EA045731B1 - INHIBITORS OF HUMAN PLASMA KALLIKREIN - Google Patents

Description

State of the art

Serine proteases constitute the largest and most extensively studied group of proteolytic enzymes. They are key to a wide range of diverse physiological processes such as blood coagulation, fibrinolysis, complement activation, reproduction, degradation and release of physiologically active peptides. The initial episode of many of these vital processes is the cleavage of one peptide bond or several peptide bonds in the protein or precursor peptides. Sequential reactions or cascades of limited proteolysis are involved in blood coagulation, fibrinolysis and complement activation. It is possible to control and also enhance the biological signals that initiate these cascades. Likewise, controlled proteolysis can turn off or inactivate proteins or peptides by cleaving individual bonds.

Kallikreins are a subgroup of serine proteases. In humans, plasma kallikrein (KLKB1) has no known homologues, with tissue kallikrein-related peptidases (KLKs) encoding a family of fifteen closely related serine proteases. Plasma kallikrein is involved in a number of pathways related to the intrinsic coagulation pathway, inflammation and the complement system.

Coagulation is the process by which blood clots form, for example to stop bleeding. The physiology of coagulation is complex and currently not fully understood, as it involves two separate initial pathways that merge into a final common pathway leading to thrombus formation. The final common pathway involves the conversion of prothrombin to thrombin, which in turn converts fibrinogen to fibrin, the latter being the main building block for the cross-linked fibrin polymers that form the hemostatic plug. Regarding the two initial pathways preceding the final common pathway, the first is known as the contact activation pathway or intrinsic pathway and the other is known as the tissue factor pathway or extrinsic pathway.

The intrinsic pathway begins with the formation of the primary collagen complex under the influence of high molecular weight kininogen (HMK), prekallikrein and FXII (factor XII; Hageman factor). Prekallikrein is converted to kallikrein, and FXII is activated to form FXIIa. FXIIa then converts factor XI (FXI) to FXIa, and FXIa in turn activates factor IX (FIX), which, together with its cofactor FVIIIa, forms a tenase complex that activates factor X (FX) to form FXa. FXa is responsible for the conversion of prothrombin to thrombin in the final common pathway.

Prekallikrein, an inactive precursor of plasma kallikrein, is synthesized in the liver and circulates in the plasma in an IUD-bound form or as a free zymogen. Prekallikrein is cleaved by activated factor XII (FXIIa) and releases activated plasma kallikrein (PK). Activated plasma kallikrein exhibits endopeptidase activity at arginine (preferred) and lysine peptide bonds. PK then produces additional FXIIa in the feedback loop, which in turn activates factor XI (FXI) to produce FXIa, thereby entering the main pathway. Although the initial activation of the intrinsic pathway occurs with a small amount of FXIIa activating a small amount of PK, subsequent activation in the feedback loop of FXII by PK controls the level of activation of the intrinsic pathway and hence subsequent coagulation. Hathaway, W. E., et al. (1965) Blood 26:521-32.

Activated plasma kallikrein also breaks down ICH, thereby releasing the highly active vasodilator peptide bradykinin. It can also cleave a number of inactive precursor proteins to form active products such as plasmin (from plasminogen) and urokinase (from prourokinase). Plasmin, a coagulation regulator, ensures the proteolytic cleavage of fibrin into fibrin degradation products, which suppress active fibrin formation.

There is clinical evidence that patients suffering from acute myocardial infarction (MI) are in a hypercoagulable state (increased blood clot formation). Paradoxically, this ability to hypercoagulate is only enhanced by fibrinolytic therapy. Increased thrombin production, as measured by thrombin-antithrombin III (TAT) levels, is observed in patients receiving this treatment compared with the already high levels observed in patients receiving heparin alone. Hoffmeister, H.M. et al. (1998) Circulation 98:2527–33. The increase in thrombin levels is hypothesized to be due to plasmin-mediated activation of the intrinsic pathway through direct activation of FXII by plasmin.

Hypercoagulability caused by fibrinolysis not only leads to increased rates of reocclusion, but is also at least partly responsible for the failure to complete fibrinolysis of the clot, which is a major disadvantage of fibrinolytic therapy (Keeley, E.C. et al. (2003) Lancet

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361: 13-20). Another concern with fibrinolytic therapy is the concomitant increased risk of intracranial hemorrhage. Menon, V. et al. (2004) Chest 126:549S-575S; Fibrinolytic Therapy Trialists' Collaborative Group (1994) Lancet 343:311-22. Thus, adjuvant anticoagulation therapy that does not increase the risk of bleeding but inhibits the formation of new thrombin may have increased effectiveness.

Thus, there is a need to develop PK inhibitors that can shift the fibrinolysis/thrombosis balance in the closing thrombus towards dissolution, thereby accelerating reperfusion and also suppressing the hypercoagulable state, thereby preventing thrombus re-formation and vessel reocclusion.

Brief description of the invention

Provided are compounds, pharmaceutical compositions containing the compounds, and methods suitable for inhibiting plasma kallikrein and treating or preventing diseases and conditions associated with plasma kallikrein. The compounds and their pharmaceutically acceptable salts are suitable inhibitors of human plasma kallikrein.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XXVI

(XXVI) where X is CH, -C(NH2) or -C(NR ^a R ^b );

-YR ⁴ is -((C1-C6)alkyl)-R ⁴ , -NH-R ⁴ or -NHCH2-R ⁴ , where the (C1-C ₆ )alkyl moiety is -((C ₁ -C ₆ )alkyl )-R ⁴ is optionally substituted;

Z represents halogen;

R ^1c represents -NH2;

R ² represents fluoro(C ₁ -C ₆ )alkyl;

R ³ represents optionally substituted aryl or heteroaryl;

R ^3a is absent or cyano; And

R ⁴ is an optionally substituted (C ₃ -C ₈ )cycloalkyl or (C ₃ -C ₈ )cycloalkyl (C ₁ -C ₆ )alkyl;

R ^a and R ^b are independently H or -S(O) ₂ R ^c ;

R ^c represents (C ₁ -C ₈ )alkyl; and any chiral center has an R-, S- stereochemical configuration or a mixture of R- and S-;

wherein aryl is an aromatic ring selected from the group consisting of phenyl, naphthyl, anthracenyl and phenanthrenyl; and heteroaryl is a monocyclic aromatic ring containing one or more heteroatoms on the ring selected from the group consisting of N, O and S;

and wherein any optional substituent is selected from halogen, (C ₁ -C ₈ )alkyl, aryl (C ₁ -C ₈ )alkyl, hydroxyl, (C ₁ -C ₈ )alkoxy, amino, oxo (=O) and cyano.

In certain aspects, the invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In certain aspects, the invention provides a method of treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat or thereby prevent a disease or condition characterized by undesirable plasma kallikrein activity. In one embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, fibrinolytic treatment-induced condition, angina pectoris, edema, angioedema, hereditary angioedema, sepsis, arthritis, bleeding, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy , neuropathy, hypertension, cerebral edema, increased albumin secretion, macroalbuminuria and nephropathy.

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Detailed description

It has been reported that plasma kallikrein inhibitors can be used in therapies and compositions suitable for use in eliminating or attenuating various forms of ischemia, including, but not limited to, perioperative blood loss, cerebral ischemia, manifestations of a systemic inflammatory response and/or reperfusion injury, for example, reperfusion injury associated with cerebral ischemia or focal cerebral ischemia. Perioperative blood loss occurs as a result of invasive surgical procedures that result in contact activation of complement components and coagulation/fibrinolysis systems. Kallikrein inhibitors may be used to attenuate or prevent perioperative blood loss and systemic inflammatory response in patients undergoing invasive surgical procedures, particularly cardiothoracic surgery. Kallikrein inhibitors can also be used to attenuate or prevent cerebral ischemia and stroke and/or reperfusion injury associated with cerebral ischemia. They may also prevent neurological and cognitive disorders associated with stroke, blood loss and cerebral ischemia, for example, events that are not associated with surgery. Additional examples of the use of kallikrein inhibitors include pediatric cardiac surgery, lung transplantation, total hip arthroplasty, and orthotopic liver transplantation where stroke attenuation or prevention is desired, and stroke attenuation or prevention during coronary artery bypass grafting (CABG) and extracorporeal membrane oxygenation therapy (ECM). ECMO).

Definitions.

The term alkyl as used herein is generally accepted in the art and refers to saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, the linear or branched alkyl contains about 30 carbon atoms per chain or less (eg, C1-C30 in the case of a straight chain, C ₃ -C ₃₀ in the case of a branched chain), or alternatively about 20 atoms or less. In one embodiment, the term alkyl refers to a C1-C10 linear alkyl group. In one embodiment, the term alkyl refers to a C1-C6 linear alkyl group. In one embodiment, the term alkyl refers to a C ₃ -C ₁₂ branched alkyl group. In one embodiment, the term alkyl refers to a C ₃ -C ₈ branched alkyl group. Cycloalkyls contain from about 3 to about 10 carbon atoms in the ring structure and alternatively about 5, 6 or 7 carbon atoms in the ring structure.

The term heterocyclyl, as used herein, refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic and tricyclic rings, which may be fully saturated or may contain one or more unsaturated moieties; for the avoidance of misinterpretation, the degree of unsaturation is not corresponds to the aromatic ring system, and contain from 3 to 12 atoms, including at least one heteroatom such as nitrogen, oxygen or sulfur. For example, examples of heterocyclic rings that should not be construed as limiting the scope of the present invention include aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl , furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, priazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinoline silt, quinoxalinil, quinazolinil x inuclidinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.

The term heteroatom is common in the art and includes atoms of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

The term cycloalkylalkyl as used herein refers to an alkyl group substituted with one or more cycloalkyl groups.

The term heterocycloalkylalkyl as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (ie, heterocyclyl) groups.

The term alkenyl as used herein means a straight or branched hydrocarbon radical containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Typical examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3 -decenyl.

The term alkynyl as used herein means linear or branched

- 3 045731 hydrocarbon radical containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Typical examples of alkynyls include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

The term alkylene is common in the art and as used herein refers to a divalent radical resulting from the removal of two hydrogen atoms from an alkyl group, as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e. to an alkane substituted at two positions with substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, simple ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, etc. Those. in one embodiment, the substituted alkyl is alkylene.

The term amino is common in the art and as used herein refers to unsubstituted and substituted amines, for example, a moiety that can be represented by the general formulas

R _b and R<

where each Ra, R _b and Rc independently represents hydrogen, alkyl, alkenyl, -(CH ₂ )x-Rd, or Ra and R _b together with the N atom to which they are attached form a heterocycle containing from 4 to 8 atoms in a ring structure; Rd is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclyl; and x is zero or an integer ranging from 1 to 8. In certain embodiments, only one of Ra and R _b may be a carbonyl, such that Ra, R _b and the nitrogen atom taken together do not form an imide. In other embodiments, Ra and R _b (and optionally R _c ) are each independently hydrogen, alkyl, alkenyl, or -(CH ₂ ) _x -R _d . In one embodiment, the term amino refers to -NH2.

The term acyl is common in the art and as used herein refers to any group or radical of the form RCO-, wherein R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl. Typical acyl groups include acetyl, benzoyl and malonyl.

The term aminoalkyl as used herein refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term aminoalkyl refers to an aminomethyl group.

The term aminoacyl is common in the art and as used herein refers to an acyl group substituted with one or more amino groups.

The term aminothionyl as used herein refers to an aminoacyl analogue in which the O atom in RC(O)- is replaced by sulfur, and thus has the formula RC(S)-.

The term phosphoryl is common in the art and can generally be represented by the formula

Q50

OR59 where Q50 is S or O and R59 is hydrogen, lower alkyl or aryl; for example -P(O)(OMe)- or -P(O)(OH) ₂ . When used as a substituent, for example in an alkyl, the phosphoryl group in a phosphorylalkyl can be represented by the general formula

Q50Q50

--Q51—р--о--- --Q ⁵¹ —Р—OR59 II

OR59OR59 wherein each Q50 and R59 are independently as defined above, and Q51 is O, S or N; for example, -OP(O)(OH)OMe or -NH-P(O)(OH) ₂ . If Q50 is S, then the phosphoryl moiety is phosphorothioate.

The term aminophosphoryl as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(O)(OH)NMe2.

The term carbonyl as used herein refers to -C(O)-.

The term thiocarbonyl as used herein refers to -C(S)-.

The term alkylphosphoryl as used herein refers to a phosphoryl group

- 4 045731 pe, substituted by at least one alkyl group, such as defined in the present description; for example, -P(O)(OH)Me.

The term alkylthio as used herein refers to alkyl-S-.

The term aryl is common in the art and as used herein refers to monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example benzene, naphthalene, anthracene and pyrene. The aromatic ring may be substituted at one or more positions of the ring with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term aryl also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings (the rings are fused rings), where at least one of the rings is an aromatic hydrocarbon, e.g. other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and/or heterocyclyl. In one embodiment, the term aryl refers to a phenyl group.

The term heteroaryl is common in the art and as used herein refers to a monocyclic, bicyclic and polycyclic aromatic group containing one or more heteroatoms in a ring structure, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, etc. Heteroaryl may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl , carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluoromethyl), cyano, etc. The term heteroaryl also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings (the rings are fused rings), wherein at least one of the rings is an aromatic group containing one or more heteroatoms in the ring structure, for example, other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls.

The term aralkyl or arylalkyl is common in the art and as used herein refers to an alkyl group substituted with an aryl group.

The term heteroaralkyl or heteroarylalkyl is common in the art and as used herein refers to an alkyl group substituted with a heteroaryl group.

The term alkoxy as used herein means an alkyl group, as defined herein, attached to the parent moiety via an oxygen atom. Typical examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2propoxy, butoxy, t-butoxy, pentyloxy and hexyloxy.

The term aryloxy as used herein means an aryl group, as defined herein, attached to the parent moiety via an oxygen atom.

The term heteroaryloxy as used herein means a heteroaryl group, as defined herein, attached to the parent moiety via an oxygen atom.

The term carbocyclyl as used herein means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms, which is fully saturated or contains one or more unsaturated bonds, wherein, To avoid misinterpretation, the degree of unsaturation does not correspond to the aromatic ring system (eg phenyl). Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.

The term cyano is common in the art and as used herein refers to -CN.

The term fluoroalkyl as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogen atoms are replaced by fluorine atoms.

The term halogen is common in the art and as used herein refers to -F, -Cl, -Br or -I.

The term hydroxy is common in the art and as used herein refers to -OH.

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Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention covers all of these compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D-isomers, ( _b )-isomers, racemic mixtures thereof and other mixtures included within the scope of the invention In addition, asymmetric carbon atoms may be present in a substituent such as an alkyl group.All of these isomers, as well as mixtures thereof, are intended to be included within the scope of the present invention.

If, for example, a particular enantiomer of a compound of the present invention is desired, it can be prepared by an asymmetric synthesis method or by conversion using a chiral auxiliary where the resulting diastereomeric mixture is separated and the auxiliary group removed to provide the pure desired enantiomers. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are prepared with the corresponding optically active acid or base, and the diastereomers thus obtained are separated using fractional crystallization or chromatographic methods well known in the art, and then the pure enantiomers are isolated.

It should be understood that substitution or substituted includes the implicit condition that the substitution occurs in accordance with the allowed valency of the atom being replaced and the substituent, and the substitution provides a stable compound that, for example, does not undergo spontaneous transformation such as rearrangement, fragmentation, decomposition, cyclization, elimination, or no other interactions.

The term substituted is also intended to include all permitted organic substituents. In broad terms, permitted substituents include acyclic and cyclic branched and straight-chain carbocyclic and heterocyclic aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above herein. The corresponding organic compounds contain one or more permitted substituents, which may be the same or different. For purposes of the present invention, heteroatoms such as nitrogen may contain hydrogen as a substituent and/or any permitted organic substituents described herein that satisfy the valency of the heteroatoms. It is intended that the present invention is not limited in any way to the permitted organic substituents.

For the purposes of the invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th ed., 1986-87, flyleaf.

Other chemical terms used herein have the traditional meaning given in The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGrawHill, San Francisco, the contents of which are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used in this specification have the meaning commonly accepted by those skilled in the art to which the present invention relates.

The term pharmaceutically acceptable salt as used herein includes salts derived from inorganic or organic acids, including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic acid, benzenesulfonic acid, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic acid and other acids. Forms of pharmaceutically acceptable salts may include forms where the ratio of the molecules constituting the salt is other than 1:1. For example, a salt may contain more than one molecule of inorganic or organic acid per molecule of base, such as two molecules of hydrochloric acid per molecule of a compound of Formula I. In another example, a salt may contain less than one molecule of inorganic or organic acid per molecule of base, such as two molecules compounds of formula I per tartaric acid molecule.

The terms carrier and pharmaceutically acceptable carrier as used herein refer to a diluent, adjuvant, excipient or excipient with which the compound is administered or the composition intended for administration is prepared. Non-limiting examples of these pharmaceutically acceptable carriers include liquids such as water, saline and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary additives, stabilizers, thickeners, lubricants, flavoring agents and coloring agents can be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, the contents of which are incorporated herein by reference in their entirety.

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The term treat as used herein means preventing, stopping or slowing the progression or eliminating a disease or condition in a subject. In one embodiment, treat means stopping or slowing the progression or eliminating a disease or condition in a subject. In one embodiment, treat means reducing at least one objective manifestation of a disease or condition in a subject.

The term effective amount as used herein refers to an amount that is sufficient to provide the intended biological effect.

The term therapeutically effective amount as used herein refers to an amount that is sufficient to provide the intended therapeutic effect.

The term inhibit as used herein means a reduction by an objectively measurable amount or level. In various embodiments, inhibit means a reduction of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% compared to the corresponding control. In one embodiment, inhibit means a reduction of 100%, i.e. stopping or eliminating.

The term subject as used herein refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, the subject is a human.

Connections.

In some aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula I

R ^3a (I) where V represents optionally substituted aryl or heteroaryl;

W represents optionally substituted aryl or heteroaryl;

X represents CH, C(OH), C(O(C1-C6)alkyl), <№), -C(NR ^a R ^b ), -OD), -C(CN), -C(NOi), -C(S(O)nR ^a ), -C[-C(=O)R ^c ], -C[-C(=O)R ^c ], -C[-C(=O)NR ^c R ^d ], -C[-C(=O)SR ^c ], -C[-S(O)R ^c ], -C[-S(O)2R ^c ], -C[S(O)(OR ^c ) ], -C[-S(O)2(OR ^c )], -C[-SO2NR ^c R ^d ], -C(halogen), -C[(C1-C8)alkyl], -C[(C4- C8)carbocyclylalkyl], -C[(C ₁ -C ₈ )substituted alkyl], -C[(C ₂ -C ₈ )alkenyl], -C[(C ₂ -C ₈ )substituted alkenyl], -C[( C ₂ -C ₈ )alkynyl], -C[(C ₂ -C ₈ )substituted alkynyl], -C[aryl(C ₁ -C ₈ )alkyl], C(O)N, CH2N, N, C(O ), P(O), -O-, S(O)N or S(O) ₂ N; with the proviso that if X is CH, then YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH), C(O(C ₁ -C ₆ )alkyl), -C(NH ₂ ), -C(NR ^a R ^b ), -C(N3), -C(CN), -C(NO2), -C(S(O)nR ^a ), -C[-C(=O)R ^c ], -C[-C(=O)R ^c ], -C[-C(= O)NR ^c R ^d ], -C[-C(=O)SR ^c ], -C[-S(O)R ^c ], -C[-S(O)2R ^c ], -C[S( O)(OR ^c )], -C[-S(O)2(OR ^c )], -C[-SO2NR ^c R ^d ], -C(halogen), -C[(C1-C8)alkyl], -C[(C4-C8)carbocyclylalkyl], -C[(C1- _C8 )-substituted alkyl], -C[( _{C2- C8} )alkenyl], -C[(C2 _{- C8} )substituted alkenyl ], -C[(C ₂ -C ₈ )alkynyl], -C[(C ₂ -C ₈ )substituted alkynyl] or -C[aryl(C ₁ -C ₈ )alkyl], then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N((C1 -C6)αalkyl)CH2-R ⁴ , -N((CH2) ₂ OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C ₆ )alkyl fragment in -((C ₁ -C ₆ )alkyl)-R ⁴ is optionally substituted;

Z is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy , amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, - SO2NH2, (C3-C8)cycloalkyl, (CH2)rOR ^a , NO2, (CH2)rNR ^a R ^b , (CH2)rC(O)R ^a , NR ^a C(O)R ^b , C(O)NR ^c R ^d , NR ^a C(O)NR ^c R ^d , -C(=NR ^a )NR ^c R ^d , NHC(=NR ^a )NR ^c R ^d , NR ^a R ^b , SO2NR ^c R ^d , NR ^a SO2NR ^c R ^d , NR ^a SO2-(C1-C6)alkyl, NR ^a SO2R ^a , S(O)pR ^a , (CF2)rCF3, NHCH2R ^a , OCH2R a , SCH2R ^{a ,} NH(CH2)2(CH2)rR ^a , O(CH2)2(CH2)rR ^a and S(CH2)2(CH2)rR ^a ; or alternatively Z is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S;

R ^1c represents halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -C(=NH)NH ₂ , -CONR ^a R ^b ,

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-(C ₁ -C ₆ )alkyl-CONR ^a R ^b , -SO2CH3, formyl, acyl, -NH2, -C(=NH)NH(OH), -C(=NH)NH(C(O)O- (C1-C ₆ ^kil), -C(=NH)NH(C(O)O-(C ₁ -C ₆ )-haloalkyl), -C(=NH)NH(C(O)S-(C ₁ -C ₆ )alkyl),

-C(=NH)NH(C(O)(OCH(C ₁ -C ₆ )alkyl)OC(O)(C ₁ -C ₆ )alkyl), optionally substituted aryl or optionally substituted heteroaryl;

R2 represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH ₃ ) ₃ , -CONH2, -C(O )OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino( C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, (C3-C8)cycloalkyl, (CH2)rOR ^a , NO2, (CH2)rNR ^a R ^b , (CH2)rC(O)R ^a , NR ^a C(O)R ^b , C(O)NR ^c R ^d , NR ^a C(O)NR ^c R ^d , -C(=NR ^a )NR ^c R ^d , NHC(=NR ^a )NR ^c R ^d , NR ^a R ^b , SO2NR ^c R ^d , NR ^a SO2NR ^c R ^d , NR ^a SO2-(C ₁ -C ₆ )alkyl, NR ^a SO2R ^a , S(O)pR ^a , (CF2)rCF3, NHCH2R ^a , OCH ₂ R ^a , SCH2R ^a , NH(CH2b(CH2)rR ^a , O(CH2b(CH2)rR ^a or S(CH2b(CH2)rR ^a ; or alternatively R ^3a is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1- C6)alkyl, -CH2S(C1-C6)alkyl, amino or cyano; or -(CR ^a R ^b )r(CR ^a R ^b ) _p -, fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NR ^a - fused at the ortho position relative to the X contained in the specified phenyl;

R ^a and R ^b are each independently H, (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, aryl(C ₁ -C ₈ )alkyl, (C ₃ -C ₈ )carbocyclylalkyl, -C(=O)R ^c , -C(=O)OR ^c , -C(=O)NR ^c R ^d , -C(=O)SR ^c , -S(O) R ^c , -S(O)2R ^c , -S(O)(OR ^c ) or -SO2NR ^c R ^d ;

each R ^c and R ^d independently represents H, (C ₁ -C ₈ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₂ -C ₈ )alkynyl, (C ₄ -C ₈ )carbocyclylalkyl, optionally substituted aryl , optionally substituted heteroaryl, -C(=O)(C ₁ -C ₈ )alkyl, -S(O) _n (C ₁ -C ₈ )alkyl or aryl(C ₁ -C ₈ )alkyl; or, if R ^c and R ^d are attached to a common nitrogen atom, they may form a 3-7 membered heterocyclic ring, wherein the carbon atom in said heterocyclic ring may optionally be replaced by -O-, -S- or -NR ^a - ;

X-Y

R ³ \ ⁴ \ ^3a can represent

\ \ \

R3a oZa oZa, K OR K n is 2 or 3;

r is independently equal to 0, 1, 2 or 3 in each case;

p is independently equal to 0, 1 or 2 in each case; and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -.

In certain embodiments, -X-Y- is -CHOCH2-.

In certain embodiments, R ³ is phenylene-R ^3a .

In certain embodiments -R ³ -R ^3a is

- 8 045731

R ^3a

In certain embodiments -R ³ -R ^3a is

In certain embodiments, R ^3a is absent.

In certain embodiments, R ⁴ is cyclopropyl.

In certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

In certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

In certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

In certain embodiments, Z is omitted.

In certain embodiments, Z is fluorine.

In certain embodiments, Z is chlorine.

In certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

In certain embodiments, Z is 6-F.

In certain embodiments, R ^1c is aminomethyl.

In certain embodiments, R ^1c is cyano.

In certain embodiments, R ^1c is -SO2CH3.

In certain embodiments, R ² is -CH ₃ or -CF ₃ .

In certain embodiments, R ² is -CF ₃ .

In certain embodiments, R ² is tert-butyl.

In certain embodiments, R ² is cyclopropyl.

In certain embodiments, R ² is -OCH ₃ .

In certain embodiments, R ² is -Si(CH ₃ ) ₃ .

In certain embodiments, R ² is -CONH2.

- 9 045731

In certain embodiments, R ² is cyano.

In certain embodiments, R ² is phenyl.

