RU2844952C1 - Plasma kallikrein inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula given below, or a pharmaceutically acceptable salt thereof. Values of the variables in the structural formula are as follows: is selected from

is selected from ; V is CH or N; X is CH or N; Y is N or NO; Z is NR⁴ or CR⁴; E is N or CH; Q is N or CH; G is N or CR⁷; J is N or CR⁷; L is N or CR⁷; M is N or CR⁸; R¹ is selected from a group consisting of halogen, cyano, R^x, OR^x and SO₂R^x; R² is halogen; R³ is halogen; R⁴ is hydrogen, R^x, OR^x, C_1-3alkyl-OR^x, C_1-3alkyl-O-C_3-6cycloalkyl or CH=CH₂; R⁵ is hydrogen or C_1-3alkyl which is optionally substituted with one to three substituents selected from halogen and hydroxy; R⁶ is hydrogen or C_1-3alkyl; or R⁵ and R⁶ can be taken together with a carbon atom in between to form a C_3-6cycloalkyl group; each R⁷ is independently selected from a group consisting of halogen, R^x, OR^x, C_1-3alkyl-OR^x, NH(C=O)OR^x and NH₂; R⁸ is selected from the group consisting of R^x or OR^x; or R⁷ and R⁸ can be taken together with carbon atoms in between to form 5-member cycloalkyl or heterocyclyl group containing 2 heteroatoms selected from O, in which said heterocyclyl group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, methyl or ethyl; R⁹ is hydrogen or C_1-3alkyl; R¹⁰ is hydrogen, hydroxy or C_1-3alkyl; R^x is hydrogen or C_1-6alkyl, which is optionally substituted with one to four substituents selected from halogen and hydroxy. Also provided is a pharmaceutical composition containing a compound of said formula, a method of treatment using said pharmaceutical composition and use of compounds.

EFFECT: disclosed compound is a selective inhibitor of plasma kallikrein and can be used to treat or prevent one or more diseased conditions, in which plasma kallikrein inhibition can help, including hereditary angioedema, uveitis, posterior uveitis, wet form of age-related macular oedema, diabetic macular oedema, diabetic retinopathy and retinal vein occlusion.

15 cl, 29 tbl, 255 ex

Description

LEVEL OF TECHNOLOGY

Plasma kallikrein is a zymogen of trypsin-like serine protease and is present in plasma. The gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein is 58% homologous to factor XI. Proteolytic activation by factor XIIa at the internal linkage I 389-R390 yields a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is located in the light chain. The light chain of plasma kallikrein interacts with protease inhibitors, including alpha-2-macroglobulin and C1 inhibitor. Interestingly, heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of high-molecular-weight kininogens (HMK). In the blood, most of the plasma kallikrein circulates in a complex with HMK. Plasma kallikrein cleaves HMK to release bradykinin. Release of bradykinin results in increased vascular permeability and vasodilation (for review, Coleman, R., “Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier A.H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128 (1998)).

Patients with genetic deficiency of C1 esterase inhibitor suffer from hereditary angioedema (HAE), a lifelong disorder that results in intermittent swelling throughout the body, including the hands, feet, face, throat, genitals, and gastrointestinal tract. Analysis of the blisters resulting from acute episodes has shown that they contain high levels of plasma kallikrein, and treatment with the protein-based reversible plasma kallikrein inhibitor, Ecallantide (Calbitor), has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L, et al., J. Allergy Clin. Immunol., 120: p.416 (2007)).

Furthermore, the plasma kallikrein-kinin system is abnormally excessive in patients with progressive diabetic macular edema (DME). Recent publications have shown that plasma kallikrein contributes to the observed retinal vascular extravasation and dysfunction in rodent diabetic models (A. Clermont, et al., Diabetes, 60:1590 (2011)) and that treatment with a small molecule inhibitor of plasma kallikrein improves the observed retinal vascular permeability and other retinal blood flow-related abnormalities.

It would be desirable in the art to develop plasma kallikrein inhibitors useful for the treatment of a wide range of disorders, including hereditary angioedema, diabetic macular edema, and diabetic retinopathy.

ESSENCE OF THE INVENTION

The present invention relates to compounds of Formula I:

and pharmaceutically acceptable salts thereof. The compounds of Formula I are inhibitors of plasma kallikrein and as such may be useful in the treatment, inhibition or amelioration of one or more disease states that may benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds of the present invention may additionally be used in combination with other therapeutically effective agents, including, but not limited to, other drugs useful in the treatment of hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. In addition, the invention relates to methods for producing compounds of Formula I and pharmaceutical compositions that contain compounds of Formula I and their pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula I:

in which selected from

or

selected from

V represents CH or N;

X represents CH or N;

Y represents N, NO, NR ^x or C=O;

Z represents NR ⁴ or CR ⁴ ;

E represents N or CH;

Q represents N or CH;

G represents N or CR ⁷ ;

J represents N or CR ⁷ ;

L represents N or CR ⁷ ;

M represents N or CR ⁸ ;

R ¹ is selected from the group consisting of hydrogen, halogen, cyano,

R ^x , OR ^x and SO ₂ R ^x ;

R ² represents hydrogen or halogen;

R ³ represents hydrogen or halogen;

R ⁴ is hydrogen, R ^x , OR ^x , C _1-3 alkyl-OR ^x , C _1-3 alkyl-OC _3-6 cycloalkyl or CH=CH ₂ ;

R ⁵ is hydrogen or C _1-3 alkyl which is optionally substituted with one to three substituents selected from

halogen and hydroxy;

R ⁶ is hydrogen or C _1-3 alkyl

or R ⁵ and R ⁶ may be taken together with the carbon atom between them to form a C _3-6 cycloalkyl group;

each R ⁷ is independently selected from the group consisting of halogen, R ^x , OR ^x , C _1-3 alkyl-OR ^x , NH(C=O)OR ^x and NH ₂ ;

R ⁸ is selected from the group consisting of R ^x or OR ^x ;

or R ⁷ and R ⁸ may be taken together with the carbon atoms therebetween to form a 5-membered cycloalkyl or heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, methyl or ethyl;

R ⁹ is hydrogen or C _1-3 alkyl;

R ¹⁰ is hydrogen, hydroxy or C _1-3 alkyl;

R ^x is hydrogen or C _1-6 alkyl which is optionally substituted with one to four substituents selected from halogen and hydroxy;

or their pharmaceutically acceptable salts.

In an embodiment of the invention represents . In another embodiment of the invention represents . In another embodiment of the invention represents . In another embodiment of the invention represents . In another embodiment of the invention represents . In another embodiment of the invention represents . In another embodiment of the invention represents In an embodiment of the invention, X is CR ² . In another embodiment of the invention, X is N.

In an embodiment of the invention represents In another embodiment of the invention represents .

In an embodiment of the invention, V is CH. In another embodiment of the invention, V is N.

In an embodiment of the invention, X is CH. In another embodiment of the invention, X is N.

In an embodiment of the invention, Y is N. In another embodiment of the invention, Y is NO. In another embodiment of the invention, Y is NR ^x . In another embodiment of the invention, Y is C=O.

In an embodiment of the invention, Z is NR ⁴ . In another embodiment of the invention, Z is CR ⁴ . In a class of invention, Z is CH.

In an embodiment of the invention, E is N. In another embodiment of the invention, E is CH.

In an embodiment of the invention, Q is N. In another embodiment of the invention, Q is CH.

In an embodiment of the invention, G is N. In another embodiment of the invention, G is CR ⁷ . In a class of invention, G is CH.

In an embodiment of the invention, J is N. In another embodiment of the invention, J is CR ⁷ . In a class of invention, J is CH.

In an embodiment of the invention, L is N. In another embodiment of the invention, L is CR ⁷ . In a class of invention, L is CH.

In an embodiment of the invention, M is N. In another embodiment of the invention, M is CR ⁸ . In a class of invention, M is CH.

In an embodiment, R ¹ is hydrogen, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ , or SO ₂ CH ₃ . In a class of embodiment, R ¹ is hydrogen. In another class of embodiment, R ¹ is CH ₃ . In another class of embodiment, R ¹ is CHF ₂ . In another class of embodiment, R ¹ is CF ₃ . In a class of embodiment, R ¹ is OCHF ₂ . In a class of embodiment, R ¹ is SO ₂ CH ₃ .

In an embodiment of the invention, R ² is hydrogen. In another embodiment of the invention, R ² is halogen. In a class of inventions, R ² is fluorine.

In an embodiment of the invention, R ³ is hydrogen. In another embodiment of the invention, R ³ is halogen. In a class of inventions, R ³ is chlorine.

In an embodiment of the invention, R ⁴ is cyano, CH ₃ , CHF ₂ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ OC(CH ₃ ) ₃ , CH ₂ O(cyclopropyl), CH(OH)CF ₃ , CH ₂ C(CH ₃ ) ₂ OH, CD ₂ OH, CH(CH ₃ )OH or OCH ₃ .

In an embodiment of the invention, R ⁵ is hydrogen, CH ₃ or CH ₂ OH. In a class of invention, R ⁵ is hydrogen. In another class of invention, R ⁵ is CH ₃ . In another class of invention, R ⁵ is CH ₂ OH.

In an embodiment of the invention, R ⁶ is hydrogen.

In an embodiment of the invention, R ⁷ is hydrogen, chlorine, fluorine, CH ₃ , OCH ₃ , CHF ₂ , OCHF ₂ , CH ₂ OH, NH ₂ and NH(C=O)OR ^x .

In an embodiment of the invention, R ⁷ and R ⁸ may be taken together with the carbon atoms between them to form a 5-membered cycloalkyl or heterocyclyl group, wherein said heterocyclyl group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, methyl or ethyl. In a class of the invention, R ⁷ and R ⁸ may be taken together with the carbon atoms between them to form a heterocyclyl group substituted with two fluorine atoms.

Reference to preferred classes and subclasses set forth above is intended to include all combinations of specific and preferred groups unless otherwise indicated.

Specific embodiments of the present invention include, but are not limited to, the compounds described herein as Examples 1 through 255, or pharmaceutically acceptable salts thereof.

Also included within the scope of the present invention is a pharmaceutical composition that comprises a compound of Formula I as described above and a pharmaceutically acceptable carrier. It is also intended that the invention encompass a pharmaceutical composition that comprises a pharmaceutically acceptable carrier and any of the compounds specifically disclosed herein. These and other aspects of the invention will be apparent from the teachings contained herein.

The invention includes compositions for treating diseases or conditions in which plasma kallikrein activity is manifested. Accordingly, the invention includes compositions for treating impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, intracerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during surgery under conditions of artificial circulation and bleeding after postoperative surgical intervention in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. The class of the invention includes compositions for the treatment of hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, anti-attreating agents and thrombolytic agents. The compositions may be added to blood, blood products or mammalian organs to effect the desired inhibition.

The invention also includes compositions for preventing or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in mammals, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, anti-attreating agents and thrombolytic agents.

The invention also includes compositions for treating inflammatory conditions of the eye, which include, but are not limited to, uveitis, posterior uveitis, macular edema, acute macular degeneration, wet age-related macular edema, retinal detachment, retinal vein occlusion, eye tumors, fungal infections, viral infections, multifocal choroiditis, diabetic uveitis, diabetic macular edema, diabetic retinopathy, proliferative vitreoretinopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, histoplasmosis and uveal diffusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiatretant agents and thrombolytic agents.

The invention also includes compositions for treating a disease of the posterior eye, which includes, but is not limited to, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, anti-atretant agents and thrombolytic agents.

It should be understood that the invention is directed to the compounds of structural Formula I described in the present application, as well as to pharmaceutically acceptable salts of the compounds of structural Formula I, as well as to salts that are not pharmaceutically acceptable when they are used as precursors of the free compounds or their pharmaceutically acceptable salts or in other synthetic transformations.

The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of the present invention, which are typically prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the base compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethyl acetate, digluconate, dihydrochloride, dodecylsulfonate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-Hydroxyethanesulfonate, Hydroxynaphthoate, Iodide, Isonicotinate, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methyl Bromide, Methyl Nitrate, Methyl Sulfate, Methanesulfonate, Mucate, 2-Naphthalenesulfonate, Napsylate, Nicotinate, Nitrate, N-Methylglucamine Ammonium Salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Pectinate, Persulfate, Phosphate/Diphosphate, Pimelinate, Phenylpropionate, Polygalacturonate, Propionate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Theoclate, Thiocyanate, Tosylate, Triethiodide, Trifluoroacetate, undeconate, valerate and the like. Furthermore, if the compounds of the invention bear an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium, zinc and the like. Also included are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Also included are basic nitrogen-containing groups which may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and others.

These salts can be prepared by known methods, for example, by mixing the compound of the present invention with an equivalent amount and a solution containing the desired acid, base or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and their salts can form solvates with a solvent such as water, ethanol or glycerol. The compounds of the present invention can simultaneously form an acid addition salt and a salt with a base according to the type of the side chain substituent.

If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the mentioned salt forms, internal salts or betaines (zwitterions).

The present invention embraces all stereoisomeric forms of the compounds of Formula I. Unless a specific stereochemistry is indicated, the present invention is intended to embrace all such isomeric forms of these compounds. All centers of asymmetry that are present in the compounds of Formula I may, independently of one another, have the (R)-configuration or the (S)-configuration. When bonds to a chiral carbon are depicted as straight lines in the structural Claims of the invention, it is intended that both the (R)- and (S)-configurations of the chiral carbon, and thus both of each individual enantiomer and mixtures thereof, are encompassed by the Claim. When a particular configuration is depicted, that entantiomer (either the (R) or (S) at that center) is intended. Similarly, when the name of a compound is given without the chiral designation of the chiral carbon, it is intended that both the (R)- and (S)-configurations of the chiral carbon, and thus the individual enantiomers and mixtures thereof, are encompassed by the name. The preparation of specific stereoisomers or mixtures thereof can be determined in the Examples where such stereoisomers or mixtures were prepared, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of the present invention.

Unless a specific enantiomer or diastereomer is indicated, the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers in all ratios. The invention thus provides enantiomers in enantiomerically pure form, both levorotatory and dextrorotatory antipodes, as racemates and as mixtures of two enantiomers in all ratios. In the case of cis/trans isomerism, the invention includes both the cis form and the trans form, as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can, if desired, be achieved by separating the mixture by standard methods, for example by chromatography or crystallization, using stereochemically homogeneous starting materials for the synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out before separating the stereoisomers. The separation of a mixture of stereoisomers may be carried out at an intermediate stage in the synthesis of a compound of Formula I, or it may be carried out on the final racemic product. The absolute stereochemistry may be determined by X-ray crystallography of the crystalline products or crystalline intermediates, which are derivatized if necessary with a reagent containing a stereogenic center of known configuration. If the compounds of the invention are capable of tautomerization, all individual tautomers as well as mixtures thereof are included within the scope of the invention. The present invention includes all such isomers as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

In the compounds of the invention, the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variations of the compounds specifically and generally described. For example, the various isotopic forms of hydrogen (H) include protium ( _1H ) and deuterium ( _2H ). Protium is the predominant isotope of hydrogen found in nature. Deuterium enrichment may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide a compound useful as a standard for characterizing biological samples. Isotopically enriched compounds can be prepared without undue experimentation by standard methods well known to those skilled in the art or by processes analogous to those described in the general process schemes and examples in this application, using appropriate isotopically enriched reagents and/or intermediates.

When any variable (e.g., R ^x , etc.) occurs more than once in any component, its definition in each instance is independent in all other instances. Furthermore, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn in ring systems from substituents indicate that the bond indicated may be attached to any of the substitutable atoms of the ring. If the ring system is bicyclic, the bond is expected to be attached to any of the appropriate atoms on either ring of the bicyclic fragment.

It is obvious that one or more silicon atoms (Si) can be introduced into the compounds of the present invention in place of one or more carbon atoms by a person skilled in the art to obtain compounds that are chemically stable and that can be easily synthesized by methods known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius, which leads to differences in bond length and steric arrangement when comparing similar bonds of a C-element and a Si-element. These differences lead to minor changes in the size and shape of silicon-containing compounds compared to carbon. A person skilled in the art will understand that differences in size and shape can lead to minor or significant changes in activity, solubility, lack of off-target activity, assembly properties, etc. (Diass, J.O. et al. Organometallics (2006) 5:1188-1198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

It will be appreciated that the substituents and substitution patterns in the compounds of the present invention can be selected by one skilled in the art to provide compounds that are chemically stable and that can be readily synthesized by methods known in the art, as well as by the methods set forth below, from readily available starting materials. Where a substituent is itself substituted by more than one group, it is understood that these multiple groups may be on the same carbon atom or on different carbon atoms, so long as a stable structure results. The phrase "optionally substituted" (by one or more substituents) should be understood to mean that the group in question is either unsubstituted or may be substituted by one or more substituents.

In addition, the compounds of the present invention may exist in amorphous form and/or in one or more crystalline forms, and it is intended that substantially all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are included within the scope of the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., a hydrate) or with standard organic solvents. Such solvates and hydrates, in particular pharmaceutically acceptable solvates and hydrates of the present compounds are likewise included within the scope of the present invention along with the unsolvated and anhydrous forms.

Furthermore, in the case of a carboxylic acid (-COOH) or an alcohol group present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl-, ethyl- or pivaloyloxymethyl-, or acyl derivatives of alcohols such as O-acetyl, O-pivaloyl, O-benzoyl and O-aminoacyl can be used. Included are such esters and acyl groups known in the art as modifying solubility or hydrolysis characteristics for use as sustained release formulations or prodrugs.

Any pharmaceutically acceptable modification of a prodrug of a compound of the present invention that results in in vivo conversion to a compound within the scope of the present invention is also within the scope of the present invention. For example, esters can optionally be prepared by esterification of an accessible carboxylic acid group or by ester formation on an accessible hydroxy group in the compound. Labile amides can be prepared in a similar manner. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs that can be hydrolyzed back to the acid (or -COO- depending on the pH of the fluid or tissue where the conversion occurs) or hydroxy form, particularly in vivo, and as such are within the scope of the present invention. Examples of pharmaceutically acceptable modifications of prodrugs include, but are not limited to, -C _1-6 alkyl esters and -C _1-6 alkyls substituted with phenyl esters.

Accordingly, compounds within the general structural formulas, embodiments, and specific compounds described and claimed herein include salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof, and any combination of these forms, as well as salts thereof, prodrug forms thereof, and salts of prodrug forms thereof, where such forms are possible, unless otherwise indicated.

Except where noted in this specification, the terms "alkyl" and "alkylene" are intended to include saturated aliphatic hydrocarbon groups, both branched and straight chain, having the specified number of carbon atoms. Common abbreviations for alkyl groups are used throughout the specification, for example, methyl may be represented by standard abbreviations including "Me" or _CH3 , or by a symbol that represents an extended bond as a terminal group, for example, , ethyl may be represented by "Et" or CH ₂ CH ₃ , propyl may be represented by "Pr" or CH ₂ CH ₂ CH ₃ , butyl may be represented by "Bu" or CH ₂ CH ₂ CH ₂ CH ₃ , etc. "C _1-4 alkyl" (or "C ₁ -C ₄ alkyl"), for example, means straight- or branched-chain alkyl groups, including all isomers having the specified number of carbon atoms. For example, the structures

have equivalent meanings. C _1-4 alkyl includes n-, iso-, sec-, and tert-butyl, n- and isopropyl, ethyl, and methyl. Unless the number is specified, 1-4 carbon atoms are intended for linear or branched alkyl groups.

Except where noted, the term "cycloalkyl" means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Except where noted, the term "aryl" as used herein represents a stable monocyclic or bicyclic ring system containing up to 10 carbon atoms in each ring in which at least one ring is aromatic. Bicyclic aryl ring systems include fused ring systems in which two rings share two atoms and spiro ring systems in which two rings share one atom. Aryl groups within the scope of this definition include, but are not limited to, phenyl, indene, isoindene, naphthalene, and tetralin.

Except where noted, the term "heteroaryl" as used herein represents a stable monocyclic or bicyclic ring system containing up to 10 atoms in each ring, in which at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Heteroaryl groups within the scope of this definition include, but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazoloxazinyl, dihydropyrazoliothiazine dioxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetrahydroquinoline and 3-oxo-3,4-dihydro-2N-benzo[b][1,4]thiazine. If the heteroaryl contains nitrogen atoms, it is obvious that its corresponding N-oxides are also covered by this definition.

As used herein, the term "heterocycle" or "heterocyclyl" is intended to mean a stable non-aromatic monocyclic or bicyclic ring system containing up to 10 atoms in each ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO or _SO2 . Bicyclic heterocyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Therefore, "heterocyclyl" includes, but is not limited to, the following: azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofurnayl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains nitrogen, it is obvious that its corresponding N-oxides are also covered by this definition.

Except where noted, the term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

Diatomaceous earth "Celite®" (Fluka) is a diatomaceous earth and may be referred to as "celite".

Except as noted herein, structures containing substituent variables, such as the variable "R" below:

which are depicted as not attached to any one particular carbon atom of the bicyclic ring represent structures in which the variable may optionally be attached to any carbon atom of the bicyclic ring. For example, the variable R shown in the structure above may be attached to any one of the 6 carbon atoms of the bicyclic ring i, ii, iii, iv, v or vi.

Except as noted herein, bicyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom.

The invention also relates to medicinal products containing at least one compound of Formula I and/or a pharmaceutically acceptable salt of a compound of Formula I and/or optionally a stereoisomeric form of a compound of Formula I or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of Formula I together with a pharmaceutically suitable and pharmaceutically acceptable filler, additive and/or other active substances and excipients.

As used herein, the term "patient" means mammals such as primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice.

The medicinal products according to the invention can be administered orally, by inhalation, rectally or transdermally or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred. It is possible to coat stents with compounds of Formula I and other surfaces that come into contact with blood in the body.

The invention also relates to a method for producing a medicinal product, which comprises bringing at least one compound of Formula I into a suitable form for administration using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally additional suitable active substances, additives or excipients.

Suitable solid or galenic preparations are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injection solutions and preparations with prolonged release of the active substance, in which, during preparation, standard excipients are used, such as fillers, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers. Frequently used excipients that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

The dosage regimen using plasma kallikrein inhibitors is selected according to a variety of factors, including the type, species, age, weight, sex, and health status of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the specific compound or salt thereof being used. Usually, a qualified physician or veterinarian can readily determine and prescribe the effective amount of the drug needed to prevent, counter, or arrest the progression of the condition.

Oral dosages of plasma kallikrein inhibitors when used to achieve the stated effects will range from about 0.01 mg per kg body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless otherwise stated, the amounts of active ingredients are expressed as the free base). For example, an 80 kg patient would receive from about 0.8 mg/day to 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day. A suitably formulated medicament for once daily administration should thus contain from 0.8 mg to 2.4 g, preferably from 2 mg to 600 mg, more preferably from 8 mg to 200 mg and most preferably from 8 mg to 40 mg, for example 8 mg, 10 mg, 20 mg and 40 mg. Preferably, the plasma kallikrein inhibitors can be administered in divided doses two, three or four times a day. For twice daily administration, a suitably formulated medicament will contain from 0.4 mg to 4 g, preferably from 1 mg to 300 mg, more preferably from 4 mg to 100 mg and most preferably from 4 mg to 20 mg, for example 4 mg, 5 mg, 10 mg and 20 mg.

Intravenously, the patient will receive the active ingredient in amounts sufficient to deliver 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day. Such amounts can be administered by a variety of suitable routes, such as large volumes of low concentrations of the active ingredient over a single, long period of time or several times a day, small volumes of high concentrations of the active ingredient over a short period of time, such as once a day. Typically, a unit formulation for intravenous administration can be prepared containing a concentration of the active ingredient from about 0.01 to 1.0 mg/mL, such as 0.1 mg/mL, 0.3 mg/mL and 0.6 mg/mL, and administered in amounts per day from 0.01 mL/kg of patient weight to 10.0 mL/kg of patient weight, such as 0.1 mL/kg, 0.2 mL/kg, 0.5 mL/kg. In one example, an 80 kg patient receiving 8 mL of an intravenous formulation with an active ingredient concentration of 0.5 mg/mL twice daily receives 8 mg of the active ingredient per day. Buffers can be glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with an acceptable buffering capacity in a pH range suitable for intravenous administration. The selection of a suitable buffer and pH of the formulation depending on the solubility of the drug to be administered can be easily made by a person skilled in the art.

The compounds of Formula I can be administered either as monotherapy or in combination with other therapeutic agents, including, but not limited to, anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, anti-attreatants, and thrombolytic agents.

An "anti-inflammatory agent" is any agent that is directly or indirectly effective in reducing inflammation when administered at a therapeutically effective level. "Anti-inflammatory agent" includes, but is not limited to, steroidal anti-inflammatory agents and glucocorticoids. Suitable anti-inflammatory agents include, but are not limited to, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

"Anti-VEGF agent" is any agent that is directly or indirectly effective in inhibiting the activity of VEGF (vascular endothelial growth factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, and aflibercept.

An "immunosuppressant" is any drug that is directly or indirectly effective in suppressing or reducing the strength of the body's immune system. Suitable immunosuppressants include, but are not limited to, corticosteroids (eg, prednisone, budesonide, prednisolone), Janus kinase inhibitors (eg, tofacitinib), calcineurin inhibitors (eg, cyclosporine, tacrolimus), mTIL inhibitors (eg, sirolimus, everolimus), IMDH inhibitors (eg, azathioprine, leflunomide, mycophenolate), biologics (eg, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), and monoclonal antibodies (eg, basiliximab, daclizumab).

Suitable anticoagulants include, but are not limited to, factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphate antiattreating agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g., for the treatment or prevention of unstable angina or for the prevention of reocclusion after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase to achieve a synergistic effect in the treatment of various vascular pathologies. Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban, and semuloparin. For example, patients with coronary artery disease and patients undergoing angioplasty procedures will benefit from co-administration of fibrinogen receptor antagonists and thrombin inhibitors.

In certain embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiattreating agents, and thrombolytic agents described herein are used in their standard dosage ranges and regimens as reported in the art, including, for example, dosages described in Physicians' Desk Reference publications such as the 70th edition (2016) and earlier editions. In other embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiattreating agents, and thrombolytic agents described herein are used in lower than their standard dosage ranges.

