR (400 MHz, MeOD) δ 5.56 (tt, J = 6.0, 3.0 Hz, 1H), 5.41 (tt, J = 6.0, 3.0 Hz, 1H), 5.05 (dddd, J = 21.6, 10.5, 6.0, 1.7 Hz, 2H), 4.84 - 4.71 (m, 2H), 2.47 (s, 3H). General procedure for SnAr (GP1) 198A

3-chloro-7-{6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 377.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.49 - 4.44 (m, 2H), 4.43 - 4.38 (m, 2H), 2.69 - 2.67 (m, 1H), 2.66 - 2.64 (m, 1H), 2.49 (s, 3H) ). SnAr (GP1) 199A

3-chloro-7-[(3S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.24 - 4.15 (m, 1H), 4.15 - 4.06 (m, 2H), 4.02 - 3.92 (m, 1H), 2.47 (s, 3H), 2.46 - 2.39 (m, 1H ), 2.18 - 2.09 (m, 1H), 2.04 - 1.94 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H). Absolute configuration (99% ee) SnAr (GP1) 199B

3-chloro-7-[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.24 - 4.06 (m, 3H), 4.01 - 3.90 (m, 1H), 2.51 - 2.37 (m, 4H), 2.19 - 2.08 (m, 1H), 2.03 - 1.90 (m , 1H), 1.31 (d, J = 6.7 Hz, 6H). Absolute configuration (99% ee) SnAr (GP1) 200A

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Methylpyrrolidine-3-carboxamide LC-MS: m/z 386.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.28 - 4.11 (m, 4H), 3.22 - 3.12 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 2.36 - 2.32 (m, 1H), 2.30 - 2.20 (m, 1H). Absolute configuration (85% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 200B

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N- Methylpyrrolidine-3-carboxamide LC-MS: m/z 386.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 8.11-8.08 (m, 1H), 4.23 - 4.00 (m, 4H), 3.14 - 3.04 (m, 1H), 2.63 (d, J = 4.6 Hz, 3H), 2.45 (s, 3H), 2.26-2.17 (m, 1H), 2.15-2.10 (m, 1H). Absolute configuration (94% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 201A

(3S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]pyrrolidine- 3-Formamide LC-MS: m/z 372.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.26-4.15 (m, 4H), 3.27 - 3.21 (m, 1H), 2.48 (s, 3H), 2.40-2.35 (m, 1H), 2.29-2.24 (m, 1H ). Absolute configuration (99% ee) SnAr (GP1) 201B

(3R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]pyrrolidine- 3-Formamide LC-MS: m/z 372.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.48 (s, 1H), 7.61 (s, 1H), 7.12 (s, 1H), 4.19 - 3.99 (m, 4H), 3.14 - 3.07 (m, 1H), 2.45 ( s, 3H), 2.30 - 2.19 (m, 1H), 2.20 - 2.09 (m, 1H) absolute configuration (99% ee) SnAr (GP1) 202A

3-Chloro-7-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b ]pyridine-6-carbonitrile LC-MS: m/z 359.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.19 - 4.06 (m, 3H), 3.94 (dd, J = 9.7, 7.4 Hz, 1H), 3.67 (qd, J = 10.9, 6.7 Hz, 2H), 2.58 (dt, J = 13.7, 6.6 Hz, 1H), 2.47 (s, 3H), 2.21 (td, J = 11.9, 6.3 Hz, 1H), 1.90 (dq, J = 12.3, 8.1 Hz, 1H). absolute configuration SnAr (GP1) 203A

3-Chloro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 345.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.58 (d, J = 3.7 Hz, 1H), 4.33 (ddd, J = 15.0, 10.2, 5.7 Hz, 2H), 4.12 - 4.03 (m, 1H), 3.85 (d, J = 10.8 Hz, 1H), 2.47 (s, 3H), 2.22 - 2.08 (m, 2H). Absolute configuration (99% ee) SnAr (GP1) 204A

3-Chloro-7-[(3S,4R)-4-(hydroxymethyl)-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 4.50 (t, J = 5.1 Hz, 1H), 3.91 (d, J = 12.2 Hz, 1H), 3.77 (d, J = 10.5 Hz , 1H), 3.62 - 3.55 (m, 1H), 3.47 - 3.39 (m, 2H), 3.12 - 3.01 (m, 1H), 2.51 (s, 3H), 1.88 (d, J = 10.4 Hz, 1H), 1.79 - 1.69 (m, 1H), 1.63 - 1.53 (m, 1H), 1.28 (s, 1H), 0.95 (d, J = 6.5 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (97% ee) General Program SnAr (GP1) 204B

3-Chloro-7-[(3R,4S)-4-(hydroxymethyl)-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 4.51 (t, J = 5.1 Hz, 1H), 3.90 (d, J = 13.0 Hz, 1H), 3.77 (d, J = 10.7 Hz , 1H), 3.63 - 3.54 (m, 1H), 3.48 - 3.39 (m, 2H), 3.13 - 3.02 (m, 1H), 2.50 (s, 3H), 1.89 (d, J = 10.4 Hz, 1H), 1.79 - 1.70 (m, 1H), 1.65 - 1.55 (m, 1H), 1.28 (s, 1H), 0.95 (d, J = 6.5 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (96% ee) General Program SnAr (GP1) 205A

3-Chloro-7-(3-hydroxy-3-methylazetidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b ]pyridine-6-carbonitrile LC-MS: m/z 345.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.68 (d, J = 12 Hz, 2H), 4.57 (d, J = 9.0 Hz, 2H), 2.46 (s, 3H), 1.60 (s, 3H). General procedure for SnAr (GP1) 206A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Methyl-N-(propan-2-yl)piperidine-4-carboxamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J = 7.4 Hz, 1H), 4.07 - 3.94 (m, 2H), 3.92 - 3.84 (m, 1H), 3.50 - 3.42 (m, 1H), 3.17 - 3.07 (m, 1H), 2.53 (s, 3H), 2.26 - 2.15 (m, 1H), 2.17 - 2.04 (m, 2H), 1.93 - 1.84 (m, 1H), 1.21 - 1.14 (m, 6H), 0.96 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 207A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-3-methylpiperidine-4-carboxamide LC-MS: m/z 440.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 8.04 (d, J = 4.1 Hz, 1H), 3.88 (d, J = 12.3 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.37 (dd, J = 12.0, 9.7 Hz, 1H), 3.09 - 3.00 (m, 1H), 2.65 (tq, J = 7.8, 3.9 Hz, 1H), 2.50 (s, 3H), 2.07 - 1.83 (m, 3H ), 1.77 (dd, J = 12.6, 2.9 Hz, 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.66 - 0.61 (m, 2H), 0.43 - 0.38 (m, 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 208A

3-Chloro-2-methyl-7-[(3R,4S)-3-methyl-4-(morpholine-4-carbonyl)piperidin-1-yl]-5-(trifluoromethyl)- 1H-pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 470.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.97 (d, J = 12.5 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.71 (d, J = 7.9 Hz, 4H), 3.67 (d, J = 3.3 Hz , 4H), 3.55 - 3.46 (m, 1H), 3.21 (t, J = 11.8 Hz, 1H), 2.77 - 2.67 (m, 1H), 2.53 (s, 3H), 2.40 - 2.27 (m, 1H), 2.09 - 1.96 (m, 1H), 1.95 - 1.85 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 209A

N-[(3R,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]acetamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.20 - 4.12 (m, 1H), 3.93 - 3.83 (m, 1H), 3.83 - 3.76 (m, 1H), 3.61 - 3.46 (m, 2H), 2.53 (s, 3H) ), 2.36 - 2.26 (m, 1H), 2.22 - 2.10 (m, 1H), 2.01 (s, 3H), 1.88 - 1.80 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 210A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Fluoro-N-(propan-2-yl)piperidine-4-carboxamide LC-MS: m/z 446.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 5.07 (s, 1H), 4.24 - 4.14 (m, 1H), 4.07 (s, 2H), 3.89 - 3.77 (m, 1H), 3.48 (t, J = 12.0 Hz, 1H), 2.81 - 2.68 (m, 1H), 2.54 (s, 3H), 2.46 (d, J = 15.6 Hz, 1H), 1.93 (d, J = 11.8 Hz, 1H), 1.18 (d, J = 4.5 Hz, 6H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 211A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-cyclopropyl-3-fluoropiperidine-4-carboxamide LC-MS: m/z 444.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 5.12 (d, J = 47.3 Hz, 1H), 4.22 - 4.05 (m, 2H), 3.90 - 3.77 (m, 1H), 3.47 (t, J = 11.8 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.54 (s, 3H), 2.50 - 2.40 (m, 1H), 1.94 (d, J = 12.9 Hz, 1H), 0.75 (d, J = 5.7 Hz, 2H), 0.54 (s, 2H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 212A

3-Chloro-7-[(3S,4R)-3-fluoro-4-(morpholine-4-carbonyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H -pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 472.2 (MH). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 5.03 (d, J = 47.4 Hz, 1H), 4.11 - 3.87 (m, 3H), 3.62 - 3.36 (m, 10H), 2.50 ( s, 3H), 2.46 (s, 1H), 1.71 (d, J = 12.0 Hz, 1H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 213A

3-Chloro-7-[(3S,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.70 (s, 1H), 3.56 - 3.50 (m, 2H), 3.43 (t, J = 11.9 Hz, 2H), 2.52 (s, 3H), 2.14 - 2.03 (m, 2H), 1.05 (d, J = 6.9 Hz, 6H). unknown absolute configuration SnAr (GP1) 214A

3-Chloro-7-[(3R,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.86 (d, J = 14.6 Hz, 2H), 3.17 (t, J = 12.0 Hz, 2H), 2.87 (t, J = 9.9 Hz, 1H), 2.53 (s, 3H ), 1.99 - 1.85 (m, 2H), 1.09 (d, J = 6.5 Hz, 6H). unknown absolute configuration SnAr (GP1) 215A

3-Chloro-2-methyl-7-[(3R,4s,5S)-4-hydroxy-3,5-dimethylpiperidin-1-yl]-5-(trifluoromethyl)-1H- Pyrrolo[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.00 - 3.91 (m, 1H), 3.74 - 3.66 (m, 1H), 3.57 - 3.50 (m, 2H), 3.16 - 3.08 (m, 1H), 2.52 (s, 3H ), 2.33 - 2.17 (m, 2H), 1.06 (t, J = 6.2 Hz, 6H). SnAr (GP1) 216A

3-Chloro-7-[(3R,4S)-3-fluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 391.2 (M+H). 1H NMR (400 MHz, MeOD) δ 5.05 (s, 0.5H), 4.93 (s, 0.5H), 4.18 (t, J = 11.9 Hz, 1H), 4.05 (d, J = 12.4 Hz, 1H), 3.86 - 3.66 (m, 2H), 3.57 (m, 1H), 3.46 (t, J = 11.1 Hz, 1H), 2.53 (s, 3H), 1.99 (m, 2H), 1.74 (d, J = 8.9 Hz, 1H). Relative stereochemistry cis-unknown absolute configuration (97% ee) General procedure for SnAr (GP1) 216B