In certain embodiments, the compound is represented by Formula II

In certain embodiments, the compound is represented by Formula IV

In certain embodiments, the compound is represented by Formula VI

In certain embodiments, the compound is represented by Formula VIII

In certain embodiments, the compound is represented by formula X

In certain embodiments, the compound is represented by Formula XII

- 10 045731

In certain embodiments, the compound is represented by Formula XIV

In certain embodiments, the compound is represented by Formula XVI

In certain embodiments, the compound is represented by Formula XVIII

In certain embodiments, the compound is represented by Formula XX

In certain embodiments, the compound is represented by Formula XXII

In certain embodiments, the compound is represented by Formula XXIV

In certain aspects, the invention provides a compound or pharmaceutically

- 11 045731 acceptable salt represented by formula III

(III) where X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N((C1 -C6)αalkyl)CH2- ^R4 , -N((CH2)2OH) ^-R4 , -N[( _C3 - _C8 )cycloalkyl( _C1 - _C6 )alkyl] ^R4 , -heterocyclyl- ^R4 , -OR ⁴ ,

-OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (^^alkyl fragment in -((C1-C6)αalkyl)R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )αalkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl , -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH ₃ , -Si(CH3)3, -CONH2, -C( O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )αalkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )αalkyl, -SO ₂ (C ₁ -C ₆ )alkyl and - SO2NH2;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted αryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C ₁ -C ₆ )αalkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

, ^χ -\

R ³ R ⁴

R ^3a may be

C=CH C=GH C=N

R ³ \-- _R 4 _R 3 _R 4 _R 3 ' _R 4 \ ^3a _z \ ^3a or ^X R ^3a ;

and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -XY- is -CHNHCH2-. In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -. In certain embodiments, -XY- is -CHOCH ₂ -.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

- 12 045731

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments

- 13 045731 tion R ^1c represents -SO2CH3.

According to any of the above embodiments, in certain embodiments, R2 is -CH3 or -CF3.

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R2 is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R2 is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R2 is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

In any of the above embodiments, in certain embodiments, R2 is phenyl.

In certain embodiments, the connection is selected from the group consisting of

In certain embodiments, the connection is selected from the group consisting of

- 14 045731

In certain embodiments, the connection is selected from the group consisting of

- 15 045731

In certain aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula V

(V) where X represents CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C ₁ -C ₆ )alkyl)- R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N( (C1-C ₆ )αalkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C ₆ )alkyl moiety in -( (C ₁ -C ₆ )alkyl)-R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl , -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH ₃ , -Si(CH ₃ ) ₃ , -CONH2, -C (O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C1- _C6 )alkyl, _-CF3 , _-OCF3 , (C1- _C6 )alkoxy, aryl, aryloxy, amino, amino(C1- _C6 )alkyl, -C(O)NH2, cyano, -NHC(O)(C1 _{- C6} )alkyl, _-SO2 ( _{C1- C6} )alkyl and -SO2NH2;

^R4 is hydrogen, hydroxy, optionally substituted (C1- _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, heterocyclyl(C1-C6)alkyl, ( _{C3 -C8 )} cycloalkyl(C1-C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl(C1- _C6 )alkyl, heteroaryl, optionally substituted heteroaryl(C1- _C6 )alkyl, _-CH2S ( _C1 - _C6 )alkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ is phenyl, may be -NH- fused at ortho- 16 045731

position relative to X contained in said phenyl;

may represent c=cn c=cn

R ³ -R ⁴ R ³ R ^{4 4} R ^3a , R ^3a or

C=N

^R3 \ ⁴ '; and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -X-Y- is -C(OH)CH2CH2-.

In certain embodiments, -X-Y- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF3.

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH ₂ .

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In other aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula VII

(VII) where X represents CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N((C1C6 )alkyl)CH2-R ⁴ , -N((CH2) ₂ OH)-R ⁴ , -N[(C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ ,

- 18 045731

-OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (^-^alkyl fragment in -((C1-C6)alkyl) R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO ₂ NH ₂ or (C ₃ -C ₈ )cycloalkyl ;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O )OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO ₂ NH ₂ ;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C1C ₆ )alkyl, amino or cyano; or -CH ₂ - fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

may represent

and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -XY- is -CHNHCH2-. In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -. In certain embodiments, XY- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

- 19 045731

According to any of the above embodiments, in certain embodiments -R3-R3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R ² is -CH3 or -CF3.

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In other aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula IX

- 20 045731

where X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N((C1 -C6)alkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C ₆ )alkyl fragment in -((C ₁ -C ₆ )alkyl)-R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl , -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH ₃ , -Si(CH ₃ ) ₃ , -CONH2, -C (O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and - SO2NH2;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl (C ₁ -C ₆ )alkyl, -CH ₂ S(C1O ₆ )alkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

R ³ R ^{4 4} _R 3a may be

C=CH C=CH C=N

R ³ -R ⁴ R ³ R ⁴ R ³ R ⁴ rZa rZa rZa

K, k, or K, and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -.

In certain embodiments, -X-Y- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R3-R3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments

- 22 045731 tion R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R2 is -CH3 or -CF3.

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R2 is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R2 is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R2 is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

In any of the above embodiments, in certain embodiments, R2 is phenyl.

In certain aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula XI

(XI) where X represents CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N((C1 -C6)αalkyl)CH2-R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ ,-OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (C ₁ -C ₆ )alkyl fragment in -((C ₁ -C ₆ )alkyl)-R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O )OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO2NH2;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl (C ₁ -C ₆ )alkyl, -CH ₂ S(C ₁ -C ₆ )alkyl, amino or cyano; or -CH2-, fused at position 4 of the ring, containing

- 23 045731 th Z, with the formation of a 5-7-membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

may represent

and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -XY- is -C(OH)CH ₂ CH2-.

In certain embodiments, -X-Y- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

o For

OR TO .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

- 24 045731

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH ₂ .

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XIII

(XIII) where X represents CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH ₂ N((C ₁ -C ₆ )alkyl )-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , - N((C1-C ₆ )alkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ ,

- 25 045731

-OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C6)alkyl fragment is in -((C ₁ -C ₆ )αalkyl)R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, - C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH ₃ ) ₃ , -CONH2, -C( O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy , amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO2NH2 ;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C1C ₆ )alkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

R ³ R ⁴ \za may represent

C=CH C=CH C=N

R ³ -R ⁴ R ³ R ⁴ R ³ \ ⁴

R ^3a , or >; and any chiral center has an R-, S- stereochemical configuration or a mixture of R-S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -XY- is -CHNHCH2-. In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -. In certain embodiments, XY- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

- 26 045731

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO ₂ CH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH ₂ .

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In some aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula XV

- 27 045731

(xv) where X represents CH, C(OH), C(O(C1- _C6 )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C ₁ -C ₆ )alkyl)- R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N( (C1-C ₆ )αalkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl]R ⁴ , - heterocyclyl-R ⁴ , -OR ⁴ ,

-OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (^^^kyl fragment in -((C1-C6)αlkyl) R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl , -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH ₃ , -Si(CH3)3, -CONH2, -C( O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and - SO2NH2;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C1C ₆ )alkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

X-Y

R ³ \ ⁴ can represent

Hch*

C=CH p=°H C=N

R ³ \-- _R 4 _R 3 _R 4 _R 3 _R 4 \ ^3a \ ^3a or ⁴ R ^3a · '' and any chiral center has an R-, S- stereochemical configuration or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -XY- is -CHNHCH ₂ -.

In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -.

In certain embodiments, -XY- is -CHOCH ₂ -.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

- 28 045731

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments

- 29 045731 tion R ² is -CH3 or -CF3.

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH3.

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by formula XVII

R ^1c (XVII) where X is CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH ₂ N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N((Cr C6)alkyl)CH2-R ⁴ , -N((CH2) ₂ OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C ₆ )alkyl fragment in -((C ₁ - C ₆ )alkyl)R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, - C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO ₂ NH ₂ or (C ₃ -C8)cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO ₂ CH ₃ , formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O )OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO ₂ NH ₂ ;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl (C ₁ -C ₆ )alkyl, -CH ₂ S(C10 ₆ )alkyl, amino or cyano; or -CH ₂ - fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ is phenyl, may be -NH- fused at ortho-

- 30 045731 position relative to X contained in the specified phenyl;

may represent

and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -X-Y- is -C(OH)CH2CH2-.

In certain embodiments, -X-Y- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments

- 31 045731 tions R ³ represents phenyl, and R ^3a represents -NH2 in the ortho, meta or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH3.

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH ₂ .

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XIX

(XIX) where X represents CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH ₂ N((C ₁ -C ₆ )alkyl )-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , - N((C1-C ₆ )alkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ ,

-OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (^-^alkyl fragment in -((C1-C6)αalkyl) R ⁴ is optionally substituted;

- 32 045731

Z is absent or represents halogen, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1 _{- C6} )alkyl, -C(O) NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH ₃ ) ₃ , -CONH2, -C( O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO2NH2;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )αalkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C1C ₆ )αalkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

, ^X "\

R ³ \ ⁴ \ ^3a can be c=сн Ρ=θ ^Η c=n

R ³ \—R ⁴ R ³ R ⁴ R ³ R ⁴

R*, I- _{or ;} and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -.

In certain embodiments, -X-Y- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

- 33 045731

rZa

OR TO .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH3.

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

According to certain aspects, the invention provides a compound or a pharmaceutically acceptable salt thereof represented by Formula XXI:

- 34 045731

where X represents CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; with the proviso that if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C ₁ -C ₆ )alkyl)- R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)alkyl)-R ⁴ , -N( (C1-C ₆ )αalkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C ₆ )alkyl moiety in -( (C ₁ -C ₆ )alkyl)-R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl , -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH ₃ , -Si(CH3)3, -CONH2, -C( O)OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkylα, -CF ₃ , -OCF ₃ , (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkylα and - SO2NH2;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )αalkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C1C ₆ )alkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

may represent c=cn

R ³ \ea

C=CH

R ³ R ⁴

R ^3a or

C=N

R ³ R ⁴ □For .

^R. and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -X-Y- is -CHNHCH2-.

In certain embodiments, -X-Y- is -C(OH)CH2CH2-.

In certain embodiments, -X-Y- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, ^R3 is phenylene- ^R3 ^

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

- 36 045731

According to any of the above embodiments, in certain embodiments, R ² is -CH3 or -CF3.

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH3.

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH3)3.

According to any of the above embodiments, in certain embodiments, R ² is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XXIII:

(XXIII) where X is CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH ₂ N, N, C(O) or -O-; provided that:

if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R3-R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C ₆ )αalkyl)-R ⁴ , -N(( C1-C6)alkyl)CH2-R ⁴ , -N((CH2) ₂ OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , - OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where the (C1-C ₆ )alkyl fragment is in -((C ₁ -C ₆ )alkyl)-R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C6)alkyl, -CF3, -OCF3, (C ₁ -C6)alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C( O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO ₂ NH ₂ or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )αalkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

R ² represents halogen, (C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl, (C ₁ -C ₆ )fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O )OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )αalkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO ₂ NH ₂ ;

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )αalkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C6)alkyl)OH, -CH(NH ₂ )CH((C ₁ -C6)alkyl) ₂ , optionally substituted aryl, optionally substituted aryl(C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C ₁ -C ₆ )alkyl, -CH ₂ S(C1C6)alkyl, amino or cyano; or -CH ₂ - fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or,

- 37 045731 if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

may represent

and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -XY- is -CHNHCH2-. In certain embodiments, -XY- is -C(OH)CH2CH2-. In certain embodiments, -XY- is -CHOCH ₂ -.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments

- 38 045731 tions R ³ represents phenyl, and R ^3a represents -OH in the ortho, meta or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

According to any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO ₂ CH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ² is -OCH ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH ₂ .

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XXV

_R 1C (XXV) where X is CH, C(OH), C(O(C ₁ -C ₆ )alkyl), C(O)N, CH2N, N, C(O) or -O-; provided that:

if X is CH, then -YR ⁴ is -H or -OH, or Y and R ⁴ are both present;

if X is C(OH) or C(O(C ₁ -C ₆ )alkyl), then -YR ⁴ is present;

if X is C(O)N, then -YR ⁴ is H; or -YR ⁴ is H and -R ³ -R ^3a is H;

if X is CH2N, then -YR ⁴ is (C ₁ -C ₆ )alkyl;

if X is N, then -YR ⁴ is H, or Y and R ⁴ are both present; and if X is C(O) or -O-, then -YR ⁴ is absent;

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C6)αalkyl)-R ⁴ , -N((C1

- 39 045731

C ₆ )alkyl)CH ₂ -R ⁴ , -N((CH2)2OH)-R ⁴ , -N[(C3-C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (C _g Sb)alkyl fragment in -(( C _g Sb)alkyl)R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C1-C ₆ )alkyl, -C (O)NH2, cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -Cb)alkyl, -SO2NH2 or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C1- _C6 )alkyl, (C1- _C6 )alkoxy, cyano, -SO2CH3, formyl, acyl or optionally substituted aryl;

^R2 represents halogen, (C1- _C6 )alkyl, ( _C3 - _C8 )cycloalkyl, (C1- _C6 )fluoroalkyl, -OCH3, -Si( _CH3 ) ₃ , -CONH2, -C(O) OH, cyano or phenyl;

R ³ , if present, is -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl or heterocyclyl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C1- _C6 )alkyl, -CF3, -OCF3, (C1- _C6 )alkoxy, aryl, aryloxy, amino, amino(C1- _C6 )alkyl, -C(O)NH2, cyano, -NHC(O)( _C1 - _C6 )alkyl, _-SO2 ( _C1 - _C6 )alkyl and -SO2NH2;

^R4 is hydrogen, hydroxy, optionally substituted ( _C1 - _C6 )alkyl, optionally substituted ( _C3 - _C8 )cycloalkyl, heterocyclyl(C1- _C6 )alkyl, ( _C3 - _C8 )cycloalkyl(C1- C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )αalkyl) ₂ , optionally substituted aryl, optionally substituted aryl(C1 -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl(C1-C ₆ )alkyl, -CH ₂ S(C1C ₆ )alkyl, amino or cyano; or -CH2- fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl;

• ^X -\

R ³ R ⁴

R ^3a may be

C=CH p= ^s _x ⁿ C=N

R ³ --R ⁴ R ³ R ⁴ R ³ R ⁴

R ³⁴ , R ³⁴ or 'in ³⁴ ; and any chiral center has an R-, S- stereochemical configuration, or a mixture of R- and S-.

In certain embodiments, X is CH, and Y and R ⁴ are both present.

In certain embodiments, -XY- is -CHNHCH2-. In certain embodiments, -XY- is -C(OH)CH ₂ CH ₂ -. In certain embodiments, XY- is -CHOCH2-.

According to any of the above embodiments, in certain embodiments, R ³ is phenylene-R ^3a .

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

- 40 045731

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments -R ³ -R ^3a is

According to any of the above embodiments, in certain embodiments R ^3a is absent.

According to any of the above embodiments, in certain embodiments, R ⁴ is cyclopropyl.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -OH in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -NH2 in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments, R ³ is phenyl, and R ^3a is -CN in the ortho, meta, or para position.

According to any of the above embodiments, in certain embodiments Z is absent.

According to any of the above embodiments, in certain embodiments, Z is fluorine.

In any of the above embodiments, in certain embodiments, Z is chlorine.

According to any of the above embodiments, in certain embodiments, Z is 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ₃ -C ₈ )cycloalkyl.

According to any of the above embodiments, in certain embodiments, Z is 6-F.

According to any of the above embodiments, in certain embodiments, R ^1c is aminomethyl.

According to any of the above embodiments, in certain embodiments, R ^1c is cyano.

According to any of the above embodiments, in certain embodiments, R ^1c is -SO2CH3.

According to any of the above embodiments, in certain embodiments, R ² is -CH ₃ or -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CF ₃ .

According to any of the above embodiments, in certain embodiments, R ² is tert-butyl.

According to any of the above embodiments, in certain embodiments, R ² is cyclopropyl.

According to any of the above embodiments, in certain embodiments

- 41 045731 tion R ² is -OCH3.

According to any of the above embodiments, in certain embodiments, R ² is -Si(CH ₃ ) ₃ .

According to any of the above embodiments, in certain embodiments, R ² is -CONH2.

According to any of the above embodiments, in certain embodiments, R ² is cyano.

According to any of the above embodiments, in certain embodiments, R ² is phenyl.

In certain aspects, the invention provides a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XXVI:

(XXVI) where X represents CH, C(OH), -C(NH ₂ ) or -C(NR ^a R ^b );

-YR ⁴ , if present, is -((C1-C6)alkyl)-R ⁴ , -CH2C(O)-R ⁴ , -CH2NH-R ⁴ , -CH2N((C1-C6)alkyl)-R ⁴ , -CR ^a R ^b -R ⁴ , -NH-R ⁴ , -NHCH2-R ⁴ , -NHC(O)-R ⁴ , -N((C1-C ₆ )alkyl)-R ⁴ , -N(( Cr C6)alkyl)CH2-R ⁴ , -N((CH2) ₂ OH)-R ⁴ , -N[(C3-C8)cycloalkyl(C1-C6)alkyl]R ⁴ , -heterocyclyl-R ⁴ , -OR ⁴ , -OCH2-R ⁴ , -OC(O)-R ⁴ , -OC(O)NR ^a R ^b , -SCH2R ⁴ or -SR ⁴ , where (C1-C ₆ ) alkyl fragment in -((C ₁ -C ₆ )αalkyl)R ⁴ is optionally substituted;

Z is absent or represents halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )αalkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, - C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl, -SO ₂ NH ₂ or (C ₃ -C ₈ )cycloalkyl;

R ^1c is halogen, amino(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, cyano, -SO2CH3, formyl, acyl, -NH ₂ or optionally substituted aryl;

R ^3a is absent or represents one or more substituents independently selected from the group consisting of halogen, hydroxy, (C ₁ -C ₆ )alkyl, -CF3, -OCF3, (C ₁ -C ₆ )alkoxy, aryl, aryloxy, amino, amino(C ₁ -C ₆ )alkyl, -C(O)NH ₂ , cyano, -NHC(O)(C ₁ -C ₆ )alkyl, -SO ₂ (C ₁ -C ₆ )alkyl and -SO ₂ NH ₂ ; And

R ⁴ represents hydrogen, hydroxy, optionally substituted (C ₁ -C ₆ )alkyl, optionally substituted (C ₃ -C ₈ )cycloalkyl, heterocyclyl(C ₁ -C ₆ )alkyl, (C ₃ -C ₈ )cycloalkyl(C ₁ -C ₆ )alkyl, -CH2OH, -CH((C ₁ -C ₆ )alkyl)OH, -CH(NH ₂ )CH((C ₁ -C ₆ )alkyl) ₂ , optionally substituted aryl, optionally substituted aryl (C ₁ -C ₆ )alkyl, heteroaryl, optionally substituted heteroaryl (C ₁ -C ₆ )alkyl, -CH ₂ S(C1C ₆ )alkyl, amino or cyano; or -CH ₂ - fused at position 4 of the ring containing Z to form a 5-7 membered heterocyclic ring, optionally containing substituents; or, if R ³ represents phenyl, may represent -NH- fused at the ortho position relative to the X contained in the specified phenyl.

In certain embodiments, the connection is selected from the group consisting of

- 42 045731

In certain embodiments, the connection is selected from the group consisting of

- 43 045731

In certain embodiments, the connection is selected from the group consisting of

- 44 045731

In certain embodiments, the connection is selected from the group consisting of

- 45 045731

In certain embodiments, the connection is selected from the group consisting of

- 46 045731

In certain embodiments, the connection is selected from the group consisting of

- 47 045731

In certain embodiments, the connection is selected from the group consisting of

- 48 045731

In certain embodiments, the connection is selected from the group consisting of

- 49 045731

In certain embodiments, the connection is selected from the group consisting of

- 50 045731

- 51 045731

In certain embodiments, the connection is selected from the group consisting of

- 52 045731

In certain embodiments, the connection is selected from the group consisting of

- 53 045731

In certain embodiments, the connection is selected from the group consisting of

- 54 045731

In certain embodiments, the connection is selected from the group consisting of

- 55 045731

Pharmaceutical compositions.

The invention provides pharmaceutical compositions, each of which contains one or more compounds of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition contains a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition contains a combination of compounds of the present invention and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent different from the compound of the present invention. The at least one additional pharmaceutically active agent may be an agent suitable for treating a disease or condition characterized by undesirable plasma kallikrein activity. For example, the at least one additional pharmaceutically active agent may be an anticoagulant agent, an antiplatelet agent, or a thrombolytic agent.

Anticoagulants prevent blood components from coagulating and thus prevent the formation of clots such as in atrial fibrillation. Anticoagulants include, but are not limited to, heparin, warfarin, coumadin, dicoumarol, phenprocoumon, acenocoumarol, ethyl bis-coumaracetate, hirudin, bivalarutin, direct thrombin inhibitors, and indanedione derivatives.

Antiplatelet agents inhibit platelet aggregation and are often used to prevent thromboembolic stroke in patients experiencing transient ischemic attack, stroke, or atrial fibrillation. Antiplatelet agents include, but are not limited to, aspirin, thienopyridine derivatives such as ticlopodine and clopidogrel, dipyridamole and sulfinpyrazone, and RGD mimics.

Thrombolytic agents provide lysis of clots that cause thromboembolic events such as stroke, myocardial infarction, and pulmonary thromboembolism. Thrombolytic agents include, but are not limited to, plasminogen, a2-antiplasmin, streptokinase, antistreplase, TNK, tissue plasminogen activator (tPA) and urokinase. Tissue plasminogen activator includes natural tPA and recombinant tPA, as well as modified forms of tPA that retain the enzymatic or fibrinolytic activity of natural tPA.

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

In certain embodiments, the invention provides a pharmaceutical composition suitable for the prophylactic or therapeutic treatment of a disease or condition characterized by undesirable plasma kallikrein activity.

- 56 045731

Methods of application.

The present invention provides compounds that inhibit the formation of thrombin through the intrinsic pathway and thus reduce the risk of new pathogenic thrombus formation (vascular occlusion or reocclusion), and also improve fibrinolytic-induced reperfusion when administered as an adjuvant therapy to a fibrinolytic therapy regimen . Diseases or conditions that are amenable to treatment using the compounds of the present invention include, but are not limited to, stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, fibrinolytic treatment-induced condition, angina pectoris, edema, angioedema, hereditary angioedema, sepsis, arthritis, bleeding, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy , neuropathy, hypertension, cerebral edema, increased albumin secretion, macroalbuminuria and nephropathy.

For example, when considering patients with angioedema, the small polypeptide PK inhibitor DX-88 (ecallantide) reduces edema in patients with hereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher. Sci. 29:255-8; Schneider, L. et al. (2007) J Allergy Clin Immunol. 120:416-22; and Levy, J.H. et al. (2006) Expert Opin. Invest. Drugs 15:1077–90. The bradykinin B2 receptor antagonist, icatibant, is also effective for the treatment of HAE. Bork, K. et al. (2007) J. Allergy Clin. Immunol. 119:1497–1503. Since plasma kallikrein produces bradykinin, inhibition of plasma kallikrein would be expected to suppress bradykinin production.

For example, in the case of coagulation caused by fibrinolytic treatment (eg, treatment with tissue plasminogen activator or streptokinase), increased plasma kallikrein levels are observed in patients undergoing fibrinolysis. Hoffmeister, H.M. et al. (1998) J. Cardiovasc. Pharmacol. 31:764-72. Plasmin-mediated activation of the intrinsic pathway has been shown to occur in plasma and blood and is significantly attenuated in the plasma of individuals deficient in any component of the intrinsic pathway. Ewald, G.A. et al. (1995) Circulation 91:28–36.

Individuals with acute MI have been shown to have elevated levels of activated plasma kallikrein and thrombin. Hoffmeister, H. M., et al. (1998) Circulation 98:2527–33.

DX-88 reduced cerebral edema, infarct volume, and neurological deficits in an animal model of ischemic stroke. Storini, C. et al. (2006) J. Pharm. Exp. Ther. 318:849-854. A C1 inhibitor reduced infarct volume in a mouse model of middle cerebral artery occlusion (MCAO). De Simoni, M. G. et al. (2004) Am. J. Pathol. 164:1857-1863; and Akita, N. et al. (2003) Neurosurgery 52:395–400). B2 receptor antagonists have been shown to reduce infarct volume, brain edema, and neutrophil accumulation, and to be neuroprotective in an animal model of OSMA. Zausinger, S. et al. (2003) Acta Neurochir. Suppl. 86:205-7; Lumenta, D. B. et al. (2006) Brain Res. 1069:227 ^r -34; Ding-Zhou, L. et al. (2003) Br. J Pharmacol. 139:1539-47.

Regarding blood loss during cardiopulmonary bypass (CPB), the kallikrein-kinin (ie, contact) system has been shown to be activated during CABG. Wachtfogel, Y.T. (1989) Blood 73:468. Activation of the contact system during SLS leads to a 20-fold increase in plasma bradykinin levels. Cugno, M. et al. (2006) Chest 120:1776-82; and Campbell, D.J. et al. (2001) Am. J. Physiol. Reg. Integr. Comp. Physiol. 281:1059-70.

The plasma kallikrein inhibitors P8720 and PKSI-527 have also been shown to reduce joint swelling in a rat model of arthritis. De La Cadena, R.A. et al. (1995) FASEB J. 9:446-52; Fujimori, Y. (1993) Agents Action 39:42-8. It has also been shown that inflammation in animal models of arthritis is accompanied by activation of the contact system. Blais, C. Jr. et al. (1997) Arthritis Rheum. 40:1327-33.

Additionally, the plasma kallikrein inhibitor P8720 has been shown to reduce inflammation in a rat model of acute and chronic inflammatory bowel disease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33; Stadnicki, A. et al. (1996) Dig. Dis. Sci. 41:912-20; and De La Cadena, R. A., et al. (1995) FASEB J. 9:446-52. Activation of the contact system occurs in acute and chronic intestinal inflammation. Sartor, R. B. et al. (1996) Gastroenterology 110:1467-81. The use of a B2 receptor antagonist, an antibody to high molecular weight kininogen, or reduction of kininogen levels has been shown to reduce clinical pathology in animal models of IBD. Ibid.; Arai, Y. et al. (1999) Dig. Dis. Sci. 44:845-51; and Keith, J.C. et al. (2005) Arthritis Res. Therapy 7:R769-76.

H-B-Pro-Phe-Arg-chloromethylketone (CMK), a PK and FXII inhibitor and physiological inhibitor (C1 inhibitor), has been shown to reduce vascular permeability in various organs and reduce lipopolysaccharide (LPS)- or bacterial-induced sepsis in animals. Liu, D. et al. (2005) Blood 105:2350-5; Persson, K. et al. (2000) J. Exp. Med. 192:1415-24. In patients with sepsis who were treated with a C1 inhibitor, improvements in clinical parameters were observed. Zeerleder, S. et al. (2003) Clin. Diagnost. Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med. 30:1722-8; and Marx, G. et al. (1999) Intensive Care Med. 25:1017-20. It has been shown that fatal cases of septicemia

- 57 045731 are accompanied by an increased level of contact activation, Martinez-Brotons, F. et al. (1987) Thromb. Haemost. 58:709-713; and Kalter, E.S. et al. (1985) J. Infect. Dis. 151:1019-27.