Alternatively or additionally, one or more additional pharmacologically active agents may be administered in combination with the compound of the invention. Additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including prodrugs that are converted to a pharmaceutically active form upon administration that is different from the compound of the invention, and also includes the free acid, free base, and pharmaceutically acceptable salts of said additional active agents when such forms are commercially available or otherwise chemically possible. In general, any suitable additional active agent or agents, including but not limited to antihypertensive agents, additional diuretics, antiatherosclerotic agents such as a lipid-modifying compound, antidiabetic agents and/or antiobesity agents, may be used in any combination with a compound of the invention in a single dosage form (fixed dose combination) or may be administered to a patient in one or more single dosage formulations that provide for simultaneous or sequential administration of the active agents (co-administration of individual active agents). Examples of additional active agents that may be used include, but are not limited to, angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists, also known as angiotensin receptor blockers or ARBs, which may be in the form of a free base, free acid, salt, or prodrug, such as azilsartan, eg, azilsartan medoxomil potassium (EDARBI®), candesartan, eg, candesartan cilexetil (ATACAND®), eprosartan, eg, eprosartan mesylate (TEVETAN®), irbesartan (AVAPRO®), losartan, eg, losartan potassium (COZAAR®), olmesartan, eg, olmesartan medoximil (BENICAR®), telmisartan (MICARDIS®), valsartan (DIOVAN®), and any of these drugs used in combination with a thiazide-like diuretic such as hydrochlorothiazide (eg, HYZAAR®, DIOVAN NST®, ATACAND NST®), etc.); potassium-sparing diuretics such as amiloride HCl, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (for example, thiorphan and phosphoramidone); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalcreine; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]octanamide hemifumarate) SPP600, SPP630, and SPP635); endothelin receptor antagonists; vasodilators (eg, nitroprusside); calcium channel blockers (eg, amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine); potassium channel activators (eg, nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam); sympatholytics; Beta-blockers (eg, acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha-blockers (eg, doxazosin, prazosin, or alpha-methyldopa); central alpha-adrenergic agonists; peripheral vasodilators (eg, hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors such as simvastatin and lovastatin, which are sold as ZOCOR® and MEVACOR® in lactone prodrug form and act as inhibitors after administration, and pharmaceutically acceptable ring-opened dihydroxy acid salts of HMG-CoA reductase inhibitors such as atorvastatin (in particular the calcium salt contained in LIPITOR®), rosuvastatin (in particular the calcium salt contained in CRESTOR®), pravastatin (in particular the sodium salt contained in PRAVACHOL®) and fluvastatin (in particular the sodium salt contained in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®) and ezetimibe in combination with any other lipid-lowering agents such as the HMG-CoA reductase inhibitors mentioned above, and in particular with simvastatin (VITORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled-release forms, and in particular niacin in combination with a DP antagonist such as laropiprant and/or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; Metabolism-altering agents, including insulin sensitizers and related compounds for the treatment of diabetes such as biguanides (eg, metformin), meglitinides (eg, repaglinide, nateglinide), sulfonylureas (eg, chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones, also called glitazones (eg, pioglitazone, rosiglitazone), alpha-glucosidase inhibitors (eg, acarbose, miglitol), dipeptidyl peptidase inhibitors (eg, sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (eg, bromocriptine), combination drugs such as JANUMET® (sitagliptin with metformin), and injectable medicines for diabetes such as exenatide and pramlintide acetate; glucose uptake inhibitors such as sodium glucose transporter (SGLT) inhibitors and its various isoforms such as SGLT-1, SGLT-2 (eg, ASP-1941, TS-071, BI-10773, tofogliflozin, LX-4211, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, remogliflozin and sotagliflozin) and SGLT-3; or with other medicines useful in the prevention or treatment of the above-mentioned diseases, including, but not limited to, diazoxide; and including free acid, free base and pharmaceutically acceptable salt forms, prodrug forms, for example esters and salts of prodrugs of the above drugs, where chemically possible. The trade names of pharmaceutical preparations mentioned above are provided as an example of the marketed form of the active agent(s); such pharmaceutical preparations may be used as a separate dosage form for simultaneous or sequential administration with a compound of the invention, or the active agent(s) therein may be used in a fixed dose combination of drugs comprising a compound of the invention.

Typical doses of the plasma kallikrein inhibitors of the invention in combination with other suitable agents may be the same as doses of plasma kallikrein inhibitors administered without the concomitant administration of additional agents, or may be substantially less than doses of plasma kallikrein inhibitors administered without the concomitant administration of additional agents, depending on the therapeutic needs of the patient.

The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of a compound of the present invention that, when administered to a mammal alone or in combination with an additional therapeutic agent, is effective in treating (i.e., preventing, inhibiting, or alleviating) a disease state or treating the progression of a disease in an organism.

The compounds of the invention are preferably administered to a mammal alone in a therapeutically effective amount. However, the compounds of the invention may also be administered to a mammal in a therapeutically effective amount in combination with an additional therapeutic agent as defined below. When administered in combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergism, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect (in this case inhibition of the desired target) of the compounds when administered in combination exceeds the additive effect of each of the compounds when administered separately as a single agent. In general, the synergistic effect is most pronounced at suboptimal concentrations of the compounds. Synergism may result in lower cytotoxicity, increased anticoagulant effect, or some other advantageous effect of the combination compared to the individual components.

By "administered in combination" or "combination therapy" is meant that the compound of the present invention and one or more additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component may be administered simultaneously or sequentially in any order at different times. Thus, each component may be administered separately, but close enough in time to provide the desired therapeutic effect. Administration of each component need not be by the same route of administration; for example, one component may be administered orally and the other may be delivered to the vitreous humor of the eye.

The present invention is not limited in scope to the specific embodiments disclosed in the examples, which are intended to illustrate certain aspects of the invention, and any embodiments that are functionally equivalent are included in the scope of the present invention. Indeed, various modifications of the invention in addition to those shown and described in the present application will become apparent to those skilled in the art and fall within the scope of the appended claims.

GENERAL METHODS

The compounds of the present invention can be prepared using standard methods or according to the methodology outlined in the following general synthetic schemes. One skilled in the art can vary the procedures and reagents shown to obtain similar intermediates and/or final compounds.

NMR spectra were measured on VARIAN or Bruker NMR systems (400, 500, or 600 MHz). Chemical shifts are reported in ppm downfield and upfield from tetramethylsilane (TMS) and are referenced to either the internal TMS resonance or the solvent resonance ( ¹ H NMR: δ 7.27 for CDCl ₃ , δ 2.50 for (CD ₃ )(CD) ₂ )SO and ¹³ C NMR: δ 77.02 for CDCl ₃ , δ 39.51 for (CD ₃ ) ₂ SO. Coupling constants (J) are expressed in hertz (Hz), and spin multiplicities are given as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), and br (broad). Chiral separations were performed on either a Waters Thar 80 or Berger MG II preparative SFC system. LC-MS data were recorded on a SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010 or Agilent 1100 series LC-MS, Agilent Prime-1260 or Waters Acguity LC-MS using C18 columns using a MeCN gradient in water containing 0.02 to 0.1% TFA. UV detection was performed at 220 and/or 254 nm and ESI ionization was used for MS detection.

When chiral resolution is achieved by chromatography using chiral columns, the chiral columns used for the chiral separation of SFCs are listed in the tables. Some of the chiral columns used were CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK AD-H, and CHIRALPAK AS-H. They will be referred to by their two- or three-letter abbreviations hereafter. As a rule, the fast eluting isomer from a chiral resolution is always listed first in this table, followed immediately by the slow eluting isomer from the same resolution. If more than two isomers were separated, they will always be listed in the tables in the order in which they eluted, e.g., Peak 1 followed by Peak 2, Peak 3, etc. The symbol next to a chiral center in a structure indicates that this chiral center has been resolved by chiral resolution without unambiguous determination of its stereochemical configuration.

Furthermore, TLC represents thin layer chromatography; UV represents ultraviolet; W represents watts; wt. % represents percent by mass; xg represents times gravity; α _D represents the specific rotation of polarized light at 589 nm; °C represents degrees Celsius; % w/v represents the percentage by mass of the first agent relative to the volume of the second agent; Hz represents hertz; cpm represents the number of counts per minute; δ _n represents the chemical shift; d represents a doublet; dd represents a doublet of doublets; MHz represents megahertz; MS represents a mass spectrum, and a mass spectrum obtained by ES-MS may be referred to herein as "LC-MS"; m/z represents the mass-to-charge ratio; n represents normal; n represents norme; nm represents nanometer; nM represents nanomolar.

Some catalysts and ligands are used in the following methods. "XANTPHOS" is also known as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. "XANTPHOS Pd G3" is also known as [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. "SPhos Pd G4" is also known as "(methanesulfonate-CO)[2'-(methylamino)-2-biphenylyl]palladium dicyclohexyl(2',6'-dimethoxy-2-biphenylyl)phosphine (1:1)". "BrettPhos" is also known as 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and "BrettPhos Pd G3" is also known as [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. "[Ir{dFCF ₃ ppy} ₂ (bpy)]PF ₆ " is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridyl]iridium hexafluorophosphate. These catalysts and ligands are available from Millipore Sigma.

For the purposes of this description, the following abbreviations have the meanings indicated:

General synthesis schemes

The starting materials used were obtained from commercial sources, prepared in the examples, or prepared as known in the literature unless otherwise stated.

The methods used to prepare the compounds of the present invention are illustrated in the following schemes.

AA circuit.

Scheme AA illustrates a synthetic sequence for the preparation of bipeteroaryl derivatives such as AA-6 from the arene AA-1 and alkylpyrazine-2-carboxylates such as AA-4. Deoxofluorination of the aldehyde AA-1 provides AA-2. Borylation of AA-2 by treatment with a trialkoxyborane such as AA-7 and a base such as LDA provides the boronate ester AA-3. Palladium-catalyzed cross-coupling of AA-3 with the halide AA-4 provides AA-5. Base-mediated hydrolysis or dealkylation of the ester AA-5 by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AA-6.

AB diagram.

Scheme AB illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AB-6 from alkylpyrazine-2-carboxylates such as AB-1 and the arene AB-3. Palladium-catalyzed displacement of the halide of AB-1 using a reagent such as hexamethylditin provides the stannane AB-2. Iodination of AB-3 by treatment with a base such as LDA, lithium 2,2,6,6-tetramethylpiperidide, or n-butyllithium and iodine provides AB-4. Palladium-catalyzed cross-coupling of AB-2 with the iodide AB-4 then provides AB-5. Base-mediated hydrolysis or dealkylation of the ester of AB-5 by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AB-6.

AS diagram.

Scheme AC illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AC-6 from pyrazine AC-1 and arene AC-2. Palladium-catalyzed cross-coupling of bromide AC-1 with boronate AC-2 provides AC-3. Palladium-catalyzed cross-coupling of AC-3 with AC-4, which may be an organometallic, organoborate, or organoborate reagent, provides AC-5. Base-mediated hydrolysis or dealkylation of ester AC-5 by treatment with reagents such as LiOH, NaOH, or LiI provides carboxylic acid AC-6.

AD scheme.

Scheme AD illustrates a synthetic sequence for the preparation of bipeteroaryl derivatives such as AD-10 from the arene AD-1 and the pyrazine AB-7. Bromination of AD-1 by treatment with a base such as LDA and a brominating agent such as 1,2-dibromo-1,1,2,2-tetrachloroethane AD-2 provides AD-3. Copper-catalyzed cross-coupling of AD-2 with potassium thioacetate provides thioether AD-4. Treatment with an aqueous base such as NaOH and an alkylating agent such as methyl iodide converts thioether AD-4 to thioether AD-5, which is subsequently oxidized to the sulfoxide AD-6 using an oxidizing agent such as m-CPBA. Palladium-catalyzed cross-coupling of bromide AD-6 with stannane AD-7 provides AD-8. Oxidation of the sulfoxide AD-8 using an oxidizing agent such as oxone® provides the sulfone AD-9. Base-mediated hydrolysis or dealkylation of the ester AD-9 by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AD-10.

AE diagram.

Scheme AE illustrates the synthetic sequence for the preparation of bipeteroaryl derivatives such as AE-5 from AE-1. Esterification of the carboxylic acid of AE-1 provides the tert-butyl ester AE-2. Oxidative cleavage of the methylidene group of AE-2 by treatment with reagents such as osmium tetroxide and sodium periodate provides the aldehyde AE-3. Deoxofluorination of AE-3 using a reagent such as bis(2-methoxyethyl)aminosulfur trifluoride provides AE-4. Acid-mediated dealkylation of the ester of AE-4 provides the carboxylic acid AE-5.

AF scheme.

Scheme AF illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AF-4 from AF-1 and the alkyl trifluoroborate salt AF-2. Cross-coupling of AF-1 and AF-2 by treatment with a Ni salt/ligand mixture such as nickel(II) dichloride ethylene glycol dimethyl ether complex and 4,4'-di-tert-butyl-2,2'-bipyridine, and an Ir complex such as [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate provides the pyrazine AF-3. Base-mediated hydrolysis of ester AF-3 by treatment with reagents such as LiOH or NaOH provides the carboxylic acid AF-4.

AG scheme.

Scheme AG illustrates the synthetic sequence for the preparation of biheteroaryl derivatives such as AG-5 from the pyridine AG-1 and the arene AG-2. Palladium-catalyzed cross-coupling of the bromide AG-1 with the boronate AG-2 provides AG-3. Oxidation of AG-3 with an oxidizing agent such as mCPBA provides the N-oxide AG-4. Base-mediated hydrolysis of the ester AG-4 by treatment with reagents such as LiOH provides the carboxylic acid AG-5.

AN scheme.

Scheme AH illustrates the synthetic sequence for the preparation of biheteroaryl derivatives such as AH-9 from pyridine AH-1 and arene AH-3. Substitution of chloropyrimidine AH-1 with (4-methoxyphenyl)methyl alcohol provides AH-2.

Palladium-catalyzed cross-coupling of AH-2 and the boronate AH-3 provides AH-4. Oxidation of the thioether AH-4 by treatment with an oxidizing agent such as Oxone® provides the sulfone AH-5. Displacement of AH-5 with a cyanide source such as sodium cyanide provides AH-6, which is converted to AH-7 by treatment with methanol under acidic conditions. Alkylation of the pyrimidine AH-7 with an alkyl electrophile provides AH-8. Base-mediated hydrolysis of the ester AH-B by treatment with reagents such as LiOH or NaOH provides the carboxylic acid AH-9.

AI scheme.

Scheme AI illustrates the synthetic sequence for the preparation of biheteroaryl derivatives such as AI-3. Amide cross-coupling of AI-1 with 1H-pyrazol-4-amine AI-2 provides amide AI-3.

AJ diagram.

Scheme AJ illustrates the synthetic sequence for the preparation of biheteroaryl derivatives such as AJ-7 from pyrazine AJ-1 and arene AJ-2. Palladium-catalyzed cross-coupling of bromide AJ-1 with boronate AJ-2 provides AJ-3. Treatment of AJ-3 with copper(II) bromide provides AJ-4. Base-mediated hydrolysis of ester AJ-4 by treatment with reagents such as LiOH provides carboxylic acid AJ-5. Nickel-catalyzed reductive cross-coupling of RJ-5 with oxirane RJ-6 provides lactone AJ-7.

AK diagram.

Scheme AK illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AK-4 from intermediate AK-1. Bromination of AK-1 by treatment with reagents such as a mixture of NBS and benzoyl peroxide provides AK-2. Treatment of AK-2 with the alcohol AK-3 and a base such as sodium hydride provides the ester AK-4.

AL scheme.

Scheme AL illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AL-5 from intermediate AL-1. Palladium-catalyzed carboxylation of AL-1 provides the methyl ester AL-2. Treatment of AL-2 with an organometallic reagent AL-3, such as an alkyl magnesium salt, or a reducing agent such as lithium aluminum hydride or lithium aluminum deuteride, provides the alcohol AL-4. Cyclization of AL-4 by treatment with a coupling agent such as EDC provides the lactone AL-5.

AM scheme.

Scheme AM illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AM-3 from intermediate AM-1. Trifluoromethylation of the aldehyde AM-1 by treatment with reagents such as (trifluoromethyl)trimethylsilane in the presence of trimethyl N-oxide provides AM-2. Acid-mediated dealkylation of the ester AM-2 provides the carboxylic acid AM-3.

AN diagram.

Scheme AN illustrates a synthetic sequence for the preparation of biheteroaryl derivatives such as AN-7 from acetylsuccinate AN-1 and arene AN-5. Condensation of AN-1 with hydrazine provides 6-oxotetrahydropyridazine AN-2, which is further oxidized by treatment with a reagent such as bromine to give dihydropyridazine AN-3. Treatment of AN-3 with a reagent such as phosphorus(V) oxybromide provides bromide AN-4. Palladium-catalyzed cross-coupling of bromide AN-4 with boronate AN-5 provides AN-6. Base-mediated hydrolysis or dealkylation of ester AN-6 by treatment with reagents such as LiOH, NaOH, or LiI provides carboxylic acid AN-7.

Scheme BA.

Scheme BA illustrates a synthetic sequence for the preparation of alcohol derivatives such as BA-4 from azaheterocycles BA-1 or BA-2. Treatment of the ester BA-1 or BA-2 with an organometallic reagent such as an alkyl magnesium salt or DIBAL provides the ketone or aldehyde BA-3, which is further converted to the alcohol BA-4 by treatment with a reducing agent such as sodium borohydride.

BB diagram.

Scheme BB illustrates a synthetic sequence for the preparation of alcohol derivatives such as BB-2 from aldehydes such as BB-1 via treatment with an organometallic reagent such as an alkyl magnesium salt.

Scheme of the aircraft.

Scheme BC illustrates the synthetic sequence for the preparation of alcohols such as BC-2 from aldehydes, ketones, esters, or carboxylic acids such as BC-1 by treatment with reducing agents such as sodium borohydride, lithium borohydride, or 6orane (for carboxylic acids).

BD diagram.

Scheme BC illustrates the synthetic sequence for the preparation of cyclopropyl alcohols such as BD-2 from esters such as BD-1 by treatment with titanium(IV) isopropoxide and ethyl magnesium bromide.

BE scheme.

Scheme BE illustrates a synthetic sequence for preparing alcohols such as BE-4 from esters such as BE-1. Ester BE-1 is treated with a reducing agent such as DIBAL to give alcohol BE-2, which is further oxidized to aldehyde BE-3 with an oxidizing agent such as DMP. Conversion of aldehyde BE-3 with an organometallic reagent such as alkyl magnesium bromide provides alcohol BE-4.

BF diagram.

Scheme BF illustrates a synthetic sequence for preparing alcohols such as BF-3 from primary alcohols such as BF-1. The alcohol BF-1 is oxidized to the aldehyde BF-2 using an oxidizing agent such as DMP. Conversion of the aldehyde BF-2 with an organometallic reagent such as an alkyl magnesium bromide provides the alcohol BF-3.

BG scheme.

Scheme BG illustrates a synthetic sequence for the preparation of alcohols such as BG-5 from arenes or heteroarenes such as BG-1. Conversion of BG-1 using an oxidizing agent such as manganese dioxide provides the aldehyde BG-2, which is treated with a deoxyfluorinating agent such as DAST to yield BG-3. A two-step sequence involving metal-halogen exchange by addition of an organometallic reagent such as isopropyl magnesium bromide, followed by quenching with the appropriate aldehyde BG-4, provides the alcohol BG-5.

HV circuit diagram.

Scheme BH illustrates a synthetic sequence for the preparation of alcohols such as BH-3 from arenes or heteroarenes such as BH-1. Palladium-catalyzed cross-coupling of BH-1 with potassium vinyl trifluoroborate BH-2 or the pinacol ester of vinyl boronic acid BH-3 affords the styrene BH-4. Hydration of BH-2 by treatment with reagents such as cobalt(II) acetylacetonate and phenylsilane affords the alcohol BH-3.

BI diagram.

Scheme BI illustrates a synthetic sequence for the preparation of alcohols such as BI-4 from arenes or heteroarenes such as BI-1. Palladium-catalyzed cross-coupling of BI-1 with tri-n-butylstannane BI-2 followed by treatment with an acid such as aqueous HCl provides the ketone BI-3. Reduction of BI-3 using a reducing agent such as sodium borohydride provides the alcohol BI-4.

BJ diagram.

Scheme BJ illustrates a synthetic sequence for the preparation of alcohols such as BJ-5 from chlorides such as BJ-1. Palladium-catalyzed cross-coupling of BJ-1 with potassium vinyl trifluoroborate BJ-2 provides the styrene BJ-3. Oxidative cleavage of the vinyl group of BJ-3 using reagents such as osmium tetroxide and sodium periodate provides the aldehyde BJ-4. Treatment of BJ-3 with a reducing agent such as sodium borohydride or an organometallic reagent such as an alkyl magnesium bromide provides the alcohol BJ-5.

BK diagram.

Scheme BK illustrates a synthetic sequence for preparing alcohols such as BK-3 from arenes or heteroarenes such as BK-1. Metal-halogen exchange of BK-1 with an organometallic reagent such as n-butyllithium, followed by addition of a ketone or aldehyde BK-2 provides BK-3.

BL scheme.

Scheme BL illustrates a synthetic sequence for the preparation of alcohols such as BL-4 from arenes or heteroarenes such as BL-1. Nucleophilic aromatic substitution of BL-1 with sodium cyanide provides the nitrile BL-2. Acid-mediated methanolysis of BL-2 provides the ester BL-3. Reduction of BL-3 using a reducing agent such as sodium borohydride provides the alcohol BL-4.

VM diagram.

Scheme BM illustrates the synthetic sequence for preparing alcohols such as BM-3 from esters such as BM-1. Nucleophilic aromatic substitution of BM-1 with sodium methoxide provides the ester BM-2. Reduction of the ester BM-2 using a reducing agent such as sodium borohydride provides the alcohol BM-3.

BN scheme.

Scheme BN illustrates a synthetic sequence for the preparation of alcohols such as BN-5 from arenes or heteroarenes such as BN-1. Sandmeyer-type halogenation of BN-1 by treatment with reagents such as tert-butyl nitrite, potassium iodide, and copper(I) iodide provides the iodide BN-2. Palladium-catalyzed cross-coupling of BN-2 with tri-n-butylstannane BN-3 followed by treatment with an acid such as aqueous HCl provides the ketone BN-4. Reduction of BN-4 using a reducing agent such as sodium borohydride provides the alcohol BN-5.

VO scheme.

Scheme BO illustrates the synthetic sequence for preparing alcohols such as BO-5 from pyridones such as BO-1. Deoxychlorination of BO-1 using a reagent such as phosphorus(V) oxychloride provides the chloropyridine BO-2. Reduction of the ester BO-2 by treatment with a reducing agent such as DIBAL provides the alcohol BO-3, which is further oxidized to the aldehyde BO-4 with an oxidizing agent such as DMP. Conversion of the aldehyde BO-4 with an organometallic reagent such as an alkyl magnesium bromide provides the alcohol BO-5.

BP diagram.

Scheme BP illustrates a synthetic sequence for the preparation of alcohols such as BP-5 from substituted pyridines such as BP-1. Ortholitation quenched with a borate ester followed by oxidative rearrangement provides the phenol BP-2. Demethylation in the presence of a strong acid, preferably boron tribromide, HBr, or the like, followed by trapping with dibromomethane in the presence of a suitable mild base such as cesium carbonate or the like, provides a dioxolane such as BP-3. Vilsmeier condensation in which lithium-halogen exchange is followed by quenching with a formyl donor such as DMF or the like provides the aldehyde BP-4, which can be reduced under mild conditions as described above in Scheme BO to give the alcohol BP-5.

BQ scheme.

Scheme BQ illustrates a synthetic sequence for the preparation of benzyl alcohols such as BQ-6 from substituted pyridines such as BQ-1. Demethylation using methods similar to those described above provides a catechol intermediate that can be trapped with thiophosgene to yield a dioxolothione such as BQ-2. Activation of the thiocarbonate with reagents such as the dibromimidazole dione above in the presence of a fluorine source such as HF/pyridine can provide a difluorodioxolane such as BQ-3. Pd-catalyzed cross-coupling with a [3.1.0]-lactam (AAA-6), as described below, can form the heteroarylamide BQ-4, which can be reacted with a suitable bromination reagent to yield BQ-5. A Stille coupling using a vinylstannane reagent such as tributyl (1-ethoxyvinyl)stannane under Pd catalysis followed by reduction of the resulting ketone can provide the benzyl alcohol BQ-6, which can be converted by following the procedures described herein to the compounds of the present invention.

SA diagram.

Scheme CA illustrates a 5-step synthetic sequence for the preparation of lactams such as CA-6 or thiolactams such as CA-7 from lactones such as CA-1. Acid-mediated conversion of CA-1 by treatment with benzylamine provides the imide CA-2. Reduction of the imide CA-2 by treatment with a reducing agent such as LAH or LiAlD ₄ provides the amine CA-3. Conversion of the protecting group of CA-3 to tert-butyl carbamate by treatment with palladium and tert-butyl carbonate under hydrogen atmosphere provides CA-4. Oxidation of CA-4 with reagents such as ruthenium trichloride and sodium periodate provides the lactam CA-5. Deprotection of CA-5 with, for example, an acid such as hydrogen chloride or TFA provides the secondary amide CA-6. CA-6 can be converted to the thiolactam CA-7 directly by treatment with Lawesson's reagent or similar.

AAA scheme.

Scheme AAA illustrates a 5-step synthetic sequence for the preparation of amide derivatives such as AAA-10 from alcohols such as AAA-1 and carboxylic acids such as AAA-9. The alcohol AAA-1 is converted to AAA-2, which is then derivatized with the pyrazole AAA-3 to yield the intermediate AAA-4. Palladium- or copper-catalyzed cross-coupling of AAA-4 with AAA-5 or AAA-6 provides the lactam AAA-7. Removal of the Boc-protecting group from AAA-7 provides the amine AAA-8, which is then coupled with the acid AAA-9 to yield the amide AAA-10.

AAB circuit.

Scheme AAB illustrates a 5-step synthetic sequence for the preparation of amide derivatives such as AAB-10 from tolyl derivatives such as AAB-1 and carboxylic acids such as AAB-9. Bromination of AAB-1 provides AAB-2, which is then derivatized with the pyrazole AAB-3 to give the intermediate AAB-4. Palladium- or copper-catalyzed cross-coupling of AAB-4 and AAB-5 or AAB-6 provides the lactam AAB-7. Removal of the Boc protecting group from AAB-7 provides the amine AAB-8, which is then coupled with the acid AAB-9 to give the amide AAB-10.

AAS diagram.

The AAC scheme illustrates a 4-step synthetic sequence for the preparation of amide derivatives such as AAC-7 from alcohols such as AAC-1 and pyrazoles such as AAC-3. The alcohol AAC-1 is converted to the bromide AAC-2. Base-mediated nucleophilic substitution of AAC-2 by AAC-3 yields the pyrazole AAC-4. Oxidation of the thioether AAC-4 yields the sulfone AAC-5, which is then coupled with the amide AAC-6 to yield the amide AAC-7.

AAD scheme.

Scheme AAD illustrates a 6-step synthetic sequence for the preparation of amide derivatives such as AAD-10 from alcohols such as AAD-1 and carboxylic acids such as AAD-9. The alcohol AAD-1 is converted to the halide AAD-2. Base-mediated nucleophilic substitution of AAD-2 with AAD-3 provides the pyrazole AAD-4. Oxidation of the thioether AAD-4 provides the sulfone AAD-5, which is then displaced by the amide AAD-6 to give the amide AAD-7. Removal of the Boe protecting group from AAD-7 provides the amine AAD-B, which is then coupled with the acid AAD-9 to give the amide AAD-10.

AAE diagram.

Scheme AAE illustrates a four-step synthetic sequence for the preparation of amide derivatives such as AAE-9 from alcohols such as AAE-1 and carboxylic acids such as AAE-8. Mitsunobu coupling of AAE-1 with the pyrazole AAE-2 provides AAE-3. Palladium- or copper-catalyzed cross-coupling of AAE-3 and the lactam AAE-4 or AAE-5 provides AAE-6. Reduction of the nitro group of AAE-6 by treatment with reagents such as platinum/H ₂ or ferric/ammonium chloride provides the amine AAE-7, which is then coupled with the acid AAE-8 to give the amide AAE-9.

AAF diagram.