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-3,3-difluoro piperidine-4-carboxamide LC-MS: m/z 422.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 4.33 (dd, J = 21.4, 8.9 Hz, 1H), 3.98 - 3.82 (m, 2H), 3.58 (s, 1H), 3.10 (d, J = 6.6 Hz, 1H), 2.52 (s, 3H), 2.18 (d, J = 12.5 Hz, 2H). racemic mixture SnAr (GP1) 217A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-fluoropiperidine-4-carboxamide LC-MS: m/z 404.2 (M+H). 1H NMR (400 MHz, MeOD) δ 5.14 - 4.95 (m, 1H), 4.24 - 4.13 (m, 1H), 3.83 (d, J = 12.1 Hz, 1H), 3.54 - 3.43 (m, 2H), 2.76 - 2.65 (m, 1H), 2.54 (s, 3H), 2.15 - 2.02 (m, 2H). Relative stereochemistry trans-unknown absolute configuration (97% ee) General procedure for SnAr (GP1) 217B

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-fluoropiperidine-4-carboxamide LC-MS: m/z 404.1 (M+H). 1H NMR (400 MHz, MeOD) δ 5.20 (d, J = 47.9 Hz, 1H), 4.20 (t, J = 10.7 Hz, 1H), 4.08 (d, J = 13.4 Hz, 1H), 3.85 (m, 1H ), 3.48 (t, J = 12.0 Hz, 1H), 2.79 (m, 1H), 2.53 (d, J = 9.1 Hz, 3H), 2.50 - 2.37 (m, 1H), 1.99 (d, J = 13.5 Hz , 1H). Relative stereochemistry cis-unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 218A

3-Chloro-7-[(3R,4S)-4-hydroxy-3,4-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 4.39 (s, 1H), 3.84 - 3.72 (m, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.49 - 3.38 ( m, 2H), 2.49 (s, 3H), 1.82 - 1.68 (m, 3H), 1.20 (s, 3H), 0.89 (d, J = 6.7 Hz, 3H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1) 218B

3-Chloro-7-[(3S,4S)-4-hydroxy-3,4-dimethylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.93 (d, J = 8.8 Hz, 1H), 3.77 (s, 1H), 3.64 (t, J = 11.1 Hz, 1H), 3.28 - 3.26 (m, 1H), 2.52 (s, 3H), 2.01 (s, 2H), 1.86 (d, J = 9.0 Hz, 1H), 1.26 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1) 219A

3-Chloro-7-[(3R,4R)-3-fluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 391.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.77 - 4.58 (m, 1H), 4.24 - 4.08 (m, 1H), 3.82 (m, 2H), 3.71 (m, 1H), 3.52 - 3.41 (m, 2H), 2.54 (s, 3H), 2.07 (d, J = 11.1 Hz, 1H), 1.96 - 1.73 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) General procedure for SnAr (GP1) 219B

3-Chloro-7-[(3S,4S)-3-fluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 391.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.67 (m, 1H), 4.21 - 4.11 (m, 1H), 3.89 - 3.79 (m, 2H), 3.71 (m, 1H), 3.47 (m, 2H), 2.54 ( s, 3H), 2.11 - 2.02 (m, 1H), 1.95 - 1.73 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) General procedure for SnAr (GP1) 220A

3-Chloro-7-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 391.2 (M+H). 1H NMR (400 MHz, MeOD) δ 5.06 - 4.92 (m, 1H), 4.10 - 4.01 (m, 1H), 3.90 - 3.70 (m, 3H), 3.55 - 3.46 (m, 4H), 2.53 (s, 3H) ), 2.27 - 2.17 (m, 1H), 2.07 - 1.97 (m, 1H) relative stereochemistry cis-unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 220B

3-Chloro-7-[(3R,4S)-3-fluoro-4-methoxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 391.2 (M+H). 1H NMR (400 MHz, MeOD) δ 5.05 - 4.92 (m, 1H), 4.11 - 3.99 (m, 1H), 3.90 - 3.70 (m, 3H), 3.55 - 3.46 (m, 4H), 2.53 (s, 3H) ), 2.27 - 2.16 (m, 1H), 2.04 - 1.98 (m, 1H). Relative stereochemistry cis-unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 221A

(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-(Trifluoromethyl)piperidine-4-carboxamide LC-MS: m/z 454.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.45 - 4.35 (m, 1H), 4.27 - 4.15 (m, 1H), 3.86 (d, J = 12.4 Hz, 1H), 3.64 (d, J = 12.7 Hz, 1H) , 3.06 (t, J = 9.8 Hz, 2H), 2.54 (s, 3H), 2.24 - 2.11 (m, 2H). Relative stereochemistry cis-unknown absolute configuration (95% ee) General procedure for SnAr (GP1) 221B

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-(Trifluoromethyl)piperidine-4-carboxamide LC-MS: m/z 454.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.44 - 4.35 (m, 1H), 4.25 - 4.16 (m, 1H), 3.86 (d, J = 9.5 Hz, 1H), 3.64 (d, J = 12.4 Hz, 1H) , 3.11 - 2.98 (m, 2H), 2.54 (s, 3H), 2.21 - 2.12 (m, 2H). Relative stereochemistry cis-unknown absolute configuration (95% ee) General procedure for SnAr (GP1) 222A

3-Chloro-7-[(3S,4S)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.98 - 3.92 (m, 1H), 3.91 - 3.84 (m, 2H), 3.82 - 3.74 (m, 1H), 3.70 - 3.63 (m, 1H), 3.53 - 3.44 (m , 1H), 3.28 - 3.23 (m, 1H), 2.53 (s, 3H), 2.05 - 2.02 (m, 1H), 1.75 - 1.65 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) General procedure for SnAr (GP1) 222B

3-Chloro-7-[(3R,4R)-3-hydroxy-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.98 - 3.91 (m, 1H), 3.91 - 3.83 (m, 2H), 3.81 - 3.74 (m, 1H), 3.69 - 3.63 (m, 1H), 3.48 (t, J = 11.4 Hz, 1H), 3.28 - 3.22 (m, 1H), 2.53 (s, 3H), 2.05 - 2.00 (m, 1H), 1.75 - 1.65 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) General procedure for SnAr (GP1) 223A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-3,3-dimethyl Piperidine-4-carboxamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.03 (d, J = 13.4 Hz, 1H), 3.58 (d, J = 11.3 Hz, 1H), 3.39 (dd, J = 13.0, 7.3 Hz, 2H), 2.53 (s , 3H), 2.44 - 2.31 (m, 2H), 1.88 (d, J = 8.7 Hz, 1H), 1.13 (s, 6H). racemic mixture General procedure for SnAr (GP1) 224A

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-(Hydroxymethyl)piperidine-4-carboxamide LC-MS: m/z 416.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.96 (d, J = 6.9 Hz, 2H), 3.69 (dd, J = 10.9, 3.4 Hz, 1H), 3.61 - 3.47 (m, 3H), 2.63 (td, J = 10.7, 3.7 Hz, 1H), 2.53 (s, 3H), 2.07 (d, J = 10.9 Hz, 2H), 1.75 (dd, J = 22.2, 12.7 Hz, 1H). Relative Stereochemistry cis-Mixture of Enantiomers General procedure for SnAr (GP1) 225A

3-Chloro-7-[(3S,4R)-4-hydroxy-3-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.84 (s, 1H), 4.86 (d, J = 4.8 Hz, 2H), 3.90 (d, J = 10.0 Hz, 1H), 3.80 (d, J = 12.5 Hz, 1H ), 3.69 (m, 1H), 3.63 - 3.54 (m, 1H), 3.45 (m, 3H), 2.50 (s, 3H), 2.04 - 1.92 (m, 1H), 1.83 - 1.74 (m, 1H), 1.73 - 1.61 (m, 1H). Relative Stereochemistry Trans-Unknown Absolute Configuration General procedure for SnAr (GP1) 225B

3-Chloro-7-[(3R,4S)-4-hydroxy-3-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.84 (s, 1H), 4.86 (d, J = 4.8 Hz, 2H), 3.90 (d, J = 10.4 Hz, 1H), 3.80 (d, J = 12.7 Hz, 1H ), 3.69 (m, 1H), 3.62 - 3.36 (m, 4H), 2.50 (s, 3H), 2.04 - 1.92 (m, 1H), 1.85 - 1.74 (m, 1H), 1.74 - 1.60 (m, 1H ). Relative Stereochemistry Trans-Unknown Absolute Configuration General procedure for SnAr (GP1) 226A

3-Chloro-7-[(3S,4R)-3-fluoro-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 392.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 4.96 (m, 1H), 4.76 (t, J = 5.1 Hz, 1H), 4.09 (t, J = 11.9 Hz, 1H), 3.98 (m , 1H), 3.83 (m, 1H), 3.50 (m, 1H), 3.40 (m, 2H), 2.51 - 2.45 (m, 3H), 1.87m, 2H), 1.69 (m, 1H). Relative stereochemistry cis-unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 227A

3-Chloro-7-[(3S,4S)-3-fluoro-4-methoxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3 ,2-b]pyridine-6-carbonitrile LC-MS: m/z 391.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.79 - 4.61 (m, 1H), 4.09 (t, J = 11.7 Hz, 1H), 3.81 - 3.73 (m, 1H), 3.67 - 3.49 (m, 6H), 2.54 ( s, 3H), 2.32 (d, J = 9.0 Hz, 1H), 1.91 - 1.80 (m, 1H). Relative Stereochemistry Trans-Mixture of Mirror Isomers General procedure for SnAr (GP1) 228A

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-fluoropiperidine-4-carboxamide LC-MS: m/z 404.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 5.14 - 4.81 (m, 1H), 4.30 - 4.02 (m, 1H), 3.76 ( m, 1H), 3.45 (m, 2H), 2.60 (m, 1H), 2.52 (s, 3H), 2.08 - 1.75 (m, 2H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) General procedure for SnAr (GP1) 228B

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-fluoropiperidine-4-carboxamide LC-MS: m/z 404.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 5.21 (m, 1H), 4.32 - 3.61 (m, 3H), 3.40 (m, 1H), 2.73 (m, 1H), 2.51 - 2.47 (m, 3H), 2.28 (m, 1H), 1.85 (d, J = 10.5 Hz, 1H). Relative stereochemistry cis-unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 229A

3-Chloro-7-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 377.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.67 - 4.48 (m, 1H), 4.12 (t, J = 10.1 Hz, 1H), 3.92 - 3.75 (m, 2H), 3.55 (t, J = 10.6 Hz, 2H) , 2.54 (s, 3H), 2.21 (d, J = 8.3 Hz, 1H), 1.87 (d, J = 10.0 Hz, 1H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) General procedure for SnAr (GP1) 229B

3-Chloro-7-[(3S,4S)-3-fluoro-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 377.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.69 - 4.50 (m, 1H), 4.13 (t, J = 9.8 Hz, 1H), 3.93 - 3.76 (m, 2H), 3.62 - 3.52 (m, 2H), 2.55 ( s, 3H), 2.27 - 2.17 (m, 1H), 1.95 - 1.80 (m, 1H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) General procedure for SnAr (GP1) 229C

3-Chloro-7-[(3S,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 377.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.77 (d, J = 6.8 Hz, 1H), 4.15 - 4.00 (m, 2H), 3.94 - 3.75 (m, 2H), 3.51 (s, 1H), 2.53 (s, 3H), 2.23 - 2.14 (m, 1H), 2.06 - 1.97 (m, 1H) relative stereochemistry cis-unknown absolute configuration (97% ee) General procedure for SnAr (GP1) 229D