It has also been shown that in diabetics, particularly those suffering from proliferative retinopathy, prePK levels are elevated and correlate with fructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13:181-8; and Kedzierska, K. et al. (2005) Archives Med. Res. 36:539-43. PrePK levels have also been shown to be highest in patients with sensorimotor neuropathy. Christie, M. et al. (1984) Thromb. Haemostas. (Stuttgart) 52:221-3. Diabetics have elevated levels of prePK, which is associated with increased blood pressure. PrePK levels independently correlate with albumin excretion levels and are elevated in diabetics with macroalbuminuria, suggesting that prePK may represent a marker of progressive nephropathy. Jaffa, A.A. et al. (2003) Diabetes 52:1215–21. B1 receptor antagonists have been shown to reduce plasma loss in streptozotocin-treated rats. Lawson, S.R. et al. (2005) Eur. J. Pharmacol. 514:69-78. B1 receptor antagonists can also prevent the development of hyperglycemia and kidney dysfunction in streptozotocin-treated mice. Zuccollo, A. et al. (1996) Can. J. Physiol. Pharmacol. 74:586-9.

In certain aspects, the invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a drug.

In certain aspects, the invention provides methods for treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat or thereby prevent a disease or condition characterized by undesirable plasma kallikrein activity. By reducing plasma kallikrein activity in a subject, a disease or condition characterized by undesirable plasma kallikrein activity is cured.

Alternatively, in certain aspects, the invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition characterized by undesirable plasma kallikrein activity.

Alternatively, in certain aspects, the invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in treating a disease or condition characterized by undesirable plasma kallikrein activity.

As used herein, a disease or condition characterized by undesirable plasma kallikrein activity refers to any disease or condition in which a decrease in plasma kallikrein activity is desired. For example, it may be desirable to reduce plasma kallikrein activity when a hypercoagulable state occurs. As another example, it may be desirable to reduce plasma kallikrein activity when tissue ischemia occurs that is associated with the presence or formation of blood clots.

In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, fibrinolytic treatment-induced condition, angina pectoris, edema, angioedema, hereditary angioedema edema, sepsis, arthritis, bleeding, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin secretion, macroalbuminuria and nephropathy.

In certain embodiments, the disease or condition characterized by undesirable plasma activity is angioedema.

In certain embodiments, the disease or condition characterized by undesirable plasma activity is hereditary angioedema (HAE).

In certain embodiments, the disease or condition characterized by undesirable plasma activity is a stroke.

In certain embodiments, the disease or condition characterized by undesirable plasma activity is reperfusion injury.

In certain embodiments, the disease or condition characterized by undesirable plasma activity is acute myocardial infarction.

In certain embodiments, the disease or condition characterized by undesirable plasma activity is bleeding.

In certain embodiments, the disease or condition characterized by unwanted plasma activity is cardiopulmonary bypass blood loss.

In certain embodiments, a disease or condition characterized by an undesirable

- 58 045731 body plasma activity, selected from the group consisting of retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration and proliferative retinopathy.

Compositions, methods of administration and dosage.

The compounds of the present invention can be formulated into pharmaceutical compositions and administered to a mammalian host, such as a human patient, in various forms suitable for the route of administration chosen, for example, oral or parenteral, intravenous, intraperitoneal, intramuscular, topical or subcutaneous. Additional routes of administration are also contemplated by the present invention.

Thus, the compounds of the present invention can be administered systemically, for example orally, in combination with a pharmaceutically acceptable excipient, such as an inert diluent or digestible edible carrier. The compounds may be enclosed in hard or soft gelatin capsules, compressed into tablets, or placed directly into the patient's food. For oral therapeutic administration, the active compound may be combined with one or more excipients and administered in the form of oral tablets, sublingual tablets, molded lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Said compositions and preparations may contain at least 0.1% of the active compound. The percentage of compositions and preparations will obviously vary and range from about 2% to about 60% by weight of a given unit dosage form. The amount of active compound in said therapeutically effective compositions is such that an effective dosage can be obtained.

Tablets, molded lozenges, pills, capsules, etc. may also contain the following diluents and carriers: binders such as gum tragacanth, gum acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame, or flavoring agents such as peppermint, oil of wintergreen or cherry flavoring. If the unit dosage form is a capsule, it may contain, in addition to materials of the type described above, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be used as shells or for other physical modification of the solid dosage unit form. For example, tablets, pills, capsules may contain a coating of gelatin, wax, shellac or sugar, etc. The syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propyl parabens as preservatives, a coloring agent or a flavoring agent such as cherry or orange flavoring. Obviously, any materials used to prepare any unit dosage forms must be pharmaceutically acceptable and substantially non-toxic in the quantities used. In addition, the active compound can be formulated into sustained release formulations and devices.

The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water or a physiologically acceptable aqueous solution and are optionally mixed with a non-toxic surfactant. It is also possible to obtain dispersions in glycerin, liquid polyethylene glycols, triacetin and mixtures thereof, as well as in oils. Under standard conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion may contain sterile aqueous solutions or dispersions or sterile powders containing the active ingredient, which are intended to immediately prepare sterile injectable or infusion solutions or dispersions, optionally included in liposomes. In all cases, the final dosage form must be sterile, liquid and stable under the conditions of manufacture and storage. The liquid carrier or excipient may be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyhydric alcohol (eg, glycerin, propylene glycol, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glycerol esters, and suitable mixtures. Appropriate fluidity can be maintained, for example, by forming liposomes, by maintaining the required particle size in the case of dispersions, or by using surfactants. The action of microorganisms can be prevented by the use of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases it is preferable to include isotonic agents such as sugars, buffers or sodium chloride. Prolonged absorption of injectable compositions can be achieved by the use of absorption delaying agents in the compositions, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by introducing the required amount of the active compound into an appropriate diluent, optionally containing the various other ingredients listed above, and subsequent sterilization. Methods for obtaining sterile powders

- 59 045731 to obtain sterile injectable solutions may involve vacuum drying and lyophilization techniques that provide a powder of the active ingredient and any additional target ingredients present in the above solutions obtained by sterile filtration.

In the case of topical administration, the compounds of the present invention can be used in pure form if they are liquids. However, in general, it is desirable to administer the compounds to the skin as compositions or formulations in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Suitable solid carriers include fine solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Suitable liquid carriers include water, alcohols or glycols or water-alcohol/glycol mixtures in which effective amounts of the compounds of the present invention can be dissolved or dispersed, optionally containing additives of non-toxic surfactants. Excipients such as fragrances and additional antimicrobial agents can be added to optimize properties for a given application. The resulting liquid compositions can be applied using absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified minerals can also be used in liquid carriers to produce pastes, gels, ointments, soaps, etc., which are easily spread, for application directly to the consumer's skin.

Examples of suitable dermatological compositions that can be used to deliver the compounds of the present invention to the skin are known in the art, see, for example, Jacquet et al. (US Patent No. 4,608,392; the contents of which are incorporated herein by reference), Geria (US Patent No. 4,992,478; the contents of which are incorporated herein by reference), Smith et al. (US Patent No. 4,559,157; the contents of which are incorporated herein by reference) and Wortzman (US Patent No. 4,820,508; the contents of which are incorporated herein by reference).

Suitable dosages of the compounds of the present invention can be determined, at least tentatively, by comparing in vitro activity and in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, US Pat. No. 4,938,949 (the contents of which are incorporated herein by reference).

The amount of a compound or active salt thereof required for use in treatment may vary depending not only on the particular compound or salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and ultimately , determined by the attending physician or clinical specialist.

In general, however, a suitable dose ranges from about 0.5 to about 100 mg/kg body weight of the consumer per day, for example, from about 3 to about 90 mg/kg body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, about 10 to about 60 mg/kg body weight per day, or about 15 to about 50 mg/kg body weight per day.

The compounds of the present invention can be effectively formulated in a unit dosage form, for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition containing a compound of the present invention in said unit dosage form. The desired dose can effectively be contained as a single dose or doses to be administered at appropriate intervals, for example, in two, three, four or more divided doses per day. The partial dose as such may be further divided, for example into a number of separate, randomly selected administrations.

The compounds of the present invention can also be administered in combination with other therapeutic agents, for example, with other agents that are suitable for treating or preventing ischemia, blood loss or reperfusion injury.

Other delivery systems may include time-modified release, delayed release, or sustained release delivery systems well known in the art. The use of these systems eliminates the need for repeated administration of the active compound, which increases convenience for the subject and the attending physician. Many types of modified release delivery systems are available and known to those skilled in the art. It may be desirable to use a long-term sustained release implant. Long-term release as used herein means that the delivery system or implant is formulated or intended to deliver a therapeutic level of active ingredient for at least 30 days and preferably 60 days.

- 60 045731

In certain embodiments, a compound of the present invention is formulated for intraocular administration, such as by injection or administration into the eye directly or using an intraocular medical device.

The compounds of the present invention can be formulated for placement in a medical device, which can include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, basket catheters, or other device that can be used or implanted for an extended period of time into the body cavity. As a specific example, it may be desirable to provide devices and methods that can deliver the compounds of the present invention to an area of the body that has been treated by surgery.

In an exemplary embodiment, a compound of the present invention can be placed in a medical device, such as a stent, and delivered to a treatment site to treat a body fragment.

Stents are used as carriers for the delivery of therapeutic agents (ie, drugs). Intravascular stents are generally implanted for an extended period in coronary or peripheral vessels. Stent designs include those proposed in US Pat. No. 4,733,655 (Palmaz), US Pat. No. 4,800,882 (Gianturco), or US Pat. No. 4,886,062 (Wiktor). These designs include metal and polymer stents, as well as self-expanding and balloon-expandable stents. Stents can also be used to deliver a drug to the site of contact with the vascular system, as proposed, for example, in US Patent No. 5102417 (Palmaz), US Patent No. 5419760 (Narciso, Jr.), US Patent No. 5429634 (Narciso, Jr.) and in international patent applications WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center).

The term "place" means that the compound is encapsulated, adsorbed, placed, or otherwise positioned within the device using methods known in the art. For example, the compound may be dipped and released (matrix type) or placed inside and released (reservoir type) of polymeric materials that coat or surround the medical device. In the last example, the compound can be contained within polymeric materials or associated with polymeric materials using one or more methods for producing these materials known in the art. In other formulations, the compound may be bound to the surface of the medical device without the need for coating, for example, through detectable bonds, and may be released over time or may be removed by active mechanical or chemical processes. In other formulations, the compound may be in a permanently immobilized form that provides bonding at the site of implantation.

In certain embodiments, the compound can be incorporated into polymer compositions during the formation of biocompatible coatings for medical devices, such as stents. Coatings made from these components are generally homogeneous and suitable for application to a variety of devices intended for implantation.

The polymer may be a biopersistent or bioadsorbable polymer depending on the desired release rate or the desired degree of stability of the polymer, but often a bioabsorbable polymer is preferred for this embodiment because, unlike a biostable polymer, it does not persist for an extended period of time after implantation. which could cause any unwanted chronic local response. Bioadsorbable polymers that can be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-glycolide) (PLLA/PGA), poly(hydroxybutyrate), poly(hydroxybutyrate- valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) ( PLA), polyC-lactide) (PLLA), poly(glycolic acid-trimethylene carbonate) (PGA/PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester, polyphosphoetherurethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, cross-linked or amphipathic block copolymers of hydrogels and other suitable bioadsorbable polymers known in the art. Biostable polymers with relatively low chronic tissue response, such as polyurethanes, silicones and polyesters, can also be used, and other polymers can be used if they can be dissolved and cured or polymerized in the medical device, such as polyolefins, polyisobutylene and ethylene copolymers -alpha-olefin; acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinylaroma

- 61 045731 chemical compounds such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers with each other and with olefins, such as ethylene methyl methacrylate copolymers, acrylonitrile styrene copolymers, ABS resins and ethylene vinyl acetate copolymers; pyran copolymers; polyhydroxypropyl methacrylamidophenol; polyhydroxyethyl aspartamide phenol; polyethylene oxide-polylysine substituted with palmitoyl residues; polyamides such as nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; viscose; viscose triacetate; cellulose; cellulose acetate; cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; carboxymethylcellulose.

Polymers and semi-permeable polymer matrices can be processed into molded products such as valves, stents, tubes, prostheses, etc.

In certain embodiments, a compound of the present invention is associated with a polymer or semipermeable polymer matrix that is formed into a stent or stent-graft device.

Typically, polymers are applied to the surface of the implantable device by spinning, dipping, or spraying. Additional methods known in the art can also be used for this task. Spraying methods include traditional methods as well as micro-deposition techniques using a jet-type applicator. In addition, the polymer can be applied to the implantable device by photolithography to place the polymer only on specific portions of the device. This method of coating a device provides a uniform layer around the device, which allows for improved diffusion of various analytes through the coating of the device.

In certain embodiments of the invention, the compound is formulated to be released from the polymer coating into the environment in which the medical device is located. Preferably, the compound is released in a controlled manner over an extended period of time (eg, several months) using at least one of several known techniques using polymeric carriers or layers to control the release. Some of these techniques are described in US Patent Application No. 2004/0243225A1, the contents of which are incorporated herein by reference in their entirety.

In addition, as described, for example, in US Pat. No. 6,770,729, the contents of which are incorporated herein by reference in their entirety, the reagents and reaction conditions of the polymer compositions can be adjusted so that the release of the compound from the polymer coating can be controlled. For example, the diffusion coefficient of one or more polymer coatings can be modulated to control the release of a compound from the polymer coating. In various embodiments of this aspect, the diffusion coefficient of one or more polymer coatings can be controlled to modulate the ability of analytes present in the environment in which the medical device is placed (for example, an analyte that accelerates the degradation or hydrolysis of some polymer moiety) to assess the level of one or more components in the polymer composition (and, for example, thereby modulating the release of the compound from the polymer coating). Another embodiment of the invention includes a device containing a plurality of polymer coatings, each of which has a plurality of diffusion coefficients. In these embodiments, the release of the compound from the polymer coating can be modulated by the combination of polymer coatings.

In another embodiment of the invention, the release of a compound from the polymer coating is controlled by modulating one or more properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds or, alternatively, the pH of the polymer composition. For example, certain polymer compositions may be designed to release a compound in response to a decrease in the pH of the polymer composition.

Sets.

The invention also provides a kit containing a compound of the present invention or a pharmaceutically acceptable salt thereof; at least one other therapeutic agent, packaging material, and instructions for administering a compound of the present invention or a pharmaceutically acceptable salt thereof and other therapeutic agent or agents to a mammal for treating or preventing ischemia, blood loss, or reperfusion injury in the mammal. In one embodiment, the mammal is a human.

Examples

The present invention is further illustrated in the following examples, which should not be construed as further limiting the invention in any way. The contents of all specified materials (including literary references, issued patents, published patent applications and pending patent applications) listed in the specified application are expressly incorporated herein in their entirety by reference.

- 62 045731

The corresponding substituted pyrazolecarboxylic acids can be prepared using various methods described in the following materials

1. Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an SO2-containing group as vanilloid receptor ligands; Frank, Robert et al; International Application PCT 2013/068464, May 16, 2013 (contents incorporated by reference)

2. Design, synthesis and biological activity of Ε-β-farnesene analogues containing pyrazole-carboxamide; Sun, Yufeng et al; Youji Huaxue, 31(9), 1425-1432; 2011

3. Preparation of heterocyclic urea derivatives as kinase inhibitors useful for the treatment of myeloproliferative diseases and other proliferative diseases; Flynn, Daniel L. et al; international application PCT 2013/036232 (contents incorporated by reference).

- 63 045731

4. Substituted phenylureas and phenylamides as vanilloid receptor ligands and their preparation; By Frank, Robert et al; US Patent Application Published 2012/0258946 (contents incorporated by reference)

5. Substituted cyclic carboxamide and urea derivatives as ligands of the vanilloid receptor; Frank, Robert et al; international application PCT 2012/022487 (contents incorporated by reference)

6. Preparation of heterocyclic urea derivatives as kinase inhibitors useful for the treatment of hyperproliferative and other diseases; Flynn, Daniel L. and Kaufman, Michael D; US Patent Application Published 2012/0225057 (contents incorporated by reference).

7. Preparation of pyrazolylpyrimidine derivatives for use as protein kinase modulators;

Casuscelli, Francesco et al; international application PCT 2012/139930 (contents incorporated by reference)

8. Preparation of substituted heteroaromatic carboxamide and urea compounds as vanilloid receptor ligands; Frank, Robert et al; US Patent Application Published 2012/0115903 (contents incorporated by reference)

9. Preparation of pyrazole derivatives as modulators of calcium release-activated calcium channel for treatment of non-small cell lung cancer; Muthuppalaniappan, Meyyappan et al; Indian Patent Application 2009CH02439

10. 3-methoxy pyridine amides with good insecticidal activity and their preparation; Li, Bin et al; Faming Zhuanli Shenqing, 102285963

11. Preparation of amidinoaneline derivatives with inhibitory activity to activated blood coagulation factor X; Matsumoto, Kayo et al; international application PCT 2011/118818 (contents incorporated by reference)

12. Preparation of l-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(l-methyl-2oxo-2,3-dihydro-lH- imidazo[4,5-b]pyridin-7-yloxy)phenyl]urea and related compounds as antitumor agents; Springer, Caroline et al; international publication PCT 2011/092469 (contents incorporated by reference)

13. 3-(l-aminoalkyl)pyrazole- and 4,5-dihydropyrazole-5-carboxylic acids as peptide bond replacements; Jones, Raymond C. F. et al; Synlett, (2), 211-214; 2011

14. New Analogues of (E)-P-Famesene with Insecticidal Activity and Binding Affinity to Aphid Odorant-Binding Proteins; Sun, Yufeng et al; Journal of Agricultural and Food Chemistry, 59(6), 2456-2461; 2011

- 64 045731

15. 1,2-Diamines as inhibitors of co-activator associated arginine methyltransferase 1 (CARMI); Therrien, Eric et al; Bioorganic & Medicinal Chemistry Letters, 19(23), 6725-6732; 2009

16. Preparation of benzamide compounds as pesticides; Li, Bin et al; Faming Zhuanli Shenqing Gongkai Shuomingshu, 101298451

17. Optimization of pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARMI); Huynh, Tram et al; Bioorganic & Medicinal Chemistry Letters, 19(11), 2924-2927; 2009

18. Pyrazole derivatives as LXR and FXR modulators and their preparation, pharmaceutical compositions and use in the treatment of diseases; Boren, Brant Clayton et al; International Application PCT 2008/073825 (contents incorporated by reference)

19. Preparation of N-(pyridylpyrimidinylaminophenyl) amides as protein kinase inhibitors; Chianelli, Donatella et al; international application PCT 2008/058037 (contents incorporated by reference)

20. Preparation of heterocyclic ureas as kinase inhibitors useful for the treatment of proliferative and inflammatory diseases; Flynn, Daniel L. et al; International Application PCT 2008/034008 (contents incorporated by reference)

21. Heterocyclic derivatives as inhibitors of protein arginine methyltransferases and their preparation, pharmaceutical compositions and use in the treatment of diseases, Wahhab, Amal et al; international application PCT 2008/104077 (contents incorporated by reference)

22. Preparation of heterocyclic ureas as kinase inhibitors useful for the treatment of proliferative and inflammatory diseases; Flynn, Daniel L. et al; international publication PCT 2008/034008 (contents incorporated by reference)

23. Novel N-heterocyclic phosphonates and phosphinates as glucokinase activators for treatment of Type II diabetes; Ryono, Dennis E. et al; international application PCT 2008/005964 (contents incorporated by reference)

24. Reductive isoxazole ring opening of the anticoagulant razaxaban is the major metabolic clearance pathway in rats and dogs; Zhang, Donglu et al; Drug Metabolism and Disposition, 36(2), 303-315; 2008

25. Structure-activity relationship and pharmacokinetic profile of 5-ketopyrazole factor Xa inhibitors; Vames, Jeffrey G. et al; Bioorganic & Medicinal Chemistry Letters, 18(2), 749-754; 2008

- 65 045731

26. Preparation of (pyrazolecarbonylamino)benzamide derivatives as insecticides and fungicides; Li, Bin et al; international application PCT 2008/134969 (contents incorporated by reference)

27. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARMI); Purandare, Ashok V. et al; Bioorganic & Medicinal Chemistry Letters, 18(15), 44384441; 2008

28. Potent Non-Nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase Complex; Sun, Aiming et al; Journal of Medicinal Chemistry, 51(13), 3731-3741; 2008

29. Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors; Vames, Jeffrey G. et al; Bioorganic & Medicinal Chemistry Letters, 17(23), 6481-6488; 2007

30. Preparation of pyrazoles for the treatment of obesity and other CNS disorders; Bennani, Youseff L. et al; international application PCT 2007/094962 (contents incorporated by reference)

31. Preparation of ureidopyrazoles as kinase inhibitors, particularly as p38 kinase inhibitors; Bastian, Jolie Anne et al; international publication PCT 2007/053394, 10 May 2007

32. Hydrazide compound and their preparation, formulation and pesticidal use; Ikegami, Hiroshi et al; international application PCT 2007/043677 (contents incorporated by reference)

33. Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase: A new use of silicon bioisosteres in medicinal chemistry; Barnes, Matthew J. et al; Bioorganic & Medicinal Chemistry Letters, 17(2), 354-357; 2007

34. Preparation of anthranilamide derivative insecticides and acaricides; Lahm, George Philip et al; International Application PCT 2006/055922 (contents incorporated by reference)

35. Preparation of amino acid derivatives as inhibitors of protein arginine methyl transferases; Purandare, Ashok Vinayak and Chen, Zhong; International Application PCT 2006/069155 (contents incorporated by reference)

36. Preparation of azole carboxamides as inhibitors of bacterial type III protein secretion systems; Li, Xiaobing et al; international application PCT 2005/113522 (contents incorporated by reference)

37. Preparation of pyrazolylbenzamides and pyrazolopyridinylbenzamides as factor Xa inhibitors for the treatment of thromboembolic disorders; Lam, Patrick Y. et al;

- 66 045731 US Patent Application Published 2006/0089496 (contents incorporated by reference)

38. Preparation of pyrazolylcarbonyl anthranilamides as insecticides; Lahm, George Philip and Selby, Thomas Paul; international application PCT 2005/118552 (contents incorporated by reference)

39. Insecticidal anthranilic diamides: A new class of potent ryanodine receptor activators; Lahm, George P. et al; Bioorganic & Medicinal Chemistry Letters, 15(22), 4898-4906; 2005

40. Process for the preparation of 1,3,5-trisubstituted pyrazoles via [3+2] cycloaddition; Shapiro, Rafael et al; US Patent Application Published 2006/0069270 (contents incorporated by reference)

41. Preparation of amides of pyrazolamines and anilines as well as analogs as cytokine inhibitors for the treatment of inflammatory diseases; Boman, Erik et al; international application PCT 2005/023761 (contents incorporated by reference)

42. Discovery of l-(3'-Aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'dimethylaminomethyl)imidazol-l-yl]phenyl]-lH-pyrazole- 5-carboxyamide Hydrochloride (Razaxaban), a Highly Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor; Quan, Mimi L. et al; Journal of Medicinal Chemistry, 48(6), 17291744; 2005

43. Preparation of N-arylheteroaryls, in particular N-phenylpiperazinyl methanones, as inhibitors of tubulin polymerization and their compositions for treatment of cancer; Le-Brun, Alain et al; International Application PCT 2004/078732 (contents incorporated by reference)

44. Preparation of 1,2-azole derivatives with hypoglycemic and hypolipidemic activity; Maekawa, Tsuyoshi et al; International Application PCT 2003/099793 (contents incorporated by reference)

45. Discovery of l-(2-Aminomethylphenyl)-3-trifluoromethyl-N-[3-fluoro-2'(aminosulfonyl)[l,l'-biphenyl)]-4-yl]-lH-pyrazole-5-carboxamide (DPC602), a Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor; Pruitt, James R. et al; Journal of Medicinal Chemistry, 46(25), 5298-5315; 2003

46. l-(2-Naphthyl)-lH-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 3: Design, synthesis and SAR of orally bioavailable benzamidine-P4 inhibitors; Jia, Zhaozhong J. et al; Bioorganic & Medicinal Chemistry Letters, 14(5), 1229-1234; 2004

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47. Preparation of novel N-[4-(lH-imidazol-l-yl)-2-fluorophenyl]-3-(trifluoromethyl)lH-pyrazole-5-carboxamides as factor Xa inhibitors; Quan, Mimi L; International Application PCT 2003/047517 (contents incorporated by reference)

48. Preparation of imidazolylphenylpyrazolopyridinones as factor Xa inhibitors; Quan, Mimi L. and Wexler, Ruth R; International Publication PCT 2003/047520 (contents incorporated by reference)

49. Preparation of novel substituted IH-dihydropyrazoles; Annis, Gary David et al; International Application PCT 2003/016282 (contents incorporated by reference)

50. Pesticidal compositions for coating plant propagation material containing anthranilamides; Berger, Richard Alan and Flexner, John Lindsey; International Application PCT 2003/024222 (contents incorporated by reference)

51. Method for controlling particular insect pests by applying anthranilamide compounds; Lahm, George Philip et al; International Application PCT 2003/015518 (contents incorporated by reference)

52. Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: Pl structure-activity relationships of the substituted l-(2-Naphthyl)-lHpyrazole-5-carboxylamides; Jia, Zhaozhong J. et al; Bioorganic & Medicinal Chemistry Letters, 12(12), 1651-1655; 2002

53. Efficient process for the preparation of a factor Xa inhibitor; Sunkara, Hari Babu and Yang, Yali; International Application PCT 2002/024690 (contents incorporated by reference), March 28, 2002

54. Preparation of pyrazolecarboxamides as inhibitors of factor Xa; Zhu, Bing-yan et al; US Patent Application Published 2002/0091116 (contents incorporated by reference)

55. Preparation of dihydrobenzo[b][l,4]diazepin-2-ones as mGluR2 antagonists for treatment of neurological disorders; Adam, Geo et al; international application PCT 2002/083652 (contents incorporated by reference)

56. Preparation of azole inhibitors of cytokine production; Bamaung, Nwe Y. et al; US Patent Application Published 2001/0044445 (contents incorporated by reference)

57. Parallel Synthesis of Potent, Pyrazole-Based Inhibitors of Helicobacter pylori Dihydroorotate Dehydrogenase; Haque, Tasir S. et al; Journal of Medicinal Chemistry, 45(21), 4669-4678; 2002

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58. Preparation of 1,3,5-trisubstituted pyrazoles for pharmaceutical use as factor Xa inhibitors; Zhou, Jiacheng et al; International Application PCT 2001/029006 (contents incorporated by reference)

59. Discovery of l-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)-[l,Tbiphenyl]-4-yl]-3-(trifluoromethyl)-lH-pyrazole- 5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa; Pinto, Donald J. P. et al; Journal of Medicinal Chemistry, 44(4), 566-578; 2001

60. Preparation of novel guanidine mimics as factor Xa inhibitors; Lam, Patrick Y. et al; International Application PCT 98/57951 (contents incorporated by reference)

61. Some reactions of β-aroylacrylic acid epoxide; By El-Sawy, A. A. et al; Journal of the Serbian Chemical Society, 56(10), 587-94; 1991

62. The effect of 1,3-diphenylpyrazolecarboxylic acid derivatives on the hepatic cytochrome P-450 system; Khlopushina, T. G. et al; Khimiko-Farmatsevticheskii Zhumal, 25(11), 10-13; 1991

63. Preparation and testing of phenylpyrazolecarboxylates as plant growth regulators and protectants; Sohn, Erich et al; Ger. Offen., 3633840

64. Action of nitrogen nucleophiles on oxiranes of β-aroylacrylic acids; Omran, S. A. et al; Egyptian Journal of Chemistry, 28(5), 399-410; 1986

65. The sequential lithiation of 1-phenylpyrazoles; Micetich, Ronald G. et al; Heterocycles, 23(4), 943-51; 1985

Scheme 1

NaOEt, EtOH

Scheme 2

ABOUT

EY

OEt

NH ₂

R ^{1b X} R ^1c

1e

^R2 / _CH3

O 1b

AcOH 2-methoxyethanol

_H2N

SnCI ₂ NaNO ₂ HCI

N.H.