Scheme AAF illustrates a 7-step synthetic sequence for the preparation of amide derivatives such as AAF-12 from pyridines such as AAF-1 and carboxylic acids such as AAF-11. Palladium-catalyzed cross-coupling of AAF-1 and the lactam AAF-2 provides AAF-3. Bromination of the pyridine AAF-3 using a reagent such as N-bromo succinimide provides AAF-4. Palladium-catalyzed cross-coupling of the bromide AAF-4 with the tri-n-butylstannane AAF-5 followed by aqueous acid workup provides the ketone AAF-6. Reduction of AAF-4 with a reducing agent such as sodium borohydride provides the alcohol AAF-7. Mitsunobu coupling of AAF-7 with the pyrazole AAF-B provides AAF-9. Reduction of the nitro group of AAF-9 by treatment with reagents such as platinum/ _H2 or ferric/ammonium chloride provides the amine AAF-10, which is then coupled with the acid AAF-11 to give the amide AAF-12.

AAG scheme.

Scheme AAG illustrates a four-step synthetic sequence for preparing alcohol derivatives such as AAG-5 from vinyl derivatives such as AAG-1. The amide AAG-1 is protected with, for example, a SEM group, yielding AAG-2. Oxidative cleavage of the vinyl group of AAG-2 by treatment with reagents such as osmium tetroxide and sodium periodate yields the aldehyde AAG-3. Reduction of AAF-3 with a reducing agent such as sodium borohydride yields the alcohol AAG-4. Deprotection of AAG-4 yields AAG-5.

AAN scheme.

Scheme AAN illustrates a B-step synthetic sequence for the preparation of alcohol derivatives such as AAG-5 from arenes or heteroarenes such as AAN-1. Palladium-catalyzed cross-coupling of the bromide AAN-1 with potassium vinyl trifluoroborate AAN-2 or the pinacol ester of vinyl boronic acid AAN-3 provides the styrene AAN-4. Palladium-catalyzed cross-coupling of AAN-4 with the lactam AAN-5 or AAN-6 provides AAN-7. Dihydroxylation of the vinyl group of AAN-7 using reagents such as osmium tetroxide and 4-methylmorphine N-oxide provides the diol AAN-8. Silylation of AAN-8 with a reagent such as tert-butyl(chloro)diphenylsilane provides the alcohol AAN-9. Mitsunobu coupling of AAN-9 with the pyrazole AAN-10 yields AAN-11. Reduction of the nitro group of AAN-11 by treatment with reagents such as platinum/ _H2 or ferric/ammonium chloride yields the amine AAN-12, which is then coupled with the acid AAN-13 to give the amide AAN-14. Deprotection of the silyl ether group of AAN-14 yields the alcohol AAN-15.

AAI scheme.

Scheme AAI illustrates a 7-step synthetic sequence for the preparation of alcohol derivatives such as AAI-13 from pyrimidines such as AAI-1 and the carboxylic acid AAI-11. Silver-mediated decarboxylating alkylation of AAI-1 with AAI-2 provides the ester AAI-3. Reduction of the ketone AAI-3 using reducing agents such as sodium borohydride provides AAI-4. Mitsunobu coupling of AAI-4 with the pyrazole AAI-5 provides AAI-6. Palladium-catalyzed cross-coupling of AAI-6 with the lactam AAI-7 or AAI-8 provides AAI-9. Reduction of the nitro group of AAI-9 by treatment with reagents such as platinum/H ₂ or ferric/ammonium chloride provides the amine AAI-10, which is then coupled with the acid AAI-11 to give the amide AAI-12. Removal of the tert-butyl ether protecting group from AAI-12 yields the alcohol AAI-13.

AAJ scheme.

Scheme AAJ illustrates a six-step synthetic sequence for the preparation of amide derivatives such as AAJ-11 from pyrimidines such as AAJ-1 and a carboxylic acid AAJ-10. A two-step sequence involving metal-halogen exchange of AAJ-1 by addition of an organometallic reagent such as isopropylmagnesium chloride followed by quenching with the appropriate aldehyde AAJ-2 provides the alcohol AAJ-3. Mitsunobu coupling of AAJ-3 with the pyrazole AAJ-4 provides AAJ-5. Nucleophilic displacement of the pyrimidine AAJ-5 with an amine or an ammonium salt such as ammonium hydroxide provides AAJ-6. Palladium-catalyzed cross-coupling of AAJ-6 with the lactam AAJ-7 provides AAJ-8. Reduction of the nitro group of AAJ-8 by treatment with reagents such as platinum/ _H2 or ferric/ammonium chloride provides the amine AAJ-9, which is then coupled with the acid AAJ-10 to give the amide AAJ-11.

AAK diagram.

Scheme AAK illustrates an 8-step synthetic sequence for the preparation of amide derivatives such as AAK-13 from alcohols such as AAK-1 and a carboxylic acid AAK-11 or a lactone AAK-12. The alcohol AAK-1 is converted to the halide AAK-2. Base-mediated nucleophilic substitution of AAK-2 with AAK-3 provides the pyrazole AAK-4. Reduction of the nitro group of AAK-4 by treatment with reagents such as platinum/H ₂ or ferric ammonium chloride provides the amine AAK-5, which is then protected as a tert-butyl carbamate to give AAK-6. Oxidation of the thioether AAK-6 provides the sulfone AAK-7, which is then displaced with the lactam AAK-8 to give AAK-9. Removal of the Boc protecting group from AAK-9 yields the amine AAK-10, which is then coupled with the acid AAK-11 or lactone AAK-12 to yield the amide AAK-13.

AAL diagram.

Scheme AAL illustrates a four-step synthetic sequence for the preparation of amide derivatives such as AAL-10 from alcohols such as AAL-1 and a carboxylic acid AAL-9. Mitsunobu coupling of AAL-1 with the triazole AAL-2 provides the regioisomers AAL-3, AAL-4, and AAL-5. Palladium-catalyzed cross-coupling of AAL-3 or AAL-4 with the lactam AAL-6 provides AAL-7. Reduction of the nitro group AAL-7 by treatment with reagents such as platinum/H ₂ or ferric/ammonium chloride provides the amine AAL-8, which is then coupled with the acid AAL-9 to give the amide AAL-10.

AAM scheme.

Scheme AAM illustrates a four-step synthetic sequence for the preparation of amide derivatives such as AAM-8 from alcohols such as AAM-1 and carboxylic acids such as AAM-7. Palladium-catalyzed cross-coupling of AAM-1 with AAM-2 provides the lactam AAM-3. Mitsunobu coupling of AAM-3 with the pyrazole AAM-4 provides AAM-5. Reduction of the nitro group AAM-5 by treatment with reagents such as platinum/or ferric ammonium chloride provides the amine AAM-6, which is then coupled with the acid AAM-7 to give the amide AAM-8.

AAN diagram.

Scheme AAN illustrates a one-step synthetic sequence for preparing amine derivatives such as AAN-2 from carbamates such as AAN-1. Deprotection of the tert-butyl carbamate protecting group from AAN-1 yields AAN-2.

AAO diagram.

Scheme AAO illustrates a 2-step synthetic sequence for preparing alcohol derivatives such as AAO-3 from the amine AAO-1 and tert-butyl ethers such as AAO-2. Amide coupling of AAO-1 and AAO-2 yields the amide AAO-3. Deprotection of AAO-3 yields the alcohol AAO-4.

AAP scheme.

Scheme AAP illustrates a 3-step synthetic sequence for the preparation of amide derivatives such as AAP-6 from amines such as AAP-1 and carboxylic acids such as AAP-2. Amide coupling of AAP-1 with AAP-2 yields AAP-3, which is then treated with an oxidizing agent such as Oxone® or mCPBA to yield the sulfone AAP-4. Nucleophilic aromatic substitution of AAP-4 with the amine AAP-5 yields AAP-6.

AAQ scheme.

Scheme AAQ illustrates a 2-step synthetic sequence for the preparation of alcohol derivatives such as AAQ-4 from amines such as AAQ-1 and carboxylic acids such as AAQ-2. Amide coupling of AAQ-1 with AAQ-2 provides AAQ-3. Transition metal-mediated hydration of the AAQ-3 olefin by treatment with reagents such as tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) and phenylsilane under an oxygen atmosphere provides the alcohol AAQ-4 and, in some cases, the hydrogenation product AAQ-5. Additionally, AAQ-5 can be prepared directly from AAQ-3 by reaction in the presence of a suitable reducing agent such as Raney nickel.

AAR diagram.

Scheme AAR illustrates a 7-step synthetic sequence for the preparation of amide derivatives such as AAR-12 from pyridines such as AAR-1 and carboxylic acids such as AAR-11. Palladium-catalyzed cross-coupling of AAR-1 and the lactam AAR-2 provides AAR-3. Palladium-catalyzed cross-coupling of the bromide AAR-3 with potassium vinyl trifluoroborate AAR-4 provides AAR-5. Oxidative cleavage of the vinyl group of AAR-5 by treatment with reagents such as osmium tetroxide and sodium periodate provides the aldehyde AAR-6. Reduction of AAR-6 with a reducing agent such as sodium borohydride provides the alcohol AAR-7. Mitsunobu coupling of AAR-7 with the pyrazole AAR-8 provides AAR-9. Reduction of the nitro group of AAR-9 by treatment with reagents such as platinum/ _H2 or iron/ammonium chloride provides the amine AAR-10, which then couples with the acid AAR-11 to give the amide AAR-12.

AAS diagram.

Scheme AAS illustrates a synthetic sequence for the preparation of amide derivatives such as AAS-11 from alkyl trifluoroborate salts such as AAS-4 and aryl or heteroaryl halides such as AAS-5. Nucleophilic displacement of the iodide AAS-1 by the pyrazole AAS-2 provides the adduct AAS-3. Treatment of the boronate of AAS-3 with potassium bifluoride provides the alkyl trifluoroborate salt AAS-4. Visible-light-activated redox reaction of iridium and double-nickel-catalyzed cross-coupling of AAS-4 and AAS-5 provides AAS-6. Palladium-catalyzed cross-coupling of AAS-6 with the lactam AAS-7 provides AAS-8. Acid-mediated deprotection of AAS-8 yields the amine AAS-9, which then couples with the acid AAS-10 to yield the amide AAS-11.

AAT diagram.

Scheme AAT illustrates a four-step synthetic sequence for the preparation of amide derivatives such as AAT-8 from pyrazoles such as AAT-1 and carboxylic acids such as AAT-7. Base-mediated cyclopropanation of AAT-1 by treatment with the diphenyl(vinyl)sulfonium salt of AAT-2 and DBU provides the cyclopropane AAT-3. Palladium-catalyzed cross-coupling of AAT-3 and the lactam AAT-4 provides AAT-5. Reduction of the nitro group of AAT-5 by treatment with reagents such as platinum/ _H2 or ferric/ammonium chloride provides the amine AAT-6, which is then coupled with the acid AAT-7 to give the amide AAT-8.

AAU scheme.

Scheme AAU illustrates a 9-step synthetic sequence for the preparation of amide derivatives such as AAU-13 from pyridines such as AAU-1 and carboxylic acids such as AAU-12. Nucleophilic aromatic substitution of AAU-1 by treatment with sodium methoxide provides the methyl ester AAU-2. Palladium-catalyzed cross-coupling of AAU-2 with the tri-n-butylstannane AAU-3 followed by treatment with an acid such as aqueous HCl provides the ketone AAU-4. Reduction of AAU-4 with a reducing agent such as sodium borohydride provides the alcohol AAU-5. Mitsunobu coupling of AAU-5 with the pyrazole AAU-6 provides AAU-7. Demethylation of the ester AAU-7 with a reagent such as boron tribromide provides the alcohol AAU-8. Base-mediated alkylation of AAU-8 by treatment with sodium chlorodifluoroacetate provides the difluoromethyl ether AAU-9. Palladium-catalyzed cross-coupling of AAU-9 and the lactam AAU-10 provides DA-11. Reduction of the nitro group of AAU-11 by treatment with reagents such as platinum/ _H2 or ferric/ammonium chloride provides the amine AAU-12, which is then coupled with the acid AAU-13 to give the amide AAU-14.

AAV scheme.

The AAV scheme illustrates a two-step synthetic sequence for the preparation of amide derivatives such as AAV-4 from amines such as AAV-1 and the lactone AAV-2. Treatment of AAV-1 and AAV-2 with a reagent such as trimethylaluminum yields AAV-3. Tert-butylation of the alcohol AAV-3 yields AAV-4.

Intermediate AA-6a

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (Scheme AA)

Step 1. 1-Chloro-4-(difluoromethyl)-2-fluorobenzene: To a solution of 4-chloro-3-fluorobenzaldehyde (300 g, 1.89 mmol) in DCM (1.5 L) under nitrogen and cooled to 0 °C was added dropwise bis(2-methoxyethyl)aminosulfur trifluoride (456 mL, 2.08 mol). The reaction mixture was stirred at rt for 12 h. The resulting mixture was slowly poured into ice water solution, then extracted with DCM. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (t, J=8.0 Hz, 1H), 7.34 (d, J=9.6 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H), 6.64 (t, J=56 Hz, 1H).

Step 2. 2-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 1-chloro-4-(difluoromethyl)-2-fluorobenzene (300 g, 1.66 mol) in THF (1.8 L) under nitrogen atmosphere cooled to -78 °C was added dropwise LDA (997 mL, 1.99 mol, 2 M in THF). The reaction mixture was stirred at -78 °C for 30 min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (508 mL, 2.49 mol) was added dropwise. The reaction mixture was stirred at -78°C for 30 min, then poured into an aqueous saturated solution of NH ₄ Cl.

The resulting mixture was filtered then extracted with EtOAc. The organic layers were combined and washed with brine, dried over _Na2SO4 and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, CDCl3) δ 7.53 (t, J ₌ 8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.02 (t, J=56 Hz, 1H), 1.39 (s, 12H).

Step 3. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: The reaction was carried out in two parallel vessels on an equivalent scale as indicated. To a solution of 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127 g, 415 mmol), methyl 6-bromopyrazine-2-carboxylate (60.0 g, 276 mmol), and potassium fluoride (48.2 g, 829 mmol, 19.4 mL) in a mixture of dioxane (720 mL) and water (120 mL) under nitrogen atmosphere was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (11.3 g, 13.8 mmol). The reaction mixture was stirred at 120 °C for 12 h. The reaction mixtures from both reactions carried out in parallel were cooled to rt, combined, then concentrated under reduced pressure. The crude residue was suspended in EtOAc and the resulting mixture was filtered. The filtrate was washed with water, brine, dried over _Na2SO4 and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, _CDCl3 ) δ 9.36 (s, _1H ), 8.96 (d, J=2.8 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 6.99 (t, J=56 Hz, 1H), 4.06 (s, 3H).

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid: To a solution of methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (350 g, 1.11 mol) in EtOH (1.75 L) at 10-20 °C was added aq. sodium hydroxide (2.10 L, 2.10 mol, 1 M aq.). The reaction mixture was stirred at rt for 30 min, then concentrated under reduced vacuum (to remove EtOH). The crude residue was extracted with MTBE. The organic layers were removed and the pH of the aq. layer was adjusted to 2-3 with aq. 2 N HCl. The resulting mixture was filtered and the filter cake was dried to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.9 (br s, 1H), 9.28 (s, 1H), 9.14 (s, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.02 (t, J=56 Hz, 1H).

Intermediate AA-6b

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (Scheme AA)

Step 3. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylate: To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (25.0 g, 134 mmol) and potassium phosphate (85.6 g, 403 mmol) in THF (500 mL) under nitrogen atmosphere was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (8.75 g, 10.7 mmol). The reaction mixture was heated to 70 °C and 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (41.1 g, 134 mmol) was added. The resulting mixture was stirred at 70 °C for 15 h. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc, 10:1) to give the title compound. MS: 331 [M+1] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (d, J = 3.1 Hz, 1H), 7.68-7.56 (m, 2H), 7.02 (t, J = 55.3 Hz, 1H), 4.03 (d, J = 3.5 Hz, 3H), 2.96 (s, 3H).

Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, step 4. MS: 317 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86 (d, J=2.6 Hz, 1H), 7.86-7.77 (m, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.04 (t, J=55.0 Hz, 1H), 2.92 (s, 3H).

Intermediate AB-6a

6-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid (Scheme AB)

Step 1. Methyl 6-(trimethyl)pyrazine-2-carboxylate: To a solution of methyl 6-bromopyrazine-2-carboxylate (4.00 g, 18.4 mmol), hexamethyldistannane (9.27 g, 28.3 mmol) in toluene (50.0 mL) under nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium (1.07 g, 0.922 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc, 5:1) to give the title compound. MS = 303.0 [M+1] ⁺ .

Step 2. 1-Chloro-2-fluoro-3-iodo-4-(trifluoromethyl)benzene: To a solution of 1-chloro-2-fluoro-4-(trifluoromethyl)benzene (250 g, 1.26 mol) in THF (2.25 L) under nitrogen and cooled to -78 °C was added dropwise n-butyllithium (757 mL, 1.89 mol, 2.5 M solution in hexane). The reaction mixture was stirred at -78 °C for 1 h, then iodine (481 g, 1.89 mol) in THF (2.25 L) was added dropwise over 2 h. The reaction mixture was stirred at -78 °C for 1 h, then warmed to -20 °C. The reaction mixture was quenched by addition of aq. sat. _NH4Cl . The resulting mixture was extracted with EtOAc. The organic layers were combined and washed with water, brine, dried over _Na2SO4 and concentrated under reduced pressure to give the title compound. MS 324 [M+ ₁ ] ⁺ .

Step 3. Methyl 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylate: To a mixture of methyl 6-(trimethylstannyl)pyrazine-2-carboxylate (1.11 g, 3.70 mmol), 1-chloro-2-fluoro-3-iodo-4-(trifluoromethyl)benzene (800 mg, 2.47 mmol) in toluene (20 mL) under nitrogen atmosphere were added tris(dibenzylideneacetone)dipalladium (226 mg, 0.247 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene (117 mg, 0.247 mmol). The reaction mixture was stirred at 120 °C for 18 h. The mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (1:0 to 5:1 petroleum ether/EtOAc) to give the title compound. MS=335.2 [M+1] ⁺ .

Step 4. 6-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid. The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 4. MS=321.2 [M+1] ⁺ .

Intermediate AC-6a

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid (Scheme AC)

Step 1. Methyl 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: To a solution of methyl 6-bromo-3-chloropyrazine-2-carboxylate (1.00 g, 3.98 mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.22 g, 3.98 mmol), and potassium phosphate (2.53 g, 11.9 mmol) in THF (15 mL) under nitrogen atmosphere was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (518 mg, 0.795 mmol). The reaction mixture was heated to 40 °C for 1.5 h. The reaction mixture was cooled to rt, then poured into a mixture of water and EtOAc. The layers were separated and the aq. layer was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (1:0 to 10:1 petroleum ether/EtOAc) to give the title compound. MS: 351.0 [M+1] ⁺ .

Step 2. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylate: To a solution of methyl 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (100 mg, 0.285 mmol) in toluene (4 mL) were added triethylaluminum (0.854 mL, 0.854 mmol, 1.0 M in hexanes) and tetrakis(triphenylphosphine)palladium (32.9 mg, 28.0 μmol) at rt under nitrogen. The reaction mixture was stirred at 80 °C for 16 h, then cooled to rt and concentrated under reduced vacuum. The crude residue was dissolved in a mixture of water and EtOAc. The layers were separated and the aq. layer was extracted with EtOAc. The organic layers were combined and washed with brine (20 mL), dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (5:1 petroleum ether/EtOAc) to give the title compound as a mixture with ethyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylate. MS: 345.1 [M+1] ⁺ and 359.0 [M+1] ⁺ .

Step 3. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 4. aq. Na ₂ SO ₄ MS: 331.0 [M+1] ⁺ .

Intermediate AD-10a

6-(3-Chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid (Scheme AD)

Step 1. 2-Bromo-4-chloro-3-fluoro-1-iodobenzene: To a mixture of 1-chloro-2-fluoro-4-iodobenzene (4 g, 15.6 mmol) in THF (50.0 mL) under nitrogen at -70 °C was added dropwise LDA (8.58 mL, 17.2 mmol, 2 M in THF). The reaction mixture was stirred at -70 °C for 30 min, then 1,2-dibromo-1,1,2,2-tetrachloroethane (6.10 g, 18.7 mmol) in THF (10 mL) was added dropwise. The resulting mixture was stirred at -70 °C for 20 min, then warmed to 10 °C and stirred for an additional 1 h. The reaction mixture was quenched by the addition of aq. sat. NH ₄ Cl and water, then extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 (dd, J=8.4, 6.9 Hz, 1H), 7.60 (dd, J=8.6, 1.6 Hz, 1H).

Step 2. S-(2-Bromo-4-chloro-3-fluorophenyl)ethanethioate: To a solution of 2-bromo-4-chloro-3-fluoro-1-iodobenzene (5.00 g, 14.9 mmol) in toluene (30.0 mL) under nitrogen were added potassium thioacetate (2.55 g, 22.4 mmol), copper(I) iodide (284 mg, 1.49 mmol), and 1,10-phenanthroline (269 g, 1.49 mmol). The resulting mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to rt, filtered, then diluted with water and extracted with EtOAc. The organic layers were combined and washed with brine, then dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc) to give the title compound. ¹ H NMR (400 MHz, _CDCl3 ) δ 7.41 (dd, J=8.6, 7.0 Hz, 1H), 7.30 (dd, J=8.6, 1.6 Hz, 1H), 2.47 (s, 3H).

Step 3. (2-Bromo-4-chloro-3-fluorophenyl)(methyl)sulfane: To a solution of S-(2-bromo-4-chloro-3-fluorophenyl)ethanethioate (2.40 g, 8.46 mmol) in EtOH (10.0 mL) was added NaOH (2.5 mL, 25.4 mmol, 10 M aq), followed by iodomethane (4.81 g, 33.9 mmol). The reaction mixture was stirred at 15 °C for 10 min. The mixture was concentrated under reduced pressure (to remove EtOH), diluted with water, then the mixture was extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (dd, J=7.0, 8.6 Hz, 1H), 6.85 (dd, J=1.4, 8.8 Hz, 1H), 2.48 (s, 3H).

Step 4. 2-Bromo-4-chloro-3-fluoro-1-(methylsulfinyl)benzene: To a solution of (2-bromo-4-chloro-3-fluorophenyl)(methyl)sulfane (1.90 g, 7.44 mmol) in DCM (20 mL) was added mCPBA (2.57 g, 14.9 mmol). The reaction mixture was stirred at rt for 1 h, then quenched _by addition of sat. aq. _Na2SO3 ( ₃₀ mL). The resulting mixture was stirred at rt for 30 min, then diluted with water and extracted with EtOAc. The organic layers were combined and washed with brine, dried over _Na2SO4 , and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72-7.67 (m, 1H), 7.65-7.59 (m, 1H), 2.84-2.79 (m, 3H).

Step 5. Methyl 6-(3-chloro-2-fluoro-6-(methylsulfinyl)phenyl)-3-methylpyrazine-2-carboxylate: To a solution of methyl 6-(trimethylstannyl)pyrazine-2-carboxylate (332 mg, 1.11 mmol) and 2-bromo-4-chloro-3-fluoro-1-(methylsulfinyl)benzene (200 mg, 0.737 mmol) in dioxane (3.0 mL) were added 1,1'-bis(di-tert-butylphosphino)ferrocene (34.9 mg, 74.0 μmol) and tris(dibenzylideneacetone)dipalladium (60 mg, 74 μmol). The reaction mixture was stirred under nitrogen at 90 °C for 15 h. The mixture was cooled to rt, filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (petroleum ether/EtOAc, 1:1) to give the title compound. MS = 328.9 [M+1] ⁺ .

Step 6. Methyl 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylate: To a solution of methyl 6-(3-chloro-2-fluoro-6-(methylsulfinyl)phenyl)pyrazine-2-carboxylate (40.0 mg, 0.122 mmol) in THF (0.5 mL) and water (0.100 mL) was added Oxone® (150 mg, 0.243 mmol). The resulting mixture was stirred at rt for 16 h. The mixture was diluted with EtOAc, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (petroleum ether/EtOAc, 1:1) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 8.92 (d, J=2.5 Hz, 1H), 8.01 (dd, J=1.5, 8.6 Hz, 1H), 7.75 (dd, J=6.9, 8.6 Hz, 1H), 4.03 (s, 3H), 3.41 (s, 3H).

Step 7. 6-(3-Chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 4. MS=330.9 [M+1] ⁺ .

Intermediate AE-5

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylic acid (Scheme AE)

Step 1. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylate: To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylic acid (700 mg, 2.13 mmol) in THF (15 mL) were added di-tert-butyl dicarbonate (697 mg, 3.19 mmol), triethylamine (0.594 mL, 4.26 mmol), and DMAP (78 mg, 0.64 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched by addition of sat. aq. _NaHCO3 and extracted with EtOAc. The organic layers _were combined and dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-15% EtOAc/petroleum ether) to give the title compound. MS=385.0 [M+1] ⁺ .

Step 2. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formylpyrazine-2-carboxylate: To a solution of tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylate (150 mg, 0.390 mmol) in THF (4.0 mL) and water (0.5 mL) were added osmium tetroxide (20 mg/mL in water, 0.991 mL, 78.0 μmol) and sodium periodate (334 mg, 1.56 mmol). The mixture was stirred at rt for 2 h, then quenched by addition _of sat. aq. _Na2S2O3 . The resulting mixture was stirred at rt for 15 min, then extracted _with EtOAc. The organic layers were combined, dried over _Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to give the title compound. _MS =330.9 [M+1-56] ⁺ .

Step 3. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylate: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 1. aq. MS=409.0 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylic acid: To a solution of tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylate (190 mg, 0.465 mmol) in DCM (6.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at rt for 2 h, then concentrated under reduced pressure to give the title compound. MS = 352.9 [M+1] ⁺ .

Intermediate AF-4a

3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (Scheme AF)

Step 1. Methyl 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: A solution of 4,4'-di-tert-butyl 2,2'-bipyridine (38.2 mg, 0.142 mmol) and ethylene glycol dimethyl ether nickel(II) chloride complex (31.3 mg, 0.142 mmol) in THF (1.0 mL) was stirred at 35 °C for 30 min. The mixture was then concentrated under reduced pressure (to remove THF). In a nitrogen-filled glove box, dibasic potassium phosphate (744 mg, 4.27 mmol), methyl 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (500 mg, 1.42 mmol), (tert-butoxymethyl)potassium trifluoroborate (553 mg, 2.85 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (Ir(dFCF ₃ ppy) ₂ bpyPF ₆ , 160 mg, 0.142 mmol), 1,4-dioxane (10.0 mL), and DMA (2.0 mL) was added to the mixture. The resulting mixture was stirred for 72 h before one 23 W CFL. The reaction mixture was poured into a mixture of water and EtOAc. The organic layer was separated and aq. extracted with EtOAc. The organic layers were combined and washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to give the title compound. _MS = 403.1 [M+1] ⁺ .

Step 2. 3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 4. aq. MS=389.1 [M+1] ⁺ .

Intermediate AG-5a

3-Carboxy-5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyridine 1-oxide (Scheme AG)

Step 1. Methyl 5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)nicotinate: To a solution of methyl 5-bromonicotinate (50.0 mg, 0.231 mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85.0 mg, 0.278 mmol), potassium phosphate (147 mg, 0.694 mmol) in THF (1.00 mL) and water (0.500 mL) was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (15.1 mg, 23.0 μmol). The reaction mixture was then heated at 80°C for 30 min in a microwave reactor, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAc/petroleum ether) to give the title compound. MS=315.9 [M+1] ⁺ .