3-Chloro-7-[(3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 377.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.82 - 4.75 (m, 1H), 4.15 - 4.01 (m, 2H), 3.93 - 3.76 (m, 2H), 3.55 - 3.46 (m, 1H), 2.54 (s, 3H) ), 2.23 - 2.13 (m, 1H), 2.06 - 1.97 (m, 1H). Relative stereochemistry cis-unknown absolute configuration (99% ee) General procedure for SnAr (GP1) 230A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxypiperidine-3-carboxamide LC-MS: m/z 402.1 (M+H). 1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 7.35 (s, 1H), 7.06 (s, 1H), 5.07 (d, J = 5.0 Hz, 1H), 3.98 - 3.72 (m, 3H) , 3.68 - 3.56 (m, 1H), 3.39 - 3.33 (m, 1H), 2.50 (s, 3H), 2.47 - 2.40 (m, 1H), 2.03 - 1.92 (m, 1H), 1.81 -1.71 (m, 1H). Relative Stereochemistry cis-Mixture of Enantiomers General procedure for SnAr (GP1) 230B

(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxypiperidine-3-carboxamide LC-MS: m/z 402.2 (M+H). 1H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 5.38 (s, 1H), 4.34 - 4.21 (m, 1H), 4.04 - 3.99 ( m, 1H), 3.77 (t, J = 9.6 Hz, 1H), 3.58 (t, J = 11.3 Hz, 2H), 2.77 - 2.67 (m, 1H), 2.50 (s, 3H), 1.96 - 1.85 (m , 1H), 1.84 - 1.72 (m, 1H). Relative Stereochemistry Trans-Mixture of Mirror Isomers General procedure for SnAr (GP1) 231A

3-Chloro-7-[(3S,4S)-4-hydroxy-3-(trifluoromethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 427.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 5.33 (s, 1H), 4.35 (s, 1H), 3.94 - 3.80 (m, 2H), 3.71 (d, J = 10.7 Hz, 1H) , 3.58 (d, J = 11.8 Hz, 1H), 2.82 (s, 1H), 2.51 (s, 3H), 1.95 (t, J = 11.1 Hz, 1H), 1.83 (d, J = 12.9 Hz, 1H) . Relative Stereochemistry Trans-Mixture of Mirror Isomers General procedure for SnAr (GP1) 232A

2-[(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]acetamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 7.36 (s, 1H), 6.81 (s, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 11.6 Hz , 1H), 3.42 (t, J = 11.6 Hz, 1H), 3.12 - 3.05 (m, 1H), 2.51 (s, 3H), 2.43 - 2.37 (m, 1H), 1.93 - 1.81 (m, 2H), 1.62 (s, 2H), 1.46 (d, J = 9.2 Hz, 1H), 0.94 (d, J = 5.8 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (97% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 232B

2-[(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]acetamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 7.37 (s, 1H), 6.82 (s, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.73 (dd, J = 11.7, 2.8 Hz, 1H), 3.55 (d, J = 9.5 Hz, 1H), 3.29 (s, 1H), 2.51 (s, 3H), 2.18 (d, J = 4.0 Hz, 1H), 2.12 - 2.07 (m, 2H), 2.03 - 1.94 (m, 1H), 1.82 (dd, J = 20.2, 10.8 Hz, 1H), 1.59 (dd, J = 13.1, 3.3 Hz, 1H), 0.92 (d, J = 6.9 Hz, 3H ). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 233A

3-Chloro-7-{6-hydroxy-3-azabicyclo[3.1.1]hept-3-yl}-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 371.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.28 - 4.18 (m, 3H), 4.11 (d, J = 10.5 Hz, 2H), 2.65 (s, 2H), 2.50 (s, 3H), 1.79 - 1.69 (m, 2H). racemic mixture General procedure for SnAr (GP1) 234A

2-[(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]-N-methylacetamide LC-MS: m/z 428.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.69 (d, J = 10.8 Hz, 1H), 7.83 (s, 1H), 3.77 (dd, J = 37.8, 12.1 Hz, 2H), 3.59 - 3.36 (m, 2H) , 3.10 (t, J = 11.3 Hz, 1H), 2.59 (d, J = 4.2 Hz, 3H), 2.50 - 2.48 (m, 3H), 2.43 (d, J = 19.5 Hz, 1H), 2.19 (s, 1H), 2.00 - 1.39 (m, 4H), 0.96 - 0.88 (m, 3H). Relative Stereochemistry cis-Mixture of Enantiomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 234B

2-[(3S,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]-N-methylacetamide LC-MS: m/z 428.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 7.84 (s, 1H), 3.84 (d, J = 10.5 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.17 (s , 1H), 3.08 (d, J = 12.1 Hz, 1H), 2.59 (d, J = 4.5 Hz, 3H), 2.51 (s, 3H), 2.40 (d, J = 3.8 Hz, 1H), 1.88 (dd , J = 13.9, 8.7 Hz, 1H), 1.78 (d, J = 12.5 Hz, 1H), 1.60 (s, 2H), 1.46 (s, 1H), 0.93 (d, J = 6.1 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 234C

2-[(3R,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]-N-methylacetamide LC-MS: m/z 428.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 7.84 (d, J = 4.6 Hz, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.55 (d, J = 9.2 Hz, 1H), 3.29 (d, J = 6.5 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.50 - 2.49 (m, 3H), 2.19 (s, 1H) , 2.10 (d, J = 6.4 Hz, 2H), 1.95 (s, 1H), 1.87 - 1.74 (m, 1H), 1.56 (d, J = 10.1 Hz, 1H), 0.91 (d, J = 6.9 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 234D

(3S,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Methylpiperidine-4-carboxamide LC-MS: m/z 384.3 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.99 (d, J = 12.8 Hz, 1H), 3.91 (d, J = 12.7 Hz, 1H), 3.47 (t, J = 11.1 Hz, 1H), 3.12 (t, J = 11.4 Hz, 1H), 2.49 (s, 3H), 2.21 - 1.94 (m, 4H), 1.00 (d, J = 5.4 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthetic Program 3, SnAr (GP1) 235A

N-[(3S,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- [yl]-4-hydroxypiperidin-3-yl]acetamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 8.66 (d, J = 5.4 Hz, 1H), 5.02 (d, J = 5.7 Hz, 1H), 4.16 - 3.94 (m, 2H), 3.74 - 3.65 (m, 1H), 3.65 - 3.50 (m, 2H), 3.12 - 3.06 (m, 1H), 2.56 (s, 3H), 2.08 - 1.92 (m, 4H), 1.62 - 1.49 (m, 1H) . Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 236A

3-Chloro-7-[4-hydroxyl-4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b ]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 4.73 (t, J = 5.6 Hz, 1H), 4.40 (s, 1H), 3.82 - 3.61 (m, 4H), 3.34 - 3.29 (m, 2H), 2.49 (s, 3H), 1.89 - 1.82 (m, 2H), 1.57 - 1.54 (m, 2H). SnAr (GP1) 237A

3-chloro-7-[(3R,4S)-3-ethyl-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 4.74 (d, J = 3.5 Hz, 1H), 3.96 (s, 1H), 3.79 (s, 1H), 3.58 - 3.43 (m, 3H) , 2.51 (s, 3H), 1.84 (s, 2H), 1.70 (s, 1H), 1.43 (dt, J = 14.5, 7.4 Hz, 1H), 1.29 (dd, J = 14.2, 7.0 Hz, 1H), 0.90 (t, J = 7.4 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) SnAr (GP1) 238A

(3S,4R)-1-[6-cyano-3-fluoro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N,3-Dimethylpiperidine-4-carboxamide LC-MS: m/z 398.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.98 (d, J = 11.7 Hz, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.47 (t, J = 11.9 Hz, 1H), 3.12 (t, J = 11.7 Hz, 1H), 2.76 (s, 3H), 2.49 (s, 3H), 2.26 - 2.16 (m, 1H), 2.13 - 2.04 (m, 2H), 1.94 - 1.85 (m, 1H), 0.94 ( d, J = 6.4 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Nucleosynthesis Procedure 3, SnAr (GP1), Ester Hydrolysis (GP2), Amide Coupling (GP3) 239A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-methoxyethyl)-3-methylpiperidine-4-carboxamide LC-MS: m/z 458.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.96 (d, J = 12.3 Hz, 1H), 3.88 (d, J = 11.4 Hz, 1H), 3.51 - 3.45 (m, 3H), 3.40 (dd, J = 13.5, 5.2 Hz, 2H), 3.36 (s, 3H), 3.12 (t, J = 11.5 Hz, 1H), 2.53 (s, 3H), 2.23 - 2.04 (m, 3H), 1.91 (d, J = 10.2 Hz, 1H), 0.96 (d, J = 6.2 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (94% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 239B

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- N-(2-methoxyethyl)-3-methylpiperidine-4-carboxamide LC-MS: m/z 458.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.96 (d, J = 12.9 Hz, 1H), 3.88 (d, J = 12.2 Hz, 1H), 3.51 - 3.45 (m, 3H), 3.45 - 3.37 (m, 2H) , 3.36 (s, 3H), 3.12 (t, J = 11.5 Hz, 1H), 2.53 (s, 3H), 2.23 - 2.04 (m, 3H), 1.91 (d, J = 10.0 Hz, 1H), 0.96 ( d, J = 6.2 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 240A

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Methylpiperidine-4-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR ( 400 MHz, MeOD) δ 3.97 (d, J = 12.5 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.12 (t, J = 11.3 Hz , 1H), 2.53 (s, 3H), 2.24 - 2.03 (m, 3H), 1.96 (dd, J = 12.5, 1.9 Hz, 1H), 1.00 (d, J = 5.7 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) SnAr (GP1) 240B

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Methylpiperidine-4-carboxamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.97 (d, J = 12.5 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.47 (t, J = 11.3 Hz, 1H), 3.12 (t, J = 11.2 Hz, 1H), 2.53 (s, 3H), 2.22 - 2.02 (m, 3H), 2.00 - 1.93 (m, 1H), 1.00 (d, J = 5.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) SnAr (GP1) 241A

N-[(3R,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]acetamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.72 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 3.85 (t, J = 11.9 Hz, 2H), 3.54 (dd, J = 22.2, 11.3 Hz , 2H), 3.17 (t, J = 11.8 Hz, 1H), 2.51 (s, 3H), 1.91 (d, J = 13.4 Hz, 1H), 1.83 (d, J = 17.9 Hz, 4H), 1.70 - 1.53 (m, 1H), 0.89 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 242A

N-[(3S,4S)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]methanesulfonamide LC-MS: m/z 450.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.73 (s, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.87 (d, J = 12.3 Hz, 2H), 3.51 (t, J = 11.8 Hz, 1H ), 3.21 - 3.14 (m, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.98 (s, 3H), 2.52 (s, 3H), 2.11 (d, J = 9.7 Hz, 1H), 1.85 - 1.71 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration SnAr (GP1), removal of Boc protecting group (GP4), synthesis of sulfonamide (GP8) 242B