R1 ^{^} _H

R ^c

1f

R ²

X

R ^{1b 4} R

_CO2R

R'

R ²

NH ₂ OCH _{3 r;}

OEt

LiOH cat. based

OEt

1d

R ² _N CONH ₂

R ^{1b 4} _R ¹ c ig

R ²

hydrolysis

OCH ₃

_N co ₂ h

R ^{1b 4} R ^1c

1h

R ²

X - halide, triflate, transition metal boronic acid or esters of boronic acid

_NCO2R

R ^{1b 4} R ^1c

2s _N with ₂ n

R ^1b

1h

- 69 045731

Scheme 3

3a°

R'

ABOUT

ABOUT

Zs

_H2N .

² NH

Rib

R ^1c

If

Scheme 4

R ²

3d

R ^1c = CN

Scheme 5

5a

Scheme 6

NaOEt

CH ₃

R

3b

^RIG

3d

_{NaH2PO4 _}

NaCIO ₂

CH ₃ CN, H ₂ O

R ²

R ²

_CO2H

^R1 ^

1h or

_KMnO4

R ²

1. L1AIH4 or

NaBH ₄ /NiCI ₂ 6H ₂ O

2. TEA/(Vos) ₂ 0

NHBoc

_{NaH2PO4 _}

NaCIO ₂

CH ₃ CN, H ₂ O or

_KMnO4

R ²

R ^1b

CO ₂ H

I 4b

NHBoc nh ₂ nh ₂

Cl

R ²

NHBoc

5d

_{NaH2PO4 _}

NaCIO ₂

CH ₃ CN, H ₂ O

6a

_{H2SO4 _}

CHO

N.H.

5b NH ₂ or

KMnO ₄ o ₂ n

SMOKE. HNO3

-10°C

R ²

ABOUT

1. VNZ, THF

2. TEA/(Voc) ₂ O

NH ₂

6d

R ²

HCI, EtOH

OH

3. SnCl ₂ , MeOH

4. TEA/(Boc) ₂ O

1.MSCI,T3A

2. NaIII, DMF

R ²

) _2H

NHBoc

5e

6b

CHO

1.NH ₂ OH.HCI h ₂ n

Ac ₂ O,100°C

2. recovery

6c

CN

R ²

NHBoc without

NaH ₂ PO ₄ NaCIO ₂ CH ₃ CN, H ₂ 0 or

_KMnO4

1. HCI, NaNO ₂

2.SnCI ₂

3. NOAC, kip.

R'

O Zs O

R ²

_CO2H

NHBoc 6f

- 70 045731

Scheme 7

Scheme 8

1. L1AIH4 or

NaBH ₄ /NiCI ₂ 6H ₂ O

2. TEA/(Vos) ₂ 0

Scheme 9

An example of the preparation of 1-(3-cyanophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxylic acid (9i).

Step 1. Preparation of 3-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9f).

To a suspension of 3-bromoaniline (9a) (30.8 ml, 283 mmol) in 12N. hydrogen chloride (85 ml, 1017 mmol), a solution of sodium nitrite (23.39 g, 339 mmol) in water (160 ml) was slowly added at 0°C. After the re

- 71 045731 stirring for 1 hour, tin (II) chloride dihydrate (127 g, 565 mmol), previously dissolved in 12N, was added to the mixture. hydrogen chloride (85 ml, 1017 mmol), at such a rate that the temperature does not exceed 5°C. After stirring for 2 h, a solution of 1,1,1-trifluoropentane-2,4-dione (9c) (39.4 mL, 325 mmol) in ethanol (650 ml) and the mixture was heated at 60°C overnight. After cooling to room temperature, the solvent was removed and the aqueous solution was made basic with solid NaHCO ₃ and diluted with water (300 ml), separated using ethyl acetate (3x500 ml). The organic phase was dried over MgSO ₄ and concentrated to give a mixture of 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (9d) and 1(3-bromomethyl)-3-methyl-5-( trifluoromethyl)-1H-pyrazole (9e) (81.6 g, 94.6% yield) as a crude residue. The reaction mixture was used as such in the next step.

Into a mixture of 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (9d) and 1-(3-bromomethyl)-3-methyl-5(trifluoromethyl)-1H-pyrazole (9e) (6.1 g, 20 mmol) in DMF (15 ml) was added copper cyanide (2.24 g, 25 mmol) and heated to reflux overnight. TLC analysis (ethyl acetate/hexanes, 20%) indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate (200 ml) and filtered. The filtrate was washed with water (200 ml) and saline (100 ml) and dried. The crude mixture was purified on an 80 g silica gel flash chromatography column using ethyl acetate/hexanes (0-50%) as eluent to give:

1. 3-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9g) (0.5 g, 20% yield, top spot) as a yellow oily liquid. 1H NMR (300 MHz, DMSO- _d6 ) δ 8.10 - 8.02 (m, 2H), 7.92 - 7.76 (m, 2H), 7.03 (s, 1H), 2.32 (s, 3H); IR (KBr) 3143, 3084, 2934, 2236, 1565, 1498, 1463, 1366, 1302, 1238, 1194, 1147, 1008, 80θ, 685, 507 cm ^-1 ; analysis, calculation for C ₁₂ H ₈ F ₃ N ₃ : C, 57.37; H, 3.21; N, 16.73; experiment: C, 57.58; H, 3.35; N, 16.83;

2. 3-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9f) (1.2 g, 4.78 mmol, 48% yield, bottom spot) as a white solid . 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.17 (t, J=1.7 Hz, 1H), 8.06 - 7.92 (m, 2H), 7.79 (t, J=8 .0 Hz, 1H), 6.83 (s, 1H), 2.40 (d, J=0.5 Hz, 3H). ICS (KBr) 3153, 3082, 2928, 2231,1588, 1488, 1434, 1379, 1252, 1189, 1126, 969, 890, 812, 701 cm'¹; analysis, calculation for CnHFjNj: C, 57.37; H, 3.21; N, 16.73; experiment: C, 57.58; H, 3.35; N, 16.83.

Step 2. Preparation of 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9h).

To a solution of 3-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9f) (2.66 g, 10.59 mmol) in carbon tetrachloride (80 ml) was added 1-bromopyrrolidine- 2,5-dione (NBS, 1.98 g, 11.12 mmol) and benzoyl peroxide (0.077 g, 0.318 mmol). The reaction mixture was refluxed for 4 hours, cooled, filtered and concentrated to give the crude bromide. The crude bromide was dissolved in a mixture of dioxane (40 ml) and water (40 ml) and calcium carbonate (1.91 g, 19.06 mmol) was added. The solution was heated at 60°C overnight with constant stirring. The reaction mixture was cooled to room temperature, filtered and washed with ethyl acetate, the filtrate was concentrated to remove volatile solvent and the aqueous solution was extracted with ethyl acetate (2x150 ml). Combine the organic layers, dry over MgSO ₄ , concentrate to give crude 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (9h). The crude residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-50% ethyl acetate/hexanes] to give 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzonitrile (9h) (520 mg, 1.946 mmol, 18.38% yield) as a white solid. 1H NMR (300 MHz, CDC13) δ 8.06 (t, J=1.7 Hz, 1H), 7.99 (ddd, J=8.1, 2.1, 1.2 Hz, 1H), 7 .75 (dt, J=7.7, 1.3 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 6.76 (s, 1H), 4.72 (t, J=9.8 Hz, 2H), 2.13 (t, J=5.5 Hz, 1H); ICS (KBr) 3370, 3076, 2946, 2235, 1484, 1463, 1256, 1192, 1127, 1019, 805, 691, 503 cm'¹; analysis, calculation for C12H ₈ F ₃ N ₃ O: C, 53.94; H, 3.02; N, 15.73; experiment: C, 53.96; H, 3.07; N, 15.48.

Step 3. Preparation of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)

Sodium periodate (32.4 g, 151 mmol), water (100 ml) and ruthenium (III) chloride hydrate (0.341 g, 1.513 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated to remove acetonitrile. The aqueous layer was made alkaline with 1N. NaOH, then washed with diethyl ether (2x100 ml) to remove organic impurities. The alkaline aqueous layer was acidified with 1N. HCl, extracted with diethyl ether (2x150 ml), concentrate the layer in diethyl ether to approximately 75 ml, then add hexanes until the mixture became cloudy, then stir at room temperature overnight. The resulting solid was collected by filtration, dried in vacuo to give 1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (7.48 g, 35% yield) as a pale yellow solid matter. 1H NMR (300 MHz, DMSO-d ₆ ) δ 13.84 (br.s, 1H), 8.22 (t, J=1.7 Hz, 1H), 8.06 - 8.00 (m, 1H ), 7.96 (ddd, J=8.2, 2.1, 1.1 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.57 (d, J= 0.4 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.96 (s); analysis, calculation for: C ₁₂ H ₆ F ₃ N ₃ O ₂ : C, 51.26; H, 2.15; N, 14.94; experiment: C, 51.19; H, 2.14; N, 14.58.

- 72 045731

Scheme 10

An example of the preparation of 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-Spirazole-5-carboxylic acid (10d).

Step 1. Preparation of 3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (10c).

In a 1.0 L three-neck flask containing a suspension of 3-aminobenzonitrile (5 g, 42.3 mmol) in 12N. HCl (12.70 mL, 152 mmol), an aqueous solution of sodium nitrite (3.50 g, 50.8 mmol) in water (15 mL) was added slowly at 0°C. The solid suspension was stirred for 1 hour and a previously prepared solution of tin(II) chloride dihydrate (19.10 g, 85 mmol) in 12N was added. HCl (12.70 mL, 152 mmol) at a rate such that the internal temperature does not exceed 5°C. After stirring for 2 hours at 0-5°C, a solution of 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (10.47 g, 50 .8 mmol) in ethanol (61 ml) and heated the mixture at 60°C overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove ethanol, basified with aqueous NaHCO ₃ (25 g in 250 ml), diluted with water (250 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol1- yl)benzonitrile (10c) (8.91 g, 69.4% yield) as a white solid.

Step 2. Preparation of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i).

A solution of 3-(5-(furan-2-yl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzonitrile (10c) (4.15 g, 13.69 mmol) in acetone (75 ml) a solution of potassium permanganate (15.14 g, 96 mmol) in water (75 ml) was added. The resulting mixture was heated at 60°C for 2 hours and cooled to room temperature. The reaction was quenched with 2propanol (75 ml) and the mixture was stirred at room temperature overnight. Filter the reaction mixture through Celite and wash the solid with acetone/water (2x50 ml), methanol (2x50 ml). The filtrate was evaporated under reduced pressure to remove organic solvents. The aqueous layer was made alkaline with 1N. NaOH and washed with diethyl ether (2x100 ml). The aqueous layer was poured into crushed ice and very carefully acidified with 2N. HCl with constant stirring. The resulting solid was collected by filtration, washed with hexanes (2x50 ml), dried over P ₂ O ₅ to give 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2, 68 g, yield 69.6%) as a white solid; 1H NMR (300 MHz, DMSO-b ₆ ) δ 14.01 (s, 1H), 8.22 (t, J=1.8 Hz, 1H), 8.03 (dt, J=7.7, 1 ,3 Hz, 1H), 7.96 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.58 (d, J=0.7 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.95.

Step 3. Preparation of 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxylic acid (10d).

To a stirred solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (100 g, 356 mmol) in anhydrous methanol (1000 ml), cooled to 0°C, was added nickel(II) chloride hexahydrate (8.45 g, 35.6 mmol), then sodium borohydride (53.8 g, 1423 mmol) in small portions over 70 min, maintaining internal temperature between 0-5°C. The reaction mixture was further stirred for 15 minutes. Add a cold solution of NaOH (28.4 g, 711 mmol) in water (250 ml), di-tert-butyl dicarbonate (124 g, 569 mmol) and THF (500 ml) at 0°C. After 2 hours, additional di-tert-butyl dicarbonate (15.52 g, 71.1 mmol) in THF (100 ml) was added and stirring continued for 10 hours. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2 -diamine (38 ml, 356 mmol), the mixture was stirred for 30 min and concentrated in vacuo. The resulting solid was dissolved in water (3000 ml) and the undissolved material was removed by filtration through a pad of celite. The filtrate was acidified by adding dropwise 1N. potassium bisulfate (2134 ml, 2134 mmol, pH~2) for 1 hour, maintaining the internal temperature between 0-5°C. Separated solids

- 73 045731 The substance was collected by filtration, washed with water (500 ml) and dissolved in dichloromethane (4000 ml). The dichloromethane layer was washed with water (1000 ml), brine (1000 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography {2 kg silica gel, eluted with CMA 80 in chloroform (0%, 5% and 10% [4000 ml of each mixture], 20%, 30% and 40% [2000 ml of each mixture], 50% (10000 ml) and 60% (4000 ml))} to give 1-(3-(((tertbutoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d ) (97 g, 252 mmol, 70.8% yield) as a light green solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.49 (t, J=6.3 Hz, 1H), 7.36 (m, 5H), 4.20 (d, J=6.0 Hz, 2H), 1.38 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75.

Scheme 11

An example of the preparation of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (11c).

Step 1. Preparation of 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b)

To a suspension of 4-methoxyaniline (3.08 g, 25 mmol) in hydrogen chloride (7.50 ml, 90 mmol) was added dropwise a solution of sodium nitrite (2.070 g, 30.0 mmol) in water (13 ml) at 0°C . After stirring for 1 hour, tin(II) chloride dihydrate (11.28 g, 50.0 mmol), previously dissolved in hydrogen chloride (7.50 ml, 90 mmol), was added to the resulting mixture at such a rate that the temperature did not exceed 5 °C. After stirring for 2 h, a solution of 4,4,4-trifluoro-1-(furan-2yl)butan-1,3-dione (10b) (5.67 g, 27.5 mmol) in ethanol (52 ml) and heated the mixture at 60°C overnight. After cooling to room temperature, the resulting solid was collected by filtration, washed with water and dried in vacuo to give 5-(furan-2-yl)-1-(4-methoxyphenyl)-3(trifluoromethyl)-1H-pyrazole (11b) ( 5.93 g, 19.22 mmol, 77% yield) as a gray solid; Mp: 81.1°C; 1H NMR (300 MHz, DMSOL) δ 7.78 (dd, J=1.8, 0.7 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.22 (s, 1H) , 7.12 - 7.08 (m, 2H), 6.54 (dd, J=3.5, 1.8 Hz, 1H), 6.12 (dd, J=3.5, 0.7 Hz , 1H), 3.85 (s, 3H); ¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ -60.39; MS (IER+) 309.0.

Step 2. Preparation of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (11c).

To a solution of 5-(furαn-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b) (5 g, 16.22 mmol) in acetone (180 ml) was added a solution of KMnO ₄ (17.94 g, 114 mmol) in water (200 ml). The reaction mixture was heated at 60°C for 3 h and cooled to room temperature. The reaction was quenched with IPA (180 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite and washed with acetone and water. The filtrate was concentrated to remove the organic solvent. The aqueous solution was acidified with acetic acid to pH 4-5 and extracted with diethyl ether. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (11c) (3.965 g, 13.85 mmol, 85% yield ) as a light yellow solid, the sample for analysis was obtained by column purification of a small portion of the crude residue. 1H NMR (300 MHz, DMSO- _d6 ) δ 13.34 (s, 1H), 7.50 - 7.38 (m, 3H), 7.10 - 6.99 (m, 2H), 3.83 (s, 3H); MS (IER+) 287.0 (M+1).

Scheme 12

An example of the preparation of 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxylic acid (12c).

Step 1. Preparation of 1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazoleα (12b).

To a suspension of 4-chloroaniline (12a) (3.19 g, 25 mmol) in hydrogen chloride (7.50 ml, 90 mmol) was added dropwise a solution of sodium nitrite (2.070 g, 30.0 mmol) in water (13 ml) at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (11.28 g, 50.0 mmol), previously dissolved in hydrogen chloride (7.50 ml, 90 mmol), was added to the resulting mixture at such a rate that the temperature did not exceed 5°C. After stirring for 2 hours, a solution of 4,4,4-trifluoro-1-(furan) was added to the mixture

- 74 045731

2-yl)butan-1,3-dione (10b) (5.67 g, 27.5 mmol) in ethanol (52 ml) and heated the mixture at 60°C overnight. After cooling to room temperature, the reaction mixture was neutralized to pH=4 using 10N. NaOH (18 ml) and 1N. NaOH. The reaction mixture was concentrated in vacuo to remove ethanol. The resulting solid was collected by filtration, washed with water and dried in vacuo. The residue was taken up in 100 ml of saturated aqueous NaHCO ₃ and extracted with ethyl acetate (300 ml). The organic layer was dried and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-50% ethyl acetate in hexane) to give 1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)- 1H-pyrazole (12b) (6.238 g, 19.95 mmol, 80% yield) as a white solid; T _pl : 62°C; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.79 (dd, J=1.9, 0.7 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.59 -7 .52 (m, 2H), 7.31 (d, J=0.6 Hz, 1H), 6.58 (dd, J=3.5, 1.8 Hz, 1H), 6.40 (dd, J=3.5, 0.7 Hz, 1H); ¹⁹ F NMR (300 MHz, DMSO-dg) δ -60.90; MS (IER+) 314.9 (M+1).

Step 2. Preparation of 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (12c).

To a solution of 1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b) (6.23 g, 19.92 mmol) in acetone (200 ml) was added a solution of KMnO ₄ (22.04 g, 139 mmol) in water (220 ml). The reaction mixture was stirred at 60°C for 3 hours and cooled to room temperature. The reaction was quenched with IPA (200 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite and washed with acetone and water. The filtrate was concentrated to remove the organic solvent. The aqueous solution was acidified with acetic acid to pH 4-5 and extracted with diethyl ether. The organic phase was dried, filtered and concentrated in vacuo to give 6.7 g of crude material, which was purified by flash column chromatography (silica gel, 80 g, eluted with methanol/chloroform mixtures) to give 1-(4-chlorophenyl)-3(trifluoromethyl) )-1H-pyrazole-5-carboxylic acid (12c) (2.5 g, 8.60 mmol, 43.2% yield) as a white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 14.06 (brs, 1H), 7.61 - 7.56 (m, 3H), 7.53 - 7.48 (m, 1H), 7 .42 (d, J=3.2 Hz, 1H); MS (IER+) 328.8 (M+K).

Scheme 13

An example of the preparation of 1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (13d).

Step 1. Preparation of 5-chloro-2-hydrazinylpyridine (13b).

A solution of 2,5-dichloropyridine (13a) (7.4 g, 50.0 mmol) and hydrazine hydrate (101 mL, 3250 mmol) in pyridine (100 mL) was heated at reflux temperature for 6 h and concentrated to dryness in vacuo . The resulting residue was dissolved in DCM (500 ml), washed with 1N. aqueous NaOH (500 ml), water (3x500 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated to dryness in vacuo to give 5-chloro-2-hydrazinylpyridine (13b) (2.95 g, 20.55 mmol, 41% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (d, J=2.5 Hz, 1H), 7.67 (s, 1H), 7.50 (dd, J=9.0, 2 .6 Hz, 1H), 6.73 (dd, J=9.0, 0.6 Hz, 1H), 4.17 (s, 2H); MS (IER+) 144.2 (M+1).

Step 2. Preparation of 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (13c).

To a solution of 5-chloro-2-hydrazinylpyridine (13b) (717.87 mg, 5.00 mmol) in EtOH (12 ml) was added 4,4,4-trifluoro-1-(furan-2-yl)butan-1 ,3-dione (10b) (1134 mg, 5.50 mmol), water (3 ml) and hydrogen chloride (HCl conc., 1.667 ml, 20.00 mmol). The resulting mixture was stirred at reflux overnight and concentrated in vacuo to remove the organic solvent. The aqueous layer was made alkaline with 1N. NaOH and then separated twice in ethyl acetate. The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% ethyl acetate in hexane) to give 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H -pyrazol-1-yl)pyridine (13c) (795 mg, 2.53 mmol, 50.7% yield) as a light yellow solid. 1H NMR analysis indicated a 2:1 mixture of the two compounds. MS (IER+) 314.0 (M+1), 335.9 (M+Na).

Step 3. Preparation of 1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

- 75 045731 (13d).

A solution of 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (13c) (750 mg, 2.39 mmol) in acetone (25 ml) and water (27.5 ml) was added KMnO ₄ (2645 mg, 16.74 mmol). The reaction mixture was heated at 60°C for 3 hours. The reaction mixture was cooled to room temperature, quenched with isopropanol (25 ml) and stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the precipitate was washed with 50 ml of acetone-water mixture (1:1). The filtrate was concentrated to remove organic solvents and the resulting aqueous solution was acidified with 1N. HCl to pH 2-3. The solution became cloudy and the resulting solid was collected by filtration, washed with some water, hexanes and dried in vacuo to give 1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid ( 13d) (345 mg, 1.183 mmol, 49.5% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 13.67 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.26 (dd, J=8.7, 2 .6 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.54 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -56; MS (IER+) 292.0 (M+1), 313.9 (M+Na), 329.9 (M+K).

Scheme 14

An example of the preparation of 1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-nirazole-5-carboxylic acid (14d).

Step 1. Preparation of 1-(6-bromonaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14b).

To a suspension of 6-bromonaphthalene-2-amine (14a) (2.6 g, 11.71 mmol) in hydrogen chloride (7.02 mL, 84 mmol) was slowly added a solution of sodium nitrite (0.969 g, 14.05 mmol) in water (12 ml) at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (5.28 g, 23.41 mmol), previously dissolved in hydrogen chloride (7.02 ml, 84 mmol), was added to the resulting mixture at such a rate that the temperature did not exceed 5°C. After stirring for 2 hours, a solution of 4,4,4trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (2.65 g, 12.88 mmol) in ethanol (24) was added to the mixture ml) and heated at 60°C overnight. After cooling to room temperature, the reaction mixture was made alkaline to pH=8 with 10N. aqueous NaOH (15 ml) and saturated NaHCO ₃ . The reaction mixture was diluted with ethyl acetate and filtered through a pad of celite. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). Combine the organic layers, dry, filter and concentrate in vacuo to give a crude residue, which is purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(6bromonaphthalene-2-yl)-5 -(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14b) (1.3 g, 3.19 mmol, 27.3% yield) as a semi-solid; 1H NMR (300 MHz, DMSO^) δ 8.39 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.10 (d, J= 8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.78 (dd, J=8.8, 2.0 Hz, 1H), 7.75 (dd, J=1.8, 0.8 Hz, 1H), 7.64 (dd, J=8.8, 2.2 Hz, 1H), 7.35 (s, 1H), 6.53 (dd, J =3.5, 1.8 Hz, 1H), 6.32 (dd, J=3.5, 0.7 Hz, 1H); ¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ -60.85; MS (IER+) 406.9, 408.8 (M+1).

Step 2. Preparation of 1-(6-chloronaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14c).

A solution of 1-(6-bromonaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14b) (1.73 g, 4.25 mmol) in DMF ( 25 ml), copper(I) iodide (0.809 g, 4.25 mmol), copper(I) chloride (4.21 g, 42.5 mmol) was added and heated at reflux temperature overnight. The mixture was cooled to room temperature, diluted with water (35 ml) and stirred for 1 hour. The precipitated solid was collected by filtration, washed several times with water and dried in vacuo to give 1-(6chloronaphthalene-2-yl)-5-(furan -2-yl)-3-(trifluoromethyl)-1H-nirazole (14c) (22 g), containing impurities of copper salts. The solid was suspended in ethyl acetate (100 ml) and filtered. Concentrate the filtrate to dryness in vacuo to give 1-(6-chloronaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1Hpyrazole (14c) (1.2 g, 3.31 mmol, yield 78%) as a light yellow solid after purification by column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane); 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.23 (t, J=1.6 Hz, 2H), 8.10 (dd, J=9.0, 1.5 Hz, 2H), 7, 75 (dd, J=1.9, 0.7 Hz, 1H), 7.66 (ddd, J=8.7, 6.6, 2.2 Hz, 2H), 7.35 (s, 1H) , 6.53 (dd, J=3.5, 1.8 Hz, 1H), 6.32 (dd, J=3.5, 0.8 Hz, 1H); analysis, calculation for C ₁₈ H ₁₀ ClF ₃ N ₂ O: C, 59.60; H, 2.78; N, 7.72; Cl, 9.77; experiment: C, 59.34; H, 2.60; N, 7.70; Cl, 9.96.

Step 3. Preparation of 1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (14d).