Step 2. 3-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-5-(methoxycarbonyl)pyridine-1-oxide: To a solution of methyl 5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)nicotinate (50.0 mg, 0.158 mmol) in DCM (1.00 mL) at rt was added mCPBA (42.6 mg, 0.190 mmol). The reaction mixture was stirred at rt for 24 h. To the reaction mixture were _added water and DCM. The layers were separated and the aq. layer was extracted with DCM. The organic layers were combined and washed with brine, dried over _Na2SO4 , and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA) - ACN, start B 27%, end B 57%) to give the title compound. MS = 332.0 [M+1] ⁺ .

Step 3. 3-Carboxy-5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyridine-1-oxide: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 4. MS=318.0 [M+1] ⁺ .

Intermediate AN-8

4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid (Scheme AN)

Step 1. 4-Chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine: To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (10.0 g, 51.3 mmol) and (4-methoxyphenyl)methanol (7.08 g, 51.3 mmol) in DMF (150 mL) under nitrogen at 0 °C was added sodium hydride (60% dispersion in mineral oil, 2.05 g, 51.3 mmol) portionwise. The resulting mixture was stirred at 0 °C for 1 h and at rt for 2 h. The reaction mixture was quenched by addition of sat. aq. NH ₄ Cl then extracted with EtOAc. The organic layers were combined and washed with water and brine, then dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-5% EtOAc/petroleum ether) to give the title compound. _MS =297.0 M+1] ⁺ .

Step 2. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine: To a solution of 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.36 g, 11.0 mmol), 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (2.50 g, 8.42 mmol), and potassium phosphate (5.36 g, 25.3 mmol) in toluene (40.0 mL) and water (8.00 mL) was added the adduct methanesulfonato(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane (SPhos Pd G4, 0.657 g, 0.842 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was concentrated under reduced vacuum. Water was added to the reaction mixture and extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , and concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give the title compound. MS = 441.1 [M+1] ⁺ .

Step 3. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine: To a solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (2.60 g, 5.90 mmol) in a mixture of THF (100 mL) and water (25 mL) was added Oxone® (36.3 g, 59.0 mmol). The reaction mixture was stirred at rt for 14 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, then dried over Na ₂ SO ₄ , filtered, and concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (25-100% EtOAc/petroleum ether) to give the title compound. MS=473.1 [M+1] ⁺ .

Step 4. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)pyrimidine-2-carbonitrile: To a solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine (1.90 g, 4.02 mmol) in a mixture of ACN (20.0 mL) and DMSO (1.00 mL) was added sodium cyanide (0.985 g, 20.1 mmol). The reaction mixture was stirred at rt for 14 h, then diluted with EtOAc. The organic layer was washed with water and brine, then dried over Na ₂ SO ₄ , filtered, and concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (0-15% EtOAc/petroleum ether) to give the title compound. MS=420.1 [M+1] ⁺ .

Step 5. Methyl 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-hydroxypyrimidine-2-carboxylate: A solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)pyrimidine-2-carbonitrile (900 mg, 2.14 mmol) in 4 M methanolic HCl (15 mL) was stirred at rt for 20 h. Triethylamine was added to the reaction mixture to quench the acid, then the mixture was concentrated under reduced pressure. The crude residue was purified by preparative reverse-phase HPLC (CIS stationary phase, water (0.1% TFA)-ACN, start B 41%, end B 62%) to give the title compound. MS=333.0 [M+1] ⁺ .

Step 6. Methyl 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylate: To a solution of methyl 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-2-carboxylate (25.0 mg, 75.0 μmol) in a mixture of DCM (1.0 mL) and MeOH (0.1 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 0.400 mL, 0.800 mmol) at rt. After complete addition, the reaction mixture was stirred for 1 h, then quenched with acetic acid (a few drops) and concentrated under reduced pressure. The residue was purified by preparative TLC (3:1 petroleum ether/EtOAc) to give the title compound. MS=347.0 [M+1] ⁺ .

Step 7. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AA-ba, Step 4. MS=332.9 [M+1] ⁺ .

Intermediate AI-3a

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AI)

To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (1.50 g, 4.96 mmol) and 1H-pyrazol-4-amine (0.618 g, 7.43 mmol) in DCM (20.0 mL) at 0 °C was added 1-propanephosphonic anhydride (5.90 mL, 9.91 mmol) followed by DIEA (3.46 mL, 19.8 mmol). The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was diluted with sat. aq. sodium carbonate and extracted with DCM. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/hexane) to give the title compound. MS 382.0 [M+1] ⁺ .

Intermediate AJ-7a

3-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one (Scheme AJ)

Step 1. Methyl 3-amino-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6b, Step 1. MS=332.1 [M+1] ⁺ .

Step 2. Methyl 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: To a solution of copper(II) bromide (1.62 g, 7.24 mmol) and tert-butyl nitrite (0.746 g, 7.24 mmol) in ACN (20.0 mL) heated to 70 °C was added methyl 3-amino-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (1.20 g, 3.62 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to rt, then water was added. The resulting mixture was extracted with EtOAc. The organic layers were combined and dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 15% EtOAc/petroleum ether) to give the title compound. MS=396.9 [M+1] ⁺ .

Step 3. 3-Bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid: The title compound was prepared according to procedures analogous to those described above for Intermediate AA-6a, step 4. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.74 (d, J=2.4 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 6.95 (t, J=54.8 Hz, 1H). MS=380.8, 382.8 [M+1] ⁺ .

Step 4. 3-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one: A solution of 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (30 mg, 0.079 mmol), 2,2-dimethyloxirane (11 mg, 0.16 mmol), zinc (10 mg, 0.16 mmol), sodium iodide (2.4 mg, 0.016 mmol), 4,4'-bipyridine (1.2 mg, 7.9 μmol), triethylamine hydrochloride (11 mg, 0.079 mmol), nickel(II) iodide (2.5 mg, 7.9 μmol), and pyridine (1.3 µL, 0.016 mmol) in DMPU (1.0 mL) was stirred at rt for 12 h. The mixture was concentrated under reduced pressure and purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA) - ACN, start B 33%, end B 63%) to give the title compound. MS = 357.0 [M+1] ⁺ .

Intermediate AK-4a

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropoxymethyl)pyrazine-2-carboxylic acid (Scheme AK)

Step 1. Methyl 3-(bromomethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: To a solution of methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylate (20 mg, 0.060 mmol), NBS (12 mg, 0.067 mmol) in CCl ₄ (1.0 mL) was added benzoyl peroxide (2.9 mg, 0.012 mmol). The mixture was stirred at 80 °C for 8 h. The reaction mixture was concentrated under reduced pressure to give the title compound. MS = 410.9 [M+1] ⁺ .

Step 2. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropoxymethyl)pyrazine-2-carboxylic acid: To a solution of cyclopropanol (14 mg, 0.24 mmol) in THF (0.5 mL) cooled to 0 °C was added sodium hydride (60% in oil dispersion, 5.3 mg, 0.22 mmol) and the mixture was stirred at rt for 30 min. Then a solution of methyl 3-(bromomethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (30 mg, 0.073 mmol) in THF (0.8 mL) was added to the reaction mixture. The resulting mixture was stirred at rt for 12 h. To the reaction mixture was added sat. aq. NH ₄ Cl and the mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA) - ACN, start B 42%, end B 72%) to give the title compound. MS = 372.9 [M+1] ⁺ .

Intermediate AL-5a

3-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethylfuro[3,4-b]pyrazin-5-(7H)-one (Scheme AL)

Step 1. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxycarbonyl)pyrazine-2-carboxylic acid: To a solution of 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (300 mg, 0.786 mmol) and DIEA (0.28 mL, 1.6 mmol) in MeOH (10.0 mL) under nitrogen atmosphere was added 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (57.5 mg, 79.0 μmol). The reaction mixture was stirred at 50 °C under CO (50 psi) for 4 h. The mixture was cooled to rt and filtered, then the filtrate was purified by preparative TLC (SiO ₂ , 20% methanol/DCM) to give the title compound. MS = 360.9 [M+1] ⁺ .

Step 2. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid: To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxycarbonyl)pyrazine-2-carboxylic acid (60 mg, 0.17 mmol) in THF (1.0 mL) cooled to 0 °C was added methyl magnesium chloride (0.055 mL, 0.17 mmol). The mixture was stirred at 0 °C for 5 min, then quenched by addition of sat. aq. NH ₄ Cl. The resulting mixture was diluted with ACN (3 mL) and filtered, then the filtrate was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 45%, end B 65%) to give the title compound. MS = 360.9 [M+1] ⁺ .

Step 3. 3-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethylfuro[3,4-b]pyrazin-5(7H)-one: To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid (40 mg, 0.11 mmol) in DMF (0.50 mL) were added EDC (21 mg, 0.11 mmol) and pyridine (0.050 mL). The reaction mixture was stirred at rt for 16 h. The mixture was diluted with EtOAc, then washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO ₂ , 1:1 EtOAc/petroleum ether) to give the title compound. MS = 343.1 [M+1] ⁺ .

Intermediate AM-3a

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylic acid (Scheme AM)

Step 1: tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylate: To a solution of tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formylpyrazine-2-carboxylate (130 mg, 0.336 mmol) in 1,2-dimethoxyethane (6.000 mL) were added trimethylamine N-oxide (25.2 mg, 0.336 mmol) and (trifluoromethyl)trimethylsilane (143 mg, 1.01 mmol). The reaction mixture was stirred at rt for 14 h under nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with EtOAc. The organic layers were combined and dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-12% EtOAc/petroleum ether) to give the title compound. MS=457.0 [M+1] ⁺ .

Step 2: 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 4. MS=400.8 [M+1] ⁺ .

Intermediate AN-7

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylic acid (Scheme AN)

Step 1. Ethyl 3-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-4-carboxylate: To a solution of diethyl 2-acetylsuccinate (1.00 g, 4.62 mmol) in EtOH (5.0 mL) was added hydrazine hydrate (0.272 g, 4.62 mmol). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 60% EtOAc/petroleum ether) to give the title compound. MS = 185.1 [M+1] ⁺ .

Step 2. Ethyl 3-methyl-6-oxo-1,6-dihydropyridazine-4-carboxylate: To a solution of ethyl 3-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-4-carboxylate (100 mg, 0.543 mmol) in AcOH (5.0 mL) was added bromine (174 mg, 1.09 mmol). The reaction mixture was stirred at rt for 15 h. The reaction mixture was diluted with water and concentrated under reduced pressure to give the title compound. MS = 183.0 [M+1] ⁺ .

Step 3. Ethyl 6-bromo-3-methylpyridazine-4-carboxylate: A mixture of ethyl 3-methyl-6-oxo-1,6-dihydropyridazine-4-carboxylate (99.0 mg, 0.543 mmol) and phosphorus(V) oxybromide (1.00 g, 3.49 mmol) was stirred under nitrogen at 80 °C for 15 h. The reaction mixture was cooled to rt, then poured into ice-cold water. The resulting mixture was stirred for 1 h, then sat. aq. NaHCO ₃ was added (to adjust the pH of the mixture to ~7). The mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (stationary phase C18, gradient water (0.2% TFA)-ACN) to afford the title compound. MS=245.0, 247.0 [M+1] ⁺ .

Step 4. Ethyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylate: To a solution of ethyl 6-bromo-3-methylpyridazine-4-carboxylate (35 mg, 0.14 mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.430 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.029 mmol) in toluene (1.5 mL) and water (0.3 mL) under nitrogen atmosphere was added cesium carbonate (140 mg, 0.430 mmol). The reaction vessel was sealed and heated in a microwave oven at 100 °C for 1 h. The reaction mixture was cooled to rt, then filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO ₂ , 1:4 EtOAc/petroleum ether) to give the title compound. MS = 345.3 [M+1] ⁺ .

Step 5. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylic acid: The title compound was prepared according to procedures similar to those described above for Intermediate AA-6a, Step 4. MS=316.9 [M+1] ⁺ .

Intermediate ΒΑ-1a

1-(5-Bromopyrimidin-2-yl)ethan-1-ol (Scheme BA)

Step 1. 1-(5-Bromopyrimidin-2-yl)ethan-1-one: To a solution of methyl 5-bromo-4-methylpyrimidine-2-carboxylate (1.00 g, 4.33 mmol) in THF (43 mL) cooled to -78 °C was added methylmagnesium bromide (4.33 mL, 4.33 mmol) in one portion and the mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched by addition of sat. aq. NH ₄ Cl, then the mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound. MS=215.0, 217.0 [M+1] ⁺

Step 2. 1-(5-Bromopyrimidin-2-yl)ethan-1-ol: To a solution of 1-(5-bromo-4-methylpyrimidin-2-yl)ethan-1-one (550 mg, 2.56 mmol) in 2-propanol (35.0 mL) cooled to 0 °C was added sodium borohydride (97.0 mg, 2.56 mmol) and the mixture was stirred at 0 °C for 1 h. To the mixture was added sat. aq. NH ₄ Cl and the mixture was extracted with DCM. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound. MS=217.0, 219.0 [M+H] ⁺

Intermediate BA-1c

1-(5-Bromo-3-fluoropyridin-2-yl)ethanol (Scheme BA)

Step 1. 1-(5-Bromo-3-fluoropyridin-2-yl)ethanone: To a solution of 5-bromo-3-fluoropicolinonitrile (2.0 g, 10 mmol) in toluene (30 mL) was added methyl magnesium bromide (6.6 mL, 20 mmol, 3 M in THF) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then quenched with water and extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to give the title compound. MS=217.9, 219.9 [M+1] ⁺ .

Step 2. 1-(5-Bromo-3-fluoropyridin-2-yl)ethanol. The title compound was prepared similarly to that described for Intermediate BA-1a. MS=219.9, 221.9 [M+1] ⁺ .

Intermediate BB-2a

1-(5,6-Dichloropyridin-3-yl)ethan-1-ol (Scheme BB)

To a solution of 5,6-dichloronicotinaldehyde (300 mg, 1.71 mmol) in THF (3.0 mL) under nitrogen atmosphere cooled to 0 °C was added methyl magnesium bromide (0.852 mL, 2.56 mmol, 3.0 M solution in diethyl ether) dropwise over 2 h. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched by addition of sat. aq. NH ₄ Cl and extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-60% EtOAc/hexane) to give the title compound. MS = 191.9 [M+1] ⁺ .

Intermediate VS-2a

(5-Chloro-6-methylpyrazin-2-yl)methanol (Scheme BC)

To a solution of 5-chloro-6-methylpyrazine-2-carbaldehyde (2.00 g, 12.8 mmol) in THF (10.0 mL) was added sodium borohydride (0.580 g, 15.3 mmol). The reaction mixture was stirred at rt for 30 min. The reaction mixture was quenched by addition of acetone, then water was added and the mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAc/petroleum ether) to give the title compound. MS = 158.9 [M+1] ⁺ .

Intermediate BD-2a

1-(2-Chloro-4-methylpyrimidin-5-yl)cyclopropan-1-ol (Scheme BD)

To a solution of methyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5.4 mmol) in diethyl ether (27 mL) cooled to -78 °C under nitrogen was added titanium(IV) isopropoxide (1.6 mL, 5.4 mmol) followed by ethyl magnesium bromide (3 M in diethyl ether, 5.7 mL, 17 mmol) dropwise over 15 min. The reaction mixture was warmed to 0 °C and stirred for 2 h and then quenched by addition of water. The resulting mixture was extracted with EtOAc and the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 10% MeOH/DCM). MS=185.0 [M+1] ⁺ .

Intermediate BE-4a

1-(5-Bromo-6-methylpyridin-2-yl)ethan-1-ol (Schedule BE)

Step 1. (5-Bromo-6-methylpyridin-2-yl)methanol: A solution of methyl 5-bromo-6-methylpicolinate (1.00 g, 4.40 mmol) in THF (22 mL) was cooled to -78 °C before the dropwise addition of DIBAL (10.9 mL, 10.9 mmol, 1 M in THF). The reaction mixture was stirred at -78 °C for 15 min and then allowed to warm slowly to rt, where it was left to stir for 1 h. The reaction mixture was cooled to 0 °C and quenched by the addition of EtOAc and 40% aq. Rochelle's salt (potassium sodium tartrate tetrahydrate, 60 mL) and stirred vigorously at rt overnight. The layers were separated and the aq. layer was extracted with EtOAc. The organic layers were combined and dried over _Na2SO4 , _filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS=203.0 [M+1] ⁺ .

Step 2. 5-Bromo-6-methylpicolinaldehyde: A solution of (5-bromo-6-methylpyridin-2-yl)methanol (523 mg, 2.60 mmol) in DCM (8.6 mL) was cooled to 0 °C and DMP (1.60 g, 3.90 mmol) was added in one portion. The reaction mixture was warmed to rt and stirred at this temperature for 2 h. The reaction was quenched by the addition of sat. aq. NaHCO ₃ (10 mL) and sat. aq. sodium thiosulfate and stirred vigorously for 1 h. The layers were separated and the aq. layer was extracted with DCM. The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS=201.0 [M+1] ⁺ .

Step 3. 1-(5-Bromo-6-methylpyridin-2-yl)ethan-1-ol: A solution of 5-bromo-6-methylpicolinaldehyde (517 mg, 2.60 mmol) was dissolved in THF (13 mL) and cooled to -78 °C, and a solution of methylmagnesium bromide (3.90 mL, 3.90 mmol, 1 M in THF) was added dropwise. The reaction mixture was allowed to warm slowly to rt and stirred at this temperature for 1 h. The reaction was quenched by adding sat. aq. NH ₄ Cl and stirred for 20 min. The resulting mixture was filtered and the filtrate was diluted with EtOAc and water. The layers were separated and the aq. layer was extracted with EtOAc. The organic layers were combined and dried over _Na2SO4 , _filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS=217.0 [M+1] ⁺ .

Intermediate BF-3a

1-(6-Bromo-5-methylpyridin-3-yl)ethan-1-ol

Step 1. 6-Bromo-5-methylnicotinaldehyde: The title compound was prepared in a similar manner as described for 5-bromo-6-methylpicolinaldehyde (en route to Intermediate BE-4a). MS=210.9 [M+1] ⁺ .

Step 2. 1-(6-Bromo-5-methylpyridin-3-yl)ethan-1-ol: The title compound was prepared similarly as described for 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol (Intermediate BE-4a). MS=217.9 [M+1] ⁺ .

Intermediate BG-5a

1-(6-Chloro-5-(difluoromethyl)pyridin-3-yl)ethan-1-ol (Scheme BG)

Step 1. 5-Bromo-2-chloronicotinaldehyde: To a solution of (5-bromo-2-chloropyridin-3-yl)methanol (4.00 g, 18.0 mmol) in DCM (10 mL) was added manganese(IV) oxide (7.82 g, 90.0 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% EtOAc/petroleum ether) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.34 (s, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.29 (d, J=2.7 Hz, 1H).

Step 2. 5-Bromo-2-chloro-3-(difluoromethyl)pyridine: To a solution of 5-bromo-2-chloronicotinaldehyde (3.70 g, 16.8 mmol) in DCM (30 mL) cooled to 0 °C was added DAST (11.1 mL, 84.0 mmol) dropwise. The reaction mixture was stirred for 1 h at 15 °C. The reaction mixture was quenched by addition of sat. aq. sodium carbonate and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% EtOAc/petroleum ether) to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.68-8.54 (m, 1H), 8.29-8.14 (m, 1H), 7.19-6.76 (m, 1H).

Step 3. 1-(6-Chloro-5-(difluoromethyl)pyridin-3-yl)ethanol: To a solution of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (2.60 g, 10.7 mmol) in THF (25 mL) cooled to 0 °C was added dropwise isopropylmagnesium bromide (16.5 mL, 21.5 mmol). After complete addition, the resulting mixture was stirred at 0 °C for 30 min, then acetaldehyde (6.4 mL, 32 mmol) was added. The reaction mixture was stirred for 16 h while warming to rt. The reaction mixture was quenched by addition of water, then extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (5% EtOAc/petroleum ether) to give the title compound. MS=208.0 [M+1] ⁺ .

Intermediate VN-5a

1-(2-Chloro-4-methylpyrimidin-5-yl)ethan-1-ol (Scheme BH)

Step 1. 2-Chloro-4-methyl-5-vinylpyrimidine: The title compound was prepared according to procedures similar to those described above for Intermediate AG-5a, Step 1. MS=154.6 [M+1] ⁺ .

Step 2. 1-(2-Chloro-4-methylpyrimidin-5-yl)ethanol: A mixture of 2-chloro-4-methyl-5-vinylpyrimidine (1.50 g, 9.70 mmol), cobalt(II) acetylacetonate (0.250 g, 0.970 mmol), and phenylsilane (2.10 g, 19.4 mmol) in THF (30 mL) was stirred at rt for 14 h under _O2 (15 psi). The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (0 to 50% EtOAc/petroleum ether) to give the title compound. MS = 172.6 [M+1] ⁺ .

Intermediate VX-4a

1-(6-Chloro-5-fluoro-4-methylpyridin-3-yl)ethan-1-ol (Schedule BI)

Step 1. 1-(6-Chloro-5-fluoro-4-methylpyridin-3-yl)ethanone: To a suspension of bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.313 mmol) in toluene (6.0 mL) were added tributyl (1-ethoxyvinyl)stannane (1.47 mL, 4.35 mmol) and 2-chloro-3-fluoro-5-iodo-4-methylpyridine (850 mg, 3.13 mmol). The resulting mixture was stirred for 16 h at 90 °C under nitrogen. The reaction mixture was cooled to rt and 6 M aq. HCl (~1 mL) was added. The resulting mixture was stirred for 1 h at rt, then sat. aq. NaHCO ₃ was added and the mixture was washed with sat. aq. potassium fluoride. The mixture was extracted with DCM. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-12% EtOAc/petroleum ether) to give the title compound. MS = 188.0 [M+1] ⁺ .

Step 2. 1-(6-Chloro-5-fluoro-4-methylpyridin-3-yl)ethanol:

The title compound was prepared according to procedures similar to those described above for Intermediate BC-2a, step 1. aq. Na ₂ SO ₄ MS=190.0 [M+1] ⁺ .

Intermediate BJ-5a and BJ-5b

(6-Chloro-5-methylpyridazin-3-yl)methanol and (6-chloro-4-methylpyridazin-3-yl)methanol (Scheme BJ)

Step 1. 3-Chloro-4-methyl-6-vinylpyridazine and 6-chloro-4-methyl-3-vinylpyridazine: To a solution of 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol) in dioxane (80 mL) and water (40 mL) were added potassium vinyl trifluoroborate (4.11 g, 30.7 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.12 g, 1.53 mmol), and potassium phosphate (13.0 g, 61.3 mmol). The reaction mixture was stirred at 90 °C under nitrogen for 16 h. The reaction mixture was cooled to rt and water was added. The mixture was filtered and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to afford the title compounds as a mixture. _MS =155.0 [M+1] ⁺ .

Step 2. 6-Chloro-4-methylpyridazine-3-carbaldehyde and 6-chloro-5-methylpyridazine-3-carbaldehyde: To a solution of a mixture of 3-chloro-4-methyl-6-vinylpyridazine and 6-chloro-4-methyl-3-vinylpyridazine (1.80 g, 5.82 mmol) in dioxane (80.0 mL) and water (20 mL) were added osmium tetroxide (25.0 mL, 1.97 mmol, 2% in water) and sodium periodate (2.49 g, 11.6 mmol). The mixture was stirred at rt for 2 h. To the mixture was added sat. aq. _{Na2SO3 ,} and the resulting mixture was stirred for 10 min. The mixture was extracted with EtOAc and the organic layers were combined and washed with brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give the title compounds as a mixture. MS=157.0 [ _M +1] ⁺ .

Step 3. (6-Chloro-4-methylpyridazin-3-yl)methanol and (6-chloro-5-methylpyridazin-3-yl)methanol: To a solution of a mixture of 6-chloro-4-methylpyridazine-3-carbaldehyde and 6-chloro-5-methylpyridazine-3-carbaldehyde (1.10 g, 3.51 mmol) in methanol (10 mL) cooled to 0 °C was added sodium borohydride (0.199 g, 5.27 mmol). The mixture was stirred at 0 °C for 30 min, then acetone was added to the mixture. The resulting mixture was stirred at rt for 30 min, and the mixture was concentrated under reduced pressure. The crude residue was purified by preparative TLC (petroleum ether/EtOAc, 1:1) to give the title compounds as a mixture. MS=158.6 [M+1] ⁺ .

Intermediate BK3a

1-(2-Chloro-4-methylpyrimidin-5-yl)cyclobutanol (Scheme BK)

To a solution of 5-bromo-2-chloro-4-methylpyrimidine (1.00 g, 4.82 mmol) in THF (10 mL) cooled to -100 °C was added n-butyllithium (2.12 mL, 5.30 mmol, 2.5 M solution in hexane). The reaction mixture was stirred at -100 °C for 30 min. Cerium(III) chloride (1.98 g, 5.30 mmol) was then added as a solution in THF (10 mL) at -100 °C and the resulting mixture was stirred at -100 °C for 30 min. At this point, cyclobutanone (0.507 g, 7.23 mmol) was added at -100 °C. The reaction mixture was stirred at -100 °C for 2 h, then the mixture was stirred at rt for 12 h. The mixture was quenched by adding sat. aq. NH ₄ Cl, then extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 15% EtOAc/petroleum ether) to give the title compound. MS = 199.0 [M+1] ⁺ .

Intermediate BL-4a

(5-Bromo-4-methylpyrimidin-2-yl)methanol (Scheme BL)

Step 1. 5-Bromo-4-methylpyrimidine-2-carbonitrile: A mixture of 5-bromo-2-chloro-4-methylpyrimidine (2.00 g, 9.64 mmol), NaCN (0.510 g, 10.4 mmol), and DABCO (0.389 g, 3.47 mmol) in DMSO (10 mL) and water (10 mL) was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (s, 1H), 2.69 (s, 3H).

Step 2. Methyl 5-bromo-4-methylpyrimidine-2-carboxylate: To a solution of 5-bromo-4-methylpyrimidine-2-carbonitrile (750 mg, 3.79 mmol) in methanol (10.0 mL) was added aq. HCl (10 mL, 122 mmol). After the addition, the mixture was stirred at 80 °C for 1.5 h. The mixture was then cooled to rt, then diluted with water and extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (s, 1H), 3.97 (s, 3H), 2.70 (s, 3H).

Step 3. (5-Bromo-4-methylpyrimidin-2-yl)methanol: The title compound was prepared according to procedures similar to those described above for Intermediate BJ-5a, step 3. Na ₂ SO ₄ ¹ H-NMR (400 MHz, CD ₃ OD) δ 8.74 (s, 1H), 4.66 (s, 2H), 2.62 (s, 3H).

Intermediate BN-5

1-(5-Bromo-4-methyl-3-nitropyridin-2-yl)ethan-1-ol (Scheme BN)

Step 1. 5-Bromo-2-iodo-4-methyl-3-nitropyridine: To a solution of 5-bromo-4-methyl-3-nitropyridine-2-amine (10.0 g, 43.1 mmol) in a mixture of 1,2-dimethoxyethane and toluene (2.5:1, 150 mL) cooled to 0 °C were added copper(I) iodide (2.50 g, 13.1 mmol) and potassium iodide (15.0 g, 90.0 mmol). The reaction mixture was stirred at 0 °C for 30 min, then tert-butyl nitrite (12.0 g, 116 mmol) was added. The reaction mixture was stirred at 60 °C for 14 h. The reaction mixture was cooled to rt, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (20% EtOAc/petroleum ether) to give the title compound. MS=342.8, 344.8 [M+1] ⁺ .