N-[(3R,4R)-1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]methanesulfonamide LC-MS: m/z 450.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.73 (s, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.87 (d, J = 12.8 Hz, 2H), 3.51 (t, J = 11.8 Hz, 1H ), 3.21 - 3.13 (m, 1H), 3.06 (d, J = 12.2 Hz, 1H), 2.98 (s, 3H), 2.52 (s, 3H), 2.11 (d, J = 9.7 Hz, 1H), 1.77 (d, J = 11.8 Hz, 2H), 1.01 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration SnAr (GP1), removal of Boc protecting group (GP4), synthesis of sulfonamide (GP8) 243A

3-Chloro-7-[(3R,4R)-4-(hydroxymethyl)-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.96 (d, J = 12.7 Hz, 1H), 3.80 - 3.74 (m, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.60 - 3.52 (m, 2H) , 3.38 - 3.32 (m, 1H), 2.52 (s, 3H), 2.24 - 2.17 (m, 1H), 2.01 - 1.90 (m, 2H), 1.69 (t, J = 10.5 Hz, 1H), 1.01 (d , J = 7.0 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (95% ee) SnAr (GP1) 243B

3-Chloro-7-[(3S,4S)-4-(hydroxymethyl)-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrole And[3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.96 (d, J = 12.7 Hz, 1H), 3.82 - 3.73 (m, 1H), 3.66 (d, J = 11.5 Hz, 1H), 3.60 - 3.50 (m, 2H) , 3.40 - 3.32 (m, 1H), 2.51 (s, 3H), 2.27 - 2.15 (m, 1H), 2.03 - 1.90 (m, 2H), 1.69 (t, J = 10.4 Hz, 1H), 1.01 (d , J = 7.0 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (98% ee) SnAr (GP1) 244A

3-Chloro-7-[(3R,4R)-4-methoxy-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.93 - 3.85 (m, 2H), 3.56 - 3.47 (m, 1H), 3.44 (s, 3H), 3.24 - 3.15 (m, 1H), 3.09 (td, J = 9.1 , 4.1 Hz, 1H), 2.53 (s, 3H), 2.37 - 2.29 (m, 1H), 2.02 - 1.93 (m, 1H), 1.76 - 1.66 (m, 1H), 1.12 - 1.05 (d, J = 8 Hz, 3H). Relative stereochemistry trans-unknown absolute configuration (94% ee) SnAr (GP1) 244B

3-Chloro-7-[(3S,4S)-4-methoxy-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[ 3,2-b]pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.95 - 3.84 (m, 2H), 3.56 - 3.48 (m, 1H), 3.44 (s, 3H), 3.23 - 3.15 (m, 1H), 3.09 (td, J = 9.5 , 4.2 Hz, 1H), 2.53 (s, 3H), 2.37 - 2.28 (m, 1H), 2.02 - 1.93 (m, 1H), 1.77 - 1.65 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) SnAr (GP1) 245A

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4-methyl ylpiperidin-4-yl}methanesulfonamide LC-MS: m/z 450.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.83 (t, J = 10.1 Hz, 2H), 3.71 (d, J = 13.0 Hz, 2H), 3.08 (s, 3H), 2.52 (s, 3H), 2.24 (d , J = 13.9 Hz, 2H), 1.95 - 1.84 (m, 2H), 1.56 (s, 3H) SnAr (GP1), removal of Boc protecting group (GP4) and synthesis of sulfonamide (GP8) 246A

2-{1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4-methyl piperidin-4-yl}acetamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 7.32 (s, 1H), 6.79 (s, 1H), 3.73 - 3.58 (m, 4H), 2.52 (s, 3H), 2.15 (s, 2H), 1.84 - 1.75 (m, 2H), 1.63 - 1.54 (m, 2H), 1.14 (s, 3H) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 247A

3-Chloro-7-[(3S,4S)-4-hydroxy-3-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 4.85 (d, J = 3.2 Hz, 1H), 4.02 (d, J = 2.6 Hz, 1H), 3.78 (m, 2H), 3.65 (m , 1H), 3.61 - 3.45 (m, 3H), 2.48 (s, 3H), 1.99 (d, J = 4.3 Hz, 1H), 1.91 - 1.68 (m, 2H) Relative stereochemistry cis-mirror isomer mixture of SnAr (GP1) 248A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-4-methylpiperidine -4-formamide LC-MS: m/z 400.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 7.33 (s, 1H), 7.04 (s, 1H), 3.72 (d, J = 12.9 Hz, 2H), 3.53 (t, J = 10.3 Hz , 2H), 2.48 (s, 3H), 2.21 (d, J = 13.9 Hz, 2H), 1.63 - 1.51 (m, 2H), 1.20 (s, 3H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 249A

3-Chloro-7-[4-(hydroxymethyl)-4-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.78 - 3.64 (m, 4H), 3.42 (s, 2H), 2.52 (s, 3H), 1.86 - 1.78 (m, 2H), 1.60 - 1.53 (m, 2H), 1.11 (s, 3H). SnAr (GP1) 250A

3-chloro-7-[(3S,4S)-3-ethyl-4-hydroxypiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 387.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 4.81 (d, J = 5.5 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.80 (d, J = 12.3 Hz, 1H ), 3.49 (t, J = 10.7 Hz, 1H), 3.36 (d, J = 4.4 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.50 - 2.48 (m, 3H), 2.01 (d, J = 9.8 Hz, 1H), 1.80 (ddd, J = 13.4, 7.6, 3.5 Hz, 1H), 1.72 - 1.47 (m, 2H), 1.17 (tt, J = 15.3, 7.5 Hz, 1H), 0.91 (t, J = 7.5 Hz, 3H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1) 251A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N,4-dimethyl Piperidine-4-carboxamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, MeOD) δ 3.82 - 3.75 (m, 2H), 3.61 - 3.54 (m, 2H), 2.79 (d, J = 3.8 Hz, 3H), 2.51 (s, 3H), 2.33 - 2.26 ( m, 2H), 1.77 (ddd, J = 13.5, 9.8, 3.6 Hz, 2H), 1.28 (s, 3H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 252A

3-Chloro-7-(4-hydroxy-4-methylpiperidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine- 6-carbonitrile LC-MS: m/z 373.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 4.51 (s, 1H), 3.75 (t, J = 9.7 Hz, 2H), 3.61 (d, J = 12.2 Hz, 2H), 2.52 (s , 3H), 1.69 (t, J = 13.8 Hz, 4H), 1.24 (s, 3H). SnAr (GP1) 253A

N-({1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine- 4-yl}methyl)cyclopropaneformamide LC-MS: m/z 440.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.94 (d, J = 12.3 Hz, 2H), 3.44 (t, J = 11.4 Hz, 2H), 3.20 (d, J = 6.7 Hz, 2H), 2.50 (s, 3H ), 1.92 (d, J = 12.8 Hz, 2H), 1.87 - 1.76 (m, 1H), 1.64 - 1.45 (m, 3H), 0.90 - 0.82 (m, 2H), 0.81 - 0.70 (m, 2H). SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 254A

N-({1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine- 4-yl}methyl)acrylamide LC-MS: m/z 428.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.94 (d, J = 12.4 Hz, 2H), 3.48 - 3.40 (m, 2H), 3.18 (d, J = 6.6 Hz, 2H), 2.52 (s, 3H), 2.23 (q, J = 7.6 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.87 - 1.76 (m, 1H), 1.59 - 1.47 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 255A

N-({1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine- 4-yl}methyl)acetamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.95 (t, J = 5.4 Hz, 1H), 3.87 (d, J = 12.3 Hz, 2H), 3.42 (s, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.48 (s, 3H), 1.82 (d, J = 11.8 Hz, 5H), 1.68 (d, J = 7.2 Hz, 1H), 1.43 - 1.29 (m, 2H) . SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 256A

3-Chloro-7-[4-(2-hydroxyethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine -6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.65 (s, 1H), 4.42 (s, 1H), 3.86 (d, J = 12.2 Hz, 2H), 3.52 (t, J = 6.3 Hz, 2H), 3.42 (t , J = 11.6 Hz, 2H), 2.50 (s, 3H), 1.85 (d, J = 12.2 Hz, 2H), 1.71 (s, 1H), 1.47 (m, 2H), 1.44 - 1.31 (m, 2H) . General procedure for SnAr (GP1) 257A

2-{1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}-N-ethylacetamide LC-MS: m/z 428.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.92 (d, J = 12.5 Hz, 2H), 3.47 (t, J = 11.5 Hz, 2H), 3.22 (q, J = 7.3 Hz, 2H), 2.52 (s, 3H ), 2.21 (d, J = 7.2 Hz, 2H), 2.07 (s, 1H), 1.89 (d, J = 12.7 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.13 (t, J = 7.3 Hz , 3H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 258A

3-Chloro-7-[4-(methoxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine -6-carbonitrile LC-MS: m/z 387.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 3.88 (d, 2H), 3.43 (t, 2H), 3.32 (s, 3H), 3.29 (s, 2H), 2.50 - 2.49 (s, 3H), 1.83 (d, 3H), 1.45 (m, 2H) General procedure for SnAr (GP1) 79B

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}ethane-1-sulfonamide LC-MS: m/z 450.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 12.5 Hz, 2H), 3.49 (t, J = 11.3 Hz, 2H ), 3.42 (d, J = 7.3 Hz, 1H), 3.06 (q, J = 7.3 Hz, 2H), 2.49 - 2.48 (m, 3H), 2.00 (d, J = 10.7 Hz, 2H), 1.73 (dd , J = 20.5, 10.4 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). SnAr (GP1), removal of Boc protecting group (GP4), synthesis of sulfonamide (GP8) 259A

2-{1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}-N,N-Dimethylacetamide LC-MS: m/z 428.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.93 (d, J = 11.9 Hz, 2H), 3.48 (t, J = 11.4 Hz, 2H), 3.10 (s, 3H), 2.96 (s, 3H), 2.52 (s , 3H), 2.44 (d, J = 6.9 Hz, 2H), 2.12 (s, 1H), 1.94 (d, J = 12.5 Hz, 2H), 1.65 - 1.52 (m, 2H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 260A

2-{1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}-N-methylacetamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.92 (d, J = 12.3 Hz, 2H), 3.47 (t, J = 11.7 Hz, 2H), 2.74 (s, 3H), 2.52 (s, 3H), 2.22 (d , J = 7.2 Hz, 2H), 2.07 (s, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.63 - 1.50 (m, 2H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 261A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 3-Hydroxy-N-methylpiperidine-4-carboxamide LC-MS: m/z 416.1 (M+H). 1H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 7.85 (d, J = 4.5 Hz, 1H), 5.29 (d, J = 4.4 Hz, 1H), 3.97 - 3.73 (m, 3H), 3.36 (d, J = 12.0 Hz, 1H), 3.19 (t, J = 10.5 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H), 2.50 - 2.49 (m, 3H), 2.24 (td, J = 10.8, 4.7 Hz, 1H), 1.87 (dt, J = 20.6, 11.2 Hz, 2H). Relative Stereochemistry Trans-Mixture of Mirror Isomers SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 262A