In a solution of 1-(6-chloronaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14c) (4.42 g,

- 76 045731

12.19 mmol) in acetone (120 ml), a solution of KMnO ₄ (13.48 g, 85 mmol) in water (120 ml) was added. The reaction mixture was stirred at 60°C for 3 hours, cooled to room temperature, quenched with isopropanol (120 ml) and stirred at room temperature overnight. The reaction mixture was filtered through a Celite pad and washed with acetone and water. The filtrate was concentrated in vacuo to remove organic solvents. The aqueous solution was washed with diethyl ether, then acidified with 1N. aqueous HCl to pH 4. The aqueous layer was partitioned in ethyl acetate, dried, filtered and concentrated in vacuo to give 1-(6-chloronaphthalene-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (14d) (0 .86 g, 2.52 mmol, 21% yield) as a light yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 13.95 (s, 1H), 8.22 (dd, J=8.0, 2.1 Hz, 2H), 8.08 (dd, J=13 ,5, 8.9 Hz, 2H), 7.75 (dd, J=8.8, 2.2 Hz, 1H), 7.66 (dd, J=8.8, 2.1 Hz, 1H) , 7.58 (s, 1H); MS (IER+) 340.9 (M+1); 338.7 (M-1).

Scheme 15

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15g).

Step 1. Preparation of (4-amino-3-fluorophenyl)methanol (15b).

To a suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF (20 ml) a solution of 4-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in THF (20 ml) was added dropwise at 0°C. . The reaction mixture was stirred at room temperature overnight. The mixture was then cooled to 0°C, the reaction was quenched with ethyl acetate (30 ml) and water (10 ml). The resulting slurry was filtered through Celite and washed with ethyl acetate (50 ml). The aqueous layer was separated and the organic layer was dried, filtered and concentrated to dryness in vacuo to obtain the crude product. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0-100% ethyl acetate in hexanes) to give (4-amino-3-fluorophenyl)methanol (15b) (2.2 g, 48.4% yield ) as a beige solid; 1H NMR (300 MHz, DMSO-d6) δ 6.91 (dd, J=12.5, 1.8 Hz, 1H), 6.81 (dd, J=8.1, 1.8 Hz, 1H) , 6.70 (dd, J=9.3, 8.0 Hz, 1H), 5.03 - 4.93 (m, 3H), 4.31 (d, J=5.5 Hz, 2H); MC (IER+) 142.0 (M+1); (IER-) 140.0 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (15c)

1-(3-cyanophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxylic acid (9i) (1.99 g, 7.09 mmol), (4-amino-3-fluorophenyl) was placed in a 100 ml one-neck round bottom flask )methanol (15b) (1 g, 7.09 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (3.3 g, 7.09 mmol), sequentially treated with N,N-dimethylformamide (42.8 ml, 553 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.17 ml, 35.4 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (2x150 ml), washed with brine (75 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated

- 77 045731 whether dry. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (15c) (1.151 g, 2.85 mmol, 40.2% yield) as a pale yellow solid; MS (IER ⁺ ): MS (IER+) 405.2 (M+1), MS (IER-) 403.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (15d)

In a stirred solution of 1-(3-cyanophenyl)-M-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15c) (1.106 g, 2.74 mmol ) in dichloromethane (20 ml), add sodium bicarbonate (1.149 g, 13.68 mmol), Dess-Martin periodinane (1.74 g, 4.10 mmol) and stir at room temperature for 5 hours. Additional amount of Dess-Martin periodinane (1.74 g, 4.10 mmol) and stirred for 30 min. Excess solvent was pumped out under reduced pressure. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 100%)] to give 1-(3-cyanophenyl)-M-(2fluoro-4-formylphenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (15d) (0.418 g, 38.0% yield) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H, exchange with D ₂ O), 9.95 (d, J=1.7 Hz, 1H), 8.18 (t, J =1.8 Hz, 1H), 8.04 - 7.98 (m, 1H), 7.97 - 7.90 (m, 2H), 7.85 - 7.78 (m, 3H), 7, 74 (t, J=8.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.97, -120.36; MS (IER ⁺ ): MS (IER+) 425.08 (M+Na), MS (IER-) 401.1 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15e).

A solution of 1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15d) (0.4 g, 0.994 mmol) in THF ( 10 ml), cooled to 0°C, phenylmagnesium bromide (2.018 ml, 2.018 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and the reaction was quenched with saturated aqueous NH ₄ Cl (60 ml). The product was extracted twice with ethyl acetate (100 ml, 75 ml). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%)] to give 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (15e) (0.377 g, 0.785 mmol, 79% yield) as a waxy solid; 1H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H, exchange with D2O), 8.12 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7, 7, 1.4 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.34 - 7 .28 (m, 2H), 7.27 - 7.22 (m, 1H), 7.20 (dt, J=8.6, 2.4 Hz, 2H), 6.06 (d, J=4 .0 Hz, 1H, exchange with D ₂ O), 5.71 (d, J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98, -121.26; IR (KBr, cm' ¹ ): 2236 cm' ¹ (stretching vibrations of CN); MS (IER ⁺ ): MS (IER+) 503.15 (M+Na), MS (IER-) 479.24 (M-1).

Step 5. Preparation of 1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15f).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15e) (0.453 g, 0.943 mmol) in cyclopropylmethanol (6.77 ml, 94 mmol), ytterbium trifluoromethanesulfonate (III) (1.170 g, 1.886 mmol) was added and heated at 80°C for 16 hours. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was purified by flash column chromatography [silica gel, 25 g, eluted with ethyl acetate in hexanes, 0-100%] to give 1(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (15f) (0.076 g, 15% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H, exchange with D ₂ O), 8.11 (t, J=1.8 Hz, 1H), 7.99 (dt, J= 7.7, 1.3 Hz, 1H), 7.89 (dd, J=8.5, 1.8 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.51 (t , J=8.0 Hz, 1H), 7.40 - 7.32 (m, 4H), 7.32 - 7.24 (m, 2H), 7.19 (dd, J=8.3, 1 .9 Hz, 1H), 5.49 (s, 1H), 3.24 (d, J=6.8 Hz, 2H), 1.11 - 1.02 (m, 1H), 0.53 - 0 .41 (m, 2H), 0.20 - 0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98, -120.92; MS (IER ⁺ ): MS (IER+) 557.1 (M+1), MS (IER-) 533.1 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-M-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15g ).

Into a stirred solution of 1-(3-cyanophenyl)-M-(4-((cyclopropylmethoxy)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15f) (0.071 g, 0.133 mmol) in anhydrous methanol (10 ml) at 0°C was added nickel (II) chloride hexahydrate (0.047 g, 0.199 mmol) and sodium borohydride (0.060 g, 1.594 mmol) in small portions over 5 min. The reaction mixture was stirred for 10 min, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.143 mL, 1.328 mmol) and stirred for an additional 30 min. Excess methanol was pumped out under reduced pressure. The reaction mixture was processed for us. NH ₄ Cl (50 ml) and the product was extracted with chloroform (2x50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 12 g, eluted with 0 to 50% methanol/chloroform)] with

- 78 045731 by preparing 1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxαmide (15g ) (48 mg, 67% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 7.55 (d, J=4.6 Hz, 2H), 7.51 (d, J=3.8 Hz, 1H), 7.45-7.40 (m, 2H), 7.39 - 7.28 (m, 6H), 7.26 (dd, J=6.0, 2.1 Hz, 1H), 7 .19 (dd, J=8.3, 1.8 Hz, 1H), 5.49 (s, 1H), 3.76 (s, 2H), 3.24 (d, J=6.7 Hz, 2H), 1.13 - 1.00 (m, 1H), 0.53 - 0.41 (m, 2H), 0.21 - 0.11 (m, 2H); ¹ H NMR (300 MHz, DMSO-d6 D2O) δ 7.55 (s, 2H), 7.53 - 7.48 (m, 1H), 7.45 - 7.40 (m, 2H), 7, 39 - 7.28 (m, 6H), 7.27 - 7.23 (m, 1H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 5.49 (s, 1H), 3.75 (s, 2H), 3.24 (d, J=6.7 Hz, 2H), 1.06 (m, 1H), 0.56 - 0.41 (m, 2H), 0.20 0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.74, -121.19; MS (IER ⁺ ): MS (IER+) 539.2 (M+1), MS (IER-) 537.2 (M-1).

Scheme 16

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (16b).

Step 1. Preparation of tert-butyl-3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (16a).

Into a stirred solution of 1-(3-cyanophenyl)-N(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-III-pyrazole-5-carboxamide (15e) (0.284 g, 0. 59 mmol) in anhydrous methanol (5 ml), cooled to 0°C, di-tert-butyl dicarbonate (0.258 g, 1.182 mmol) and nickel (II) chloride (0.035 g, 0.148 mmol) were added. Sodium borohydride (0.134 g, 3.55 mmol) was added to the reaction mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min at 0°C. TLC analysis (50% EtOAc in hexanes) indicated complete consumption of the starting material. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.128 mL, 1.182 mmol), the mixture was stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (20 ml) and water (20 ml). The organic layer was separated, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give tert-butyl-3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl )-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (16a) (0.185 g, 0.316 mmol, 53.5% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.57 (s, 1H), 7.50 (q, J=7.7 Hz, 2H), 7.44 - 7 .37 (m, 3H), 7.37 - 7.31 (m, 4H), 7.29 (dt, J=6.3, 0.8 Hz, 2H), 7.25 - 7.15 (m , 2H), 6.04 (d, J=4.0 Hz, 1H), 5.70 (d, J=4.1 Hz, 1H), 4.18 (d, J=6.2 Hz, 2H ), 1.36 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82, -121.61; MC (IER+) 607.3 (M+Na); (IER-) 583.2 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (16b) .

Into a stirred solution of tert-butyl-3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (16a) (0.17 g, 0.291 mmol) in acetonitrile (5 ml) at room temperature, conc. HCl (1.212 ml, 14.54 mmol) and water (1.25 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(methoxy(phenyl) )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16c) (0.040 g, 0.080 mmol, 27.6% yield) as a white solid which contained the impurity 1-(3-( aminomethyl)phenyl)-N-(4(chloro(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxαmide (16d). Additional elution provided 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16b) (0.022 g, 0.045 mmol, 15.62% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.34 (s, 3H), 7.71 (d, J=2.0 Hz, 1H), 7.67 ( s, 1H), 7.59 (td, J=5.4, 2.6 Hz, 1H), 7.55-7.46 (m, 3H), 7.40 - 7.35 (m,

- 79 045731

2H), 7.34 - 7.27 (m, 2H), 7.26 - 7.16 (m, 3H), 6.07 (d, J=4.0 Hz, 1H), 5.71 (d , J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82, -121.23; MS (IER+) 485.1 (M+1); (IER-) 483.2 (M-1).

Scheme 17

An example of the preparation of 1-(3-(aminomethyl)phenyl)-C-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (17d).

Step 1. Preparation of 1-(3-cyanophenyl)-C-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (17b).

K1-phenylbenzene-1,3-diamine was added to a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (400 mg, 1.423 mmol) in DMF (10 ml). (17a) (262 mg, 1.423 mmol), K-ethyl-Kisopropylpropan-2-amine (2.0 mL, 11.48 mmol) and bromotripyrrolidin-1ylphosphonium hexafluorophosphate (V) (PyBrOP, 682 mg, 1.434 mmol), then stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x75 ml), brine (75 ml), dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give 1-(3-cyanophenyl)-K-(3-(phenylamino)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5carboxamide (17b) (316 mg, 50%) as a brown viscous substance. 1H NMR (300 MHz, DMSO-dg) δ 10.57 (s, 1H), 8.31 - 6.73 (m, 14H); MS (IER+) 448.3 (M+1).

Step 2. Preparation of tert-butyl-3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (17c).

A solution of 1-(3-cyanophenyl)-C-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17b) (200 mg, 0.447 mmol) in methanol (4 ml) was cooled in ice/water and treated with di-tert-butyl dicarbonate (296 mg, 1.341 mmol) and nickel(II) chloride hexahydrate (21.85 mg, 0.092 mmol), then sodium borohydride (104 mg, 2.68 mmol) was added slowly over 5 min and stirred at room temperature for 1 h. The reaction was quenched with K1-(2-aminoethyl)ethane-1,2-diamine (0.104 ml, 0.952 mmol), then the mixture was stirred at room temperature for 0.5 h. Reaction the mixture was concentrated to dryness in vacuo. The resulting residue was treated with ethyl acetate (100 ml), washed with water (50 ml). The aqueous phase was again extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ then filtered and concentrated. The crude residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give tert-butyl-3-(5-((3-(phenylamino)phenyl)carbamoyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (17c) (160 mg, 65%) as a brown solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.63 (s, 1H), 8.24 (s, 1H), 7.67 - 6.51 (m, 14H), 4.20 (d, J =6.3 Hz, 2H), 1.37 (s, 9H); MS (IER+) 552.4 (M+1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-C-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (17d).

A solution of tert-butyl-3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (17c) (127 mg, 0.230 mmol) in 1,4- dioxane (12 ml) was treated by adding dropwise hydrogen chloride (2.4 ml, 9.60 mmol, 4M in 1,4-dioxane), then stirred at room temperature for 13 hours. The reaction mixture was diluted with hexanes, decanted, washed with hexanes and decanted again. The insoluble portion was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-K-(3(phenylamino )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17d) (23 mg, 22%) as a white solid; T _P l: 73.8°C; 1H NMR (300 MHz, DMSO-d^δ 10.62 (s, 1H), 8.25 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.48 (t, J=2.1 Hz, 1H), 7.45-7.41 (m, 2H), 7.35-7.29 (m, 1H), 7.23 (t, J=7.9 Hz, 2H), 7.16 (d, J=8.0

- 80 045731

Hz, 1H), 7.08 (d, J=2.2 Hz, 2H), 7.05 (s, 1H), 6.87 - 6.78 (m, 2H), 3.78 (s, 2H ); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.70; MS (IER+) 452.3 (M+1). Scheme 18

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-C-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18f).

An example of the preparation of 1-(3 -(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3 -(trifluoromethyl)1H-pyrazole-5-carboxamide (18g).

An example of the preparation of 1 -(3 -(aminomethyl)phenyl)-N-(3 -(phenyl(propoxy)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h).

An example of the preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18i).

An example of the preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18j).

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18k).

Step 1. Preparation of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18b).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (5.42 g, 19.27 mmol) in DMF (100 ml) was added 3-aminobenzophenone (18a ) (3.8 g, 19.27 mmol), N-ethyl-Nisopropylpropan-2-amine (27 ml, 155 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (9.24 g, 19.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 39 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (600 ml), washed with water (2x300 ml), brine (200 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H- pyrazole-5-carboxamide (18b) (5.633 g, 63% yield) as a yellow solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 8.19 (t, J=1.8 Hz, 1H), 8.07 - 7.98 (m, 3H) , 7.93 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 - 7.67 (m, 6H), 7.61 -7.55 (m, 2H) , 7.50 (dt, J=7.7, 1.5 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.98; MS (IER+) 461.162 (M+1), 483.134 (M+Na).

Step 2. Preparation of tert-butyl-3-(5-((3-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (18c).

Into a stirred solution of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (18b) (4.704 g, 10.22 mmol) in anhydrous methanol (100 ml), cooled to 0°C, add di-tert-butyl dicarbonate (6.76 g, 30.7 mmol), nickel (II) chloride hexahydrate (0.5 g, 2.103 mmol), then sodium borohydride (2.367 g, 61.3 mmol) in parts for 5 minutes. The reaction mixture was stirred for 30 min at room temperature, quenched with M-(2-aminoethyl)ethane-1,2-diamine (2.3 mL, 21.08 mmol), stirred for 30 min and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (400 ml), washed with water (200 ml), brine (200 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 80 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give tert-butyl-3-(5((3-(hydroxy-(phenyl)methyl) phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate

- 81 045731 (18c) (2.71 g, 46.8% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 7.62 (t, J=1.8 Hz, 1H), 7.59 - 7.46 (m, 3H), 7.45 - 7.40 (m, 2H), 7.38 - 7.25 (m, 7H), 7.23 - 7.20 (m, 1H), 7.13 (dt, J=7.7 , 1.3 Hz, 1H), 5.94 (d, J=3.9 Hz, 1H), 5.66 (d, J=3.8 Hz, 1H), 4.19 (d, J=6 .2 Hz, 2H), 1.37 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.80; MS (IER+) 589.3 (M+1), (IER-) 565.3 (M-1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-C-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18d).

In a solution of tert-butyl-3-(5-((3-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (65 mg, 0.115 mmol) Hydrogen chloride (1.2 mL, 4.80 mmol, 4M in 1,4-dioxane) was added dropwise to 1,4-dioxane (6 mL) and stirred at room temperature for 13 hours. The reaction mixture was diluted with hexanes and decanted. The residue was triturated with hexanes and decanted to give 1-(3-(aminomethyl)phenyl)-C-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) as a white solid.

An example of the preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18f).

A solution of 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (18d) in chloroform/methanol (40 ml /15 ml) 2 g of silica gel were added and concentrated in vacuo to give a slurry which was purified by flash column chromatography [silica gel, 2 x 4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1- (3(aminomethyl)phenyl)-N-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18f) (26 mg, 47%) as a white solid substances, melting _point : 89.5°C; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.71 (s, 1H), 7.65-7.62 (m, 1H), 7.60 - 7.49 (m, 3H), 7.46 - 7.38 (m, 2H), 7.33 (d, J=4.3 Hz, 5H), 7.31 - 7.23 (m, 2H), 7.12 (d, J=7.7 Hz, 1H), 5.30 (s, 1H), 3.78 (s, 2H), 3.26 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.74. MS (IER+) 481.3 (M+1).

An example of the preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18g).

In a solution of tert-butyl-3-(5-((3-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (193 mg, 0.341 mmol) Hydrogen chloride (3.60 mL, 14.39 mmol, 4M in 1,4-dioxane) was added dropwise to 1,4-dioxane (18 ml), then stirred at room temperature for 21 hours. The reaction mixture was diluted with hexanes, decanted and the resulting residue was washed with hexanes and decanted. To the residue of 1-(3-(aminomethyl)phenyl)-C-(3-(chloro-(phenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d), dissolved in a chloroform/ ethanol (40 ml/15 ml), added 2 g of silica gel and concentrated in vacuo to obtain a slurry, which was purified by flash column chromatography (silica gel, 2x4 g, eluted with chloroform/CMA 80 mixtures (1:0 to 2:1) ) to give 1-(3-(aminomethyl)phenyl)-K-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18g) as a white solid ( 24 mg, 14%); 1H NMR (300 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.57 (s, 2H), 7.52 (s, 1H), 7.42 (d, J=6.2 Hz , 2H), 7.35-7.31 (m, 5H), 7.27 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 5 .41 (s, 1H), 3.76 (s, 2H), 3.47 - 3.37 (m, 2H), 1.17 (t, J=7.0 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.73. MS (IER+) 495.3 (M+1).

An example of the preparation of 1-(3-(aminomethyl)phenyl)-C-(3-(phenyl(propoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h).

In a solution of tert-butyl-3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (80 mg, 0.141 mmol) in 1, Hydrogen chloride (1.5 ml, 6 mmol, 4M in 1,4-dioxane) was added dropwise to 4-dioxane (8 ml), then stirred at room temperature for 16 hours. The reaction mixture was diluted with hexanes, decanted and the resulting residue was washed with hexanes , decanted. To the residue of 1-(3-(aminomethyl)phenyl)-C-(3-(chloro(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d), dissolved in a mixture of chloroform/1 -propanol (40 ml/15 ml), 2 g of silica gel were added and concentrated in vacuo to obtain a slurry, which was purified by flash column chromatography (silica gel, 2 x 4 g, eluted with chloroform/CMA 80 mixtures (1:0 to 2:1 )) to give 1-(3-(aminomethyl)phenyl)-K-(3-(phenyl(propoxy)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h) (31 mg, 43 %) in the form of a colorless oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.61 (t, J=1.8 Hz, 1H), 7.59 - 7.51 (m, 3H), 7 .45 - 7.38 (m, 2H), 7.36 - 7.28 (m, 6H), 7.27 - 7.22 (m, 1H), 7.12 (d, J=7.6 Hz , 1H), 5.39 (s, 1H), 3.77 (s, 2H), 3.47 - 3.39 (m, 2H), 1.64 - 1.50 (m, 2H), 0, 89 (t, J=7.4 Hz, 3H); 1H NMR (300 MHz, methanol^) δ 7.57 (t, J=1.9 Hz, 1H), 7.53 (s, 1H), 7.52 - 7.45 (m, 3H), 7, 40 (dt, J=4.5, 2.4 Hz, 1H), 7.35-7.22 (m, 7H), 7.17 - 7.11 (m, 1H), 5.34 (s, 1H), 3.86 (s, 2H), 3.40 (td, J=6.4, 1.0 Hz, 2H), 1.64 (dtd, J=13.8, 7.4, 6, 5 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, methanol-d4) δ -63.73; MS (IER+): 509.3 (M+1); (IER-) 507.3 (M-1).

An example of the preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (18i).

In a solution of tert-butyl-3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (80 mg, 0.141 mmol) in 1, Hydrogen chloride (1.5 mL, 6 mmol, 4M in 1,4-dioxane) was added dropwise to 4-dioxane (8 ml), then stirred at room temperature for

- 82 045731 16 h. The reaction mixture was diluted with hexanes, decanted, and the resulting residue was washed with hexanes and decanted. To the residue of 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d), dissolved in a chloroform/isobutanol mixture (40 ml/15 ml), 2 g of silica gel were added and concentrated in vacuo to obtain a slurry which was purified by flash column chromatography (silica gel, 2 x 4 g, eluted with chloroform/CMA 80 mixtures (1:0 to 2:1)) to give 1-(3-(aminomethyl)phenyl)-N-(3-(uzobutoxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18i) (14 mg, 19%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.59 - 7.50 (m, 3H), 7 .42 (d, J=6.7 Hz, 2H), 7.32 (t, J=6.4 Hz, 5H), 7.27 - 7.21 (m, 1H), 7.12 (d, J=7.7 Hz, 1H), 5.38 (s, 1H), 3.77 (s, 2H), 3.20 - 3.10 (m, 2H), 1.87 (dq, J=13 ,3, 6.6 Hz, 1H), 0.88 (dd, J=6.6, 1.3 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.71; MS (IER+) 523.3 (M+1); (IER-) 521.4 (M-1).

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (18j).

In a solution of tert-butyl-3-(5-(3 -(hydroxy(phenyl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 Hpyrazol-1-yl)benzylcarbamate (18c) (80 mg, 0.141 mmol) in 1 ,4-dioxane (8 ml) was added dropwise with hydrogen chloride (1.5 ml, 6 mmol, 4M in 1,4-dioxane), then stirred at room temperature for 16 hours. The reaction mixture was diluted with hexanes, decanted and the resulting residue was washed hexanes and decanted. To the residue of 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d), dissolved in a mixture of chloroform/1 -butanol (40 ml/15 ml), 2 g of silica gel were added and concentrated in vacuo to obtain a slurry which was purified by flash column chromatography (silica gel, 2 x 4 g, eluted with chloroform/CMA 80 mixtures (1:0 to 2:1 )) to give 1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18j) (14 mg, 19 %) in the form of a colorless semi-solid; 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.64 - 7.49 (m, 4H), 7.44 - 7.37 (m, 2H), 7.36 - 7.20 (m, 7H), 7.12 (d, J=8.0 Hz, 1H), 5.39 (s, 1H), 3.77 (s, 2H), 3.43 - 3.34 (m, 2H), 1.54 (dq, J=8.3, 6.3 Hz, 2H), 1.36 (dq, J=9.4, 7.2 Hz, 2H), 0.85 ( t, J=7.3 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.73. MS (IER+): 523.4 (M+1).

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (18k).

In a solution of tert-butyl-3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (1 g, 1.765 mmol) in 1, A 4M solution of hydrogen chloride in dioxane (19.00 mL, 76 mmol) was added to 4-dioxane (90 mL). The reaction mixture was stirred at room temperature for 16 hours and diluted with hexanes. The organic solution was decanted and the residue was washed with hexanes. The residue was dissolved in chloroform/cyclopropanemethanol (120 ml/7 ml) and stirred at room temperature for 68 hours. Silica gel (3 g) was added to the reaction mixture and the mixture was concentrated to dryness in vacuo. The suspension was purified twice by CombiFlash column chromatography (silica gel, 12 g, eluted with chloroform/CMA 80 mixtures, 0-25%) to give 1-(3(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (18k) (124 mg, 13.5%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.72 (s, 1H), 7.64 - 7.50 (m, 4H), 7.46 - 7.38 (m, 2H), 7.36 - 7.27 (m, 6H), 7.27 -7.20 (m, 1H), 7.13 (d, J=7.7 Hz, 1H), 5.44 (s, 1H), 3, 77 (s, 2H), 3.23 (dd, J=6.7, 1.3 Hz, 2H), 1.14 - 0.97 (m, 1H), 0.50 - 0.42 (m, 2H), 0.19 0.10 (m, 2H); ¹⁹ F NMR (300 MHz, DMSO^) δ -60.73; MS (IER+) 521.3 (M+1).

Scheme 19

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (19d).

- 83 045731

Step 1. Preparation of N-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (19b).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (400 mg, 1.423 mmol) in DMF (10 ml) was added 3-benzylaniline (19a) (261 mg, 1.423 mmol ), N-ethyl-Nisopropylpropan-2-amine (2.0 mL, 11.48 mmol) and bromotripyrrolidin-1ylphosphonium hexafluorophosphate (V) (PyBrOP, 682 mg, 1.434 mmol) and stirred at room temperature for 14 h. Reaction the mixture was diluted with ethyl acetate (200 ml), washed with water (2x75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give N-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl) -1H-pyrazole-5carboxamide (19b) (330 mg) as a yellow viscous substance, which was used as such in the next step; MS (IER+) 469.3 (M+23).

Step 2. Preparation of tert-butyl-3-(5-((3-benzylphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (19c).