Step 2. 1-(5-Bromo-4-methyl-3-nitropyridin-2-yl)ethanone: The title compound was prepared according to procedures similar to those described above for Intermediate B1-4a, step 1. MS=258.9, 260.9. [M+1] ⁺ .

Step 3. 1-(5-Bromo-4-methyl-3-nitropyridin-2-yl)ethanol: The title compound was prepared according to procedures similar to those described above for Intermediate BJ-5a, Step 3. MS=260.9, 262.9. [M+1] ⁺ .

Intermediate VO-5

1-(1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)ethan-1-ol (Scheme BO)

Step 1. Methyl 1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylate: A solution of methyl 1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridine-4-carboxylate (2.00 g, 10.4 mmol) in phosphorus(V) oxychloride (9.65 mL, 104 mmol) was stirred at 90 °C for 4 h. The reaction mixture was cooled to rt and then quenched by addition of sat. aq. NaHCO ₃ . Additional sat. aq. NaHCO ₃ was added to adjust pH to ~7. The resulting mixture was extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 20% EtOAc/petroleum ether) to give the title compound. MS=212.1 [M+1] ⁺ .

Step 2. (1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methanol: To a solution of methyl 1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylate (2.00 g, 9.45 mmol) in THF (50 mL) was added DIBAL (18.9 mL, 18.9 mmol) at 0 °C. The resulting mixture was stirred at rt for 2 h. The mixture was quenched by adding water and then extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS = 184.1 [M+1] ⁺ .

Step 3. 1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde: The title compound was prepared in a similar manner as described for 5-bromo-6-methylpicolinaldehyde (en route to Intermediate BE-4a). MS=182.1 [M+1] ⁺ .

Step 4. 1-(1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)ethanol: The title compound was prepared similarly as described for 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol (Intermediate BE-4a). MS=198.1 [M+1] ⁺ .

Intermediate VR-5

(4-Chloro-[1,3]dioxolo[4,5-c]pyridin-7-yl)methanol (Scheme BP)

Step 1: 5-Bromo-2-chloro-4-methoxypyridin-3-ol: A solution of 5-bromo-2-chloro-4-methoxypyridine (5.60 g, 25.2 mmol) in THF (80 mL) was cooled to -78 °C. To this solution was added dropwise a solution of LDA (13.8 mL, 27.7 mmol, 2 M in hexanes) and the resulting solution was stirred at -78 °C for 30 min. Trimethyl borate (6.54 g, 62.9 mmol) was added and the reaction mixture was continued to stir at -78 °C for 2 h, after which hydrogen peroxide (6.61 mL, 76 mmol) was added. The mixture was allowed to warm to 0°C with stirring for 2 h, then sodium dithionite (20 g in 20 mL water) was added dropwise. The mixture was adjusted to pH=3 with 2N HCl and extracted with ethyl acetate. The organic layers were dried, concentrated and the residue was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to give the title compound. ¹ H NMR (400 MHz, _CDCl3 ) δ 8.04 (s, 1H), 4.08 (s, 3H); MS=239.9 (M+1).

Step 2: 5-Bromo-2-chloropyridine-3,4-diol: To a solution of 5-bromo-2-chloro-4-methoxypyridin-3-ol (2.00 g, 8.39 mmol) in DCM (30 mL) was added Br2S (1.59 mL, 16.8 mmol) at 0 °C. The mixture was stirred at rt for 16 h, after which time the mixture was cooled to 0 °C and quenched with MeOH, concentrated and purified by silica gel chromatography (0-30% MeOH/DCM) to give the title compound. MS = 225.8 (M+1).

Step 3: 7-Bromo-4-chloro-[1,3]dioxolo[4,5-c]pyridine: To a solution of 5-bromo-2-chloropyridine-3,4-diol (0.90 g, 4.0 mmol) in DMF (15 mL) were added _{Cs2CO3 (} 2.61 g, 8.02 mmol) and dibromomethane (0.836 g, 4.81 mmol) and the resulting mixture was heated to 60 °C for 16 h. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to give a crude residue, which was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to give the title compound. MS = 237.8 (M+1).

Step 4: 4-Chloro-[1,3]dioxolo[4,5-c]pyridine-7-carbaldehyde: To a solution of 7-bromo-4-chloro-[1,3]dioxolo[4,5-c]pyridine (300 mg, 1.27 mmol) in THF (4 mL) was added n-butyllithium (0.558 mL, 1.396 mmol, 2.5 M in hexane) at -78 °C. After stirring the mixture at -78 °C for 0.5 h, DMF (0.49 mL, 6.3 mmol) (dissolved in 0.5 mL THF) was added dropwise and the reaction mixture was continued stirring at -78 °C for 1 h. The mixture was poured into sat. aq. NH ₄ Cl and extracted with EtOAc. The organic layer was washed with brine, dried ( _Na2SO4 ) and concentrated to _give a crude residue which was purified by preparative TLC eluting with EtOAc to give the title compound. ¹ H NMR (400 MHz, _CDCl3 ) δ 10.11 (s, 1H), 8.39 (s, 1H), 6.31 (s, 2H). MS=186.0 (M+1).

Step 5: (4-Chloro-[1,3]dioxolo[4,5-c]pyridin-7-yl)methanol: To a solution of 4-chloro-[1,3]dioxolo[4,5-c]pyridine-7-carbaldehyde (190 mg, 1.02 mmol) in THF (2 mL) and MeOH (0.2 mL) was added sodium borohydride (39 mg, 1.02 mmol) at 0 °C. After stirring the mixture at 0 °C for 5 min, acetone was added to the mixture and heated to rt for 1 h. The reaction mixture was concentrated to give a crude residue which was purified by preparative TLC eluting with EtOAc to give the title compound. MS = 188.0 (M+1).

Intermediate BQ-6

(1R,5S)-3-(2,2-Difluoro-7-(1-hydroxyethyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (Scheme BQ)

Step 1: 2-Chloropyridine-3,4-diol. To a solution of 2-chloro-4-methoxypyridin-3-ol (9.00 g, 56.4 mmol) in DCM (200 mL) was added _BBr3 (5.33 mL, 56.4 mmol) at 0 °C. The mixture was stirred at rt for 12 h. The mixture was quenched with MeOH and concentrated to give a crude residue, which was purified by silica gel chromatography (10-20% MeOH/DCM) to give the title compound. MS = 146.1 (M+1).

Step 2: 4-Chloro-[1,3]dioxolo[4,5-c]pyridine-2-thione. 2-Chloropyridine-3,4-diol (8.00 g, 55.0 mmol) and DMAP (26.9 g, 220 mmol) were suspended in DCM (200 mL) and the resulting mixture was cooled to 0 °C. Thiophosgene (12.0 mL, 165 mmol) was added dropwise and after 10 min the reaction mixture was warmed to rt. After 1 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated to give a crude residue, which was purified by silica gel chromatography (10-30% EtOAc/petroleum ether) _to give the title compound. MS=188.0 (M+1).

Step 3: 4-Chloro-2,2-difluoro-[1,3]dioxolo[4,5- c ]pyridine. 4-Chloro-[1,3]dioxolo[4,5- c ]pyridine-2-thione (2.00 g, 10.7 mmol) was dissolved in DCM (20 mL) and cooled to -78 °C. Pyridine hydrofluoride (20.0 mL, 155 mmol) was added dropwise, followed by the addition of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (9.14 g, 32.0 mmol) in several portions. After 20 min, the reaction mixture was warmed to -20 °C. After an additional 40 min, the reaction pH was adjusted to 7 by careful addition of 5 M NaOH. Sodium thiosulfate was added and the resulting mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give a crude residue which was purified by silica gel chromatography (10-30% EtOAc/petroleum ether) to give the title compound. MS = 194.0 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 5.5 Hz, 1H), 7.07 (d, J = 5.1 Hz, 1H).

Step 4: (1R,5S)-3-(2,2-Difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one. To a solution of (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (750 mg, 7.72 mmol), 4-chloro-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridine (1.50 g, 7.75 _mmol ), _Cs2CO3 (7.58 g, 23.3 mmol) and XANTPHOS (224 mg, 0.388 mmol) in 1,4-dioxane (20 mL) was added _Pd2 (dba) ₃ (355 mg, 0.388 mmol). The mixture was degassed and filled with _N2 , and the resulting mixture was heated to 90°C for 14 h. The reaction mixture was cooled to rt and concentrated to give a crude residue, which was purified by silica gel chromatography (30-40% EtOAc/petroleum ether) to give the title compound. MS=255.1 (M+1). ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (d, J = 5.3 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 4.34 (dd, J = 5.1, 10.6 Hz, 1H), 3.76-3.79 (m, 1H), 2.08-2.11 (m, 1H), 1.28 (br.dd, J = 3.1, 8.1 Hz, 1H), 0.95 (q, J = 4.3 Hz, 1H), 0.84-0.88 (m, 1H).

Step 5: (1R,5S)-3-(7-Bromo-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one. To a solution of (1R,5S)-3-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (500 mg, 1.97 mmol) in AcOH (10 mL) and TFA (1.0 mL, 13 mmol) was added 2-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (619 mg, 2.36 mmol), and the resulting mixture was heated to 100 °C. After 16 h, the reaction mixture was concentrated to give a crude residue which was purified by reverse phase preparative HPLC (C18 stationary phase, ACN/water + 0.1% TFA) to give the title compound. MS = 332.9, 334.9 (M+1). ¹ H NMR (400 MHz, _CDCl3 ) δ 8.20 (s, 1H), 4.31 (dd, J=4.9, 10.8 Hz, 1H), 3.76 (d, J=11.0 Hz, 1H), 2.04-2.18 (m, 2H), 1.30 (dt, J=5.1, 8.0 Hz, 1H), 0.88-1.01 (m, 1H).

Step 6: (1R,5S)-3-(7-Acetyl-2,2-difluoro-[1,3]dioxolo[4,5-c]-pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one. To a solution of (1R,5S)-3-(7-bromo-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (300 mg, 0.901 mmol) and tributyl(1-ethoxyvinyl)stannane (395 µL, 1.17 mmol) in toluene (5 mL) was added Pd( _PPh3 ) _{2Cl2 (} 63 mg, 0.090 mmol) and the resulting mixture was heated to 90 °C. After 14 h, the reaction mixture was cooled to rt, 6 M HCl (2 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with sat. aq. KF, stirred for 1 h and extracted with EtOAc. The combined organic layers _were dried over _Na2SO4 , filtered and concentrated to give a crude residue which was purified by silica gel chromatography (30-50% EtOAc/petroleum ether) to give the title compound. MS=297.1 (M+1).

Step 7: (1R,5S)-3-(2,2-Difluoro-7-(1-hydroxyethyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one. To a solution of (1R,5S)-3-(7-acetyl-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (250 mg, 0.844 mmol) in THF (3 mL) and MeOH (0.3 mL) at 0 °C was added NaBH ₄ (31.9 mg, 0.844 mmol). The resulting mixture was stirred at 0 °C for 1 h, at which time excess acetone was added and the resulting mixture was warmed to rt. After 1 h, the reaction mixture was concentrated to give a crude residue, which was purified by silica gel chromatography (40-50% EtOAc/petroleum ether) to give the title compound. MS = 299.1 (M+1).

Intermediate CA-6a and CA-6b

(15,5R)-3-Azabicyclo[3.1.0]hexan-2-one and (1R,5S)-3-Azabicyclo[3.1.0]hexan-2-one (Scheme CA)

Step 1. 3-Benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione: The following sequence was performed in two batches in parallel on an equivalent scale. The batches were combined for post reaction workup. To a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (400 g, 3.57 mol) in acetic acid (2.00 L) at 15 °C was added benzylamine (574 g, 5.35 mol). The reaction mixture was stirred at 120 °C for 12 h. The reactions were cooled to rt and combined by pouring into water. The resulting mixture was stirred for 30 min then filtered. The filtered solid was washed with water then dissolved by addition of EtOAc. The mixture was washed with water and brine, then dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound. MS=202.1 [M+ ₁ ] ⁺ .

Step 2. 3-Benzyl-3-azabicyclo[3.1.0]hexane: The following sequence was carried out in three batches in parallel on an equivalent scale. To a suspension of LAH (87.9 g, 2.32 mol) in THF (700 mL) was added a solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (333 g, 1.65 mol) in THF (1.40 L) dropwise at 10 °C. The resulting mixture was stirred at 40 °C for 12 h, then cooled to 0 °C. Water (87 mL), aq. sodium hydroxide (87 mL, 15% v/v), then water (261 mL) were added dropwise sequentially to the mixture. _Na2SO4 was added to the mixture and the resulting mixture _was stirred for 30 min and then filtered. The filtered solid was washed with EtOAc and the filtrate was concentrated under reduced pressure to give the title compound. MS=174.2 [M+1] ⁺ .

Step 3. tert-Butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate: The following sequence was performed in 8 batches in parallel on an equivalent scale. To a solution of 3-benzyl 3-azabicyclo[3.1.0]hexane (110 g, 635 mmol) and di-tert-butyl dicarbonate (208 g, 952 mmol) in MeOH (770 mL) was added palladium on carbon (11.0 g, 10.4 mmol, 10 wt %). The reaction mixture was stirred at 40 °C for 2 h under H ₂ (45 psi). The reactions were run in parallel and combined and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% to 20% EtOAc/petroleum ether) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.47-3.59 (m, 2H), 3.30-3.34 (m, 2H), 1.44-1.46 (m, 11H), 0.63-0.68 (m, 1H), 0.15-0.18 (m, 1H), 0.15-0.18 (m, 1H).

Step 4. tert-Butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate. The following sequence was performed in two batches in parallel on an equivalent scale. To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (330 g, 1.80 mol) and ruthenium trichloride (11.2 g, 54.0 mmol) in EtOAc (1.6 L) and water (1.60 L) at rt was added sodium perioxide (770 g, 3.60 mol) portionwise. The resulting mixture was stirred for 12 h. The parallel reactions were combined and filtered. The layers were separated and the aq. layer was extracted with EtOAc. The organic layers were combined and washed with sat. aq. sodium dithionite, dried over _Na2SO4 , _filtered , then concentrated under reduced pressure to give the title compounds as a racemate. ¹ H NMR (400 MHz, _CDCl3 ) δ 3.82-3.78 (m, 1H), 3.72-3.69 (m, 1H), 2.05-2.00 (m, 1H), 1.90-1.89 (m, 1H), 1.52 (s, 9H), 1.26-1.18 (m, 1H), 0.80-0.78 (m, 1H). The enantiomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRAEPAK IC; 0.1% _NH3H2O -EtOH, start B 25%, end B 25%) to afford the individual isomeric compounds in pure form. The faster eluting enantiomer of _the title compounds (Intermediate CA-5a). Slower eluting enantiomer of the title compounds (Intermediate CA-5a): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 3.81-3.77 (m, 1H), 3.72-3.68 (m, 1H), 2.00-1.99 (m, 1H), 1.99-1.87 (m, 1H), 1.48 (s, 9H), 1.25-1.17 (m, 1H), 0.78-0.77 (m, 1H).

Step 5. (1S,5R)-3-Azabicyclo[3.1.0]hexan-2-one and (1R,5S)-3-Azabicyclo[3.1.0]hexan-2-one: A mixture of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (650 g, 3.30 mol) in HCl/EtOAc (4 M, 3.25 L) at 15 °C for 1 h. The reaction mixture was filtered and the filtered solid was washed with EtOAc (2.0 L, 1.0 L) then dried to give the title compounds as a mixture of enantiomers. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (br.s, 1H), 7.09 (br.s, 1H), 3.35-3.31 (m, 1H), 3.14-3.12 (m, 1H), 1.92-1.88 (m, 1H), 1.61-1.60 (m, 1H), 1.02-0.97 (m, 1H), 0.45-0.42 (m, 1H).

Step 5. (1R,5S)-3-Azabicyclo[3.1.0]hexan-2-one: A mixture of tert-butyl (1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (slower eluting enantiomer from previous step, 370 g, 1.88 mol) in HCl/EtOAc (4 M, 1.4 L) at 0~10 °C for 1 h. The reaction mixture was filtered and the filtered solid was washed with EtOAc (500 mL) then dried to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.0 (s, 1H), 7.07 (s, 1H), 3.34-3.30 (m, 1H), 3.13 (d, J=10.4 Hz, 1H), 1.90-1.87 (m, 1H), 1.60-1.59 (m, 1H), 1.01-0.96 (m, 1H), 0.44-0.41 (m, 1H). MS=98.1 [M+1] ⁺ .

Intermediate CA-7

(1R,5S)-3-Azabicyclo[3.1.0]hexane-2-thione (Scheme CA)

To a vial containing (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 1.03 mmol) was added DCM (5.2 mL). In a separate vial, DCM (5.2 mL) was added to Lawesson's reagent (208 mg, 0.520 mmol). The lactam solution was slowly added to Lawesson's reagent solution and stirred at rt for 15 h. The reaction mixture was concentrated and purified by silica gel chromatography (EtOAc/hexane). The fractions were combined and concentrated under reduced pressure to give the title compound. MS = 114.0 [M+1] ⁺ .

Examples 1 and 2

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane)-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAA)

Step 1. 5-Bromo-2-(1-bromoethyl)-4-methylpyrimidine: To a mixture of 1-(5-bromo-4-methylpyrimidin-2-yl)ethan-1-ol (550 mg, 2.53 mmol) and triphenylphosphine (997 mg, 3.80 mmol) in THF (8.5 mL) cooled to 0 °C was added carbon tetrabromide (1.26 g, 3.80 mmol) and the mixture was stirred at rt for 6 h. The mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel (EtOAc/hexane) to give the title compound. MS = 280.9 [M+1] ⁺ .

Step 2. tert-Butyl (1-(1-(5-bromo-4-methylpyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate: To a solution of 5-bromo-2-(1-bromoethyl)-4-methylpyrimidine (210 mg, 0.750 mmol) in DMF (10 mL) were added tert-butyl (1H-pyrazol-4-yl)carbamate (210 mg, 0.750 mmol) and _Cs2CO3 (733 mg, 2.25 mmol) at rt. The mixture was stirred at rt for 16 _h . The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound. MS=284.1 [M+1] ⁺ .

Step 3. tert-Butyl (1-(1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate: A mixture of (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (15 mg, 0.16 mmol), tert-butyl (1-(1-(5-bromo-4-methylpyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate (30 mg, 0.078 mmol), Xantphos-Pd-G3 (7.4 mg, 7.9 μmol), and cesium carbonate (77 mg, 0.24 mmol) in 1,4-dioxane (0.79 mL) was stirred at 100 °C for 3 h. After cooling to rt, the mixture was filtered (eluting with additional EtOAc). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (MeOH/DCM) to give the title compound. MS = 399.3 [M+1] ⁺ .

Step 4. (1R,5S)-3-(2-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-5-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 4. MS=299.1 [M+1] ⁺ .

Step 5. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To the mixture 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (127 mg, 0.402 mmol), (1R,5S)-3-(2-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-5-yl)-3-azabicyclo[3.1.0]hexan-2-one (80.0 mg, 0.268 mmol) in pyridine (2.68 mL) cooled to 0 °C was added EDC (103 mg, 0.536 mmol). The reaction mixture was stirred at rt overnight, then sat. aq. NaHCO ₃ was added and the mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (stationary phase C18, ACN/water + 0.1% TFA) to afford a mixture of diastereomeric title compounds. The isomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD-H; neutral EtOH, start B 40%, end B 40%) to afford the individual isomers in pure form. The faster eluting diastereomer of the title compounds (Example 1): ¹ H NMR (600 MHz, CD ₃ OD) δ 8.85 (d, J=2.4 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.90-7.74 (m, 1H), 7.75-7.59 (m, 2H), 6.94 (t, J=54.6 Hz, 1H), 5.70 (q, J=7.1 Hz, 1H), 4.05 (dd, J=10.2, 5.9 Hz, 1H), 3.75-3.54 (m, 1H), 2.99 (s, 3H), 2.36 (s, 3H), 2.21-2.13 (m, 1H), 2.09-1.97 (m, 1H), 1.93 (d, J=7.1 Hz, 3H), 1.36-1.24 (m, 2H), 0.93 (d, J=3.4 Hz, 1H). MS=597.1 [M+1] ⁺ . Slower eluting diastereomer of the title compounds (Example 2): ¹ H NMR (600 MHz, CD ₃ OD) δ 8.85 (d, J=2.4 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.84-7.78 (m, 1H), 7.69-7.64 (m, 2H), 6.94 (t, J=54.6 Hz, 1H), 5.70 (q, J=7.1 Hz, 1H), 4.05 (dd, J=10.2, 5.9 Hz, 1H), 3.67 (d, J=10.2 Hz, 1H), 2.99 (s, 3H), 2.36 (s, 3H), 2.21-2.14 (m, 1H), 2.08-2.01 (m, 1H), 1.93 (d, J=7.1 Hz, 3H), 1.36-1.25 (m, 1H), 0.96-0.87 (m, 1H). MS=597.1 [M+1]+.

Example 21

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (Scheme AAB)

Step 1. 3-(Bromomethyl)-6-chloropyridazine: A mixture of 3-chloro-6-methylpyridazine (1 g, 7.78 mmol), NBS (1.384 g, 7.78 mmol), and AIBN (0.128 g, 0.778 mmol) in _CCl4 (26 mL) was stirred at 90 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane) to give the title compound. MS = 208.9 [M+1] ⁺

Step 2. tert-Butyl (1-((6-chloropyridazin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate: To a solution of 3-(bromomethyl)-6-chloropyridazine (530 mg, 2.55 mmol) in DMF (10 mL) were added tert-butyl (1H-pyrazol-4-yl) carbamate (702 mg, 3.83 mmol) and cesium carbonate (2.50 g, 7.66 mmol) at rt. The mixture was stirred at rt for 16 h, diluted with EtOAc and washed with water then brine. The organic layer was dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound. MS=310.0 [M+1] ⁺ .

Step 3. tert-Butyl (1-((6-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate: To a suspension of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (500 mg, 0.936 mmol) in DCM (20 mL) was added mCPBA (441 mg, 2.0 mmol) at rt. The mixture was stirred at rt for 1 h, diluted with DCM, washed with 1 N aq. Na ₂ CO ₃ . The organic layer was dried ( _Na2SO4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane _to give 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide. A mixture of tert-butyl (1-((6-chloropyridazin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate (250 mg, 0.807 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (118 mg, 1.21 mmol), ethylenediamine (5.5 μL, 0.081 mmol), and CuI (15.4 mg, 0.081 mmol) in 1,4-dioxane (4.0 mL) was stirred at 100 °C for 2 h. The mixture was cooled to rt and filtered through Celite® (rinsing with DCM). The filtrate was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound. MS=371.1 [M+1] ⁺ .

Step 4. (1R,5S)-3-(6-((4-Amino-1H-pyrazol-1-yl)methyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 4. MS=271.1 [M+1] ⁺ .

Step 5. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures analogous to those described in Example 1, Step 5 above. aq. ¹ H NMR (600 MHz, CD ₃ OD) δ 8.88 (d, J=1.9 Hz, 1H), 8.55 (d, J=9.3 Hz, 1H), 8.30 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.45 (d, J=9.4 Hz, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 4.26 (dd, J=11.5, 5.6 Hz, 1H), 4.20 (d, J=11.6 Hz, 1H), 3.01 (s, 3H), 2.22 (p, J=6.0 Hz, 1H), 2.16 (d, J=4.5 Hz, 1H), 1.36-1.30 (m, 1H), 0.94-0.86 (m, 1H). MS=555.3 [M+1] ⁺

Examples 22 and 23

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide u6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (AAC diagram)

Step 1. 5-(1-Bromoethyl)-4-methyl-2-(methylthio)pyrimidine: The title compound was prepared according to procedures similar to those described in Example AAA-10a, Step 1 above. MS=248.9 [M+1] ⁺ .

Step 2. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide. To a solution of 5-(1-bromoethyl)-4-methyl-2-(methylthio)pyrimidine (310 mg, 1.25 mmol) in DMF (3.4 mL) were added 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1H-pyrazol-4-yl)pyrazine-2-carboxamide (461 mg, 1.25 mmol) and cesium carbonate (1.23 g, 3.76 mmol) at rt. The mixture was stirred at rt for 16 h, diluted with EtOAc, then washed with water and brine. The organic layer was dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EtOAc/hexane) to give the title compound. MS=533.9 [M+1] ⁺ .

Step 3. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To a suspension of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (500 mg, 0.936 mmol) in DCM (20 mL) was added mCPBA (441 mg, 2.00 mmol). The mixture was stirred at rt for 1 h, diluted with DCM, washed with 1 N aqueous sodium carbonate. The organic layer was dried ( _Na2SO4 ), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane _to give the title compound. MS=565.9 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: Mixture 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (200 mg, 0.353 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (137 mg, 1.40 mmol) and cesium carbonate (461 mg, 1.40 mmol) in 1,4-dioxane (3.5 mL) were stirred at 90°C for 30 min. The mixture was cooled to rt and purified by preparative reversed-phase HPLC (stationary phase C18, ACN/water + 0.1% TFA) to afford the diastereomeric title compound as a mixture. The isomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALEL IA, 0.1% DEA-EtOH, start B 35%, end B 35%) to afford the individual isomers in pure form. Faster eluting isomer of the title compounds (Example 22): ¹ H NMR (600 MHz, CD ₃ OD) δ 9.38 (s, 1H), 9.01 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.00 (t, J=54.7 Hz, 1H), 5.80 (q, J=7.0 Hz, 1H), 4.18 (dd, J=11.5, 5.0 Hz, 1H), 3.99 (d, J=11.5 Hz, 1H), 2.43 (s, 3H), 2.10 (dt, J=8.2, 4.5 Hz, 2H), 1.89 (d, J=7.0 Hz, 3H), 1.27 (td, J=7.7, 4.1 Hz, 1H), 0.82 (k, J=3.7 Hz, 1H). MC=583.0 [M+1] ⁺ . Slower eluting isomer of the title compounds (Example 23): ¹ H NMR (600 MHz, CD ₃ OD) δ 9.39 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.41 (d, J=3.7 Hz, 1H), 8.26 (s, 1H), 7.87-7.81 (m, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.00 (t, J=54.7 Hz, 1H), 5.85 (q, J=7.0 Hz, 1H), 4.18 (dq, J=11.3, 4.5, 4.0 Hz, 1H), 4.05 (d, J=11.5 Hz, 1H), 2.51 (s, 3H), 2.17 (dt, J=8.2, 4.7 Hz, 2H), 1.90 (d, J=6.9 Hz, 3H), 1.37-1.30 (m, 1H), 0.89 (k, J=4.1 Hz, 1H). MS=583.0 [M+1] ⁺ .

Examples 33 and 34

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAD)

Step 1. 5-(Bromomethyl)-4-methyl-2-(methylthio)pyrimidine: To a solution of (4-methyl-2-(methylthio)pyrimidin-5-yl)methanol (500 mg, 2.94 mmol) in DCM (5.0 mL) cooled to 0 °C were added carbon tetrabromide (1.267 mg, 3.82 mmol) and triphenylphosphine (1.00 g, 3.82 mmol). The mixture was stirred at 0 °C for 2 h, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 20% EtOAc/hexanes) to give the title compound. MS = 234.9.0 [M+1] ⁺ .

Step 2. tert-Butyl (1-((4-methyl-2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate: To a solution of tert-butyl (1H-pyrazol)-4-yl)carbamate (754 mg, 4.12 mmol) in DMF (10.0 mL) were added 5-(bromomethyl)-4-methyl-2-(methylthio)pyrimidine (640 mg, 2.75 mmol) and cesium carbonate (3.58 g, 11.0 mmol). The mixture was stirred at rt for 16 h, then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5 to 60% EtOAc/hexane) to give the title compound. MS=336.0 [M+1] ⁺ .