3-fluoro-7-[(3S,4S)-4-hydroxyl-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridine-6-carbonitrile LC-MS: m/z 357.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.99 - 3.83 (m, 2H), 3.58 - 3.48 (m, 1H), 3.41 - 3.34 (m, 1H), 3.19 - 3.11 (m, 1H), 2.49 (d, J = 1.3 Hz, 3H), 2.17 - 2.08 (m, 1H), 1.92 - 1.76 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthetic Program 3, SnAr (GP1) 263A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-[(3S) - Oxolan-3-yl]piperidine-4-carboxamide LC-MS: m/z 456.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.39 (s, 1H), 4.00 - 3.85 (m, 4H), 3.84 - 3.77 (m, 1H), 3.64 - 3.58 (m, 1H), 3.50 (t, J = 10.8 Hz, 2H), 2.57 - 2.47 (m, 4H), 2.28 - 2.18 (m, 1H), 2.08 - 1.91 (m, 4H), 1.89 - 1.81 (m, 1H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 263B

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-[(3R) -Oxolan-3-yl]piperidine-4-carboxamide LC-MS: m/z 456.1 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.39 (s, 1H), 4.00 - 3.85 (m, 4H), 3.83 - 3.77 (m, 1H), 3.65 - 3.59 (m, 1H), 3.50 (t, J = 10.8 Hz, 2H), 2.58 - 2.48 (m, 4H), 2.28 - 2.18 (m, 1H), 2.08 - 1.91 (m, 4H), 1.89 - 1.78 (m, 1H). Single Spiegelmer - unknown absolute configuration (99% ee) SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 264A

3-Chloro-2-methyl-7-[4-(pyrrolidin-1-carbonyl)piperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 440.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.98 (d, J = 12.5 Hz, 2H), 3.64 (t, J = 6.7 Hz, 2H), 3.54 (t, J = 11.0 Hz, 2H), 3.44 (t, J = 6.9 Hz, 2H), 2.89 - 2.80 (m, 1H), 2.53 (s, 3H), 2.08 - 1.99 (m, 4H), 1.97 - 1.89 (m, 4H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 265A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-(oxoheterocycle Butane-3-yl)piperidine-4-carboxamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.65 (d, J = 6.5 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.73 (t, J = 6.7 Hz, 2H) , 4.44 (t, J = 6.2 Hz, 2H), 3.89 (d, J = 12.3 Hz, 2H), 3.45 (t, J = 10.1 Hz, 2H), 2.50 - 2.49 (m, 4H), 1.92 - 1.78 ( m, 4H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 266A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-(oxoheterocycle Hexan-4-yl)piperidine-4-carboxamide LC-MS: m/z 442.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.02 - 3.86 (m, 5H), 3.54 - 3.44 (m, 4H), 2.58 - 2.42 (m, 4H), 2.09 - 1.91 (m, 4H), 1.83 (d, J = 12.6 Hz, 2H), 1.61 - 1.48 (m, 2H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 267A

7-[4-(azetidine-1-carbonyl)piperidin-1-yl]-3-chloro-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2 -b]pyridine-6-carbonitrile LC-MS: m/z 426.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.34 (t, J = 7.7 Hz, 2H), 4.03 (t, J = 7.8 Hz, 2H), 3.95 (d, J = 12.6 Hz, 2H), 3.55 - 3.47 (m , 2H), 2.64 - 2.56 (m, 1H), 2.53 (s, 3H), 2.38 - 2.29 (m, 2H), 2.04 - 1.95 (m, 2H), 1.89 (d, J = 10.3 Hz, 2H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 268A

3-Chloro-2-methyl-7-[4-(morpholine-4-carbonyl)piperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-6-carbonitrile LC-MS: m/z 456.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.97 (d, J = 12.6 Hz, 2H), 3.72 - 3.51 (m, 10H), 3.00 (t, J = 11.2 Hz, 1H), 2.53 (s, 3H), 2.10 - 1.99 (m, 2H), 1.92 (d, J = 10.9 Hz, 2H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 78C

1-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}-3-methylurea LC-MS: m/z 415.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 4.7 Hz, 1H), 3.83 (d, J = 12.3 Hz, 2H ), 3.67 (d, J = 7.3 Hz, 1H), 3.50 (t, J = 10.9 Hz, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.51 (s, 3H), 1.95 (d, J = 10.4 Hz, 2H), 1.58 (dd, J = 20.1, 10.3 Hz, 2H). SnAr (GP1), removal of Boc protecting group (GP4), urea synthesis (GP7) 269A

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}methylsulfonamide LC-MS: m/z 436.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.93 (d, J = 13.0 Hz, 2H), 3.55 (t, J = 10.9 Hz, 3H), 3.01 (s, 3H), 2.53 (s, 3H), 2.17 (d , J = 10.3 Hz, 2H), 1.87 (td, J = 14.8, 3.7 Hz, 2H). SnAr (GP1), removal of Boc protecting group, synthesis of sulfonamide (GP8) 270A

3-Chloro-7-[4-(hydroxymethyl)piperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6 -Formonitrile LC-MS: m/z 373.2 (M+H). 1H NMR (400 MHz, DMSO) δ 11.67 (s, 1H), 4.58 (t, J = 5.2 Hz, 1H), 3.89 (d, J = 12.4 Hz, 2H), 3.47 - 3.34 (m, 4H), 2.51 (s, 3H), 1.84 (d, J = 11.5 Hz, 2H), 1.67 (s, 1H), 1.48 - 1.31 (m, 2H). General Program SnAr (GP1) 271A

3-Chloro-7-(4-methoxypiperidin-1-yl)-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-methyl Nitrile LC-MS: m/z 373.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.91 - 3.83 (m, 2H), 3.61 - 3.55 (m, 2H), 3.55 - 3.51 (m, 1H), 3.43 (s, 3H), 2.52 (s, 3H), 2.18 - 2.08 (m, 2H), 1.92 - 1.80 (m, 2H). General Program SnAr (GP1) 272A

3-Chloro-2-methyl-7-[4-(1H-pyrazol-4-yl)piperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2- b] pyridine-6-carbonitrile LC-MS: m/z 409.2 (M+H). 1H NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 11.64 (brs, 1H), 7.53 (s, 2H), 3.92 (d, J = 12.7 Hz, 2H), 3.55 (t, J = 11.2 Hz , 2H), 2.87 - 2.76 (m, 1H), 2.51 (s, 3H), 2.12 - 2.02 (m, 2H), 1.82 - 1.72 (m, 2H). General Program SnAr (GP1) 273A

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}-3-methoxypropionamide LC-MS: m/z 444 (M+H). 1H NMR (400 MHz, CD3OD) δ 4.00 - 3.90 (m, 3H), 3.66 (t, J = 6.2 Hz, 2H), 3.55 (t, J = 11.0 Hz, 2H), 3.34 (s, 3H), 2.53 (s, 3H), 2.45 (t, J = 6.2 Hz, 2H), 2.07 (d, J = 9.3 Hz, 2H), 1.84 - 1.74 (m, 2H). SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 274A

N-{1-[3-chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]piperidine-4 -yl}acrylamide LC-MS: m/z 414.2 (M+H). 1H NMR (400 MHz, MeOD) δ 3.95 (dd, J = 15.1, 11.7 Hz, 3H), 3.60 - 3.47 (m, 2H), 2.53 (s, 3H), 2.22 (q, J = 7.6 Hz, 2H) , 2.06 (d, J = 9.8 Hz, 2H), 1.79 (qd, J = 12.0, 4.0 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). SnAr (GP1), removal of Boc protecting group (GP4), amide coupling (GP3) 275A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-cyclopropylpiper Pyridine-4-carboxamide LC-MS: m/z 426.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.94 (d, J = 4.0 Hz, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.45 - 3.40 (m, 2H) , 2.64 (d, J = 7.2, 3.8 Hz, 1H), 2.49 (s, 3H), 2.34 (dd, J = 14.8, 7.6 Hz, 1H), 1.82 (d, J = 3.5 Hz, 4H), 0.65 - 0.58 (m, 2H), 0.45 - 0.37 (m, 2H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 276A

1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-N-ethylpiperidine -4-formamide LC-MS: m/z 414.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.88 (t, J = 5.4 Hz, 1H), 3.88 (d, J = 12.4 Hz, 2H), 3.43 (dd, J = 12.7, 6.7 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.50 (s, 3H), 2.39 (dd, J = 14.9, 7.3 Hz, 1H), 1.84 (dd, J = 10.1, 6.6 Hz, 4H), 1.04 (t, J = 7.2 Hz, 3H). SnAr (GP1), ester hydrolysis (GP2), amide coupling (GP3) 277A

(3S,4R)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methyl-N-(1-methylcyclopropyl)piperidine-4-carboxamide LC-MS: m/z 470.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 3.83 - 3.70 (m, 2H), 3.65 - 3.59 (m, 1H), 3.51 (t,J = 11.8 Hz, 1H), 2.51 (d,J = 9.9 Hz, 3H) , 2.48 - 2.39 (m, 2H), 1.71 (d,J = 13.8 Hz, 1H), 1.37 (s, 3H), 0.85 (d,J = 6.8 Hz, 3H), 0.75 (s, 2H), 0.66 ( d, J = 2.9 Hz, 2H). Single Spiegelmer - unknown absolute configuration (94% ee) Amide coupling (GP3), debenzylation (GP6), followed by SnAr (GP1) 277B

(3R,4S)-1-[3-Chloro-6-cyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]- 4-Hydroxy-3-methyl-N-(1-methylcyclopropyl)piperidine-4-carboxamide LC-MS: m/z 470.2 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 3.84 - 3.70 (m, 2H), 3.65 - 3.58 (m, 1H), 3.51 (t,J = 11.8 Hz, 1H), 2.53 (s, 3H), 2.49 - 2.38 (m, 2H), 1.71 (d,J = 13.6 Hz, 1H), 1.37 (s, 3H), 0.85 (d,J = 6.8 Hz, 3H), 0.75 (s, 2H), 0.66 (d,J = 2.9 Hz, 2H). Single Spiegelmer - unknown absolute configuration (99% ee) Amide coupling (GP3), debenzylation (GP6), followed by SnAr (GP1) 278A

N-{[(3R,4R)-1-[3-chloro-6-cyano-2-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}propanamide LC-MS: m/z 458.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.83 (d,J = 5.3 Hz, 2H), 4.00 (d,J = 13.4 Hz, 1H), 3.79 (dd,J = 11.7, 3.0 Hz, 1H), 3.70 (dd ,J = 11.7, 2.0 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.21 (d,J = 7.1 Hz, 2H), 2.23 (q,J = 7.6 Hz, 2H), 2.12 (dd,J = 6.9, 3.4 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.69 (dd,J = 12.5, 3.1 Hz, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.03 (d,J = 7.0 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (95% ee) Nucleosynthesis procedure 4, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 278B

N-{[(3S,4S)-1-[3-chloro-6-cyano-2-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}propanamide LC-MS: m/z 458.2 (M+H). 1H NMR (400 MHz, MeOD) δ 4.83 (d,J = 5.4 Hz, 2H), 4.00 (d,J = 13.3 Hz, 1H), 3.79 (dd,J = 11.7, 2.9 Hz, 1H), 3.70 (d ,J = 11.4 Hz, 1H), 3.41 - 3.34 (m, 1H), 3.21 (d,J = 7.1 Hz, 2H), 2.23 (q,J = 7.7 Hz, 2H), 2.12 (d,J = 3.0 Hz , 1H), 2.00 (dd,J = 20.4, 9.1 Hz, 2H), 1.69 (d,J = 12.9 Hz, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.03 (d,J = 7.0 Hz , 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Nucleosynthesis procedure 4, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 278C