A solution of N-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19b) (200 mg, 0.448 mmol) in methanol (4 ml), cooled in ice/water mixture, di-tert-butyl dicarbonate (296 mg, 1.344 mmol), nickel (II) chloride hexahydrate (22.00 mg, 0.093 mmol) were added, then sodium borohydride (104 mg, 2.69 mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.914 mmol), stirred at room temperature for 0.5 hour and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with water (50 ml). The aqueous phase was again extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting crude product was purified by flash column chromatography [silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 4:1)] to give tert-butyl-3-(5-(3-benzylphenylcarbamoyl)-3( trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (19c) (121 mg, 26% in two steps) as a white solid; ¹ H NMR (300 MHz, DMSOC) δ 10.68 (s, 1H), 7.72 - 6.87 (m, 15H), 4.19 (d, J=6.4 Hz, 2H), 3, 91 (s, 2H), 1.37 (s, 9H); MS (IER+) 473.4 (M+23).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (19d).

In a solution of tert-butyl-3-(5-(3-benzylphenylcarbamoyl)-3-(trifluoromethyl)-1H-nirazol-1-yl)benzylcarbamate (19c) (105 mg, 0.191 mmol) in 1,4-dioxane (9 ml) hydrogen chloride (2.0 ml, 8.0 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble portion was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl )3-(trifluoromethyl)-1H-nyrαzol-5-carboxamideα (19d) (33 mg, 38%) as an off-white solid;

Melting _point : 69.9°C; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.66 (s, 1H), 7.56 - 7.41 (m, 6H), 7.33 - 7.25 (m, 4H), 7.24 7.17 (m, 3H), 7.01 (d, J=7.6 Hz, 1H), 3.91 (s, 2H), 3.77 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73; MS (IER+) 451.3 (M+1).

Scheme 20

NiCI ₂ 6H ₂ O

NaBH ₄

Oh Oh

DIPEA PyBrOP

CN

20b

O. ,N.H.

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (20d).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (20b).

- 84 045731

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxylic acid (9i) (400 mg, 1.423 mmol) in DMF (10 ml) was added 3-phenoxyaniline (20a) (263 mg , 1.423 mmol), N-ethyl-Nisopropylpropan-2-amine (2.0 ml, 11.48 mmol) and bromotripyrrolidin-1ylphosphonium hexafluorophosphate (V) (PyBrOP, 682 mg, 1.434 mmol) and stirred at room temperature for 14 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuum. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give 1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl )-1H-pyrazole-5carboxamide (20b) (296 mg, 46%) as an off-white solid; 1H NMR (300 MHz, DMSO-th ₆ ) δ 10.73 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.7, 1 .3 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.78 - 7.64 (m, 2H), 7.51 7.27 (m, 5H), 7.22 - 7 .11 (m, 1H), 7.08 - 6.99 (m, 2H), 6.83 - 6.78 (m, 1H); MS (IER+) 471.2 (M+23).

Step 2. Preparation of tert-butyl-3-(5-((3-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol1-yl)benzylcarbamate (20c).

A solution of 1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20b) (200 mg, 0.446 mmol) in methanol (4 ml), cooled in ice/water mixture, di-tert-butyl dicarbonate (295 mg, 1.338 mmol), nickel (II) chloride hexahydrate (22.00 mg, 0.093 mmol) were added, then sodium borohydride (103 mg, 2.68 mmol) was slowly added piecemeal to for 5 minutes The reaction mixture was stirred at room temperature for 1 hour, quenched with N1-(2-aminoethyl)ethane-1,2diamine (0.100 mL, 0.912 mmol), stirred at room temperature for 0.5 hour and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with water (50 ml). The aqueous phase was again extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting crude product was purified by flash column chromatography [silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give tert-butyl-3-(5-(3-phenoxyphenylcarbamoyl)3-( trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (20c) (173 mg, 70%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.78 (s, 1H), 7.57 (s, 1H), 7.53 - 6.75 (m, 14H), 4.19 (d, J =6.3 Hz, 2H), 1.37 (s, 9H); MS (IER+) 475.4 (M+23).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (20d).

In a solution of tert-butyl-3-(5-(3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (20c) (115 mg, 0.208 mmol) in 1,4-dioxane ( 9 ml), hydrogen chloride (2.2 ml, 8.8 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble portion was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl )-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (20d) (70 mg, 74%) as an off-white solid; _{Melting point} : 89.0°C; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.80 (s, 1H), 7.60 (s, 2H), 7.52 - 7.48 (m, 2H), 7.46 - 7.32 (m, 6H), 7.16 (t, J=7.4 Hz, 1H), 7.06 - 7.01 (m, 2H), 6.82 - 6.77 (m, 1H), 5, 71 (s, 2H), 3.95 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.78; MS (IER+) 453.3 (M+1).

Scheme 21

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (21e).

Step 1. Preparation of 3-nitro-N-phenylbenzamide (21b).

To a solution of aniline (2.94 ml, 32.2 mmol) in ethyl acetate (30 ml) at room temperature was added triethylamine (5.39 ml, 38.7 mmol), followed by a solution of 3-nitrobenzoyl chloride (5.98 g, 32. 2 mmol) in ethyl acetate (30 ml). The reaction mixture was stirred at room temperature for 20 hours and the reaction

- 85 045731 extinguished with water (30 ml). The aqueous layer was separated and extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give 3nitro-N-phenylbenzamide (21b) (2.93 g, 12.1 mmol, 37.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H, exchange with D ₂ O), 8.79 (t, J=2.0 Hz, 1H), 8.43 (dddd, J=12 ,0, 7.8, 2.1, 1.1 Hz, 2H), 7.85 (t, J=8.0 Hz, 1H), 7.82 - 7.75 (m, 2H), 7, 44 - 7.35 (m, 2H), 7.20 - 7.10 (m, 1H).

Step 2. Preparation of 3-amino-N-phenylbenzamide (21c).

To a suspension of carbon-supported palladium (5%) (0.149 g, 1.404 mmol) in ethanol (120 ml) was added 3-nitro-N-phenylbenzamide (3.4 g, 14.04 mmol) and hydrogenated at 45 psi (310 kPa ) in a Parr apparatus for 3 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dried to give 3-amino-N-phenylbenzamide (21c) (2.872 g, 13.53 mmol, 96% yield) as a colorless solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.09 (s, 1H), 7.84 - 7.71 (m, 2H), 7.43 - 7.25 (m, 2H), 7.15 (t, J=7.7 Hz, 1H), 7.12 - 7.04 (m, 3H), 6.75 (ddd, J=7.9, 2.3, 1.1 Hz, 1H), 5.35 (s, 2H, exchange with D2O).

Step 3. Preparation of tert-butyl-3-(5-((3-(phenylcarbamoyl)phenyl)carbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (21d).

In a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (0.1 g, 0.26 mmol) in N,N-dimethylformamide (2 ml) added 3-amino-Nphenylbenzamide (0.066 g, 0.311 mmol), I-ethyl-I-isopropylpropan-2-amine (0.362 ml, 2.076 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP, 0.133 g, 0.285 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (2x20 ml). Combine the organic layers, wash with water (10 ml), dry over anhydrous MgSO ₄ , filter and concentrate to dryness under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with ethyl acetate/hexanes, 0-100%) to give tert-butyl-3-(5-(3-(phenylcarbamoyl)phenylcarbamoyl)-3-(trifluoromethyl) -1H-pyrazol-1-yl)benzylcarbamate (21d) (77 mg, 0.133 mmol, 51.2% yield); 1H NMR (300 MHz, DMSO^) δ 10.92 (s, 1H), 10.29 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.79 -7.69 (m, 3H), 7.65 (s, 1H), 7.56 - 7.31 (m, 8H), 7.16 - 7 .06 (m, 1H), 4.20 (d, J=6.2 Hz, 2H), 1.37 (s, 9H); MS (IER+) 580.3 (M+1), 602.3 (M+23), (IER-) 578.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-I-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (21e).

Into a stirred solution of tert-butyl 3-(5-(3-(phenylcarbamoyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (21d) (50 mg, 0.086 mmol) in methanol (5 ml) added conc. hydrochloric acid (0.052 ml, 1.725 mmol) and stirred the reaction mixture overnight. Added 20 eq. HCl and stirred at reflux temperature for 30 min. The reaction mixture was concentrated to dryness in vacuo. The residue was dried in vacuo overnight, suspended in diethyl ether (25 ml), heated at reflux temperature for 30 minutes and stirred at room temperature overnight. The resulting solid was collected by filtration, dried to give 1-(3-(aminomethyl)phenyl)-N(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride (21e) (45 mg, 0.081 mmol, 94% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.99 (s, 1H, exchange with D2O), 10.32 (s, 1H, exchange with _D2O ), 8.34 (s, 3H, exchange with D ₂ O), 8.23 (t, J=1.9 Hz, 1H), 7.92 - 7.82 (m, 1H), 7.80 - 7.71 (m, 5H), 7.657.47 (m, 4H), 7.40 - 7.30 (m, 2H), 7.15 - 7.06 (m, 1H), 4.14 (s, 2H); MS (IER+) 480.2 (M+1); (IER-) 478.2 (M1), 514.12 (M+35); analysis, calculation for C ₂₅ H ₂₀ F ₃ N ₅ O ₂ (HCl) ₂ : C, 54.43; H, 4.02; N, 12.72; experiment C, 54.59; H, 4.55; N, 12.52.

Scheme 22

An example of the preparation of 1 -(3 -(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 carboxamide (22b).

Step 1. Preparation of tert-butyl-3-(5-((3-benzoylphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol1-yl)benzylcarbamate (22a).

To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (200 mg, 0.519 mmol) in DMF (5 ml) was added (3- aminophenyl)(phenyl)meta

- 86 045731 non (18a) (102 mg, 0.518 mmol), N-ethyl-N-isopropylpropan-2-amine (0.730 ml, 4.19 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBrOP, 248 mg , 0.552 mmol) and stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (100.75 ml), brine (100 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzylcarbamate (22a) (182 mg, 62%) as a light yellow viscous substance. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.78 -7.28 (m, 13H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s, 9H); MS (IER+) 587.3 (M+23).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (22b).

In a solution of tert-butyl-3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (22a) (0.15 g, 0.266 mmol) in 1,4- dioxane (14 ml), hydrogen chloride (2.80 ml, 11.21 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 17 hours. The reaction mixture was diluted with hexanes and the resulting solid was collected by filtration. The light yellow solid was purified by flash column chromatography [silica gel, 2x4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-( 3benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (22b) (75 mg, 61%) as an off-white solid; 1H NMR (300 MHz, DMSO-b6) δ 10.92 (s, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H ), 7.75 (d, J=1.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.71 - 7.65 (m, 1H), 7.61 (s, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 7.56 7.52 (m, 2H), 7.51 - 7.47 (m, 1H), 7 .45-7.41 (m, 2H), 7.33 (dt, J=5.3, 2.5 Hz, 1H), 3.78 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.75; MC (IER+) 465.2 (M+1).

Scheme 23

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (23c).

Step 1. Preparation of tert-butyl-3-(5-((2-fluoro-3-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (23b).

2 -fluoro-3-phenoxyaniline (23a) (105 mg, 0.519 mmol), N-ethyl-N-isopropylpropan-2-amine (0.730 ml, 4.19 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBrOP, 249 mg, 0.523 mmol) and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2x75 ml), brine (750 ml), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-((2-fluoro-3-phenoxyphenyl)carbamoyl) -3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (23b) (72 mg, 24%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-d6) δ 7.80 - 6.72 (m, 13H), 3.78 (s, 2H); MS (IER+): 593.2 (M+23).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (23c).

In a solution of tert-butyl-3-(5-(2-fluoro-3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (23b) (70 mg, 0.123 mmol) in 1,4-dioxane (5 ml) was added dropwise hydrogen chloride (1.3 ml, 5.2 mmol, 4M in 1,4-dioxane) and stirred at room temperature for 16 hours. The reaction mixture was diluted with hexanes and the resulting solid was collected by filtration. The light yellow solid was purified by flash column chromatography [silica gel, 2x4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-( 2fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (23c) (32 mg, 55%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.60 (s, 1H), 7.53 (s, 1H), 7.48 - 7.32 (m, 6H), 7.24 - 7.11 (m, 2H), 7.06 - 6.97 (m, 3H), 3.78 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.76, -139.25; MS (IER+), 471.2 (M+1).

- 87 045731

Scheme 24

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (24c).

Step 1. Preparation of tert-butyl-3-(5-((2-fluoro-5-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-Spirazol-1-yl)benzylcarbamate (24b).

In a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxylic acid (10d) (152 mg, 0.394 mmol) in DMF (3.5 ml) added 2-fluoro-5-phenoxyaniline (24a) (80 mg, 0.394 mmol), N-ethyl-N-isopropylpropan-2-amine (0.550 ml, 3.16 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) ( PyBrOP, 189 mg, 0.398 mmol) and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2x50 ml), brine (50 ml), dried over MgSO ₄ , filtered and concentrated in vacuum. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give tert-butyl-3-(5-(2-fluoro-5-phenoxyphenylcarbamoyl)-3( trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (24b) (57 mg, 25%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.65 (s, 1H), 7.58 (s, 1H), 7.53 - 6.86 (m, 13H), 4.18 (d, J =6.3 Hz, 2H), 1.37 (s, 9H); (IER+) 593.3 (M+23).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (24c).

In a solution of tert-butyl-3-(5-(2-fluoro-5-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (24b) (55 mg, 0.096 mmol) in 1,4-dioxane (4 ml), hydrogen chloride (1.0 ml, 4.0 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was diluted with hexanes and the resulting solid was collected by filtration. The resulting solid was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-K-(2- fluoro-5phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (24c) (20 mg, 44%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.68 (s, 1H), 7.65-7.55 (m, 2H), 7.52 - 7.30 (m, 7H), 7.15 (tt, J=6.9, 1.2 Hz, 1H), 7.03 - 6.98 (m, 2H), 6.96 - 6.89 (m, 1H), 3.95 (s, 2H ); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 60.80, -127.85; MS (IER+) 471.2 (M+1); (IER-) 469.1 (M-1).

Scheme 25

An example of the preparation of 1-(3-(aminomethyl)phenyl)-X-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (25b) and 1 -(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (25c).

Step 1. Preparation of tert-butyl-3-(5-((2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-carbamoyl)-3(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate ( 25 a).

To a solution of 1-(3-((tert-butoxycarbonylαamino)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazole-5carboxylic acid (10d) (284 mg, 0.737 mmol) in DMF (6.5 ml) was added ( 3-amino-4-fluorophenyl)(phenyl)methanol (26c) (160 mg, 0.737 mmol), N-ethyl-N-isopropylpropan-2-amine (1.05 ml, 6.03 mmol) and hexafluorophosphate (V) bromotripyrrolidin-1-ylphosphonium (PyBrOP, 353 mg, 0.742 mmol) and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate

- 88 045731 (150 ml), washed with water (2x75 ml), brine (60 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-(2-fluoro5-(hydroxy(phenyl)methyl) phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (25a) (196 mg, 46%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 7.64 - 7.14 (m, 14H), 6.00 (d, J=3.9 Hz, 1H), 5.69 (d, J=4.0 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.38 (s, 9H); MS (IER+) 607.3 (M+23).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-nirazole-5-carboxamide (25b) and 1 -(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25c).

Into a solution of tert-butyl-3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)1H-nirazol-1-yl)benzylcarbamate (25a) (0.18 g , 0.308 mmol) in 1,4-dioxane (16 ml), hydrogen chloride (3.2 ml, 12.81 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 26 hours. The reaction mixture was diluted hexanes (~80 ml) and decanted to obtain a yellow oily substance. A portion of the undissolved yellow oily substance was dissolved in ethanol and suspended in silica gel. The suspension was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give 1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy (phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25b) (61 mg, 39%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 7.54 (d, J=18.4 Hz, 3H), 7.45-7.38 (m, 2H), 7.33 (M, 5H), 7.27 - 7.22 (m, 3H), 5.45 (s, 1H), 3.77 (s, 2H), 3.42 (q, J=7, 0 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.76, -122.95; MS (IER+) 513.3 (M+1); (IER-) 511.2 (M-1).

The other part of the undissolved yellow oily substance was dissolved in methanol and suspended in silica gel. The suspension was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give 1-(3-(aminomethyl)phenyl)-N(2-fluoro-5 -(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25c) (11 mg, 7.2%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.58 (s, 1H), 7.61 - 7.52 (m, 3H), 7.52 - 7.34 (m, 2H), 7.40 - 7.29 (m, 6H), 7.29 - 7.21 (m, 4H), 5.34 (s, 1H), 3.80 (s, 2H), 3.25 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77, -122.99; MS (IER+) 499.3 (M+1); (IER-) 497.3 (M-1); 533.3 (M+Cl).

Scheme 26

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (26f).

Step 1. Preparation of (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b).

Phenylmagnesium bromide (48.0 mL, 48.0 mmol) was added dropwise to a solution of 4-fluoro-3-nitrobenzaldehyde (26a) (4 g, 23.65 mmol) in THF (60 mL) cooled to 0°C. and stirred at room temperature for 14 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (240 ml), the mixture was extracted with ethyl acetate (300 ml, 150 ml). The combined extracts were washed with brine (150 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 80 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b) (3.265 g, 56%) in the form of a brown viscous substance. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.63 (s, 1H), 8.24 (s, 1H), 7.67 - 6.51 (m, 14H), 4.20 (d, J =6.3 Hz, 2H), 1.37 (s, 9H); MS (IER+) 270.1 (M+1).

Step 2. Preparation of (3-amino-4-fluorophenyl)(phenyl)methanol (26c) and 5-benzyl-2-fluoroaniline (26d).

To a solution of (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b) (2 g, 8.09 mmol) in ethanol (70 ml) and ethyl acetate (35 ml) was added 10% Pd/C (0.440 g, 0.413 mmol), then hydrogenated (~50 psi, 345 kPa) for 4.5 hours. The reaction mixture was filtered through a Celite pad and treated with 4 M HCl in

- 89 045731

1,4-dioxane (~0.2 ml) and 4N. HCl (aq, ~0.2 ml) to pH= ~5. Concentrate the filtrate in vacuo and the resulting residue was purified by flash column chromatography [silica gel, 25 g, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give:

1. (3-amino-4-fluorophenyl)(phenyl)methanol (26c) (175 mg, 10%) as a light brown viscous substance; 1H NMR (300 MHz, DMSO-dg) δ 7.37 - 7.14 (m, 5H), 6.87 (dd, J=11.5, 8.3 Hz, 1H), 6.76 (dd, J=9.0, 2.2 Hz, 1H), 6.50 (dd, J=8.3, 4.6, 2.2, 0.6 Hz, 1H), 5.75 (d, J= 3.9 Hz, 1H), 5.52 (d, J=3.9 Hz, 1H), 5.06 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -137.89; MS (IER+): 218.2 (M+1);

2. 5-benzyl-2-fluoroaniline (26d) (1.084 g, 67%) as a brown viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.34 - 7.11 (m, 5H), 6.86 (dd, J=11.6, 8.2 Hz, 1H), 6.57 (dd , J=8.9, 2.2 Hz, 1H), 6.36 (ddd, J=8.2, 4.5, 2.2 Hz, 1H), 5.04 (s, 2H), 3, 76 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -139.01; MS (IER+): 202.1 (M+1).

Step 3. Preparation of tert-butyl-3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (26e).

5 -benzyl-2-fluoroaniline (26d) (158 mg, 0.786 mmol), N-ethyl-N-isopropylpropan-2-amine (1.1 ml, 6.31 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) ( PyBrOP, 377 mg, 0.793 mmol) and stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2x75 ml), brine (60 ml), dried over MgSO ₄ , filtered and concentrated in vacuum. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 3:1)] to give tert-butyl-3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3( trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (26e) (228 mg) as a white solid, which was used as such in the next step; MS (IER+) 591.3 (M+23).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (26f).

In a solution of tert-butyl-3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (26e) (0.202 g, 0.355 mmol) in 1,4-dioxane (18 mL), hydrogen chloride (3.7 mL, 14.78 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 21 hours. The reaction mixture was diluted with hexanes and the resulting yellow solid was collected by filtration. The yellow solid was purified by flash column chromatography [silica gel, 12 g, eluted with chloroform/methanol (1:0 to 9:1)] to give 1-(3-(aminomethyl)phenyl)-N(5benzyl-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (26f) (99 mg) as a colorless viscous substance; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.54 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.47-7.40 (m, 3H ), 7.35-7.25 (m, 3H), 7.27-7.15 (m, 4H), 7.13 (ddt, J=8.5, 5.0, 2.2 Hz, 1H ), 3.92 (s, 2H), 3.78 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75, -125.06; MS (IER+) 469.3 (M+1); (IER-) 467.2 (M-1).

Scheme 27

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (27f).

Step 1. Preparation of 3-nitro-N-phenyl-N-propylaniline (27c).

To a solution of 1-bromo-3-nitrobenzene (27a) (3 g, 14.85 mmol) and N-propylaniline (27b) (2.41 g, 17.82 mmol) in toluene (15 ml), 2-methylpropane- Sodium 2-olate (1.142 g, 11.88 mmol), (9,9-dimethyl9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.859 g, 1.485 mmol) and tris(dibenzylideneacetone)dipalladium (0) ( 0.408 g, 0.446 mmol). The reaction mixture was stirred at 110°C for 16 h under a positive nitrogen flow. The reaction mixture was cooled to room temperature, quenched with water (75 ml),

- 90 045731 was extracted with ethyl acetate (2x100 ml). The organic layers were combined, dried over MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [(silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give 3-nitro-Lphenyl-N-propylaniline (27c) (2.931 g, 11.44 mmol , yield 77%) in the form of a brown-yellow oily liquid. The isolated product was not of sufficiently high purity, but it was sufficient for use in this form in the next step; MS (IER+) 257.2 (M+1).

Step 2. Preparation of N1-phenyl-N1-propylbenzene-1,3-diamine (27d).

Palladium (10% Pd on carbon support, 0.241 g) was added to a solution of 3-nitro-N-phenyl-N-propylaniline (27c) (2.9 g, 11.31 mmol) in methanol (30 mL). The mixture was hydrogenated for 2 hours, filtered through a pad of Celite, and the filtrate was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes) to give N1-phenyl-N1-propylbenzene-1,3-diamine (27d) (1.195 g, 5.28 mmol, yield 46.7%) in the form of a dark green oily liquid; MS (IER+) 227.2 (M+1).

Step 3. Preparation of tert-butyl-3-(5-((3-(phenyl(propyl)amino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (27e).

To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (0.19 g, 0.493 mmol) in DMF (3 ml) was added N1 -phenyl-N1-propylbenzene-1,3diamine (27d) (0.134 g, 0.592 mmol), N-ethyl-N-isopropylpron-2-amine (0.687 ml, 3.94 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop , 0.253 g, 0.542 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours and concentrated to dryness in vacuo. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (50, 20 ml). The organic layers were combined, dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give tert-butyl-3-(5-(3-(phenyl(propyl)amino)phenylcarbamoyl)-3 -(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (27e) (0.199 g, 0.335 mmol, 68.0% yield) as a white solid; MS (IER+) 616.3 (M+Na), (IER-) 592.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideα (27f).

Into a solution of tert-butyl-3-(5-(3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (27e) (0.183 g, 0.308 mmol) in dioxane ( 4 ml), hydrogen chloride (4M in dioxane, 4.32 ml, 17.26 mmol) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of methanol in chloroform, 0-100%) to give 1 -(3-(aminomethyl)phenyl)-N-(3 -(phenyl(propyl)amino)phenyl)-3 -(trifluoromethyl)-1H -pyrazole5-carboxamide (27f) (0.086 g, 0.174 mmol, 56.5% yield) as a pale yellow solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.61 (s, 1H, exchange with D2O), 7.53 (s, 2H), 7.49 - 7.42 (m, 2H), 7.34 -7.23 (m, 4H), 7.22 - 7.17 (m, 2H), 7.05 - 6.93 (m, 3H), 6.71 - 6.67 (m, 1H), 3 .81 (s, 2H), 3.68 - 3.54 (m, 2H), 1.57 (h, J=7.5 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.73; MS (IER+) 494.3 (M+1), (IER-) 492.2 (M-1), 528.2 (M+Cl).

Scheme 28

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (28f).

Step 1. Preparation of N-methyl-N-(3-nitrobenzyl)aniline (28c).

To a solution of 1-(chloromethyl)-3-nitrobenzene (28a) (4 g, 23.31 mmol) in DMF (50 ml) was added Nmethylaniline (28b) (2.53 ml, 23.31 mmol), then potassium carbonate ( 20.94 g, 152 mmol). The reaction mixture was stirred at room temperature for 20 hours, poured into water (200 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with water (100 ml), brine (50 ml), dry, filter and concentrate in vacuo to give the crude product. Not

- 91 045731 the purified residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give N-methyl-N-(3-nitrobenzyl)aniline (28c), which was of sufficient purity to application at the next stage; MS (IER+) 243.2 (M+1).

Step 2. Preparation of N-(3-aminobenzyl)-N-methylaniline (28d).

Iron powder (1.729 g, 31.0 mmol) was added to a stirred solution of K-methyl-K-(3-nitrobenzyl)aniline (28c) (1.5 g, 6.19 mmol) in acetic acid (20 ml), and heated to 60°C and stirred for 30 minutes. The reaction was quenched by adding water (100 ml) and the mixture was filtered. The filtrate was extracted with ethyl acetate (2x100 ml). Combine the layers in ethyl acetate, wash with water (2x100 ml), brine (50 ml), dry and concentrate in vacuo. The resulting residue was purified by flash column chromatography to give N-(3-aminobenzyl)-N-methylαniline (28d) (533 mg, 2.51 mmol, 40.6% yield); 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.19 - 7.06 (m, 2H), 7.02 - 6.92 (m, 1H), 6.73 - 6.64 (m, 2H) , 6.58 (tt, J=7.2, 1.0 Hz, 1H), 6.49 - 6.36 (m, 3H), 5.46 (s, 2H, exchange with D ₂ O), 4 .39 (s, 2H), 2.98 (s, 3H); MS (IER+) 213.2 (M+1).

Step 3. Preparation of tert-butyl-3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (28e ).