Step 3. tert-Butyl (1-((4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate: The title compound was prepared according to procedures similar to those described in Example 22, Step 3 above. aq. MS=368.0 [M+1] ⁺ .

Step 4. tert-Butyl (1-((4-methyl-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate: A mixture of (1-((4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate (660 mg, 1.80 mmol), 3-azabicyclo[3.1.0]hexan-2-one (523 mg, 5.39 mmol), and cesium carbonate (1.76 g, 5.39 mmol) in 1,4-dioxane (18.0 mL) was stirred at 90°C for 30 min. The reaction mixture was cooled to rt and then filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (MeOH/DCM) to afford the title compound. MS=385.1 [M+1] ⁺ .

Step 5. 3-(5-((4-Amino-1H-pyrazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 4. MS=285.1 [M+1] ⁺ .

Step 6. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures analogous to those described in Example above. 1, step 5. The isomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRACEL AS-H; MeOH start B 25%, end B 25%) to afford the individual isomers in pure form. The faster eluting isomer of the title compounds (Example 33): ¹ H NMR (600 MHz, CD ₃ OD) δ 8.85 (d, J=2.4 Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.84-7.78 (m, 1H), 7.70 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 6.93 (t, J=54.6 Hz, 1H), 5.37 (s, 2H), 4.19 (dd, J=11.5, 5.1 Hz, 1H), 4.00 (d, J=11.1 Hz, 1H), 2.98 (s, 3H), 2.46 (s, 3H), 2.14-2.08 (m, 2H), 1.27 (dt, J=12.6, 4.4 Hz, 1H), 0.83 (k, J=4.2 Hz, 1H). MS=583.0 [M+1] ⁺ . Slower eluting isomer of the title compounds (Example 34): ¹ H NMR (600 MHz, CD ₃ OD) δ 8.85 (d, J=2.4 Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.84-7.78 (m, 1H), 7.70 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 6.93 (t, J=54.6 Hz, 1H), 5.37 (s, 2H), 4.19 (dd, J=11.5, 5.1 Hz, 1H), 4.00 (d, J=11.1 Hz, 1H), 2.98 (s, 3H), 2.46 (s, 3H), 2.14-2.08 (m, 2H), 1.31-1.24 (m, 1H), 0.92-0.80 (m, 1H). MC=583.0 [M+1] ⁺ .

Examples 37 and 38

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

Step 1. 3-Chloro-4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine: To a solution of a mixture of 1-(6-chloro-4-methylpyridazin)-3-yl)ethanol and 1-(6-chloro-5-methylpyridazin-3-yl)ethanol (480 mg, 1.39 mmol), 4-nitro-1H-pyrazole (377 mg, 3.34 mmol), and triphenylphosphine (875 mg, 3.34 mmol) in THF (10 mL) was added di-tert-butyl azodicarboxylate (960 mg, 4.17 mmol) at 0 °C. The reaction mixture was stirred for 2 h, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 4% EtOAc/petroleum ether) to give the title compound as a mixture with 6-chloro-4-methyl-3-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine. MS = 267.9 [M+1] ⁺ .

Step 2. (1R,5S)-3-(4-Methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of a mixture of 3-chloro-4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine and 6-chloro-4-methyl-3-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine (600 mg, 1.12 mmol) in dioxane (10.0 mL) was added (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (218 mg, 2.24 mmol), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (130 mg, 0.224 mmol), tris(dibenzylideneacetone)dipalladium (205 mg, 0.224 mmol) and cesium carbonate (730 mg, 2.24 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to rt, filtered and the filtrate was concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (30% EtOAc/petroleum ether) followed by preparative TLC (50% EtOAc/petroleum ether) to afford the title compound. MS = 329.2 [M+1] ⁺ .

Step 3. (1R,5S)-3-(6-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of (1R,5S)-3-(4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (80.0 mg, 0.244 mmol) in a mixture of EtOAc (0.6 mL) and MeOH (0.2 mL) was added platinum(IV) oxide (5.5 mg, 0.024 mmol). The reaction mixture was stirred at rt for 2 h under _H2 (15 psi). The reaction mixture was filtered and then concentrated under reduced pressure to give the title compound. MS=299 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: Solution (1R,5S)-3-(6-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (16.0 mg, 54 μmol), 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (16.2 mg, 54 μmol), pyridine (22 μL, 0.268 mmol), and EDC (21 mg, 0.11 mmol) in DCM (2.0 mL) were stirred at rt for 16 h. The mixture was concentrated under reduced pressure and purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 45%, end B 75%) with to obtain a diastereomeric mixture of the title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD; neutral IPA, start B 55%, end B 55%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 37): ¹ H NMR (500 MHz, CD ₃ OD) δ 9.30 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.03-6.79 (m, 1H), 5.76 (d, J=1.2 Hz, 1H), 4.37 (dd, J=5.8, 10.4 Hz, 1H), 3.71 (d, J=10.1 Hz, 1H), 2.15-2.11 (m, 1H), 2.0 V (s, 3H), 1.96 (br s, 1H), 1.90 (d, J=7.2 Hz, 3H), 1.23 (dt, J=4.7, 8.0 Hz, 1H), 0.90-0.86 (m, 1H). MC=583.2 [M+1] ⁺ . Slower eluting diastereomer of the title compounds (Example 38): ¹ H NMR (500 MHz, CD ₃ OD) δ 9.30 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.24 (s, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.26 (s, 1H), 7.04-6.78 (m, 1H), 5.77 (d, J=7.2 Hz, 1H), 4.37 (dd, J=5.9, 10.5 Hz, 1H), 3.71 (d, J=9.9 Hz, 1H), 2.16-2.10 (m, 1H), 2.08 (s, 3H), 1.97 (br.s, 1H), 1.90 (d, J=7.0 Hz, 3H), 1.27-1.22 (m, 1H), 0.91-0.86 (m, 1H). MS=583.2 [M+1] ⁺ .

Examples 39 and 40

6-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((5)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane)-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

Step 5. 6-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((5)-1-(5-methyl-6-(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To the solution 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (140 mg, 0.421 mmol) and (1R,5S)-3-(6-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (151 mg, 0.505 mmol) in pyridine (2.0 mL) was added EDC (161 mg, 0.842 mmol). After complete addition, the reaction mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure and the crude residue was purified by reversed phase preparative HPLC (stationary phase C18, water (0.1% TFA) - ACN, start B 37%, end B 67%) to give _a diastereomeric mixture of the title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRAL PAK AD; 0.1% _NH3H2O -IPS, start B 50%, end B 50%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 39): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.32 (s, 1H), 7.77 (s, 1H), 7.74-7.68 (m, 1H), 7.36 (d, J=0.8 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.93 (t, J=72.8 Hz, 1H), 5.85 (q, J=7.3 Hz, 1H), 4.47 (dd, J=10.6, 5.9 Hz, 1H), 3.82 (d, J=9.4 Hz, 1H), 2.98 (s, 3H), 2.27-2.20 (m, 1H), 2.18 (d, J=0.8 Hz, 3H), 2.10-2.03 (m, 1H), 2.00 (d, J=7.4 Hz, 3H), 1.37-1.32 (m, 1H), 1.01-0.96 (m, 1H). MS=613.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 40): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.31 (s, 1H), 7.77 (s, 1H), 7.71 (t, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.93 (t, J=72.8 Hz, 1H), 5.86 (q, J=7.0 Hz, 1H), 4.47 (dd, J=10.6, 5.9 Hz, 1H), 3.81 (d, J=9.4 Hz, 1H), 2.98 (s, 3H), 2.27-2.20 (m, 1H), 2.18 (s, 3H), 2.10-2.04 (m, 1H), 2.00 (d, J=7.0 Hz, 3H), 1.37-1.33 (m, 1H), 1.01-0.96 (m, 1H). MS=613.2 [M+1] ⁺ .

Example 41

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

Step 1. 2-Bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridine: To a solution of (6-bromo-5-methylpyridin-3-yl)methanol (10.0 g, 49.5 mmol), 4-nitro-1H-pyrazole (8.39 g, 74.2 mmol), and triphenylphosphine (19.5 g, 74.2 mmol) in THF (200 mL) cooled to 0 °C was added diisopropyl azodicarboxylate (14.4 mL, 74.2 mmol). After complete addition, the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/hexane) to give the title compound. MS=297.0, 299.0 [M+1] ⁺ .

Step 2. (1R,5S)-3-(3-Methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a vessel containing [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 4.69 g, 4.95 mmol), cesium carbonate (48.4 g, 148 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (7.21 g, 74.2 mmol) and 2-Bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridine (14.7 g, 49.5 mmol) was added 1,4-dioxane (200 mL) under nitrogen atmosphere at rt. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 6% MeOH/DCM) to give the title compound. MS = 314.1 [M+1] ⁺ .

Step 3. (1R,5S)-3-(5-((4-Amino-1H-pyrazol-1-yl)methyl)-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a flask containing (1R,5S)-3-(3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16.1 g, 17.5 mmol), iron (7.80 g, 140 mmol), and NH ₄ Cl (9.34 g, 175 mmol) were added EtOH (70 mL) and water (18 mL) at rt. The resulting mixture was stirred at 80°C for 6 h. The reaction mixture was cooled to rt and filtered through a pad of Celite® (eluting with additional DCM). The filtrate was concentrated under reduced pressure and the resulting residue was suspended in EtOH and filtered to give the title compound. MS=284.1 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To a solution of (1R,5S)-3-(5-((4-amino-1H-pyrazol-1-yl)methyl)-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16.5 g, 17.5 mmol) in ACN (87 mL) cooled to 0°C was added 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (6.92 g, 21.8 mmol) and HATU (8.30 g, 21.8 mmol) followed by the addition of DIEA (9.15 mL, 52.4 mmol). The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 10% MeOH/DCM) to give the title compound. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.77 (s, 1H), 8.95 (d, J=3.4 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.15 (s, 1H), 7.75-7.66 (m, 2H), 7.60 (s, 1H), 7.46 (d, J=1.9 Hz, 1H), 6.60 (t, J=54.0 Hz, 1H), 5.27 (s, 2H), 4.42-4.33 (m, 1H), 3.68 (d, J=10.0 Hz, 1H), 3.15 (s, 3H), 2.17 (s, 3H), 2.09-2.00 (m, 2H), 1.27-1.23 (m, 1H), 0.91 (k, J=3.8 Hz, 1H). MS=582.0 [M+1] ⁺ .

Examples 42 and 43

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane)-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

Step 1. 2-Chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine: To a solution of 4-nitro-1H-pyrazole (197 mg, 1.74 mmol), 1-(2-chloro-4-methylpyrimidin-5-yl)ethanol (150 mg, 0.869 mmol), and triphenylphosphine (456 mg, 1.738 mmol) in THF (5.0 mL) under nitrogen atmosphere was added di-tert-butyl azodicarboxylate (400 mg, 1.74 mmol). The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (0 to 40% EtOAc/hexane) to give the title compound. MS = 268.0 [M+1] ⁺ .

Step 2. (1R,5S)-3-(4-Methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a mixture of 2-chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (185 mg, 0.691 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (87.0 mg, 0.898 mmol), cesium carbonate (450 mg, 1.38 mmol) in dioxane (5.0 mL) under nitrogen atmosphere was added tris(dibenzylideneacetone)dipalladium (63 mg, 69 μmol) and Xantphos (40 mg, 69 μmol). The reaction mixture was stirred at 90 °C for 16 h, then cooled to rt and concentrated under reduced pressure. The resulting mixture was added water and extracted with EtOAc. The organic layers were combined and washed with brine and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 EtOAc/petroleum ether) to afford the title compound. MS = 329.1 [M+1] ⁺ .

Step 3. (1R,5S)-3-(5-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of (1R,5S)-3-(4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (80 mg, 0.24 mmol) in EtOAc (3.0 mL) and MeOH (1.0 mL) was added platinum(IV) oxide (5.5 mg, 0.024 mmol). The resulting mixture was stirred under hydrogen atmosphere (pressure: 15 psi) at 15°C for 1 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound. MS=299.0 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S))-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compounds were prepared as a starting mixture of diastereomers according to procedures similar to those described above for Intermediate AL-5a, step 3. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD; neutral EtOH, start B 50%, end B 50%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 42): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (d, J=2.5 Hz, 1H), 8.47-8.26 (m, 1H), 8.25-8.07 (m, 1H), 7.83-7.74 (m, 1H), 7.69 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.05-6.77 (m, 1H), 5.77 (q, J=6.9 Hz, 1H), 4.22-4.09 (m, 1H), 4.03-3.91 (m, 1H), 2.95 (s, 3H), 2.41 (s, 3H), 2.12-2.03 (m, 2H), 1.86 (d, J=7.1 Hz, 3H), 1.25 (dt, J=4.7, 8.0 Hz, 1H), 0.84-0.77 (m, 1H). MS=597.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 43): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (d, J=2.5 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.82-7.75 (m, 1H), 7.68 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.17-6.68 (m, 1H), 5.77 (q, J=7.10 Hz, 1H), 4.24-4.11 (m, 1H), 3.96 (d, J=11.3 Hz, 1H), 2.95 (s, 3H), 2.41 (s, 3H), 2.14-2.02 (m, 2H), 1.86 (d, J=7.1 Hz, 3H), 1.25 (td, J=3.9, 8.01 Hz, 1H), 0.80 (k, J=4.1 Hz, 1H). MC=597.2 [M+1] ⁺ .

Examples 44 and 45

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl))-2-fluorophenyl)-N-(1-((R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane)-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

Step 1. (1R,5S)-3-(3-Fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 1, Step 3 above. MS=207.1 [M+1] ⁺ .

Step 2. (1R,5S)-3-(4-Bromo-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: N-Bromosuccinimide (4.00 g, 22.5 mmol) was added to a stirred solution of (1R,5S)-3-(3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (3.09 g, 15.0 mmol) and TFA (1.73 mL, 22.5 mmol) in ACN (50 mL), and the resulting mixture was heated to 50 °C overnight. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting crude mixture was partitioned between sat. aq. NaHCO ₃ and EtOAc. The layers were separated and the aq. layer was extracted with EtOAc. The combined organic layers were concentrated to give a crude residue and purified by silica gel chromatography (0 to 80% EtOAc/hexane) to give the title compound. MS = 284.9, 286.9 [M+1, M+3] ⁺ .

Step 3. (1R,5S)-3-(5-Acetyl-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: (1R,5S)-3-(4-Bromo-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.50 g, 5.26 mmol) was added to a vial containing tetrakis(triphenylphosphine)palladium(0) (608 mg, 0.526 mmol), and the resulting solid mixture was degassed by replacing the atmosphere with N ₂ . Tributyl(1-ethoxyvinyl)tin (2.49 mL, 7.37 mmol) and toluene (26 mL) were added and the resulting mixture was heated to 100 °C overnight. The reaction mixture was cooled to rt, quenched with concentrated HCl and stirred at rt for 1 h. The mixture was then added to sat. aq. NaHCO ₃ and extracted with EtOAc. The combined organic layers were concentrated to give a crude residue and purified by silica gel chromatography (0 to 10% MeOH/DCM) to give the title compound. MS = 249.0 [M+1] ⁺ .

Step 4. (1R,5S)-3-(3-Fluoro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: Sodium borohydride (220 mg, 5.81 mmol) was added to a stirred solution of (1R,5S)-3-(5-acetyl-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.11 g, 4.47 mmol) in a mixture of THF (17 mL) and MeOH (5.5 mL). The resulting mixture was stirred at rt for 30 min, at which time the reaction mixture was concentrated to give the crude mixture, which was added to sat. aq. NaHCO ₃ and extracted with EtOAc. The combined organic layers were dried (MgSO _{4 )} , filtered and concentrated to give a crude residue to afford the title compound. MS=251.0 [M+1] ⁺ .

Step 5. (1R,5S)-3-(3-Fluoro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: (1R,5S)-3-(3-Fluoro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (900 mg, 3.60 mmol) was added to a stirred solution of 4-nitro-1H-pyrazole (529 mg, 4.67 mmol) and triphenylphosphine (1.23 g, 4.67 mmol) in THF (18 mL). DIAD (910 µL, 4.7 mmol) was added and the resulting mixture was heated to 50 °C for 1 h. The reaction mixture was cooled to rt and concentrated to give a crude residue, which was purified by silica gel chromatography (0 to 10% MeOH/DCM) to give the title compound. MS = 346.0 [M+1] ⁺ .

Step 6. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: (1R,5S)-3-(3-Fluoro)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.04 g, 3.00 mmol) was added to a stirred suspension of iron powder (1.68 g, 30.0 mmol) and ammonium chloride (1.93 g, 36.0 mmol) in a mixture of EtOH (11 mL) and water (3.8 mL). The resulting mixture was heated to 50 °C for 2 h, after which the reaction mixture was cooled to rt and filtered. The filtrate was concentrated, sat. aq. NaHCO ₃ was added and extracted with DCM. The combined organic layers were dried (MgSO ₄ ), filtered and concentrated to give the title compound, which was immediately taken up and combined with HATU (1.37 g, 3.60 mmol) and dissolved in DMF (15 mL). 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (1.09 g, 3.60 mmol) and TEA (1.25 mL, 9.00 mmol) were added and the resulting mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layers were washed with water and brine and concentrated to give a crude residue which was purified by silica gel chromatography (0 to 10% MeOH/DCM) to give the title compound. MS=600.0 [M+1] ⁺ . The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK OD-H; neutral EtOH, start B 20%, finish B 20%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 44): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.40 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 6.86-7.17 (m, 1H), 5.85 (q, J=7.3 Hz, 1H), 4.29 (dd, J=10.2, 5.9 Hz, 1H), 3.68 (d, J=10.6 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H), 2.14-2.21 (m, 1H), 2.03 (br.s, 1H), 1.92 (d, J=7.0 Hz, 3H), 1.29-1.31 (m, 1H), 0.86-0.91 (m, 1H). MS=600.1 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 45): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.39 (s, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.81-7.88 (m, 1H), 7.79 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 6.86-7.17 (m, 1H), 5.85 (q, J=6.9 Hz, 1H), 4.27 (dd, J=10.6, 5.9 Hz, 1H), 3.70 (d, J=11.0 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H), 2.13-2.20 (m, 1H), 2.03 (br s, 1H), 1.92 (d, J=7.0 Hz, 3H), 1.32 (br d, J=3.5 Hz, 1H), 0.89 (br d, J=3.1 Hz, 1H). MC=600.1 [M+1] ⁺ .

Examples 150 and 151

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5)-1-(5-fluoro-2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-fluoro-2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane)-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAF)

Step 1. (1R,5S)-3-(3-Fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 2-chloro-3-fluoro-6-methylpyridine (1.00 g, 6.87 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (0.667 g, 6.87 mmol), and cesium carbonate (4.48 g, 13.7 mmol) in dioxane (10 mL) were added Xantphos (0.398 g, 0.687 mmol) and tris(dibenzylideneacetone) dipalladium (556 mg, 0.687 mmol). The reaction mixture was stirred at 100 °C for 12 h. The mixture was cooled to rt and water was added to the mixture, which was then extracted with EtOAc. The organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc/petroleum ether) to afford the title compound. MS = 207.1 [M+1] ⁺ .

Step 2. (1R,5S)-3-(5-Bromo-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of (1R,5S)-3-(3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (700 mg, 3.39 mmol) in ACN (10 mL) was added NBS (665 mg, 3.73 mmol).

The resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to give the title compound. MS = 284.9, 286.9 [M+1] ⁺ .

Step 3. (1R,5S)-3-(5-Acetyl-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate B1-4a, step 1. MS=249.2 [M+1] ⁺ .

Step 4. (1R,5S)-3-(3-Fluoro-5-(1-hydroxyethyl)-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate BJ-5a, Step 3. MS=251.1 [M+1] ⁺ .

Step 5: (1R,5S)-3-(3-Fluoro-6-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (600 mg, 2.40 mmol), 4-nitro-1H-pyrazole (325 mg, 2.88 mmol), and triphenylphosphine (943 mg, 3.60 mmol) in THF (10 mL) was added di-isopropyl azodicarboxylate (0.699 mL, 3.60 mmol) at 10°C. 0°C. The reaction mixture was stirred at 0°C for 2 h, then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to give the title compound. MS=346.2 [M+1] ⁺ .

Step 6. (1R,5S)-3-(5-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. MS=316.2 [M+1] ⁺ .

Step 7. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(5-fluoro-2-methyl-6-((1R,5S))-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compounds were prepared as a starting mixture of diastereomers according to procedures similar to those described in Example 1, Step 5 above. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD; 0.1% NH ₃ H ₂ O EtOH, start B 35%, end B 35%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 150): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.39 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.86-7.84 (m, 1H), 7.78 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.41 (d, J=10.6 Hz, 1H), 7.18-6.84 (m, 1H), 5.81 (d, J=7.0 Hz, 1H), 4.29 (dd, J=10.6, 5.9 Hz, 1H), 3.67 (d, J=10.2 Hz, 1H), 2.48 (d, J=0.8 Hz, 3H), 2.15 (br.d, J=7.4 Hz, 1H), 2.01 (br.s, 1H), 1.86 (d, J=7.0 Hz, 3H), 1.32-1.26 (m, 1H), 0.91-0.84 (m, 1H). MS=600.1 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 151): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.39 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 7.88-7.81 (m, 1H), 7.79 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.44 (d, J=10.6 Hz, 1H), 7.18-6.83 (m, 1H), 5.81 (d, J=7.0 Hz, 1H), 4.28 (dd, J=10.6, 5.9 Hz, 1H), 3.70 (d, J=9.4 Hz, 1H), 2.48 (s, 3H), 2.20-2.13 (m, 1H), 2.02 (br.d, J=7.0 Hz, 1H), 1.86 (d, J=7.0 Hz, 3H), 1.32-1.26 (m, 1H), 0.92-0.85 (m, 1H). MS=600.2 [M+1] ⁺ .

Example 156

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAG)

Step 1. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-3-vinylpyrazine-2-carboxamide: To a mixture of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-2-((1R-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide (120 mg, 0.202 mmol) in DMF (2.0 mL) cooled to 0 °C was added sodium hydride (16 mg, 0.40 mmol, 60% oil dispersion). The resulting mixture was stirred at 0 °C for 5 min, then 2-(trimethylsilyl)ethoxymethyl chloride (71.5 mL, 0.403 mmol) was added. The mixture was stirred at 0 °C for 2 h, then quenched by adding sat. aq. NH ₄ Cl and the mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound. MS = 752.2 [M+1] ⁺ .

Step 2. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrazine-2-carboxamide: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 2. MS = 745.1 [M+H ₂ O+1] ⁺ .

Step 3. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrazine-2-carboxamide: The title compound was prepared according to procedures analogous to those described above for Intermediate BA-1a, step 2. MS = 731.2 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures analogous to those described above for Intermediate AE-5, step 4. ¹ H NMR (600 MHz, CD ₃ OD) δ 8.98 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 6.95 (t, J=54.6 Hz, 1H), 5.37 (s, 2H), 5.23 (s, 2H), 4.19 (dd, J=11.5, 5.0 Hz, 1H), 4.00 (d, J=11.5 Hz, 1H), 2.45 (s, 3H), 2.10 (dt, J=8.0, 4.6 Hz, 2H), 1.27 (dk, J=8.0, 4.4 Hz, 1H), 0.83 (k, J=4.0 Hz, 1H). MC=599.4 [M+1] ⁺ .

Examples 157-160

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexane)-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAN)

Step 1. 2-Chloro-4-methyl-5-vinylpyrimidine: A solution of 5-bromo-2-chloro-4-methylpyrimidine (7.00 g, 33.7 mmol), TEA (7.05 mL, 50.6 mmol), potassium vinyl trifluoroborate (4.97 g, 37.1 mmol), and bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.741 g, 1.01 mmol) in ethanol (100 mL) was stirred at 90 °C for 3 h. Water was added to the mixture and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 20% EtOAc/petroleum ether) to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.64 (s, 1H), 6.93-6.83 (m, 1H), 5.90-5.85 (m, 1H), 5.58-5.52 (m, 1H), 2.52 (d, J=1.2 Hz, 3H).

Step 2. 3-(4-Methyl-5-vinylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: A mixture of 2-chloro-4-methyl-5-vinyl pyrimidine (1.10 g, 7.12 mmol), 3-azabicyclo[3.1.0]hexan-2-one (898 mg, 9.25 mmol), cesium carbonate (4.64 g, 14.2 mmol), tris(dibenzylideneacetone)dipalladium (652 mg, 0.712 mmol), and Xantphos (412 mg, 0.712 mmol) in dioxane (20 mL) was stirred at 100 °C for 14 h under nitrogen. The reaction mixture was cooled to rt and concentrated under reduced pressure. Water was added to the mixture and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 95% EtOAc/petroleum ether) to give the title compound. MS=216.0 [M+1] ⁺ .

Step 3. 3-(5-(1,2-Dihydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 3-(4-methyl-5-vinylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (815 mg, 3.79 mmol) in a mixture of ACN (15 mL) and water (5.0 mL) were added aq. osmium tetroxide (9.63 mL, 0.379 mmol, 10 mg/mL) and 4-methylmorpholine N-oxide (444 mg, 3.79 mmol). The resulting mixture was stirred for 12 h at rt. The mixture was cooled to 0 °C, then sat. aq. Na ₂ S ₂ O ₃ and the resulting mixture was stirred for 30 min. The mixture was then filtered through a pad of diatomaceous earth (eluting with ACN) and the filtrate was concentrated under reduced pressure to give the title compound. MS=250.3 [M+1] ⁺ .

Step 4. 3-(5-(2-((tert-Butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 3-(5-(1,2-dihydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.25 g, 5.01 mmol) in DMF (30 mL) were added 1H-imidazole (750 mg, 11.0 mmol) and TBDPSCl (1.65 g, 6.01 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to rt. Water was added to the mixture and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 95% EtOAc/petroleum ether, then 0 to 10% MeOH/DCM) to give the title compound. MS = 488.2 [M+1] ⁺ .

Step 5: 3-(5-(2-((tert-Butyldiphenylsilyl)oxy)-1-(4-nitro-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 3-(5-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.46 g, 2.99 mmol), di-tert-butyl azodicarboxylate (1.38 g, 5.99 mmol), and triphenylphosphine (1.57 g, 5.99 mmol) in THF (20 mL) was added 4-nitro-1H-pyrazole (0.677 g, 5.99 mmol). The reaction mixture was stirred at 50 °C for 4 h. The mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/petroleum ether) to give the title compound. MS = 583.6 [M+1] ⁺ .

Step 6: 3-(5-(1-(4-Amino-1H-pyrazol-1-yl)-2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. MS=553.3 [M+1] ⁺ .

Step 7. N-(1-(2-((tert-Butyldiphenylsilyl)oxy)-1-(4-methyl-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide: The title compound was prepared according to procedures similar to those described in Example 41, Step 4 above. MS = 837.3 [M+1] ⁺ .