N-{[(3S,4R)-1-[3-chloro-6-cyano-2-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}propanamide LC-MS: m/z 458.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.97 (s, 1H), 4.83 (s, 2H), 4.00 (d,J = 12.3 Hz, 1H), 3.89 (d,J = 10.8 Hz, 1H), 3.59 - 3.44 (m, 2H), 3.13 (dd,J = 19.7, 8.4 Hz, 2H), 2.23 (q,J = 7.6 Hz, 2H), 1.94 (dd,J = 13.0, 2.9 Hz, 1H), 1.84 - 1.70 ( m, 1H), 1.68 - 1.45 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthesis procedure 4, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 278D

N-{[(3R,4S)-1-[3-chloro-6-cyano-2-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridin-7-yl]-3-methylpiperidin-4-yl]methyl}propanamide LC-MS: m/z 458.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.97 (s, 1H), 4.83 (s, 2H), 4.00 (d,J = 12.3 Hz, 1H), 3.88 (dd,J = 9.4, 3.0 Hz, 1H), 3.58 - 3.44 (m, 2H), 3.18 - 3.08 (m, 2H), 2.23 (q, J = 7.6 Hz, 2H), 1.94 (dd, J = 13.1, 3.0 Hz, 1H), 1.77 (dt, J = 10.4 , 6.5 Hz, 1H), 1.66 - 1.55 (m, 1H), 1.54 - 1.45 (m, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.08 (d,J = 6.5 Hz, 3H). Relative stereochemistry trans- unknown absolute configuration (96% ee) Nucleosynthesis procedure 4, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 279A

N-{[(3R,4R)-1-[3,6-dicyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 433.3 (M+H). 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 3.98 (d,J = 12.4 Hz, 1H), 3.87 (d,J = 10.8 Hz, 1H), 3.58 - 3.51 (m, 1H), 3.50 - 3.42 (m, 1H), 3.16 - 3.07 (m, 2H), 2.68 (s, 3H), 2.24 (q,J = 7.6 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.83 - 1.71 (m , 1H), 1.67 - 1.56 (m, 1H), 1.48 (s, 1H), 1.15 (t,J = 7.6 Hz, 3H), 1.08 (d,J = 6.5 Hz, 3H). Relative stereochemistry cis-unknown absolute configuration (99% ee) Nucleosynthesis procedure 5, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 279B

N-{[(3R,4S)-1-[3,6-dicyano-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-7- Base]-3-methylpiperidin-4-yl]methyl}propionamide LC-MS: m/z 433.2 (M+H). 1H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 7.79 (t,J = 5.6 Hz, 1H), 3.92 (d,J = 12.3 Hz, 1H), 3.79 (d,J = 11.7 Hz, 1H ), 3.48 - 3.33 (m, 2H), 3.13 - 3.04 (m, 1H), 3.00 - 2.88 (m, 1H), 2.65 (s, 3H), 2.15 - 2.04 (m,2H), 1.84 (d,J = 10.4 Hz, 1H), 1.68 - 1.53 (m, 1H), 1.51 - 1.32 (m, 2H), 1.07 - 0.87 (m, 6H). Relative Stereochemistry Trans-Mixture of Mirror Isomers Nucleosynthesis procedure 5, amide coupling (GP3), removal of Boc protecting group (GP4), and SnAr (GP1) 280A

3-Chloro-7-[(3R,4R)-4-hydroxy-3-methylpiperidin-1-yl]-2-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.83 (s, 2H), 4.01 - 3.87 (m, 2H), 3.57 (td,J = 12.2, 2.6 Hz, 1H), 3.38 (td,J = 10.1, 4.5 Hz, 1H), 3.18 (dd, J = 12.5, 10.6 Hz, 1H), 2.19 - 2.08 (m, 1H), 1.95 - 1.76 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H). Relative Stereochemistry Trans-Unknown Absolute Configuration (98% ee) Nucleosynthetic Program 4, SnAr (GP1) 280B

3-Chloro-7-[(3S,4S)-4-hydroxy-3-methylpiperidin-1-yl]-2-(hydroxymethyl)-5-(trifluoromethyl)-1H-pyrrolo [3,2-b]pyridine-6-carbonitrile LC-MS: m/z 389.1 (M+H). 1H NMR (400 MHz, MeOD) δ 4.83 (s, 2H), 4.02 - 3.87 (m, 2H), 3.57 (td,J = 12.2, 2.6 Hz, 1H), 3.38 (td,J = 10.0, 4.5 Hz, 1H), 3.18 (dd, J = 12.4, 10.6 Hz, 1H), 2.13 (dd, J = 12.7, 3.9 Hz, 1H), 1.93 - 1.75 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H ). Relative Stereochemistry Trans-Unknown Absolute Configuration (99% ee) Nucleosynthetic Program 4, SnAr (GP1) 281A

7-[(3S,4S)-4-Hydroxy-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-3,6-dicarbonitrile LC-MS: m/z 364.1 (M+H). 1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 4.84 (d, J = 5.5 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.56 - 3.44 (m, 1H), 3.29 - 3.21 ( m, 1H), 3.17 - 3.07 (m, 1H), 2.65 (s, 3H), 2.05 - 1.94 (m, 1H), 1.78 - 1.58 (m, 2H), 0.99 (d,J = 6.6 Hz, 3H) . Absolute configuration (99% de) Nucleosynthetic Program 5, SnAr (GP1) 281B

7-[(3R,4R)-4-Hydroxy-3-methylpiperidin-1-yl]-2-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b] Pyridine-3,6-dicarbonitrile LC-MS: m/z 364.1 (M+H). 1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 4.84 (d, J = 5.5 Hz, 1H), 3.94 - 3.73 (m, 2H), 3.57 - 3.43 (m, 1H), 3.30 - 3.22 ( m, 1H), 3.16 - 3.05 (m, 1H), 2.65 (s, 3H), 2.05 - 1.95 (m, 1H), 1.78 - 1.58 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H) . Absolute configuration (94% de) Nucleosynthetic Program 5, SnAr (GP1)

INCORPORATION BY REFERENCE All US Patents and US Patent Application Publications cited herein are hereby incorporated by reference .

Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the claims of the appended applications.

Figure 1 is a table summarizing the SLC34A1 transport inhibitory activity of exemplary compounds of the present invention. A+ = <0.5; A = 0.5-0.99; B = 1-4.99; C = 5-9.99; D = ≥10 (μM). Figure 2 is a table summarizing the SLC34A1 transport inhibitory activity of exemplary compounds of the present invention. A+ = <0.5; A = 0.5-0.99; B = 1-4.99; C = 5-9.99; D = ≥10 (μM).

Claims (118)

A kind of compound, it has formula (I) structure:

Wherein X ₁ does not exist or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -; X ₂ is selected from -H, alkane and -SO ₂ -X ₂ ''; X ₂ '' is alkyl; each X ₃ is independently selected from -H and alkyl; R ₁ is selected from optionally substituted aminoalkyl, optionally substituted Substituted alkylaminoalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted Heteroaryl; and _R is selected from -H, halogen (such as chlorine), nitrile and alkyl; _R is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and aryl; R ₂ '' is selected from H, alkyl and acyl; the restriction is that when X ₁ is -O- or -N(X ₂ )- and R ₁ is a nitrogen-containing heterocyclic group, then the -O- Or -N(X ₂ )-Nitrogen that is not directly bonded to the heterocyclic group; the restriction is that when X ₁ does not exist, R ₂ is -Cl, R ₂ ' is -CH ₃ and R ₂ '' is -H, then _R1 is not

or a pharmaceutically acceptable salt thereof. The compound as claimed in item 1, wherein X ₁ does not exist or is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -; X ₂ is selected from -H, alkyl, and _-SO2 - _X2 ''; _X2 '' is alkyl; each _X3 is independently selected from -H and alkyl; _R1 is selected from optionally substituted amines Alkyl, optionally substituted alkylaminoalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and _R2 is selected from -H, halogen (such as chlorine) and alkyl; _R2 ' is selected from alkyl, alkenyl, alkynyl, cycloalkyl and aryl ; R ₂ '' is selected from H, alkyl and acyl; the restriction is that when X ₁ is -O- or -N(X ₂ )- and R ₁ is a nitrogen-containing heterocyclic group, then the -O -or-N(X ₂ )-nitrogen that is not directly bonded to the heterocyclic group; the restriction is that when X ₁ does not exist, R ₂ is -Cl, R ₂ ' is -CH ₃ and R ₂ '' When it is -H, then R ₁ is not

or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or 2, wherein X ₁ does not exist, or is selected from -SO ₂ -, -C(O)- and -C(X ₃ ) ₂ -. The compound as claimed in item 3, wherein X ₁ does not exist. The compound of claim 3 or 4, wherein R ₁ is an unsubstituted heterocyclic group. Such as the compound of claim 5, wherein _R is selected from unsubstituted azetidinyl, unsubstituted pyrrolidinyl, unsubstituted piperone, unsubstituted piperone, unsubstituted Substituted morpholinyl, unsubstituted dioxythiomorpholinyl, unsubstituted tetrahydrofuranyl and unsubstituted tetrahydropyranyl. As the compound of claim 6, wherein _R is selected from

. The compound as claimed in claim 3 or 4, wherein R ₁ is a substituted heterocyclic group. Such as the compound of claim 8, wherein R ₁ is -NR ₃ R ₄ ; and R ₃ and R ₄ combine to form substituted azetidinyl, substituted pyrrolidinyl, substituted piperhydrinyl, Substituted piperidonyl, substituted morpholinyl or substituted dioxythiomorpholinyl. Such as the compound of claim 9, wherein R ₁ is