In a solution of 1 -(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (193 mg, 0.5 mmol) in N,N-dimethylformamide (3 ml) N-ethyl-Nisopropylpropan-2-amine (0.697 ml, 4.00 mmol), X-ethyl-N-isopropylpropan-2-amine (0.697 ml, 4.00 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate ( PyBroP, 256 mg, 0.55 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours, diluted with water (20 ml) and extracted with ethyl acetate (2x50 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with hexanes in ethyl acetate/hexanes, 0-100%) to give tert-butyl-3-(5-((3-((methyl(phenyl)amino) methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (28e) (110 mg, 0.190 mmol, 37.9% yield) as a colorless sticky substance; 1H NMR (300 MHz, DMSO-dg) δ 10.71 (s, 1H, exchange with D2O), 7.59 - 7.45 (m, 4H), 7.457.38 (m, 2H), 7.34 ( d, J=7.7 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.20 - 7.07 (m, 2H), 6.97 (d, J=7 ,7 Hz, 1H), 6.69 (d, J=8.1 Hz, 2H), 6.60 (t, J=7.2 Hz, 1H), 4.52 (s, 2H), 4, 19 (d, J=6.2 Hz, 2H), 3.01 (s, 3H), 1.37 (s, 9H); MS (IER+) 580.4 (M+1), 602.4 (M+23), (IER-) 578.4 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-X-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (28f) .

Into a stirred solution of tert-butyl-3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)-carbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (28e) ( 100 mg, 0.173 mmol) in methanol (10 ml), HCl (0.575 ml, 6.90 mmol) was added and stirred at room temperature overnight. The reaction mixture was heated to reflux temperature for 30 min and concentrated to dryness in vacuo. The residue was dried in vacuo overnight, suspended in diethyl ether (25 ml), heated for 30 minutes and stirred at room temperature overnight. The isolated solid was collected by filtration, dried to give 1-(3-(aminomethyl)phenyl)-K(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 hydrochloride -carboxamide (28f) (75 mg, 0.145 mmol, 84% yield). 1H NMR (300 MHz, DMSO- _d6 ) δ 10.79 (s, 1H), 8.38 (s, 3H), 7.72 (s, 1H), 7.66 (s, 1H), 7. 61 (d, J=7.5 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.54 - 7.47 (m, 2H), 7.28 (t, J=7, 8 Hz, 1H), 7.16 (t, J=7.7 Hz, 2H), 7.00 (d, J=7.5 Hz, 1H), 6.70 (d, J=25.7 Hz , 3H), 4.54 (s, 2H), 4.13 (d, J=5.7 Hz, 3H), 3.02 (s, 3H); MS (IER+) 480.3 (M+1); (IER-) 478.2 (M-1), 514.2 (M+35).

Scheme 29

- 92 045731

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (29e).

Step 1. Preparation of 2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b).

To a solution of 1-bromo-2-fluoro-3-nitrobenzene (29a) (3 g, 13.64 mmol) and N-propylaniline (27b) (2.213 g, 16.36 mmol) in toluene (80 ml) was added 2- sodium methylpropan-2-olate (1.048 g, 10.91 mmol), biphenyl2-yl-di-tert-butylphosphine (0.407 g, 1.364 mmol) and tris(dibenzylideneacetone) dipalladium (0) (0.375 g, 0.409 mmol). The reaction mixture was stirred at 110°C for 16 h under a positive nitrogen flow. The reaction was quenched with water (75 ml), the mixture was extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes) to give 2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b) (3.451 g, 12 .58 mmol, 92% yield) as a brown-yellow oily liquid, which was of sufficient purity for use in the next step; MS (IER+) 275.2 (M+1).

Step 2. Preparation of 2-fluoro-N1-phenyl-N1-propylbenzene-1,3-diamine (29c).

Palladium (10% on carbon support, 0.264 g, 2.479 mmol). The mixture was hydrogenated for 2.5 hours, filtered through a pad of Celite and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes) to give 2-fluoro-N1-phenyl-N1-propylbenzene-1,3-diamine (29c) (0.295 g , 1.207 mmol, yield 9.74%) as a brown oily liquid; MS (IER+) 245.2 (M+1); (IER-) 243.2 (M-1).

Step 3. Preparation of tert-butyl-3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (29d).

In a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (0.190 g, 0.493 mmol) in N,N-dimethylformamide (2.98 ml, 38.5 mmol) added 2-fluoro-1H-phenyl-N1-propylbenzene-1,3-diamine (29c) (0.145 g, 0.592 mmol), N-ethyl-N-isopropylpropan-2-amine (0.687 ml , 3.94 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP, 0.253 g, 0.542 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 17 hours. Excess DMF was pumped out under reduced pressure. The reaction mixture was extracted with ethyl acetate (50 ml, 20 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 120 g, eluted with ethyl acetate/hexanes, 0-100%) to give tert-butyl-3-(5-(2-fluoro-3-(phenyl-(propyl)amino) Phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (29d) (0.182 g, 0.298 mmol, 60.3% yield) as a white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 10.54 (s, 1H, exchange with D2O), 7.57 (s, 1H), 7.53 - 7.31 (m, 4H), 7.28 7.15 (m, 4H), 6.94 - 6.83 (m, 4H), 4.18 (d, J=6.2 Hz, 2H), 3.68 - 3.51 (m, 2H) , 1.55 (q, J=7.5 Hz, 2H), 1.37 (s, 9H), 0.87 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82, -129.49; MS (IER+) 634.33 (M+Na), MS (IER-) 610.31 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (29e).

In a solution of tert-butyl-3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (29d) (0.166 g, 0.271 mmol ) in dioxane (4 ml), hydrogen chloride (4N in dioxane) (3.80 ml, 15.20 mmol) was added dropwise and stirred at room temperature for 15 hours. TLC analysis (CHCl ₃ /MeOH, 8/2, v/v) indicated the completion of the interaction. Excess solvent was pumped off under reduced pressure and the residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of methanol in chloroform, 0-100%) to give 1(3 -(aminomethyl)phenyl)-N-(2-fluoro-3 - (phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (29e) as a pale yellow solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 7.57 (s, 1H), 7.52 (s, 1H), 7.48 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.29 7.16 (m, 4H), 6.95- 6.82 (m, 4H), 3.79 (s, 2H), 3.65- 3.51 (m, 2H), 1.54 (h, J=7.3 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75, -129.55; MS (IER+): MS (IER+) 512.3 (M+1), (IER-) 510.3 (M-1), 546.2 (M+Cl).

- 93 045731

Scheme 30

An example of the preparation of N-(5-(( 1 H-imidazol-1 -yl)methyl)-2-fluorophenyl)-1 -(3 -(aminomethyl)phenyl)-3 (trifluoromethyl)-1 N-pyrazol-5-carboxamide (30g).

Step 1. Preparation of (3-amino-4-fluorophenyl)methanol (30b).

To a solution of (4-fluoro-3-nitrophenyl)methanol (30a) (3.81 g, 22.24 mmol) in methanol (30 ml) was added carbon-supported palladium (10%) (0.39 g, 3.67 mmol) and hydrogenated at 60 psi (414 kPa) for 1 hour. Remove the catalyst by filtration through Celite and concentrate the filtrate in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% ethyl acetate/methanol (9:1) in hexanes] to give (3-amino-4-fluorophenyl)methanol (30b) (3.05 g, 21.61 mmol, 97% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 6.89 (dd, J=11.6, 8.2 Hz, 1H), 6.73 (dd, J=9.1, 2.1 Hz, 1H ), 6.52 - 6.33 (m, 1H), 5.20 - 4.91 (m, 3H), 4.32 (dd, J=5.8, 0.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -138.13.

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (30c).

(3-Amino- 4-fluorophenyl)methanol (30b) (2.37 g, 16.79 mmol), N-ethyl-Nisopropylpropan-2-amine (14.62 ml, 84 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (8 .61 g, 18.47 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml), extracted with ethyl acetate (2x50 ml), washed with brine (25 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% ethyl acetate/methanol (9/1) in hexanes] to give 1-(3-cyanophenyl)-N-(2-fluoro-5- (hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30c) (1.66 g, 4.11 mmol, 24.45% yield) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.57 (s, 1H), 8.18 - 8.09 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H ), 7.91 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.57 - 7.45 (m, 1H ), 7.33 -7.15 (m, 2H), 5.30 (t, J=5.7 Hz, 1H), 4.46 (d, J=5.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.98, -124.32; MS (IER+) 427.2 (M+Na), (IER-) 403.2 (M-1).

Step 3. Preparation of N-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (30d).

Into a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-nirazol-5

- 94 045731 carboxamide (30c) (1.66 g, 4.11 mmol) in dichloromethane (30 ml) at 0°C, add thionyl chloride (1.798 ml, 24.63 mmol) and stir for 2.5 hours. Concentrate the reaction mixture under vacuum to obtain a white residue. The residue was dissolved in CHCl ₃ and treated with silica gel (2 g). The resulting slurry was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-50%) to give K-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (30d) (1.353 g, 78% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.18 - 8.11 (m, 1H), 8.01 (dt, J=7.7, 1.3 Hz , 1H), 7.91 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.80 - 7.65 (m, 3H), 7.43 - 7.22 (m , 2H), 4.77 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98 (d, J=6.8 Hz), -121.36.

Step 4. Preparation of N-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (30e ).

Into a stirred solution of K-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (30d) (0.15 g, 0.355 mmol) in To,K-dimethylformamide (4 ml) was added imidazole (0.121 g, 1.774 mmol) and potassium carbonate (0.343 g, 2.484 mmol) and stirred at room temperature for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in methanol and filtered through a Celite® pad. The filtrate was evaporated to dryness and the resulting crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% methanol in chloroform) to give N-(5-((1H-imidazol-1-yl)methyl)-2fluorophenyl )-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30e) (0.107 g, 66.4% yield) as a white solid foam; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.13 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1 ,3 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.77 - 7.71 (m, 3H), 7.43 (d, J=7.1 Hz, 1H), 7 ,31 (dd, J=10.4, 8.5 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.90 (t, J=1.1 Hz, 1H), 5, 19 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98 (d, J=5.4 Hz), -122.18; MS (IER+) 455.2 (M+1), (IER-) 453.2 (M-1).

Step 5. Preparation of tert-butyl-3-(5-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (30f ).

Into a stirred solution of N-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide (30e) ( 0.1 g, 0.22 mmol) in anhydrous methanol (10 ml), cooled to 0°C, add di-tert-butyl dicarbonate [(Boc) _2O ] (0.144 g, 0.66 mmol), nickel chloride hexahydrate (II) (10.46 mg, 0.044 mmol), then sodium borohydride (0.050 g, 1.320 mmol) was added in small portions over 5 min. The reaction was quenched with K1-(2-aminoethyl)ethane-1,2-diamine (0.048 mL, 0.440 mmol), the mixture was stirred at room temperature for 30 min and concentrated to dryness in vacuo. The residue was dissolved in a mixture of water/ethyl acetate (1:1, 25 ml each). The organic layer was separated and concentrated to dryness in vacuo, and the resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-50% ethyl acetate/hexanes) to give tert-butyl-3-(5-(5-(( 1 H-imidazol- 1 -yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (30f) (0.042 g, 0.075 mmol, 34.2% yield) as a white solid; MS (IER+) 559.3 (M+1), (IER-) 557.2 (M-1).

Step 6. Preparation of N-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide (30g).

In a solution of tert-butyl-3-(5-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (30f) (0.022 g, 0.039 mmol) in dioxane (4 ml), hydrogen chloride (4N in dioxane, 0.551 ml, 2.206 mmol) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% methanol in chloroform) to give N-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3- (aminomethyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (30g) (0.016 g, 0.035 mmol, 89% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 14.58 (s, 1H, exchange with _D2O ), 10.77 (s, 1H, exchange with D2O), 9.21 (s, 1H), 8 .37 (s, 3H, exchange with D2O), 7.75 (t, J=1.6 Hz, 1H), 7.69 (ddd, J=11.3, 3.6, 1.7 Hz, 4H ), 7.64 - 7.54 (m, 2H), 7.54 - 7.48 (m, 1H), 7.40 - 7.33 (m, 2H), 5.42 (s, 2H), 4.12 (d, J=5.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, -121.10; MS (IER+): MS (IER+) 459.3 (M+1), (IER-) 457.3 (M-1), 493.2 (M+Cl).

- 95 045731

Scheme 31

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(hydroxy(niridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (31f).

Step 1. Preparation of (3-nitrophenyl)(pyridin-3-yl)methanol (31c).

To a solution of 3-bromopyridine (31b) (2.89 ml, 30.0 mmol) in diethyl ether (20 ml) at -78°C, n-BuLi (15.94 ml, 25.5 mmol) was added dropwise and stirred for 30 min at -78°C. A solution of 3-nitrobenzaldehyde (31a) (4.53 g, 30 mmol) in THF (30 ml) was added dropwise to the 3-lithium-containing pyridine at -78°C and stirred at -78°C for 2 hours and at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (50 ml). The organic layer was separated, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0-100% ethyl acetate in hexanes) to give (3-nitrophenyl)(pyridin-3-yl)methanol (31c) (2.842 g, 12.34 mmol , yield 41.1%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d6) δ 8.66 (d, J=2.2 Hz, 1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H), 8, 30 (t, J=2.0 Hz, 1H), 8.12 (ddd, J=8.2, 2.5, 1.1 Hz, 1H), 7.85 (d, J=7.5 Hz , 1H), 7.78 (dt, J=7.9, 2.0 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.36 (ddd, J=7, 9, 4.7, 0.9 Hz, 1H), 6.45 (d, J=4.2 Hz, 1H), 5.99 (d, J=4.0 Hz, 1H); MC (IER+) 231.1 (M+1), (IER-) 459.4 (2M-1).

Step 2. Preparation of (3-aminophenyl)(pyridin-3-yl)methanol (31d).

To a solution of (3-nitrophenyl)(pyridin-3-yl)methanol (31c) (1 g, 4.34 mmol) in ethanol (36 ml) and ethyl acetate (18 ml) was added 10% Pd/C (0.1 g ) and hydrogenated at ~50 psi (345 kPa) for 2 hours. The reaction mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 2x12 g, eluted with chloroform/methanol (1:0 to 9:1)] to give (3-aminophenyl)(pyridin-3-yl)methanol (31d) (209 mg, 24%) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.55 (dt, J=2.2, 0.7 Hz, 1H), 8.40 (dd, J=4.8, 1.7 Hz, 1H ), 7.68 (dddd, J=7.8, 2.3, 1.7, 0.6 Hz, 1H), 7.31 (ddd, J=7.8, 4.7, 0.9 Hz , 1H), 6.94 (t, J=7.7 Hz, 1H), 6.61 - 6.56 (m, 1H), 6.55- 6.48 (m, 1H), 6.40 ( ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.89 (d, J=3.9 Hz, 1H), 5.58 (d, J=3.9 Hz, 1H ), 5.05 (s, 2H); MS (IER+) 201.1 (M+1).

Step 3. Preparation of tert-butyl-3-(5-(3-(hydroxy(pyridin-3-yl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-πirazol-1-yl)benzylcarbamαtα (31e).

To a solution of (3-aminophenyl)(pyridin-3-yl)methanol (31d) (80 mg, 0.400 mmol) in N,Ndimethylformamide (4 ml) was added 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (154 mg, 0.400 mmol), N-ethyl-N-isopropylpropan-2amine (0.560 ml, 3.22 mmol) and bromo-hexafluorophosphate (V) tripyrrolidin-1-ylphosphonium (PyBroP, 192 mg, 0.403 mmol) at room temperature. The reaction mixture was stirred at 25°C for 22 hours and diluted with ethyl acetate (120 ml). The reaction mixture was washed with water (2x60 ml), brine (60 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with chloroform/methanol (1:0 to 9:1)] to give tert-butyl-3-(5-(3-(hydroxy(pyridine-3 -yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (31e) (153 mg, 68%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1 .7 Hz, 1H), 7.70 (dt, J=8.1, 2.1 Hz, 1H), 7.64 (t, J=1.9 Hz, 1H), 7.60 - 7.11 (m, 10H), 6.14 (d, J=4.0 Hz, 1H), 5.76 (d, J=4.0 Hz, 1H), 4.19 (d, J=6.2 Hz , 2H), 1.36 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.80; MS (IER+) 568.3 (M+1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (31f).

In a stirred solution of tert-butyl-3-(5-(3-(hydroxy(pyridin-3-yl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (31e) (135 mg, 0.238 mmol) in 1,4-dioxane (12 ml)

- 96 045731 4M HCl in dioxane (2.5 ml, 10.0 mmol) was added and stirred at room temperature for 17 hours. The reaction mixture was diluted with hexanes and decanted. The residue was washed with hexanes and decanted again. The insoluble product was dissolved in chloroform (40 ml)/ethanol (10.00 ml) and suspended using 2 g of silica gel. The suspension was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give 1-(3(aminomethyl)phenyl)-N-(3-(hydroxy(pyridin-3-yl) )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (31f) (93 mg, 84%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1 .7 Hz, 1H), 7.70 (dt, J=8.0, 2.0 Hz, 1H), 7.66 (t, J=1.8 Hz, 1H), 7.56 (d, J =3.2 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.38 (m, 2H), 7.37 - 7.26 (m, 3H), 7, 16 (d, J=7.6 Hz, 1H), 6.15 (d, J=4.0 Hz, 1H), 5.76 (s, 1H), 3.77 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73; MS (IER+) 468.3 (M+1).

Scheme 32

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (32f).

Step 1. Preparation of 1-(3-aminophenyl)-1-phenylpentan-1-ol (32a).

To a stirred solution of (3-aminophenyl)(phenyl)methanone (18a) (2 g, 10.14 mmol) in tetrahydrofuran (40 ml) was added n-BuLi (19.01 ml, 30.4 mmol, 1.6 M in hexanes ) at 0°C. The reaction mixture was left to warm to room temperature overnight, quenched by adding ammonium chloride solution (50 ml) and extracted with ethyl acetate (2x150 ml). The combined organic layers were washed with water (2x50 ml), brine (50 ml), dried, filtered and concentrated to dryness in vacuo. The crude 1-(3-aminophenyl)-1-phenylpentan-1-ol residue (32a) was used as such in the next step without further purification; MS (IER-) 254.1 (M-1).

Step 2. Preparation of 3-(1-phenylpentyl)aniline (32b) and (2)-3-(1-phenylpent-1-en-1-yl)aniline (32c).

To a solution of 1-(3-aminophenyl)-1-phenylpentan-1-ol (32a) (0.7 g, 2.74 mmol) in dichloromethane (10 ml) at 0°C was added diethyl ether boron trifluoride complex (0.695 ml, 5.48 mmol), triethylsilane (1.751 ml, 10.97 mmol) and stirred at room temperature overnight. The reaction was quenched by adding ammonium chloride solution and the mixture was extracted with dichloromethane (2x50 ml). Combine the organic layers, wash with water, brine, dry, filter and concentrate in vacuo. The residue was purified by flash column chromatography to give a compound containing an inseparable mixture of 3-(1-phenylpentyl)aniline (32b) and (2)-3-(1-phenylpent-1-en-1yl)aniline (32c). The resulting mixture was used in this form in the next stage; MS (IER+) 238.2 (M+1) (32c) and 240.2 (M+1, 32b), (IER-) 239.1 (M-1, 32b).

Step 3. Preparation of pure 3-(1-phenylpentyl)aniline (32b).

A mixture of 3-(1-phenylpentyl)aniline (32b) and (2)-3-(1- phenylpent-1-en-1-yl)aniline (32c) (240 mg, 1.011 mmol) and hydrogenated at 60 psi (414 kPa) for 3 hours. Filter the reaction mixture and concentrate

- 97 045731 dug in a vacuum. The crude residue was purified by flash column chromatography to give 3-(1-phenylpentyl)aniline (155 mg, 0.648 mmol, 64.0% yield) as an oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.25 (d, J=4.9 Hz, 4H), 7.18 - 7.09 (m, 1H), 6.89 (t, J=7, 7 Hz, 1H), 6.49 - 6.41 (m, 2H), 6.34 (ddd, J=7.9, 2.2, 1.0 Hz, 1H), 4.96 (s, 2H ), 3.69 (t, J=7.8 Hz, 1H), 2.00 - 1.86 (m, 2H), 1.37 - 1.22 (m, 2H), 1.22 - 1, 05 (m, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (IER+) 240.2 (M+1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (32d).

In a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (147 mg, 0.522 mmol) in N,N-dimethylformamide (3.16 ml, 40.8 mmol ) added a solution of 3-(1-phenylpentyl)aniline (32b) (150 mg, 0.627 mmol) in N,N-dimethylformamide (3.16 ml, 40.8 mmol), bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBroP, 268 mg, 0.575 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 h and the reaction was quenched with water (25 ml). The reaction mixture was extracted with ethyl acetate (100 ml, 50 ml) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered, concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with hexanes in ethyl acetate/hexanes, 0-20%) to give 1-(3-cyanophenyl)-N-(3-(1-phenylpentyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (32d) (155 mg, 0.308 mmol, 59.0% yield) as an oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1, 3 Hz, 1H), 7.90 (ddd, J=8.1, 2.3, 1.2 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.55-7.48 (m, 2H), 7.32 - 7.22 (m, 5H), 7.21 - 7.13 (m, 1H), 7.12 - 7.06 (m, 1H), 3.88 (t , J=7.8 Hz, 1H), 1.95 (d, J=8.0 Hz, 2H), 1.36 - 1.25 (m, 2H), 1.16 (d, J=7, 1 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (IER+) 525.3, (IER-) 501.2 (M-1).

Step 5. Preparation of tert-butyl-3-(5-((3-(1-phenylpentyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (32e).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (32d) (137 mg, 0.273 mmol) in anhydrous methanol (20 ml), cooled to 0°C, di-tert-butyl dicarbonate (178 mg, 0.818 mmol), nickel (II) chloride (12.96 mg, 0.055 mmol) and sodium borohydride (61.9 mg, 1.636 mmol) were added portionwise ) for 5 min. The reaction mixture was stirred for 36 min at room temperature, the reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.059 ml, 0.545 mmol). The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. Water (25 ml) was added to the residue and extracted with ethyl acetate (2x25 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 12 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give tert-butyl-3-(5-(3-(1-phenylpentyl)phenylcarbamoyl)- 3-(trifluoromethyl)-1H-pyrazol1-yl)benzylcarbamate (32e) (75 mg, 45.3% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=2.2 Hz, 3H), 7.45- 7 .38 (m, 2H), 7.35 (d, J=7.6 Hz, 2H), 7.31 - 7.21 (m, 5H), 7.15 (dt, J=8.6, 4 .0 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.87 (t, J=7.8 Hz, 1H), 1.98 (d, J=8.3 Hz, 2H), 1.36 (s, 9H), 1.28 (d, J=7.2 Hz, 2H), 1.22 - 1.10 (m, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (ESI+) 629.3 (M+Na), (ESI-) 605.2 (M-1), 641.3 (M+Cl).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (32f).

Into a stirred solution of tert-butyl 3-(5-(3-(1-phenylpentyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (32e) (0.065 g, 0.107 mmol) in methanol (5 ml) was added 4M HCl in dioxane (0.357 ml, 4.29 mmol) and heated to reflux temperature for 30 min. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. Methanol (50 ml) was added to the residue and concentrated to dryness in vacuo. The residue was triturated with diethyl ether (25 ml) and the isolated solid was collected by filtration, dried in vacuo to give 1 -(3 -(aminomethyl)phenyl)-N-(3 -(1-phenylpentyl)phenyl)-3 -(trifluoromethyl )-1 H-pyrazole-5-carboxamide (32f) (60 mg) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H, exchange with D2O), 8.31 (s, 3H, exchange with D2O), 7.71(d, J=1.9 Hz , 1H), 7.66 (s, 1H), 7.62 - 7.57 (m, 1H), 7.56 7.48 (m, 4H), 7.32 - 7.20 (m, 5H) , 7.20 - 7.13 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.13 (s, 2H), 3.87 (t, J=7.8 Hz, 1H), 1.98 (d, J=7.5 Hz, 2H), 1.29 (p, J=7.3 Hz, 2H), 1.16 (d, J=7.7 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H); MS (IER+) 507.3 (M+1), 508.3 (M+2), (IER-) 505.2 (M-1), 541.2 (M+35).

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Scheme 33

An example of the preparation of 1-(3-(aminomethyl)phenyl)-C-(2-chloro-5-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (33e) and 1 -(3-(aminomethyl)phenyl)-N-(2-chloro-5-(hydroxy(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (33f).

Step 1. Preparation of (4-chloro-3-nitrophenyl)(phenyl)methanol (33b).

Phenylmagnesium bromide (8.08 mL, 8.08 mmol, 1M solution in THF) for 2 min. The reaction mixture was allowed to warm to room temperature for 14 hours, quenched with saturated ammonium chloride (50 ml) and extracted with ethyl acetate (100 ml, 50 ml). The combined extracts were washed with brine (50 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with hexanes/ethyl acetate, 0-100%) to give pure (4-chloro-3-nitrophenyl)(phenyl)methanol (33b) (653 mg, yield 46 .0%) as a yellow semi-solid; 1H NMR (300 MHz, DMSO-a ₆ ) δ 8.09 (d, J=1.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.67 (dd, J=8.4, 1.9 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.38 - 7.29 (m, 2H), 7.28 - 7.21 (m, 1H), 6.31 (d, J=4.0 Hz, 1H), 5.84 (d, J=4.0 Hz, 1H); MS (IER+) 286.1 (M+23), 262.1 (M-1), 308.1 (M+35).

Step 2. Preparation of (3-amino-4-chlorophenyl)(phenyl)methanol (33c).

Iron powder (762 mg, 13.65 mmol) was added to a stirred solution of (4-chloro-3-nitrophenyl)(phenyl)methanol (33b) (600 mg, 2.276 mmol) in acetic acid (10 ml) and heated at 60° C for 3 hours. The reaction mixture was diluted with ethanol (100 ml) and filtered through celite. Concentrate the filtrate in vacuo and purify by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give (3-amino-4-chlorophenyl)(phenyl)methanol (33 sec) (383 mg , 1.639 mmol, yield 72.0%) as an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.37 - 7.25 (m, 4H), 7.23 - 7.16 (m, 1H), 7.07 (d, J=8.2 Hz , 1H), 6.82 (d, J=2.0 Hz, 1H), 6.53 (dd, J=8.3, 2.1 Hz, 1H), 5.82 (s, 1H, exchange with D ₂ O), 5.53 (s, 1H), 5.29 (s, 2H, exchange with D ₂ O); MC (IER+) 234.1 (M+1), 236.1 (M+3).

Step 3. Preparation of tert-butyl-3-(5-(2-chloro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (33d).