Step 8. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide,6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compounds were prepared as a starting mixture of diastereomers according to procedures analogous to those described above for Intermediate AE-5, step 4. The diastereomeric title compounds were separated by chiral chromatography (SFC, REGIS (S,S) WHELK-01; 0.1% NH ₃ H ₂ O EtOH start B 40%, end B 40%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 157): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.03-6.80 (m, 1H), 5.61-5.56 (m, 1H), 4.21 (dd, J=11.8, 7.2 Hz, 1H), 4.09 (dd, J=11.6, 5.2 Hz, 2H), 3.89 (d, J=11.3 Hz, 1H), 2.40 (s, 3H), 2.05-1.96 (m, 2H), 1.18 (dd, J=8.1, 4.4 Hz, 1H), 0.72 (k, J=4.1 Hz, 1H). MC=599.1 [M+1] ⁺ . The second eluting diastereomer of the title compounds (Example 158): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.41 (s, 1H), 9.07-9.03 (m, 1H), 8.54 (s, 1H), 8.37-8.31 (m, 1H), 7.89-7.82 (m, 2H), 7.69 (d, J=8.5 Hz, 1H), 7.16-6.92 (m, 1H), 5.73 (br t, J=5.8 Hz, 1H), 4.33 (dd, J=11.9, 7.0 Hz, 1H), 4.27-4.17 (m, 2H), 4.05 (br d, J=11.6 Hz, 1H), 2.55 (s, 3H), 2.16 (br.d, J=4.3 Hz, 2H), 1.38-1.29 (m, 1H), 0.89 (br.d, J=3.7 Hz, 1H). MS=599.1 [M+1] ⁺ . The third eluting diastereomer of the title compounds (Example 159): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.04-6.80 (m, 1H), 5.60-5.56 (m, 1H), 4.21 (dd, J=11.8, 7.2 Hz, 1H), 4.09 (dd, J=11.6, 5.2 Hz, 2H), 3.89 (d, J=11.3 Hz, 1H), 2.40 (s, 3H), 2.00 (dd, J=7.5, 4.1 Hz, 2H), 1.18 (dt, J=7.9, 4.0 Hz, 1H), 0.72 (k, J=4.0 Hz, 1H). MC=599.2 [M+1] ⁺ . The fourth eluting isomer of the title compounds (Example 160): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (s, 1H), 8.92 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.74 (br t, J=7.5 Hz, 1H), 7.72-7.70 (m, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.03-6.80 (m, 1H), 5.57 (t, J=6.3 Hz, 1H), 4.21 (dd, J=11.4, 7.2 Hz, 1H), 4.09 (dd, J=11.6, 5.2 Hz, 2H), 3.89 (d, J=11.6 Hz, 1H), 2.39 (s, 3H), 2.00 (broad long, J=4.6 Hz, 2H), 1.18 (broad long, J=9.2 Hz, 1H), 0.72 (broad long, J=4.0 Hz, 1H). MC=599.1 [M+1] ⁺ .

Example 169

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-(hydroxymethyl)-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide

Step 1. 1-(4-(tert-Butoxymethyl)-2-chloropyrimidin-5-yl)ethanone: To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (400 mg, 2.55 mmol) in ACN (9.0 mL) and water (9.0 mL) were added 2-(tert-Butoxy)acetic acid (675 mg, 5.11 mmol), silver nitrate (1.2 g, 7.06 mmol), and ammonium persulfate (2.10 g, 9.20 mmol) at rt. After complete addition, the mixture was stirred at 6 °C for 1 h. The mixture was poured into water and extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (0-8% EtOAc/petroleum ether) to give the title compound. MS=243.3 [M+1] ⁺ .

Step 2. 1-(4-(tert-Butoxymethyl)-2-chloropyrimidin-5-yl)ethanol: The title compound was prepared according to procedures similar to those described above for Intermediate BJ-5a, Step 3. aq. MS=245.1 [M+1] ⁺ .

Step 3. 4-(tert-Butoxymethyl)-2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine: To a solution of 1-(4-(tert-butoxymethyl)-2-chloropyrimidin-5-yl)ethanol (150 mg, 0.613 mmol), 4-nitro-1H-pyrazole (90 mg, 0.80 mmol), and triphenylphosphine (241 mg, 0.919 mmol) in toluene (5.0 mL) under nitrogen atmosphere and cooled to 0 °C was added diisopropyl azodicarboxylate (186 mg, 0.919 mmol). After complete addition, the reaction mixture was stirred at rt for 15 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined and dried _{over Na2SO4} , filtered and concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (0 to 18% EtOAc/petroleum ether) to give the title compound. MS=339.9 [M+1] ⁺ .

Step 4. (1S,5R)-3-(4-(tert-Butoxymethyl)-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To solution 4-(tert-butoxymethyl)-2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (90.0 mg, 0.265 mmol), (1S,5R)-3-azabicyclo[3.1.0]hexan-2-one (36.0 mg, 0.371 mmol), Xantphos (16.0 mg, 28.0 µmol) and cesium carbonate (173 mg, 0.530 mmol) in dioxane (2.0 ml) in Under nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium (25 mg, 27 μmol) was added at rt. The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (1:1 EtOAc/petroleum ether) to give the title compound. MS = 401.1 [M+1] ⁺ .

Step 5. 3-(5-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-4-(tert-butoxymethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. MS=371.5 [M+1] ⁺ .

Step 6. N-(1-(1-(4-(tert-Butoxymethyl)-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide: The title compound was prepared according to procedures similar to those described in Example 1, Step 5 above. MS = 655.2 [M+1] ⁺ .

Step 7. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-(hydroxymethyl)-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures analogous to those described above for Intermediate AE-5, step 4. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.51-9.48 (m, 1H), 9.06 (d, J=2.9 Hz, 1H), 8.55 (br d, J=7.6 Hz, 1H), 8.14 (s, 1H), 7.70-7.76 (m, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.61 (br.s, 1H), 6.73-6.46 (m, 1H), 5.57 (br.d, J=7.2 Hz, 1H), 4.82-4.69 (m, 1H), 4.60 (br.s, 1H), 4.18 (br.d, J=3.5 Hz, 1H), 4.07 (br.d, J=10.4 Hz, 1H), 2.17 (b.s., 1H), 2.07 (b.s., 1H), 1.93 (br.d, J=1.0 Hz, 3H), 1.27 (br.d, J=6.1 Hz, 1H), 0.90 (us.s, 1H). MS=599.2 [M+1] ⁺ .

Examples 170 and 171.

N-(1-((S)-1-(4-Amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide and N-(1-((R)-1-(4-Amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide (Scheme AAJ)

Step 1. 1-(2,4-Dichloropyrimidin-5-yl)ethanol: To a solution of 2,4-dichloro-5-iodopyrimidine (8.00 g, 29.1 mmol) in THF (100 mL) cooled to -78 °C under nitrogen atmosphere was added dropwise isopropylmagnesium chloride (17.5 mL, 34.9 mmol, 2 M in THF). The resulting mixture was stirred at -78 °C for 20 min, then acetaldehyde (11.6 mL, 58.2 mmol, 5 M in THF) was added dropwise and the resulting mixture was stirred at -78 °C for 2 h and at rt for an additional 1 h. The reaction mixture was quenched by addition of sat. aq. NH ₄ Cl and the resulting mixture was extracted with EtOAc. The organic layers were combined and dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-25% EtOAc/petroleum ether) to give the title compound. MS=192.6 [M+1] ⁺ .

Step 2. 2,4-Dichloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine: A mixture of 1-(2,4-dichloropyrimidin-5-yl)ethanol (3.70 g, 19.2 mmol), 4-nitro-1h-pyrazole (3.25 g, 28.8 mmol), triphenylphosphine (10.1 g, 38.3 mmol), and di-tert-butyl azodicarboxylate (8.83 g, 38.3 mmol) in THF (50 mL) was stirred at rt for 14 h. The reaction mixture was concentrated under reduced pressure and the residue was purified successively by silica gel chromatography (0 to 15% EtOAc/petroleum ether) followed by preparative reverse-phase HPLC (stationary phase: C18, water (0.1% TFA)-ACN, start B 40%, end B 70%) to give the title compound. ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 8.55 (d, J = 3.2 Hz, 1H), 8.31 (d, J = 3.2 Hz, 1H), 8.11 (d, J = 3.2 Hz, 1H), 5.81 (m, 1H), 1.98 (dd, J = 3.3, 7.0 Hz, 3H).

Step 3. 2-Chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-4-amine: A mixture of 2,4-dichloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (800 mg, 2.78 mmol) in THF (15 mL) and ammonium hydroxide (10 mL) was stirred at rt for 14 h. The reaction mixture was diluted with sat. aq. NH ₄ Cl and extracted with DCM. The organic layers were combined and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 24%, end B 44%) to give the title compound. MS = 268.6 [M+1] ⁺ .

Step 4. (1R,5S)-3-(4-Amino-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: A mixture of 2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-4-amine (320 mg, 1.19 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (174 mg, 1.79 mmol), cesium carbonate (1.16 g, 3.57 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 113 mg, 0.119 mmol) in dioxane (6.0 mL) was stirred at 100 °C for 14 h under nitrogen. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by reversed-phase MPLC (C18 stationary phase, 0 to 18% ACN/water (0.5% TFA) to afford the title compound. MS = 329.6 [M+1] ⁺ .

Step 5. (1R,5S)-3-(4-Amino-5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 42, Step 3 above. MS=300.0 [M+1] ⁺ .

Step 6. N-(1-((R)-1-(4-Amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide and N-(1-((5)-1-(4-Amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide: The title compounds were prepared as a starting mixture diastereomers according to procedures similar to those described above in Example 41, step 4. _The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD; 0.1% _NH3H2O IPA, start B 60%, end B 60%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 170): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (s, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.71-7.78 (m, 1H), 7.69 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.05-6.64 (m, 2H), 5.44 (m, 1H), 4.00 (m, 1H), 3.82 (d, J=11.0 Hz, 1H), 1.97-1.94 (m, 2H), 1.76 (d, J=7.1 Hz, 3H), 1.14 (m, 1H), 0.83-0.81 (m, 1 h). MS=584.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 171): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (s, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.77-7.71 (m, 1H), 7.69 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.06-6.78 (m, 2H), 5.49-5.39 (m, 1H), 4.01 (m, 1H), 3.82 (d, J=11.5 Hz, 1H), 1.95-1.97 (m, 2H), 1.75 (m, 3H), 1.14 (m, 1H), 0.83-0.81 (m, 1H). MC=584.2 [M+1] ⁺ .

Example 172

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (Scheme AAK)

Step 1. 5-(1-Chloroethyl)-2-(methylthio)pyrimidine: To a solution of 1-(2-(methylthio)pyrimidin-5-yl)ethan-1-ol (370 g, 2.17 mol) in DCM (1.11 L) cooled to 0 °C was added thionyl chloride (388 g, 3.26 mmol, 237 mL). After complete addition, the resulting mixture was stirred at 0 °C for 10 min, then the reaction mixture was concentrated under reduced pressure. DCM was added to the crude residue and the mixture was stirred, then filtered and concentrated under reduced pressure to give the title compound. TLC (R _f = 0.7, 1:4 EtOAc/petroleum ether).

Step 2. 2-(Methylthio)-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine: To a solution of 5-(1-chloroethyl)-2-(methylthio)pyrimidine (336 g, 1.78 mol), 4-nitro-1H-pyrazole (201 g, 1.78 mol) in DMF (1.69 L) cooled to 0 °C was added cesium carbonate (1.74 kg, 5.34 mol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with water then brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/petroleum ether) to give the title compound. TLC (R _f = 0.15, 1:5 EtOAc/petroleum ether).

Step 3. 1-(1-(2-(Methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-amine: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. MS=236.2 [M+1] ⁺ .

Step 4. tert-Butyl (1-(1-(2-(methylthio)pyrimidin-Byl)ethyl)-1H-pyrazol-4-yl)carbamate: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 1. MS=336.1 [M+1] ⁺ .

Step 5. tert-Butyl (1-(1-(2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate: The following sequence was performed in two batches in parallel on an equivalent scale. The batches were combined for post-reaction workup. To a solution of tert-butyl (1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate (200 g, 596 mmol) in DCM (1.40 L) under nitrogen and cooled to -10 °C was added mCPBA (326 g, 1.49 mol, 80% purity). The resulting mixture was stirred at rt for 1 h. The reactions were combined and quenched by adding sat. aq. sodium carbonate and extracted with DCM. The organic layers were combined and washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title _compound . ¹ H NMR (400 MHz, DMSO- _d6 ) δ 9.20 (s, 1H), 8.95 (s, 2H), 7.91 (s, 1H), 7.28 (s, 1H), 5.83-5.78 (m, 1H), 3.40 (s, 3H), 1.88 (d, J=7.2 Hz, 3H), 1.45 (s, 9H).

Step 6. tert-Butyl (1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate: To a solution of tert-butyl (1-(1-(2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate (250 g, 680 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (99.1 g, 1.02 mol) in dioxane (1.75 L) was added cesium carbonate (333 g, 1.02 mol). The reaction mixture was stirred at 50 °C for 2.5 h. The reaction mixture was cooled to rt then quenched by addition of brine and extracted with MTBE. The organic layers were combined and dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound. The crude residue was purified by silica gel chromatography (0:0: ₁ to 1:10:0 MeOH/EtOAc/petroleum ether) to give the title compound as a mixture of diastereomers. The diastereomeric compounds were separated by chiral chromatography (SFC, DAICEL _CHIRALPAK AY; 0.1% _NH3H2OEtOH , start B 45%, end B 45%) to afford the individual isomeric compounds in pure form. The title compound is the slower eluting diastereomer, which was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.05% HCl)-ACN, start B 5%, end B 45%) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.17 (s, 1H), 8.56 (s, 2H), 7.81 (s, 1H), 7.31 (s, 1H), 5.55-5.60 (m, 1H), 4.08-4.04 (m, 1H), 3.81 (d, J=12 Hz, 1H), 2.06-1.99 (m, 2H), 1.78 (d, J=7.2 Hz, 3H), 1.43 (s, 9H), 1.17-1.15 (m, 1H), 0.78-0.76 (m, 1H).

Step 7. (1R,5S)-3-(5-((S)-1-(4-Amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of tert-butyl (1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl) carbamate (26.0 g, 67.6 mmol) in DCM (210 mL) cooled to 0°C was added HCl (4 M solution in EtOAc, 169 mL). The reaction mixture was stirred at 25°C for 12 h, then concentrated under reduced pressure to give the title compound as a hydrochloride salt. MS=285.2 [M+1] ⁺ .

Step 8. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The following sequence was performed in three batches in parallel on an equivalent scale. The batches were pooled for subsequent post-reaction workup. To a solution of (1R,5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (5.00 g, 17.6 mmol) in DCM (35 mL) cooled to 0°C were added sequentially 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (4.43 g, 14.7 mmol), a solution of 1-propanephosphonic anhydride (T3P, 22.4 g, 35.2 mmol, 20.9 mL, 50% purity) and DIEA (9.09 g, 70.3 mmol, 12.3 mL). The reaction mixture was stirred at 20 °C for 2 h. The reactions were combined and quenched by adding sat. aq. NaHCO ₃ and extracted with DCM. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/petroleum ether) to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.8 (s, 1H), 9.34 (s, 1H), 9.16 (s, 1H), 8.61 (s, 2H), 8.30 (s, 1H), 7.99 (t, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.20 (t, J=54 Hz, 1H), 5.72-5.67 (m, 1H), 4.09-4.02 (m, 1H), 3.83-3.80 (M, 1H), 2.05-1.99 (M, 2H), 1.83 (d, J=6.8 Hz, 3H), 1.19-1.15 (m, 1H), 0.78-0.76 (M, 1H). MS=569.1 [M+1] ⁺ .

Example 180

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAK)

To a solution of (1R,5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16 mg, 0.056 mmol) in toluene (0.5 mL) was added trimethylaluminum (0.084 mL, 0.17 mmol). The reaction mixture was stirred at rt for 30 min, then 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one (20 mg, 0.056 mmol) in toluene (0.5 mL) was added. The resulting mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure and purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 37%, end B 67%) to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (d, J=2.4 Hz, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.83-7.75 (m, 1H), 7.70 (s, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.92 (t, J=54.4 Hz, 1H), 5.64 (q, J=6.8 Hz, 1H), 4.15 (dd, J=10.9, 4.8 Hz, 1H), 3.98 (d, J=11.7 Hz, 1H), 3.57 (s, 2H), 2.09 (br.dd, J=7.8, 3.2 Hz, 2H), 1.90 (d, J=7.1 Hz, 3H), 1.32-1.21 (m, 7H), 0.82 (br.d, J=4.2 Hz, 1H). MS=641.2 [M+1] ⁺ .

Example 183

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide (Scheme AAL)

Step 1. 2-Chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine and 2-Chloro-4-methyl-5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)pyrimidine: To a solution of (2-chloro-4-methylpyrimidin-5-yl)methanol (500 mg, 3.15 mmol), 4-nitro-1,2,3-triazole (396 mg, 3.47 mmol) and triphenylphosphine (1.24 g, 4.73 mmol) in toluene (0.6 mL) cooled to 0°C was added diisopropyl azodicarboxylate (0.92 mL, 4.7 mmol). The reaction mixture was stirred at rt for 12 h then concentrated under reduced pressure. The crude residue was purified by reverse-phase MPLC (C1B stationary phase, 10-20% ACN/water (0.5% TFA)) to afford the regioisomeric title compounds in isolated form. The faster eluting regioisomer is 2-chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.43 (s, 1H), 6.00 (s, 2H), 2.68 ppm (s, 3H). MS = 254.9 [M+1] ⁺ . The second eluting isomer is 2-chloro-4-methyl-5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)pyrimidine: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 8.21 (s, 1H), 5.68 (s, 2H), 2.66 ppm (s, 3H). MS = 254.9 [M+1] ⁺ . The third eluting isomer is 2-chloro-4-methyl-5-((4-nitro-3H-1,2,3-triazol-2-yl)methyl)pyrimidine: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.53 (s, 1H), 8.27 (s, 1H), 5.66 (s, 2H), 2.61 ppm (s, 3H). MS = 254.9 [M+1] ⁺ .

Step 2. (1R,5S)-3-(4-Methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 2-chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine (120 mg, 0.471 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (46 mg, 0.47 mmol), and cesium carbonate (307 mg, 0.943 mmol) in dioxane (2.0 mL) was added [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 45 mg, 0.047 mmol). The reaction mixture was stirred at 100 °C for 12 h, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (40-60% EtOAc/petroleum ether) to give the title compound. MS = 316.0 [M+1] ⁺ .

Step 3. (1R,5S)-3-(5-((4-Amino-1H-1,2,3-triazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. aq. MS=286.0 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide: To a solution of (1R,5S)-3-(5-((4-amino-1H-1,2,3-triazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (11 mg, 0.038 mmol), To 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (12 mg, 0.038 mmol) and 1-methyl-1H-imidazole (3.1 mg, 0.038 mmol) in ACN (0.5 mL) was added chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (11 mg, 0.038 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.2 m MHFBA + 0.1% TFA)-ACN, start B 40%, end B 70%) to afford the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.92 (d, J=2.7 Hz, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 7.87-7.77 (m, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.11-6.76 (m, 1H), 5.70 (s, 2H), 4.20 (dd, J=11.3, 5.1 Hz, 1H), 4.04 (d, J=11.0 Hz, 1H), 2.99 (s, 3H), 2.53 (s, 3H), 2.18-2.07 (m, 2H), 1.36-1.22 (br.m, 1H), 0.87 ppm. (b.d., J=3.9 Hz, 1H). MS=584.2 [M+1] ⁺ .

Example 188

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)cyclobutyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAM)

Step 1. (1R,5S)-3-(5-(1-Hydroxycyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 1-(2-chloro-4-methylpyrimidin-5-yl)cyclobutanol (200 mg, 1.01 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (196 mg, 2.01 mmol), and cesium carbonate (984 mg, 3.02 mmol) in dioxane (1.0 mL) were added Xantphos (58 mg, 0.10 mmol) and tris(dibenzylideneacetone) dipalladium (81 mg, 0.10 mmol). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:0 EtOAc/petroleum ether) to give the title compound. MS = 260.0 [M+1] ⁺ .

Step 2. (1R,5S)-3-(4-Methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of (1R,5S)-3-(5-(1-hydroxycyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (180 mg, 0.694 mmol), 4-nitro-1H-pyrazole (94 mg, 0.83 mmol), and triphenylphosphine (273 mg, 1.04 mmol) in toluene (3.0 mL) was added di-tert-butyl azodicarboxylate (240 mg, 1.04 mmol). The reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:0 EtOAc/petroleum ether) to give the title compound. MS = 355.0 [M+1] ⁺ .

Step 3. (1R,5S)-3-(5-(1-(4-Amino-1H-pyrazol-1-yl)cyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. aq. MS=325.0 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)cyclobutyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures analogous to those described in Example 1, step 5 above. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.88 (d, J=2.4 Hz, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.08-6.81 (m, 1H), 4.30-4.17 (m, 1H), 4.07 (d, J=11.6 Hz, 1H), 3.18-3.06 (m, 2H), 3.00 (s, 3H), 2.95 (br.d, J=8.9 Hz, 2H), 2.31-2.23 (m, 4H), 2.21-2.15 (m, 2H), 2.05-1.96 (m, 1H), 1.35 (td, J=8.1, 4.9 Hz, 1H), 0.91 (br.d, J=4.0 Hz, 1H). MS=623.2 [M+1] ⁺ .

Example 189 and 190

N-(1-((S)-1-(5-Amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazin-2-carboxamide and N-(1-((R)-1-(5-Amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl) pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazin-2-carboxamide (AAN Scheme)

The title compounds were prepared as a starting mixture of diastereomers according to procedures similar to those described above for Intermediate AE-5, step 4. The diastereomeric title compounds were separated by chiral chromatography (SFC, REGIS (S,S) WHELK-O1; _0.1 % _NH3H2O EtOH start B 55%, end B 55%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 189): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.88 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.18 (s, 1H), 6.96 (s, 1H), 5.60 (br d, J=7.0 Hz, 1H), 4.22 (dd, J=10.5, 6.0 Hz, 1H), 3.69 (d, J=10.7 Hz, 1H), 3.01 (s, 3H), 2.13-2.23 (m, 1H), 2.08-1.99 (m, 1H), 1.91 (d, J=7.3 Hz, 3H), 1.30 (br.dd, J=8.2, 4.6 Hz, 1H), 1.04-0.97 (m, 1H). MS=597.0 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 190): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.88 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.76-7.74 (m, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.11-6.81 (m, 1H), 5.60 (q, J=7.0 Hz, 1H), 4.22 (dd, J=10.7, 5.8 Hz, 1H), 3.69 (d, J=10.4 Hz, 1H), 3.01 (s, 3H), 2.19-2.10 (m, 1H), 2.10-2.02 (m, 1H), 1.91 (d, J=7.3 Hz, 3H), 1.32-1.23 (m, 1H), 1.01 (br.d, J=3.4 Hz, 1H). MS=597.0 [M+1] ⁺ .

Example 192

3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-ox o-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (AAO Scheme)

The title compound was prepared according to procedures similar to those described in Example 41, step 4 above. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90 (d, J=2.5 Hz, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.09-6.78 (m, 1H), 5.64 (d, J=7.1 Hz, 1H), 5.06 (s, 2H), 4.15 (dd, J=4.3, 11.6 Hz, 1H), 3.97 (d, J=11.5 Hz, 1H), 2.09 (dd, J=3.4, 8.1 Hz, 2H), 1.90 (d, J=7.1 Hz, 3H), 1.26 (br.s, 1H), 1.24 (s, 9H), 0.85-0.76 (m, 1H). MS=655.1 [M+1] ⁺ .

Example 193

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (AAO Diagram)

The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, step 4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.82 (br s, 1H), 8.99 (d, J=2.5 Hz, 1H), 8.51 (s, 2H), 8.20 (s, 1H), 7.74-7.68 (m, 1H), 7.67-7.62 (m, 1H), 7.60 (s, 1H), 6.81-6.34 (m, 1H), 5.52 (q, J=1.0 Hz, 1H), 5.28 (s, 2H), 4.14 (dd, J=5.7, 11.37 Hz, 1H), 3.98 (br s, 1H), 2.15 (br.s, 1H), 2.07-1.99 (m, 1H), 1.93 (br.d, J=6.8 Hz, 3H), 1.28-1.17 (m, 1H), 0.86 (br.d, J=3.4 Hz, 1H). MS=599.2 [M+1] ⁺ .

Example 207

(S)-6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1)-(1)-(4-methyl-2-(3-methyl-2-oxoimidazolidin-1-yl)pyrimidin-1-yl)ethyl)-1N-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAP)

Step 1. (S)-6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures similar to those described in Example AAA-10a, Step 5 above. MS=548.1 [M+1] ⁺ .

Step 2. (5)-6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylsulfonyl))pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To a solution of (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (70 mg, 0.130 mmol) in MeOH (3.0 mL) and water (0.5 mL) was added Oxone® (240 mg, 0.38 mmol). The reaction mixture was stirred at rt for 2 h. Water was added to the mixture and the resulting mixture was extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 EtOAc/petroleum ether) to give the title compound. MS = 580.1 [M+1] ⁺ .

Step 3. (5)-6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(3-methyl-2-oxoimidazolidin-1-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To a solution of (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (50 mg, 0.086 mmol) in ACN (1.0 mL) were added 1-methylimidazolidin-2-one (26 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol). The resulting mixture was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure. The crude residue was purified by preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN, start B 33%, end B 63%) to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86 (d, J=2.3 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.86-7.77 (m, 1H), 7.73 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.08-6.75 (m, 1H), 5.87 (d, J=6.7 Hz, 1H), 4.10 (br d, J=8.2 Hz, 2H), 3.66-3.56 (m, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.56 (s, 3H), 1.90 (d, J=7.0 Hz, 3H). MS=600.2 [M+1] ⁺ .

Example 208 and 209

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((R)-1-hydroxyethyl)-N-(1-((5-methyl-6-((1R,5S)-2-ok co-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide u6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((S)-1-hydroxyethyl)-N-(1-((5-methyl-6-((1R,5S)-2-ok co-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (AAQ Scheme)

Step 1. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide: To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylic acid (127 mg, 0.387 mmol), EDC (202 mg, 1.06 mmol), and pyridine (57 µL, 0.70 mmol) in DCM (10 mL) was added (1R,5S)-3-(6-((4-amino-1H-pyrazol-1-yl)methyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 0.352 mmol). The mixture was stirred at rt for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 45%, end B 65%) to give the title compound. MS = 595.1 [M+1] ⁺ .

Step 2. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(1-hydroxyethyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide (60 mg, 0.10 mmol) in Phenylsilane (27 mg, 0.25 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (12 mg, 0.020 mmol) were added to 2-propanol (5.0 mL) at rt under oxygen atmosphere. The reaction mixture was stirred at rt for 2 h then concentrated under reduced pressure. Water was added to the mixture and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC (stationary phase _C18 , water (0.1% TFA)-ACN, start B 35%, end B 55%) to give a mixture of diastereoisomeric title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALCEL OJ-H; 0.1% _NH3H2OMeOH , start B 25%, end B 25%) to afford the individual isomeric _compounds in pure form. The faster eluting diastereomer of the title compounds (Example 208): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.98 (d, J=2.5 Hz, 1H), 8.31 (s, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.36 (s, 1H), 6.93 (t, J=54.4 Hz, 1H), 5.80 (q, J=6.6 Hz, 1H), 5.60 (s, 2H), 4.45 (dd, J=5.7, 10.39 Hz, 1H), 3.80 (d, J=9.5 Hz, 1H), 2.25-2.18 (m, 1H), 2.17 (s, 3H), 2.09-2.01 (m, 1H), 1.60 (d, J=6.4 Hz, 3H), 1.35-1.31 (m, 1H), 1.00-0.93 (m, 1H). MS=613.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 209): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.97 (d, J=2.5 Hz, 1H), 8.30 (s, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.36 (s, 1H), 6.95 (t, J=54.8 Hz, 1H), 5.80 (q, J=6.6 Hz, 1H), 5.60 (s, 2H), 4.45 (dd, J=5.7, 10.39 Hz, 1H), 3.80 (d, J=10.5 Hz, 1H), 2.26-2.15 (m, 4H), 2.05 (br.t, J=5.6 Hz, 1H), 1.60 (d, J=6.4 Hz, 3H), 1.36-1.31 (m, 1H), 1.01-0.93 (m, 1H). MS=613.2 [M+1] ⁺ .