; R _{a ,} R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , Re , R _f , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -OR ₅ , -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R ₆ , -SO ₂ R ₇ , -NHSO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C (O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ , Alkyl-SO ₂ NR ₅ R ₆ and -NHC (O)NR ₇ , or R _c and R _d and the carbon atom to which it is bonded together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl, or R _e Form unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl together with R _f and the carbon atom to which it is bonded, or R _c and R _e and the bonded carbon atom The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl group, or R _d and R _f together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkane group, or R _c and R _i together form a methylene bridge, or R _d and R _j together form a methylene bridge, or R _c and R _g together form a methylene bridge, or R _d and _Rh together form a methylene bridge Methyl bridge; each occurrence of _R5 and _R6 is independently selected from -H, _-CF3 , alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl , haloalkyl, aryl, and heteroaryl, or with the restriction that -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R In the case of ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ and the nitrogen atom to which it is bonded together can form an unsubstituted or substituted C ₄ -C ₆ heterocyclic ring and R ₇ at each occurrence is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that R _a , R _b , R _c , R _d , R _e , R At least one of _f , R _g , _Rh , R _i and R _j is not -H. Such as the compound of claim 8, wherein R ₁ is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl _; R _c , R _d , Re , R _f , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C (O)NR ₅ R ₆ , -SO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C (O)R ₇ , alkyl-NR ₅ C(O)NR ₅ R ₆ , alkyl-SO ₂ R ₇ and alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d and their bonded The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl, or R _e and R _f together with the carbon atom to which they are bonded form an unsubstituted or substituted Substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl, aryl And heteroaryl, or its restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ In the case of C(O)NR ₅ R ₆ , the R ₅ and R ₆ and the nitrogen atom to which they are bonded together can form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ in each The second occurrence is selected from alkyl _, heteroalkyl, haloalkyl, aryl, and heteroaryl; with the proviso that R _a , R _b , R _c , R _d , Re , R _f , R _g , _Rh , at least one of R _i and R _j is not -H. The compound of claim 10 or 11, wherein R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; and R _c , R _d , R _e , R _f , R _g and _Rh are independently selected from -H, halogen, -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkane group, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , alkane group-C(O)NR ₅ R ₆ , alkyl-NR ₅ C(O)R ₆ and alkyl-C(O)R ₇ . The compound of claim 10 or 11, wherein R _a , R _b , R _i and R _j are each -H; and R _c , R _d , R _e , R _f , R _g and R _h are independently selected from -H , halogen, -OH, -CO ₂ H, -alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O )R ₆ , C(O)R ₇ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)R ₆ . The compound of claim 13, wherein R _a , R _b , R _i and R _j are each -H; and R _c , R _d , Re , R _f , _{R g and} R _h are independently selected from -H, - F, -OH, -CH ₂ OH, CH ₂ OCH ₃ , -CH ₂ NH ₂ , -CO ₂ H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C (O)NH ₂ , -C(O)N(H)(CH ₃ ), -C(O)N(CH ₃ ) ₂ , Alkyl-C(O)N(H)(CH ₃ ), -CH ₂ -C(O)N(CH ₃ ) ₂ , -N(H)C(O)CH ₃ , -N(CH ₃ )C(O)CH ₃ , -CH ₂ -N(H)C(O) CH ₃ , -CH ₂ -N(CH ₃ )C(O)CH ₃ , -CH(CH ₂ ) ₂ and

. The compound of claim 10, wherein R _a , R _b , R _i and R _j are each -H; and R _c , R _d , Re , R _f , _{R g and} R _h are independently selected from -H, - F, -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ F, -NHSO ₂ CH ₃ , -NHSO ₂ CH ₂ CH ₃ , -NHC(O)NHCH ₃ , -NHC(O)CH ₃ , -C(O)NH ₂ , -C(O )NHCH ₃ , -C(O)NHCH ₂ CH ₃ , -C(O)NHCH(CH ₃ ) ₂ , -C(O)NHCH ₂ CH ₂ OCH ₃ , -CH ₂ NHC(O)CH ₃ , -CH ₂ NHC(O)CH ₂ CH ₃ , -CH ₂ NHC(O)CH ₂ NH ₂ , -CH ₂ NHC(O)C(CH ₃ ) ₂ CH ₃ , -CH ₂ NHC(O)C(CH ₃ ) ₂ NH ₂ , -CH ₂ NHC(O)C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ NHC(O)C(CH ₃ ) ₂ CH ₂ OCH ₃ , -CH ₂ NHC(O)C(CH ₃ ) ₂ OCH ₃ , —CH ₂ C(O)NH ₂ , —CH ₂ C(O)NHCH ₃ , and —CH ₂ C(O)N(CH ₃ ) ₂ . The compound of claim 10, wherein R _a , R _b , R _i and R _j are each -H; and R _c , R _d , Re , R _f , _{R g and} R _h are independently selected from -H, - F, -OH, -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ F, -O-cyclopropyl, -C(O)NH-cyclopropyl, -C(O)NH-oxetanyl, -C(O)NH-tetrahydrofuryl, -C(O)NH-tetrahydropyranyl, -CH ₂ NHC(O)-cyclopropyl,

. The compound according to any one of claims 10 to 16, wherein R ₁ is:

. As the compound of claim 17, wherein _R is selected from:

. As the compound of claim 18, wherein _R is selected from:

. As the compound of claim 18, wherein _R is selected from:

. As the compound of claim 17, wherein _R is selected from:

. Such as the compound of claim 21, wherein R ₁ is

,

. The compound according to any one of claims 10 to 16, wherein _R is selected from:

. As the compound of claim 23, wherein _R is selected from:

. The compound according to any one of claims 10 to 16, wherein _R is selected from:

. As the compound of claim 25, wherein _R is selected from:

. As the compound of claim 25, wherein _R is selected from:

. The compound of claim 10 or 11, wherein R _a , R _b , Re , R _f , R _g , _Rh , R _i and R _j are independently selected _from -H, halogen, -CN, -CF ₃ and alkane and R _c and R _d together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclic group. The compound as claimed in item 28, wherein R _c and R _d and the carbon atom to which they are bonded together form unsubstituted or substituted azetidinyl, pyrrolidinyl, piperhydrinyl, oxetane group, tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl. The compound of claim 29, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ , alkyl and acetyl. The compound of claim 10 or 11, wherein R _a , R _b , R _c , R _d , R _g , _Rh , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkane and R _e together with R _f and the carbon atom to which it is bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclic group. The compound as claimed in item 31, wherein R _e and R _f and the carbon atom to which they are bonded together form unsubstituted or substituted azetidinyl, pyrrolidinyl, piperhydrinyl, oxetane group, tetrahydrofuryl group, tetrahydropyranyl group and cyclobutanyl group. The compound according to claim 32, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ , alkyl and acetyl. The compound as claimed in item 28 or 31, wherein _R is selected from

. Such as the compound of claim 10, wherein R _a , R _b , R _g , Rh , R _i and R _j are each -H; one of R _e and _{R f is} -H and one of R _e and R _f The other is -OH; R _c and R _d together with the carbon atom to which they are bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclic group. The compound of claim 10, wherein R _a , R _b , R _d , R _g , Rh , R _i and _{R j are} each -H; R _f is -OH; and R _c and R _e and their bonds The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl group. The compound of claim 10, wherein R _a , R _b , R _c , R _g , Rh , _{R i and} R _j are each -H; R _e is -OH; and R _d and R _f and their bonds The carbon atoms together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl group. Such as the compound of claim 10, wherein R _a , R _b , R _d , R _g , _Rh and R _j are each -H; one of R _e and R _f is -H and one of R _e and R _f The other is -OH; and R _c and R _i together form a methylene bridge. Such as the compound of claim 10, wherein R _a , R _b , R _c , R _g , R _h and R _i are each -H; one of R _e and R _f is -H and one of R _e and R _f The other is -OH; and R _d and R _j together form a methylene bridge. Such as the compound of claim 10, wherein R _a , R _b , R _c , R _g , R _h and R _i are each -H; one of R _e and R _f is -H and one of R _e and R _f The other is -OH; and _Rj and _Rd together form a methylene bridge. Such as the compound of claim 10, wherein R _a , R _b , R _d , R _f , R _h and R _i are each -H; one of R _e and R _f is -H and one of R _e and R _f The other is -OH; and _Rc and _Rg together form a methylene bridge. Such as the compound of claim 10, wherein R _a , R _b , R _c , R _g , R _h and R _i are each -H; one of R _e and R _f is -H and one of R _e and R _f The other is -OH; and R _d and _Rh together form a methylene bridge. The compound according to any one of claims 35 to 42, wherein _R is selected from

,

. Such as the compound of claim 9, wherein R ₁ is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -CO ₂ H, -alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, Aryl, Heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R _{6 ,} -SO ₂ R _7. -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl- _{NR 5} C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C (O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ and Alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d together with the carbon atom to which it is bonded form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl group, or its restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O ) In the case of NR ₅ R ₆ , said R ₅ and R ₆ together with the nitrogen atom to which it is bonded may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ at each occurrence selected from alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl; the limitation is that at least one of R _a , R _b , R _c , R _d , R _g , _Rh , R _i and R _j One is not -H. The compound of claim 44, wherein R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and R _h are independently selected from -H, halogen, -CN, -CF ₃ , -CO ₂ H, -alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cyclo Alkyl, Heteroalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ and alkyl-C(O)R ₇ . The compound of claim 44 or 45, wherein R _a , R _b , R _i and R _j are each -H; and R _c , R _d , R _g and _Rh are independently selected from -H, halogen, -CO ₂ H, -Alkyl, Hydroxyalkyl, Aminoalkyl, Alkoxyalkyl, Cycloalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R _7. Alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)R ₆ . The compound of claim 46, wherein R _a , R _b , R _i and R _j are each -H; and R _c , R _d , R _g and R _h are independently selected from -H, -F, -CH ₂ OH , -CH ₂ OCH ₃ , -CH ₂ NH ₂ , -CO ₂ H, -CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -C(O)NH ₂ , -C (O)N(H)(CH ₃ ), -C(O)N(CH ₃ ) ₂ , Alkyl-C(O)N(H)(CH ₃ ), -CH ₂ -C(O)N( CH ₃ ) ₂ , -N(H)C(O)CH ₃ , -N(CH ₃ )C(O)CH ₃ , -CH ₂ -N(H)C(O)CH ₃ , -CH ₂ -N (CH ₃ )C(O)CH ₃ , -CH(CH ₂ ) ₂ and

. The compound as claimed in any one of items 44 to 47, wherein R ₁ is

. As the compound of claim 48, wherein _R is selected from:

. As the compound of claim 49, wherein _R is selected from:

. The compound of claim 44, wherein R _a , R _b , R _g , _Rh , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; and R _c and R _d And the carbon atom to which it is bonded together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclic group. Such as the compound of claim 51, wherein R _c and R _d and the carbon atom to which it is bonded together form unsubstituted or substituted azetidinyl, pyrrolidinyl, piperhexidine, oxetane group, tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl. The compound of claim 52, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ , alkyl and acetyl. As the compound of claim 51, wherein _R is selected from:

. Such as the compound of claim 9, wherein R ₁ is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -CO ₂ H, -alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, Aryl, Heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R ₆ , -SO ₂ R _7. -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C (O)NR ₅ R ₆ , alkyl-SO ₂ R ₇ and alkyl-SO ₂ NR ₅ R ₆ ; R _k is selected from -H, alkyl and cycloalkyl; R ₅ and R ₆ appear in each are independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl, or are limited to -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR In the case of ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ together with the nitrogen atom to which they are bonded may form Unsubstituted or substituted C ₄ -C ₆ heterocyclyl; and R ₇ at each occurrence is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl; provided that R _a , R _b , R _c , R _d , R _g , Rh _h , R _i , R _j and R _k are not -H. The compound of claim 55, wherein each of R _a , R _b , R _c , R _d , R _g , Rh , R _i and _{R j is} -H; and R _k is selected from alkyl and cycloalkyl. As the compound of claim 56, wherein _R is selected from:

. Such as the compound of claim 9, wherein R ₁ is

and _R is selected from alkyl and cycloalkyl. As the compound of claim 58, wherein R ₁ is:

. Such as the compound of claim 9, wherein R ₁ is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkane radical, heteroalkyl, aryl, heteroaryl, -OR ₅ , -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O )NR ₅ R ₆ , -SO ₂ R ₇ , -NHSO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl-NR ₅ C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ , Alkyl-SO ₂ NR ₅ R ₆ and -NHC(O)NR ₇ , Or R _c and R _d and the carbon atom to which they are bonded together form an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl, or R _c and R _g or R _d Together with _Rh and the carbon atom to which it is bonded, an unsubstituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl is formed; R ₅ and R ₆ are independently at each occurrence selected from -H, -CF ₃ , alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or restrictions thereof Between -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ In some cases, the R ₅ and R ₆ and the nitrogen atom to which they are bonded together may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ is selected from the group consisting of alkyl, hetero Alkyl, haloalkyl, aryl and heteroaryl; provided that at least one of R _a , R _b , R _c , R _d , R _g , _Rh , R _i and R _j is not -H . Such as the compound of claim 9, wherein R ₁ is

; R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c , R _d , R _g and _Rh are independently selected from -H, halogen , -CN, -CF ₃ , -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkane radical, heteroalkyl, aryl, heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R _6. -SO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl- _{NR 5} C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ and Alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d together with the carbon atom to which they are bonded form a Substituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, cycloalkyl, heteroalkyl , haloalkyl, aryl, and heteroaryl, or with the restriction that -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R In the case of ₆ and alkyl-NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ and the nitrogen atom to which it is bonded together can form an unsubstituted or substituted C ₄ -C ₆ heterocyclic ring and R ₇ at each occurrence is selected from alkyl, heteroalkyl, haloalkyl, aryl and heteroaryl; with the proviso that R _a , R _b , R _c , R _d , R _g , R At least one of _h , R _i and R _j is not -H. The compound of claim 60 or 61, wherein R _a , R _b , R _i and R _j are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; and R _c , R _d , R _g and _Rh is independently selected from -H, halogen, -CN, _-CF3 , -OH, _-CO2H , _-NH2 , alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkane radical, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , alkyl-C(O) NR ₅ R ₆ , alkyl-NR ₅ C(O)R ₆ and alkyl-C(O)R ₇ . The compound according to any one of claims 60 to 62, wherein R _c , R _d , R _g and _Rh are independently selected from -H, alkyl, hydroxyalkyl, aminoalkyl and alkoxyalkyl. The compound as claimed in item 60 or 61, wherein _R has the structure:

. As the compound of claim 64, wherein _R is selected from:

. As the compound of claim 64, wherein _R is selected from:

. As the compound of claim 65 or 66, wherein _R is selected from:

. Such as the compound of claim 60 or 61, wherein R _a , R _b , R _g , _Rh , R _i and R _j are each -H; and R _c and R _d and the carbon atom to which they are bonded together form a Substituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl. Such as the compound of claim 68, wherein R _c and R _d and the carbon atom to which it is bonded together form unsubstituted or substituted azetidinyl, pyrrolidinyl, piperhexidine, oxetane group, tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl. The compound according to claim 69, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ , alkyl and acetyl. As the compound of claim 65 or 69, wherein _R is selected from:

. The compound of claim 60, wherein R _d and R _h are each -H; and R _c and R _g and the carbon atom to which they are bonded together form a substituted C ₃ -C ₆ cycloalkyl group. The compound of claim 60, wherein R _c and R _g are each -H; and R _d and R _h and the carbon atom to which they are bonded together form a substituted C ₃ -C ₆ cycloalkyl group. The compound according to claim 72 or 73, wherein the substituted C ₃ -C ₆ cycloalkyl is substituted by halo or hydroxyl. As the compound of claim 72 or 73, wherein _R is selected from:

. Such as the compound of claim 9, wherein R ₁ is

; R _a , R _b , _Re and R _f are independently selected from -H, halogen, -CN, -CF ₃ and alkyl; R _c and R _d are independently selected from -H, halogen, -CN, -CF _3. -OH, -CO ₂ H, -NH ₂ , alkyl, haloalkyl, hydroxyalkyl, methoxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkane radical, heteroalkyl, aryl, heteroaryl, -C(O)NR ₅ R ₆ , -NR ₅ C(O)R ₆ , C(O)R ₇ , -NR ₅ C(O)NR ₅ R _6. -SO ₂ R ₇ , -SO ₂ NR ₅ R ₆ , Alkyl-C(O)NR ₅ R ₆ , Alkyl- _{NR 5} C(O)R ₆ , Alkyl-C(O)R ₇ , Alkyl-NR ₅ C(O)NR ₅ R ₆ , Alkyl-SO ₂ R ₇ and Alkyl-SO ₂ NR ₅ R ₆ , or R _c and R _d together with the carbon atom to which they are bonded form a Substituted or substituted C ₃ -C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl; R ₅ and R ₆ are independently selected from each occurrence of -H, alkyl, heteroalkyl, haloalkyl , aryl and heteroaryl, or the restriction is -C(O)NR ₅ R ₆ , -NR ₅ C(O)NR ₅ R ₆ , alkyl-C(O)NR ₅ R ₆ and alkyl In the case of -NR ₅ C(O)NR ₅ R ₆ , the R ₅ and R ₆ together with the nitrogen atom to which it is bonded may form an unsubstituted or substituted C ₄ -C ₆ heterocyclic group; and R ₇ is selected at each occurrence from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, with the proviso that one of R _a , R _b , R _c , R _d , R _e , and R _f Those who are not -H. The compound of claim 76, wherein R _a , R _b , R _e and R _f are each -H; and R _c and R _d are independently selected from -H, alkyl, hydroxyalkyl, aminoalkyl and alkane Oxyalkyl. Such as the compound of claim 76, wherein R _a , R _b , _Re and R _f are each -H; and R _c and R _d and the carbon atom to which they are bonded together form an unsubstituted or substituted C ₃ - C ₆ cycloalkyl or C ₄ -C ₆ heterocyclyl. The compound as claimed in item 78, wherein R _c and R _d and the carbon atom to which they are bonded together form unsubstituted or substituted azetidinyl, pyrrolidinyl, piperhydrinyl, oxetane group, tetrahydrofuranyl, tetrahydropyranyl or cyclobutanyl. The compound according to claim 79, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ , alkyl and acetyl. The compound as claimed in item 76, wherein _R is selected from:

. The compound as claimed in item 76, wherein _R is selected from:

. The compound as claimed in any one of claims 1 to 4, wherein _R is unsubstituted heteroaryl. The compound of claim 83, wherein _R is selected from unsubstituted oxazolyl, unsubstituted pyrazolyl and unsubstituted triazolyl. The compound as claimed in item 84, wherein _R is selected from

. The compound according to claim 1 or 2, wherein X ₁ is selected from -O-, -SO ₂ -, -C(O)-, -N(X ₂ )- and -C(X ₃ ) ₂ -. The compound as claimed in item 1 or 2, wherein _X does not exist. The compound of claim 86 or 87, wherein R ₁ is an unsubstituted cycloalkyl group. Such as the compound of claim 88, wherein R ₁ is

. The compound of claim 86 or 87, wherein R ₁ is a substituted cycloalkyl group. The compound as claimed in item 90, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ and alkyl. Such as the compound of claim 91, wherein R ₁ is

. The compound as claimed in item 91, wherein _R is selected from

. The compound according to claim 86, wherein X ₁ is -N(X ₂ )-, wherein X ₂ is -H or -CH ₃ . The compound of claim 86 or 94, wherein _R is selected from optionally substituted alkylaminoalkyl, alkoxyalkyl and cycloalkyl. The compound as claimed in item 95, wherein each substituent is independently selected from halogen, -OH, -CN, -CF ₃ and alkyl. The compound as claimed in item 95, wherein R ₁ is selected from -NH-(alkyl)-N(CH ₃ ) ₂ , -N(CH ₃ )-(alkyl)-N(CH ₃ ) ₂ , -NH- (Alkyl)-OCH ₃ and -N(CH ₃ )-(Alkyl)-OCH ₃ . Such as the compound of claim 95, wherein R ₁ is

. The compound according to any one of claims 1 to 98, wherein R ₂ is selected from -CH ₃ , -Cl and -F. The compound as claimed in any one of items 1 to 98, wherein R ₂ is selected from -Br and -CN. The compound according to any one of claims 1 to 100, wherein R ₂ ' is -CH ₃ . The compound according to any one of claims 1 to 100, wherein R ₂ ' is -CH ₂ -OH. The compound according to any one of claims 1 to 102, wherein R ₂ ″ is -H, -CH ₃ or -C(O)CH ₃ . The compound according to any one of claims 1 to 102, wherein R ₂ '' is -H. The compound as claimed in claim 1, which has any structure of the compounds listed in Table 1. The compound as claimed in claim 1, which has any structure of the compounds listed in Table 2. A pharmaceutical composition comprising the compound according to any one of claims 1 to 106; and a pharmaceutically acceptable excipient. A method for treating or preventing chronic kidney disease, the method comprising administering an effective amount of the compound according to any one of claims 1 to 106 to an individual in need. The method of claim 108, wherein the chronic kidney disease is selected from the group consisting of Alport syndrome (Alport syndrome), C3-glomerular disease, tubulointerstitial nephritis, diabetic nephropathy, idiopathic nephrosclerosis, hemolysis uremic syndrome, local segmental glomerulosclerosis, ApoL1 nephropathy, hypertensive nephrosclerosis, IgA nephropathy, membranous nephropathy and acute phosphate nephropathy. A method of treating or preventing medial calcification, the method comprising administering an effective amount of the compound according to any one of claims 1 to 106 to an individual in need. A method of treating or preventing vascular calcification, the method comprising administering an effective amount of the compound according to any one of claims 1 to 106 to an individual in need thereof. The method of claim 110 or 111, wherein the medial calcification or vascular calcification is associated with chronic kidney disease in the individual. The method of claim 110 or 111, wherein the medial calcification or vascular calcification is associated with heart disease in the individual. The method of claim 113, wherein the heart disease is associated with elevated levels of FGF-23 in the individual. The method of claim 110 or 111, wherein the medial calcification or vascular calcification is associated with: Moenckeberg's medial sclerosis, atherosclerosis, intimal calcification, postmenopausal osteoporosis, II type diabetes, aging, hypophosphaturia, hyperparathyroidism, vitamin D disorders, vitamin K deficiency, Kawasaki disease, arterial calcification due to CD73 deficiency (ACDC), systemic arterial calcification in infancy ( GACI), idiopathic basal ganglia calcification (IBGC), pseudoxanthoma elasticum (PXE), morbus fahr ferrocalcinosis, Singleton-Merten syndrome, P-thalassemia, calcium hypersensitivity, heterotopic ossification, preterm placental calcification, uterine calcification, calcified uterine fibroma, idiopathic basal ganglia calcification (FIBGC), fasciferrocalcinosis, idiopathic basal Ganglion calcification, aortic valve calcification, brain calcification, tumor calcification, or tumor lysis syndrome. A method of treating or preventing the following: acromegaly, rhabdomyolysis, hemolysis, hyperphosphatemia, familial hyperphosphatemia, hypoparathyroidism, pseudoparathyroidism, secondary hyperparathyroidism osteodystrophy, CKD-mineral and bone disorders, diabetic ketoacidosis, metabolic acidosis, respiratory acidosis, fulminant hepatitis, hepatic osteodystrophy, fever, malignant fever, sarcoidosis, arterial Hypertension, peripheral arterial disease, rheumatoid arthritis, calcium phosphate mediated inflammatory disease, alveolar microlithiasis or heart disease, the method comprises administering an effective amount of the above claims 1 to 106 to an individual in need any one of the compounds. A method of treating or preventing a disease or condition associated with elevated FGF23 levels, the method comprising administering an effective amount of the compound according to any one of claims 1 to 106 to an individual in need thereof. The method according to claim 117, wherein the disease or condition is heart disease.

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