Example 215

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazin-2-carboxamide (AAR Scheme)

Step 1. (1R,5S)-3-(6-Chloro-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (300 mg, 1.11 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (150 mg, 1.55 mmol), and cesium carbonate (1.08 g, 3.32 mmol) in toluene (5.0 mL) was added [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 60 mg, 58 μmol) at rt in a glove box filled with nitrogen. After addition, the reaction vessel was sealed and stirred at 80 °C for 15 h. The reaction mixture was cooled to rt, then filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO ₂ , 2:1 EtOAc/petroleum ether) to give the title compound. MS = 241.0 [M+1] ⁺ .

Step 2. (1R,5S)-3-(5-Fluoro-4-methyl-6-vinylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a mixture of (1R,5S)-3-(6-chloro-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 0.416 mmol), potassium vinyl trifluoroborate (111 mg, 0.831 mmol), and TEA (126 mg, 1.25 mmol) in ethanol (5.0 mL) was added bis(di-tert-butylphosphino)ferrocene palladium dichloride (30 mg, 41 μmol). The reaction mixture was stirred at 80 °C under nitrogen for 15 h. The reaction mixture was cooled to rt, then filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO ₂ , 3:2 EtOAc/petroleum ether) to give the title compound. MS = 233.1 [M+1] ⁺ .

Step 3. 3-Fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)picolinaldehyde: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 2. MS=235.1 [M+1] ⁺ .

Step 4. (1R,5S)-3-(5-Fluoro-6-(hydroxymethyl)-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate BJ-5a, Step 3. MS=237.1 [M+1] ⁺ .

Step 5. (1R,5S)-3-(5-Fluoro-4-methyl-6-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 150, Step 5 above. MS=332.1 [M+1] ⁺ .

Step 6. (1R,5S)-3-(6-((4-Amino-1H-pyrazol-1-yl)methyl)-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 42, Step 3 above. MS=302.1 [M+1] ⁺ .

Stage 7. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazin-2-carboxamide: Specified The title compound was prepared according to procedures similar to those described above in Example 1, Step 5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.76 (s, 1H), 8.94 (d, J=3.1 Hz, 1H), 8.24 (br.d, J=15.7 Hz, 2H), 7.78-7.60 (m, 3H), 6.76-6.39 (m, 1H), 5.57-5.44 (m, 2H), 4.03 (dd, J=10.0, 5.3 Hz, 1H), 3.64 (br.d, J=10.2 Hz, 1H), 3.15 (s, 3H), 2.19-2.08 (m, 5H), 1.34 (td, J=8.0, 5.5 Hz, 1H), 0.90 (k, J=4.2 Hz, 1H). MS=600.2 [M+1] ⁺ .

Example 216 and 217

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazin-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazin-2-carboxamide (AAS Diagram)

Step 1. tert-Butyl (1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate: The following sequence was performed in three batches in parallel on an equivalent scale. The batches were combined for post-reaction workup. To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (65.0 g, 355 mmol) in DMF (1.30 L) at 0 °C was added sodium hydride (17.0 g, 426 mmol, 60% dispersion in mineral oil). The resulting mixture was maintained at 0 °C for 1 h, then 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 g, 461 mmol) was added dropwise. After complete addition, the reaction mixture was stirred at rt for 11 h. The reactions were combined and quenched by addition of sat. aq. NH ₄ Cl and extracted with 10:1 EtOAc/MeOH. The organic layers were combined and washed with water then brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)boronic acid. The following sequence was performed in two batches in parallel on an equivalent scale. These batches were combined for subsequent post-reaction workup. To a solution of (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)boronic acid (165 g, 401 mmol) in THF (1.20 L) was added 2,3-dimethylbutane-2,3-diol (47.4 g, 401 mmol) and the resulting mixture was stirred at 35 °C under nitrogen for 6 h. The reaction mixtures were combined and concentrated under reduced pressure to give the title compound.

Step 2. Potassium (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)trifluoroborate: The following sequence was performed in three batches in parallel on an equivalent scale. The batches were combined for post-reaction workup. To a solution of tert-butyl (1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate (135 g, 400 mmol) in MeOH (1.35 L) was added potassium bifluoride (125 g, 1.60 mol). The resulting mixture was stirred at rt for 12 h. The reaction mixtures were combined and concentrated under reduced pressure. The crude residue was suspended in EtOAc and filtered. The solid was washed with acetone and the combined filtrate was concentrated under reduced pressure to give the title compound: ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 7.56 (s, 1H), 7.09 (s, 1H), 3.13 (br d, J=3.2 Hz, 1H), 1.44 (s, 9H), 1.10 (d, J=7.2 Hz, 3H).

Step 3. tert-Butyl (1-(1-(6-chloro-5-((4-methoxybenzyl)oxy)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)carbamate: To a solution of 5-bromo-2-chloro-3-((4-methoxybenzyl)oxy)pyridine (500 mg, 1.52 mmol) and potassium 1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)trifluoroborate (483 mg, 1.52 mmol) in 1,3-dimethyl-2-imidazolidinone (5.0 mL) were added lithium hydroxide (109 mg, 4.56 mmol), 4,4'-di-tert-butyl 2,2'-bipyridine (49 mg, 0.18 mmol), [Ir{dFCF ₃ ppy} ₂ (bpy)]PF ₆ (33 mg, 38 μmol) in a glovebox filled with nitrogen. The reaction mixture was stirred for 6 h in front of one blue LED (450 nm) at rt. The mixture was quenched by adding water and extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to give the title compound. MS = 459.2 [M+1] ⁺ .

Step 4. tert-Butyl (1-(1-(5-((4-methoxybenzyl)oxy)-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)carbamate: A mixture of tert-butyl (1-(1-(6-chloro-5-((4-methoxybenzyl)oxy)pyridin-3)-yl)ethyl)-1H-pyrazol-4-yl)carbamate (150 mg, 0.327 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (48 mg, 0.49 mmol), cesium carbonate (319 mg, 0.981 mmol) and (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19 mg, 33 μmol) and tris(dibenzylideneacetone)dipalladium (40 mg, 49 μmol) in 1,4-dioxane (2.0 mL) were stirred at 100 °C for 14 h under nitrogen. The mixture was cooled to rt, then quenched by adding water and extracted with EtOAc. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered, then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 10% MeOH/DCM) to give the title compound. MS = 520.3 [M+1] ⁺ .

Step 5. (1R,5S)-3-(5-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-3-hydroxypyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described above for Intermediate AE-5, Step 4. MS=300.1 [M+1] ⁺ .

Step 6. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide: The title compounds were prepared as the starting mixture of diastereomers according to procedures similar to those described above in Example 1, step 5. _The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALCEL AD; 0.1% _NH3H2O IPA, start B 40%, end B 40%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 216): ¹ H NMR (500 MHz, CD ₃ OD) δ 8.88 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.85 (dd, J=15.3, 7.2 Hz, 2H), 7.78-7.64 (m, 2H), 7.18 (s, 1H), 7.12-6.73 (t, J=54.4 Hz, 1H), 5.63 (q, J=7.0 Hz, 1H), 4.24 (br dd, J=10.9, 6.0 Hz, 1H), 3.86 (br d, J=11.0 Hz, 1H), 3.01 (s, 3H), 2.24-2.04 (m, 2H), 1.92 (d, J=7.2 Hz, 3H), 1.39-1.31 (m, 1H), 0.95 (br.d, J=3.4 Hz, 1H). MS=598.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 217): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.84 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 7.90-7.75 (m, 2H), 7.71 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.13 (s, 1H), 7.07-6.77 (t, J=54.4 Hz, 1H), 5.65-5.53 (m, 1H), 4.20 (br dd, J=11.1, 6.0 Hz, 1H), 3.81 (br d, J=11.0 Hz, 1H), 2.97 (s, 3H), 2.17-2.02 (m, 2H), 1.87 (d, J=7.1 Hz, 3H), 1.30-1.25 (m, 1H), 0.91 (br.d, J=3.4 Hz, 1H). MS=598.2 [M+1] ⁺ .

Example 220

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)cyclopropyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAT)

Step 1. 2-Bromo-3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazine: To a solution of 2-bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyrazine (200 mg, 0.671 mmol) in DMF (8.0 mL) were added diphenyl(vinyl)sulfonium triflate (486 mg, 1.34 mmol) and DBU (0.30 mL, 2.0 mmol). The reaction mixture was stirred at rt for 14 h under nitrogen. EtOAc was added and the resulting mixture was washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-25% EtOAc/petroleum ether) to give the title compound. MS=324.0, 326.0 [M+1] ⁺ .

Step 2. (1R,5S)-3-(3-Methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a mixture of (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (81.0 mg, 0.833 mmol), 2-bromo-3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazine (180 mg, 0.555 mmol), and cesium carbonate (543 mg, 1.67 mmol) under nitrogen atmosphere were added tris(dibenzylideneacetone)dipalladium (51 mg, 56 μmol) and Xantphos (32 mg, 56 μmol). The reaction mixture was stirred at 100 °C for 14 h. The mixture was cooled to rt and concentrated under reduced pressure. Water was added to the mixture and then the resulting mixture was extracted with DCM. The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc/petroleum ether) to give the title compound. MS = 341.1 [M+1] ⁺ .

Step 3. (1R,5S)-3-(5-(1-(4-Amino-1H-pyrazol-1-yl)cyclopropyl)-3-methylpyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: A mixture of (1R,5S)-3-(3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (50 mg, 0.15 mmol) and platinum(IV) oxide (3.3 mg, 0.015 mmol) in EtOAc (3.0 mL) and MeOH (1.0 mL) was stirred under hydrogen atmosphere (pressure: 15 psi) at rt for 2 h. The crude mixture filtered and the filtrate was concentrated under reduced pressure to give the title compound. MS=311.1 [M+1] ⁺ .

Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)cyclopropyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared according to procedures similar to those described in Example 41, Step 4 above. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.87 (d, J=2.4 Hz, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.84-7.80 (m, 1H), 7.68-7.66 (m, 1H), 7.27 (s, 1H), 6.95 (t, J=54.8 Hz, 1H), 4.29-4.25 (m, 1H), 3.68-3.65 (m, 1H), 3.00 (s, 3H), 2.35 (s, 3H), 2.16-2.01 (m, 1H), 1.93-1.90 (m, 1H), 1.87-1.84 (m, 1H), 1.79-1.78 (m, 1H), 1.32-1.30 (m, 2H), 1.29-1.27 (m, 1H), 0.92-0.91 (m, 1H). MC=609.1 [M+1] ⁺ .

Example 224 and 225

6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5)-1-(5-(difluoromethoxy)-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide and 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-(difluoromethoxy)-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl) ethyl)-1H-pyrazol-4-yl)-3-methylpyrazin-2-carboxamide (Scheme AAU)

Step 1. 2-Chloro-5-iodo-3-methoxy-4-methylpyridine: To a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (2.3 g, 8.5 mmol) in MeOH (40 mL) was added sodium methoxide (0.69 g, 13 mmol) at rt. The reaction mixture was stirred at 80 °C for 48 h. The reaction mixture was cooled to rt and water was added. The resulting mixture was extracted with EtOAc, then the organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 7% EtOAc/petroleum ether) followed by preparative reversed-phase HPLC (C18 stationary phase, 30% ACN/ _H2O + 0.5% TFA) to afford the title compound. MS = 283.9 [M+1] ⁺ .

Step 2. 1-(6-Chloro-5-methoxy-4-methylpyridin-3-yl)ethan-1-one: The title compound was prepared according to procedures similar to those described above for Intermediate BI-4a, step 1. aq. MS=200.1 [M+1] ⁺ .

Step 3. 1-(6-Chloro-5-methoxy-4-methylpyridin-3-yl)ethane-Tol: To a solution of 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-1-one (1.4 g, 7.0 mmol) in THF (20 mL) and MeOH (2.0 mL) was added sodium borohydride (0.32 g, 8.4 mmol) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The reaction mixture was quenched by addition of sat. aq. NH ₄ Cl and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0 to 50% EtOAc/petroleum ether) to give the title compound. MS=202.1 [M+1] ⁺ .

Step 4. 2-Chloro-3-methoxy-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine: The title compound was prepared according to procedures similar to those described in Example 183, Step 1 above. MS=297.0 [M+1] ⁺ .

Step 5. 2-Chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-3-ol: To a stirred solution of 2-chloro-3-methoxy-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine (1.1 g, 1.9 mmol) in DCM (15 mL) was added boron tribromide (1.0 mL, 11 mmol) dropwise at 0 °C. After complete addition, the reaction mixture was stirred for 12 h at rt. The reaction mixture was diluted with DCM (10 mL), cooled to 0 °C, then quenched by addition of MeOH (5 mL). The mixture was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to give the title compound. MS=283.0 [M+1] ⁺ .

Step 6. 2-Chloro-3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine: To a stirred solution of 2-chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-3-ol (420 mg, 1.49 mmol) in DMF (8.0 mL) were added sodium 2-chloro-2,2-difluoroacetate (340 mg, 2.23 mmol) and cesium carbonate (968 mg, 2.97 mmol) at rt and the reaction mixture was then stirred at 70 °C for 12 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0 to 30% EtOAc/petroleum ether) to give the title compound. MS=333.0 [M+1] ⁺ .

Step 7. (1R,5S)-3-(3-(Difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a solution of 2-chloro-3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine (360 mg, 1.08 mmol) in toluene (8.0 mL) were added (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (137 mg, 1.41 mmol), Xantphos (63 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (99 mg, 0.11 mmol) and cesium carbonate (705 mg, 2.16 mmol). The resulting mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0 to 75% EtOAc/petroleum ether) to give the title compound. MS = 394.1 [M+1] ⁺ .

Step 8. (1R,5S)-3-(5-(1-(4-Amino-1H-pyrazol-1-yl)ethyl)-3-(difluoromethoxy)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: The title compound was prepared according to procedures similar to those described in Example 41, Step 3 above. MS=364.1 [M+1] ⁺ .

Step 9. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(5-(difluoromethoxy)-4-methyl-6-((1R,5S))-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide: The title compounds were prepared as a starting mixture of diastereomers according to procedures similar to those described in Example 1, Step 5 above. The diastereomeric title compounds were separated by chiral chromatography (SFC, Phenomenex-Cellulose-2; 0.1% NH ₃ H ₂ O EtOH, start B 55%, end B 55%) to afford the individual isomers in pure form. The faster eluting diastereomer of the title compounds (Example 224): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (d, J=2.4 Hz, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.78-7.85 (m, 1H), 7.74 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.10-6.78 (t, J=54.8 Hz, 1H), 6.76-6.36 (t, J=72.8 Hz, 1H), 5.86 (q, J=7.0 Hz, 1H), 4.26 (dd, J=10.3, 5.9 Hz, 1H), 3.67 (d, J=10.3 Hz, 1H), 2.98 (s, 3H), 2.34 (s, 3H), 2.21-2.12 (m, 1H), 2.05-1.97 (m, 1H), 1.92 (d, J=6.8 Hz, 3H), 1.28-1.22 (m, 1H), 1.00-0.93 (m, 1H). MS=662.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 225): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.86 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.81 (t, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.09-6.77 (t, J=54.8 Hz, 1H), 6.73-6.33 (t, J=73.2 Hz, 1H), 5.86 (q, J=7.1 Hz, 1H), 4.28 (dd, J=10.3, 5.9 Hz, 1H), 3.65 (d, J=10.5 Hz, 1H), 2.98 (s, 3H), 2.33 (s, 3H), 2.23-2.13 (m, 1H), 2.06-1.97 (m, 1H), 1.92 (d, J=7.1 Hz, 3H), 1.25 (dt, J=8.0, 3.9 Hz), 1H), 1.00-0.93 (m, 1H). MS=662.2 [M+1] ⁺ .

Example 226 and 227

6-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2 -oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide And 6-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-ok co-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (Scheme AAV)

To a solution of (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (11 mg, 36 μmol) in toluene (2.0 mL) was added trimethylaluminum (0.018 mL, 36 μmol, 2 M in toluene). The reaction mixture was stirred at rt for 30 min, then 3-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)furo[3,4-b]pyrazin-5(7H)-one (10 mg, 30 μmol) in DCM (1.0 mL) was added. The resulting mixture was stirred at rt for 16 h. The mixture was quenched by addition of water (0.5 mL), then concentrated under reduced pressure and purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 33%, end B 63%) to give a mixture of diastereomeric title compounds. The diastereomeric title compounds were separated by _chiral chromatography (SFC, DAICEL CHIRALCEL AD; 0.1% _NH3H2O EtOH, start B 45%, end B 45%) to afford the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compounds (Example 226): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90 (s, 1H), 8.26 (s, 1H), 8.16 (d, J=1.7 Hz, 1H), 7.77-7.67 (m, 2H), 7.61 (d, J=1.7 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 7.13-6.72 (m, 1H), 5.62 (d, J=7.1 Hz, 1H), 5.21 (s, 2H), 4.22 (dd, J=5.9, 10.5 Hz, 1H), 3.65 (d, J=10.3 Hz, 1H), 2.13 (s, 4H), 2.03-1.96 (m, 1H), 1.89 (d, J=7.1 Hz, 3H), 1.26 (br.s, 1H), 0.94-0.87 (m, 1H). MS=628.2 [M+1] ⁺ . The slower eluting diastereomer of the title compounds (Example 227): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.82 (br s, 1H), 8.18 (s, 1H), 8.09 (d, J=1.9 Hz, 1H), 7.66 (s, 1H), 7.62 (t, J=8.7 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.16 (d, J=9.1 Hz, 1H), 7.04-6.65 (m, 1H), 5.54 (q, J=7.1 Hz, 1H), 5.13 (s, 2H), 4.14 (dd, J=6.0, 10.4 Hz, 1H), 3.57 (d, J=10.3 Hz, 1H), 2.10-2.02 (m, 4H), 1.96-1.88 (m, 1H), 1.81 (d, J=7.1 Hz, 3H), 1.21-1.19 (m, 1H), 0.85-0.80 (m, 1H). MS=628.2 [M+1] ⁺ .

Example 228

3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((R and S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (Scheme AAV)

To the solution 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-(1-(5-methyl-6-((1R,5S))-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazin-2-carboxamide (60 mg, 0.096 mmol) in DCM (1.0 ml) was added tert-butyl acetate (110 mg, 0.960 mmol) and sulfuric acid (0.5 μl, 10 μmol). The reaction mixture was stirred at rt for 12 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative reversed-phase HPLC (stationary phase C18, water (0.1% TFA)-ACN, start B 45%, end B 75%) to give a mixture of diastereomeric title compounds. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.28 (s, 1H), 8.21 (br d, J=5.3 Hz, 1H), 7.72-7.76 (m, 2H), 7.64 (br s, 1H), 7.27 (br d, J=9.3 Hz, 1H), 7.10-6.77 (m, 1H), 5.73-5.64 (m, 1H), 5.09 (s, 2H), 4.26 (dd, J=5.9, 10.3 Hz, 1H), 3.70 (d, J=11.4 Hz, 1H), 2.18 (s, 4H), 2.04 (br d, J=5.2 Hz, 1H), 1.94 (d, J=7.2 Hz, 3H), 1.33-1.31 (m, 1H), 1.28 (s, 9H), 0.96 (br.s, 1H). MS=684.0 [M+1] ⁺ .

Factor XIa Analysis

The potency of a compound of the present invention as an inhibitor of coagulation factor XIa can be determined using an appropriate purified serine protease and an appropriate synthetic substrate. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the appropriate serine protease was measured both in the absence and presence of the compounds of the present invention. The assays were performed at room temperature or at 37°C. Hydrolysis of the substrate resulted in the release of aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring an increase in emission at 510 nm upon excitation at 405 nm. A decrease in the rate of change of fluorescence in the presence of the inhibitor indicates inhibition of the enzyme. Such methods are known to those skilled in the art. The results of this assay are expressed as half-maximal inhibitory concentrations (IC50) or inhibition constants _Ki .

Compounds were pre-incubated for 30 min at 25°C with human (0.04 nM) factor XIa in 50 mM HEPES buffer with 150 mM sodium chloride, 5 mM calcium chloride, 0.1% PEG 8000, pH 7.4. Factor XIa enzymatic activity was determined by adding glycine-proline-arginine-7-amido-4-trifluoromethylcoumarin (GPR-AFC) substrate and measuring fluorescence at 400/505 nm after 60 min incubation at 25°C. % inhibition for each data point was calculated from the data and analyzed using the log(inhibitor) equation and a four-parameter reaction to determine half-maximal inhibitory concentrations (IC ₅₀ ). IC ₅₀ were converted to equilibrium inhibition constants (K _i ) using the Cheng-Prusoff equation.

The activity demonstrated in this assay indicates that the compounds of the invention may be therapeutically useful for the treatment or prevention of various cardiovascular and/or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndrome, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, stroke such as thrombotic stroke or embolic stroke, venous thrombosis, coronary and cerebral arterial thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation syndrome and reocclusion or restenosis of recanalized vessels.

Kallikrein assay

The potency of a compound of the present invention as an inhibitor of kallikrein can be determined using an appropriate purified serine protease and an appropriate synthetic substrate. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the appropriate serine protease was measured both in the absence and presence of the compounds of the present invention. Assays were performed at room temperature or at 37°C. Hydrolysis of the substrate resulted in the release of aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm upon excitation at 405 nm. A decrease in the rate of change of fluorescence in the presence of the inhibitor indicates inhibition of the enzyme. Such methods are known to those skilled in the art. The results of this assay are expressed as half-maximal inhibitory concentrations (IC ₅₀ ) or inhibition constants _Ki .

Kallikrein assays were performed in 50 mM HEPES buffer at pH 7.4 containing 150 mM NaCl, 5 mM _CaCl2 , and 0.1% PEG 8000 (polyethylene glycol; Fisher Scientific). Assays were performed using purified human plasma kallikrein at a final concentration of 0.5 nM (Enzyme Research Laboratories) and the synthetic substrate, Acetyl-KPR-AFC (Sigma No. C6608), at a concentration of 100 mM.

Activity assays were performed by diluting the substrate stock solution at least tenfold to a final concentration of ≤0.2 Km in a solution containing the enzyme or enzyme equilibrated with inhibitor. The time required for equilibrium between enzyme and inhibitor was determined in control experiments. Reactions were performed under linear progress curve conditions and the increase in fluorescence was measured at 405 Ex/510 Em nm. Values were converted to percent inhibition of the control reaction (after subtracting 100% inhibition). IC ₅₀ was determined from the inflection point of the four-parameter logistic curve. Κ _i was calculated using the Cheng-Prusoff equation, Κ _i = IC ₅₀ /(1+([S]/Km)).

The activity demonstrated in this assay indicates that the compounds of the invention may be therapeutically useful for the treatment or prevention of various ophthalmological, cardiovascular and/or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndrome, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, stroke such as thrombotic stroke or embolic stroke, venous thrombosis, coronary and cerebral arterial thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation syndrome, reocclusion or restenosis of recanalized vessels, hereditary angioedema, uveitis, posterior uveitis, wet form of age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.

Plasma kallikrein (PKal) and factor XIa (FXIa) IC ₅₀ (nM) for selected compounds are as follows:

Claims (65)

1. Compound of formula: in which selected from selected from V represents CH or N; X represents CH or N; Y represents N or NO; Z represents NR ⁴ or CR ⁴ ; E represents N or CH; Q represents N or CH; G represents N or CR ⁷ ; J represents N or CR ⁷ ; L represents N or CR ⁷ ; M represents N or CR ⁸ ; R ¹ is selected from the group consisting of halogen, cyano, R ^x , OR ^x and SO ₂ R ^x ; R ² is a halogen; R ³ is halogen; R ⁴ represents hydrogen, R ^x , OR ^x , C _1-3 alkyl-OR ^x , C _1-3 alkyl-O-C _3-6 cycloalkyl or CH=CH ₂ ; R ⁵ is hydrogen or C _1-3 alkyl which is optionally substituted with one to three substituents selected from halogen and hydroxy; R ⁶ is hydrogen or C _1-3 alkyl; or R ⁵ and R ⁶ may be taken together with the carbon atom between them to form a C _3-6 cycloalkyl group; each R ⁷ is independently selected from the group consisting of halogen, R ^x , OR ^x , C _1-3 alkyl-OR ^x , NH (C=O) OR ^x and NH ₂ ; R ⁸ is selected from the group consisting of R ^x or OR ^x ; or R ⁷ and R ⁸ may be taken together with the carbon atoms between them to form a 5-membered cycloalkyl or heterocyclyl group containing 2 heteroatoms selected from O, wherein said heterocyclyl group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, methyl or ethyl; R ⁹ is hydrogen or C _1-3 alkyl; R ¹⁰ is hydrogen, hydroxy or C _1-3 alkyl; R ^x is hydrogen or C _1-6 alkyl which is optionally substituted with one to four substituents selected from halogen and hydroxy; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein E is CH and Z is CH; or a pharmaceutically acceptable salt thereof. 3. The compound according to item 1 or 2, in which represents or a pharmaceutically acceptable salt thereof. 4. A compound according to any one of claims 1 to 3, wherein R ¹ is selected from the group consisting of CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and SO ₂ CH ₃ ; or a pharmaceutically acceptable salt thereof. 5. The compound of any one of claims 1 to 4, wherein R ⁴ is selected from the group consisting of CH ₃ , CHF ₂ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ OC(CH ₃ ) ₃ , CH ₂ O (cyclopropyl), CH(OH)CF ₃ , CH ₂ C (CH ₃ ) ₂ OH, CD ₂ OH, CH (CH ₃ ) OH and OCH ₃ ; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1 to 5, wherein R ⁵ is hydrogen, CH ₃ or CH ₂ OH; or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1 to 6, wherein X is N; Y is N; V is CH; or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 7, wherein each R ⁷ is independently selected from the group consisting of hydrogen, chlorine, fluorine, CH ₃ , OCH ₃ , CHF ₂ , OCHF ₂ , CH ₂ OH, NH ₂ and NH(C=O)OR ^x ; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, selected from any of the following compounds or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition for the treatment of diseases or conditions in which plasma kallikrein activity is manifested, comprising an effective amount of a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 11. A method for treating diseases or conditions in which plasma kallikrein activity is manifested in a mammal, comprising administering the composition of claim 10 to a mammal in need of such treatment. 12. The method of claim 11, wherein the disease or condition in which plasma kallikrein activity is manifested is impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, intracerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, intraoperative blood coagulation under conditions of artificial circulation or bleeding after postoperative surgical intervention. 13. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the treatment of diseases or conditions in which plasma kallikrein activity is manifested. 14. The composition according to claim 10, further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents and thrombolytic agents. 15. The method of claim 11, further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.