In a solution of 1 -(3 -((tert-butoxycarbonylamino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-nirazole-5carboxylic acid (10d) (0.193 g, 0.5 mmol) in X,N-dimethylformamide ( 3.02 ml, 39.0 mmol) added (3-amino-4-chlorophenyl)(phenyl)methanol (33c) (0.140 g, 0.6 mmol), X-ethyl-N-isopropylpropan-2-amine (0.697 ml, 4.0 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP) (0.256 g, 0.55 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml and 50 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with ethyl acetate/hexanes, 0100%) to give tert-butyl-3-(5-(2-chloro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (33d) (0.059 g, 19.63% yield) as an oily liquid. MS (IER-) 599.2, 601.2 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-X-(2-chloro-5-(ethoxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide (33e) and 1-(3-(aminomethyl)phenyl)-X-(2-chloro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (33f).

Into a stirred solution of tert-butyl-3-(5-(2-chloro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamαtα (33d) (0.053 g, 0.088 mmol) in ethanol (5 ml) adding

- 99 045731 li conc. HCl (0.294 ml, 3.53 mmol) and stirred overnight at room temperature. The reaction mixture was heated at reflux temperature for 2 hours and concentrated in vacuo to remove excess hydrochloric acid. The residue was dissolved in ethanol and applied to silica gel. The silica gel suspension was purified by flash column chromatography (eluted with mixtures of methanol in chloroform, 0-20%) to obtain:

1. 1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (33e) (7 mg, 15.01%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H, exchange with D2O), 7.53 (t, J=8.9 Hz, 4H), 7.49 - 7.40 (m , 3H), 7.34 (t, J=4.5 Hz, 6H), 7.30 - 7.23 (m, 2H), 5.47 (s, 1H), 3.78 (s, 2H) , 3.42 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); MS (IER+) 529.2 (M), 531.2 (M+2); (IER-) 529.1 (M), 527.1 (M-2);

2. 1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (33f) (8 mg, yield 18.11%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.19 (d, J=190.4 Hz, 1H, exchange with D2O), 7.55 (d, J=7.6 Hz, 3H), 7.49 - 7.40 (m, 3H), 7.39 - 7.16 (m, 9H), 6.08 (d, J=4.2 Hz, 1H, exchange with D ₂ O), 5.70 (s , 1H), 3.80 (s, 2H). MS (IER+) 501.1 (M), 503.1 (M+2); (IER-) 499.1 (M-1).

Scheme 34

9i

34c

Alternative way

I O O I

34f 34c

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34c) and 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34d).

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Step 1. Preparation of (3-amino-4-fluorophenyl)(phenyl)methanol (26c).

Nickel (II) chloride hexahydrate ( 0.259 g, 1.089 mmol), then sodium borohydride (0.989 g, 26.1 mmol) in parts over 30 minutes. The reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.941 mL, 8.71 mmol), the mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (25 ml), washed with water (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0 to 50% ethyl acetate/hexanes) to give (3-amino-4-fluorophenyl)(phenyl)methanol (26c) (0.813 g, 86% yield) %) in the form of an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.36 - 7.25 (m, 4H), 7.22 - 7.14 (m, 1H), 6.87 (dd, J=11.5, 8.2 Hz, 1H), 6.76 (dd, J=8.9, 2.2 Hz, 1H), 6.50 (ddd, J=8.2, 4.5, 2.2 Hz, 1H ), 5.76 (d, J=3.9 Hz, 1H), 5.52 (d, J=3.9 Hz, 1H), 5.06 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -137.80 - -137.95 (m); MC (IER+) 218 (M+1); (IER-) 216 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34a).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1 g, 3.56 mmol) in N,N-dimethylformamide (21.48 mL ), (3-amino-4-fluorophenyl)(phenyl)methanol (26c) (0.773 g, 3.56 mmol), bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop) (1.658 g, 3.56 mmol) and N-ethyl were added sequentially -N-isopropylpropan-2-amine (3.10 mL, 17.78 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours and the reaction was quenched with water (100 ml). The reaction mixture was extracted with ethyl acetate (2x100 ml) and the combined organic layers were washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% ethyl acetate in hexanes] to give (34a) (0.763 g, 45% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H, exchange with D2O), 8.12 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7 .7, 1.3 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.76 - 7.68 (m, 2H), 7.52 (dd, J=7.6, 2 ,1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.35- 7.31 (m, 2H), 7.30 (d, J=1.0 Hz, 1H ), 7.27 (q, J=1.9 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.24 - 7.17 (m, 1H), 6.01 (d, J=3.9 Hz, 1H, exchange with D2O), 5.69 (d, J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.99, -123.32; MS (IER+): MS (IER+) 503.1 (M+Na), (IER-) 479.1 (M-1), 959.3 (2M-1).

Step 3. Preparation of tert-butyl-3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (34b).

Into a stirred solution of 1-(3-cyanophenyl)-M-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (34a) (0.730 g, 1.520 mmol) in anhydrous methanol (15 ml), cooled to 0°C, added di-tert-butyl dicarbonate [(Boc) ₂ O] (0.995 g, 4.56 mmol), nickel (II) chloride hexahydrate (0.072 g, 0.304 mmol) and small portions of sodium borohydride (0.345 g, 9.12 mmol) over 5 minutes. The reaction mixture was stirred for 20 min at room temperature, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.328 mL, 3.04 mmol) and stirred for 30 min. Concentrate the reaction mixture in vacuo and treat the residue with water (50 ml) and extract with ethyl acetate (2x25 ml). The organic layers were combined, dried over MgSO ₄ and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give tert-butyl-3-(5-(2fluoro-5-(hydroxy(phenyl)methyl) phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (34b) (0.458 g, 52% yield) as an oily solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H, exchange with D2O), 7.57 (m, 2H), 7.51 (t, J=6.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.38 - 7.31 (m, 4H), 7.30 (d, J=0.9 Hz, 1H), 7.29 - 7.17 ( m, 3H), 6.00 (d, J=4.0 Hz, 1H, exchange with D2O), 5.69 (d, J=3.9 Hz, 1H), 4.19 (d, J=6 .2 Hz, 2H), 1.38 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.82, -123.71; MS (IER+) 607.2 (M+Na), (IER-) 583.2 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(5-((cyclopropylmethoxy)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34c) and 1-(3-(aminomethyl)phenyl)-M-(2-fluoro5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34d).

Into a solution of tert-butyl-3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (34b) (0.277 g, 0.474 mmol) in 1,4-dioxane (10 ml) at room temperature, add hydrogen chloride (4M in 1,4-dioxane, 6.87 ml, 27.5 mmol) dropwise and stir at room temperature for 14 hours. The reaction mixture diluted with 75 ml of hexanes and collected the resulting oily solid by filtration. The residue (oily solid) was redissolved in chloroform (40 ml)/cyclopropylmethanol (1.880 ml, 22.75 mmol), 3 g of silica gel was added and stirred at room temperature for 30 minutes. The mixture was concentrated to dryness in vacuo and the resulting slurry was purified by flash column chromatography [(silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0-100%)] to obtain:

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1. 1-(3-(aminomethyl)phenyl)-M-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (34d) (19 mg, yield 8%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 7.58 (d, J=4.2 Hz, 2H), 7.52 (s, 1H), 7.47 - 7.40 (m, 2H), 7.38 - 7.17 (m, 8H), 6.01 (d, J=4.0 Hz, 1H), 5.68 (d, J=2.1 Hz , 1H), 3.78 (s, 2H); ¹ H NMR (300 MHz, DMSO-d6 D2O) δ 7.62 - 7.54 (m, 2H), 7.53 - 7.42 (m, 3H), 7.38 - 7.18 (m, 8H ), 5.68 (s, 1H), 3.77 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.75, -123.78; MS (IER ⁺ ): MS (IER+) 485.2 (M+1), 969.4 (2M+1), (IER-) 483.2 (M-1), 519.2 (M+Cl) , 967.3 (2M-1);

2. a second purification of the fractions containing impurities on a column [(silica gel, 12 g, eluted with mixtures of methanol in chloroform, from 0 to 100%)] led to the preparation of 1-(3-(aminomethyl)phenyl)-N-(5( (cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34c) (39 mg, 15% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 7.58 (d, J=5.1 Hz, 2H), 7.52 (d, J=2.0 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.33 (d, J=4.4 Hz, 5H), 7.28 - 7.20 (m, 3H), 5.47 (s , 1H), 3.77 (s, 2H), 3.22 (d, J=6.7 Hz, 2H), 1.05 (m, 1H), 0.54 - 0.38 (m, 2H) , 0.21 - 0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.75, -122.96; MS (IER ⁺ ): MS (IER+) 539.3 (M+1), (IER-) 537.2 (M-1); analysis, calculation for C2 ₉ H2 ₆ F4N ₄ O ₂ : C, 64.68; H, 4.87; N, 10.40; experiment: C, 64.58; H, 5.07; N, 10.19.

An alternative method for the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34c ).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34e).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (34a) (1.1 g, 2.290 mmol) in cyclopropylmethanol (14.80 ml, 206 mmol) was added ytterbium(III) trifluoromethanesulfonate (1.065 g, 1.717 mmol) and heated with stirring at 80°C for 16 hours. Excess solvent was pumped off and the residue was dried under reduced pressure. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34e) (1.014 g, 83% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H, exchange with D2O), 8.18 - 8.09 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.79 - 7.67 (m, 2H), 7.59 - 7.48 (m, 1H), 7.38 - 7.31 (m, 4H), 7.29 -7.20 (m, 3H), 5.48 (s, 1H), 3.22 (d, J=6.7 Hz, 2H), 1, 04 (dddd, J=12.2, 8.1, 4.0, 2.6 Hz, 1H), 0.53 - 0.39 (m, 2H), 0.14 (tq, J=4.6 , 2.1 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.99, -122.52; MS (IER ⁺ ): MS (IER+) 557.2 (M+Na), MS (IER-) 533.1 (M-1); IR (KBr, ^cm'1 ): 2235 ^cm'1 (stretching vibrations of CN).

Step 2. Preparation of tert-butyl-3-(5-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (34f).

Into a stirred solution of 1-(3-cyanophenyl)-M-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34e) (0.996 g , 1.863 mmol) in anhydrous methanol (10 ml), cooled to 0°C, di-tert-butyl dicarbonate [(Boc) ₂ O] (1.220 g, 5.59 mmol) was added in small portions of sodium borohydride (0.423 g, 11 .18 mmol) for 5 min. The interaction took place with the release of heat and gas. The reaction mixture was stirred for 15 minutes and concentrated in vacuo. The residue was treated with water (15 ml) and extracted with ethyl acetate (2x25 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give tert-butyl-3-(5-(5-((cyclopropylmethoxy)(phenyl)methyl) -2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (34f) (445 mg, 37% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H, exchange with D2O), 7.58 (d, J=5.9 Hz, 2H), 7.51 (t, J=6 ,2 Hz, 1H), 7.45-7.30 (m, 7H), 7.29 - 7.21 (m, 3H), 5.47 (s, 1H), 4.19 (d, J= 6.3 Hz, 2H), 3.22 (d, J=6.8 Hz, 2H), 1.38 (s, 9H), 1.10 - 0.99 (m, 1H), 0.51 - 0.41 (m, 2H), 0.19 0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.83, -122.90; MS (IER ⁺ ): MS (IER+) 661.29 (M+Na), MS (IER-) 637.2 (M-1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34c).

In a solution of tert-butyl 3-(5-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (34f) (0.431 g, 0.675 mmol) in 1,4-dioxane (20 ml), a 4M solution of hydrogen chloride in 1,4-dioxane (9.79 ml, 39.1 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture was evaporated to dryness and the resulting the residue was purified by flash column chromatography [(silica gel, 40 g, eluted with mixtures of methanol in chloroform, 0-100%)] to give 1-(3-(aminomethyl)phenyl)-M-(5-((cyclopropylmethoxy)(phenyl )methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (34c) (0.209 g, 0.388 mmol, 57.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H, exchange with D2O), 7.58 (d, J=5.1 Hz, 2H), 7.52 (d, J=2 ,0 Hz, 1H), 7.47-7.38 (m, 2H), 7.33 (d, J=4.4 Hz, 5H), 7.28-7.20 (m, 3H), 5 .47 (s, 1H), 3.77 (s, 2H), 3.22 (d, J=6.7 Hz, 2H), 1.05 (m, 1H), 0.54-0.38 ( m, 2H), 0.21-0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75, -122.96; MS (IER+) 539.3 (M+1), (IER-) 537.2 (M-1). Analysis, calculation for

- 102 045731

C29H26F4N4O2: C, 64.68; H, 4.87; N, 10.40; experiment: C, 64.58; H, 5.07; N, 10.19.

Scheme 35

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (35g).

Step 1. Preparation of 2-fluoro-N-methoxy-N-methyl-3-nitrobenzamide (35b).

To a solution of 2-fluoro-3-nitrobenzoic acid (35a) (5.0 g, 27.0 mmol) in toluene (20.0 ml) was added thionyl chloride (19.71 ml, 270 mmol), one drop of DMF and heated at temperature of reverse condensation for 1 hour. The reaction mixture was concentrated to dryness in vacuum, distilled once with toluene (10 ml) and dried in vacuum to remove traces of thionyl chloride. The resulting acid chloride was dissolved in dichloromethane (40 ml) and N,Odimethylhydroxylamine hydrochloride (3.95 g, 40.5 mmol) and triethylamine (18.82 ml, 135 mmol) were added at room temperature. The reaction mixture was stirred at room temperature overnight, washed with water (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 2-fluoro-N-methoxy-N-methyl-3-nitrobenzamide (35b) (5.062 g, 82 yield %) as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 8.25 (ddd, J=8.3, 7.4, 1.7 Hz, 1H), 7.93 (ddd, J=7.5, 5.6, 1.7 Hz, 1H), 7.54 (ddd, J=8.5, 7.7, 1.0 Hz, 1H), 3.50 (s, 3H), 3.32 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ 123.00 (t, J=6.6 Hz); MS (ESI+) 251.1 (M+Na).

Step 2. Preparation of methyl 3-amino-2-fluoro-N-methoxy-N-methylbenzamide (35c).

To a solution of 2-fluoro-N-methoxy-N-methyl-3-nitrobenzamide (35b) (3.792 g, 16.62 mmol) in methanol (30 ml) was added carbon-supported palladium (0.8 g) and the mixture was hydrogenated at 50 psi (345 kPa) for 4 hours. Filter the reaction mixture through Celite and concentrate the filtrate in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0100% ethyl acetate in hexanes) to give methyl 3-amino-2-fluoro-N-methoxy-N-methylbenzamide (35 sec) (3.072 g, 15 .50 mmol, yield 93%) as a light brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.90 (t, J=7.7 Hz, 1H), 6.80 (td, J=8.3, 1.8 Hz, 1H), 6, 49 (ddd, J=7.5, 5.7, 1.8 Hz, 1H), 5.30 (s, 2H), 3.62 - 3.43 (m, 3H), 3.22 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ -138.16; MS (ESI+) 221.1 (M+Na).

Step 3. Preparation of (3-amino-2-fluorophenyl)(phenyl)methanone (35d).

A solution of methyl 3-amino-2-fluoro-N-methoxy-N-methylbenzamide (35c) (2.8 g, 14.13 mmol) in THF (60 ml) was cooled to 0°C and slowly treated with phenylmagnesium bromide (28 .7 ml, 28.7 mmol), then warmed to room temperature and stirred at room temperature for 14 hours. The reaction was quenched. ammonium chloride (120 ml) and the mixture was extracted with ethyl acetate (2x100 ml). The combined extracts were dried over MgSO ₄ , filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 80 g, eluted with 0 to 50% ethyl acetate in hexanes)] to give (3-amino-2-fluorophenyl)(phenyl)methanone (35d) (1.297 g, yield 43%) in the form of a pale yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 - 7.73 (m, 2H), 7.73 7.66 (m, 1H), 7.62 -7.52 (m, 2H), 7.08 - 6.92 (m, 2H), 6.67 - 6.55 (m, 1H), 5.44 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -135.94; MS (IER+): MS (IER+) 238.1 (M+Na), MC (IER-) 214.0 (M-1).

Step 4. Preparation of N-(3-benzoyl-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (35e).

In a 100 mL one-neck flask containing a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxylic acid (9i) (1.38 g, 4.91 mmol), (3-amino-2- fluorophenyl)(phenyl)methanone (35d) (1.056 g, 4.91 mmol) in N,N-dimethylformamide (30 ml), bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop) (2.288 g, 4.91 mmol) was added sequentially, N- ethyl-N-isopropylpropan-2-amine (4.27 mL, 24.54 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was transferred

- 103 045731 was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction was quenched with water (100 ml) and the mixture was extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The residue was purified twice by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give N-(3-benzoyl-2-fluorophenyl)-1-(3-cyanophenyl)-3-( trifluoromethyl)-1Hpyrazole-5-carboxamide (35e) (0.287 g, 12% yield) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.73 (s, 1H, exchange with D2O), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.85 (td, J=7.4, 2.1 Hz, 1H ), 7.78 (d, J=2.6 Hz, 2H), 7.76 (d, J=1.9 Hz, 2H), 7.73 (s, 1H), 7.58 (dd, J =8.3, 7.0 Hz, 2H), 7.48 - 7.35 (m, 2H); ¹ H NMR (300 MHz, DMSOL D2O) δ 8.13 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.1, 2.3, 1.2 Hz, 1H), 7.84 (td, J=7.3, 2.5 Hz, 1H), 7.80 - 7.70 (m , 5H), 7.59 (t, J=7.7 Hz, 2H), 7.48 - 7.36 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -61.00, -122.24; IR (KBr, cm- ¹ ): 2233 cm- ¹ (CN stretching vibrations); MS (IER ⁺ ): MS (IER+) 479.1 (M+1), 501.1 (M+Na), (IER-) 477.1 (M-1), 955.2 (M+Cl) .

Step 5. Preparation of tert-butyl-3-(5-(2-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (35f).

Into a stirred solution of N-(3-benzoyl-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (35e) (0.276 g, 0.577 mmol) in anhydrous methanol (20 ml ), cooled to 0°C, di-tert-butyl dicarbonate [(Boc) ₂ O] (0.378 g, 1.731 mmol), nickel (II) chloride hexahydrate (0.027 g, 0.115 mmol) were added, then sodium borohydride ( 0.131 g, 3.46 mmol) over 5 min. The reaction mixture was stirred for 50 min at 0°C, quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.125 ml, 1.154 mmol), stirred for 30 min and concentrated to dryness in vacuo. The residue was treated with water (25 ml) and extracted with ethyl acetate (2x25 ml). The combined organic layers were dried over MgSO ₄ , filtered and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give tert-butyl-3-(5-(2-fluoro-3(hydroxy-(phenyl) methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (35f) (0.212 g, 63% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.54 (s, 1H, exchange with D2O), 7.58 (s, 1H), 7.54 - 7.46 (m, 3H), 7.46 - 7.38 (m, 2H), 7.38 - 7.30 (m, 5H), 7.26 - 7.15 (m, 2H), 6.08 (d, J=4.3 Hz, 1H , exchange with D2O), 5.93 (d, J=4.2 Hz, 1H), 4.18 (d, J=6.2 Hz, 2H), 1.37 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.83, -127.57; MS (IER ⁺ ): MS (IER+) 607.2 (M+Na), (IER-) 583.2 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (35 g ).

Into a solution of tert-butyl-3-(5-(2-fluoro-3 -(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (35f) (0.151 g, 0.258 mmol) in 1,4-dioxane (18 ml), hydrogen chloride (2.78 ml, 11.11 mmol, 4M in 1,4-dioxane) was added dropwise and stirred at room temperature for 14 hours. Excess solvent was pumped off under reduced pressure. pressure. The residue was dissolved in chloroform/cyclopropylmethanol (1.452 ml, 17.57 mmol) and suspended using 2 g of silica gel, then the residue was purified by flash column chromatography [(silica gel, 25 g, eluted with mixtures of methanol in chloroform, 0 to 100% )] to obtain VSKH-6967 (0.109 g, 87% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.56 (s, 1H, exchange with D2O), 7.64 (s, 2H), 7.557.43 (m, 5H), 7.32 (d, J =6.5 Hz, 4H), 7.26 - 7.14 (m, 2H), 6.10 (d, J=4.2 Hz, 1H, exchange with D2O), 5.92 (d, J= 3.9 Hz, 1H), 4.00 (s, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.81, -127.34; MS (IER ⁺ ): MS (IER+) 485.2 (M+1), (IER-) 483.2 (M-1), 519.1 (M+Cl).

Scheme 36

- 104 045731

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (36d).

Step 1. Preparation of (3-amino-2-fluorophenyl)(phenyl)methanol (36a).

Nickel(II) chloride was added to a stirred solution of (3-amino-2-fluorophenyl)(phenyl)methanone (35d) (1.25 g, 5.81 mmol) in anhydrous methanol (50 ml), cooled to 0°C. (0.345 g, 1.452 mmol) and sodium borohydride (0.879 g, 23.23 mmol) in small portions over 5 minutes. The reaction mixture was stirred for 15 min, quenched with N-(2-aminoethyl)ethane-1,2-diamine (1.255 ml, 11.62 mmol), stirred for another 30 min and concentrated to dryness in vacuo. The resulting residue was treated with water (50 ml) and extracted with ethyl acetate (2x75 ml). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 50% ethyl acetate in hexanes)] to give (3-amino-2-fluorophenyl)(phenyl)methanol (36a) (0.834 g, yield 66%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.37 - 7.24 (m, 4H), 7.23 - 7.16 (m, 1H), 6.88 - 6.78 (m, 1H) , 6.64 (dddd, J=18.3, 9.3, 7.1, 1.8 Hz, 2H), 5.94 - 5.74 (m, 2H), 5.03 (s, 2H, exchange with D ₂ O); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -140.94; MS (IER ⁺ ): MS (IER+) 240.1 (M+Na), MS (IER-) 216.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (36b).

In a 250 mL one-neck flask containing a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxylic acid (9i) (1.263 g, 4.49 mmol), (3-amino-2-fluorophenyl) (phenyl)methanol (36a) (0.813 g, 3.74 mmol) in N,N-dimethylformamide (DMF) (22.60 ml, 292 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop, 2.094 g, 4) was added successively .49 mmol) and N-ethyl-Nisopropylpropan-2-amine (DIPEA) (3.26 mL, 18.71 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours, diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The resulting residue was purified twice by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(2-fluoro-3(hydroxy(phenyl)methyl) )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (36b) (1.378 g, 77% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 8.17 - 8.10 (m, 1H), 7.99 (dt, J=7.7, 1.3 Hz , 1H), 7.89 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.46 (t, J=7 ,1 Hz, 2H), 7.39 - 7.27 (m, 4H), 7.26 - 7.15 (m, 2H), 6.09 (d, J=4.3 Hz, 1H, exchange with D2O), 5.93 (d, J=3.7 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -61.00, -127.24; MS (IER ⁺ ): MS (IER+) 503.1 (M+Na), MS (IER-) 479.1 (M-1); IR (KBr, cm ^-1 ): 2235 cm ^-1 (stretching vibrations of CN).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (3 6c).

Into a solution of 1 -(3-cyanophenyl)-N-(2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 Hpyrazole-5-carboxamide (36b) (0.193 g, 0.402 mmol ) ytterbium(III) trifluoromethanesulfonate (0.498 g, 0.803 mmol) was added to cyclopropylmethanol (2.89 ml, 40.2 mmol) and heated at 80°C for 16 hours. Excess solvent was siphoned off, diluted with chloroform (2x50 ml) and filtered through a Celite backing. Concentrate the filtrate in vacuo and the resulting residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (36c) (63 mg, 29% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 8.17 - 8.08 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz , 1H), 7.94 - 7.87 (m, 1H), 7.78 7.68 (m, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.42 - 7 .31 (m, 5H), 7.29 - 7.17 (m, 2H), 5.72 (s, 1H), 3.27 (d, J=6.8 Hz, 2H), 1.09 - 1.02 (m, 1H), 0.52 - 0.42 (m, 2H), 0.20 - 0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.99, 126.92; MS (IER ⁺ ): MS (IER+) 557.16 (M+Na), (IER-) 533.22 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (3 6d ).

Into a stirred solution of 1-(3-cyanophenyl)-M-(3-((cyclopropylmethoxy)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (36c) (0.060 g, 0.112 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.027 g, 0.112 mmol) and sodium borohydride (0.025 g, 0.674 mmol) were added in small portions over 5 min. The reaction mixture was stirred for 15 minutes and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 2x12 g, eluted with methanol/chloroform, 0-100%)] to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)() phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (36d) (24 mg, 40% yield) as a white solid; 1H NMR (300 MHz, DMSO^) δ 7.58 (s, 1H), 7.55-7.49 (m, 2H), 7.46 - 7.40 (m, 2H), 7.40 - 7 .30 (m, 6H), 7.30 -7.18 (m, 2H), 5.72 (s, 1H), 3.78 (s, 2H), 3.27 (d, J=6.8 Hz, 2H), 1.12 - 0.98 (m, 1H), 0.54 - 0.41 (m, 2H), 0.15 (ddd, J=5.5, 4.7, 3.6 Hz, 2H); 1H NMR (300 MHz, DMSO-d ₆ D ₂ O) δ 7.54 (s, 1H), 7.51 - 7.44 (m, 4H), 7.43 - 7.39 (m, 1H), 7.36 (d, J=4.5 Hz, 5H), 7.31 - 7.21 (m, 2H), 5.72 (s, 1H), 3.76 (s, 2H), 3.27 (d, J=6.8

- 105 045731

Hz, 2H), 1.13 - 0.98 (m, 1H), 0.56 - 0.40 (m, 2H), 0.15 (dt, J=4.4, 2.8 Hz, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.76, -127.15; MS (IER ⁺ ): MS (IER+) 539.2 (M+1), MS (IER-) 537.2 (M-1), 573.1 (M+Cl).

Scheme 37

34 _C 37a = (+)-isomer

37b = (-)-isomer

An example of the preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (37a ) and (-)-1-(3-(aminomethyl)phenyl)-N-(5((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 37b)

1-(3-(Aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (34c) (1 .24 g) was purified by chiral separation by HPLC using a Chiral AD-H column (80/20/0.1 hexane/ethanol/TEA), 0.8 ml/min, UV 260 nm, cycle 20 min (temperature 20° C) with receipt:

1. (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (37a) (213 mg, ee=18.32%), Rt=14.453 [40.8415% (-)-isomer]; Rt=15.713 [59.1585%, (+)-isomer]. The resulting material was purified again by flash column chromatography (silica gel, 2x12 g, eluted with 0-100% ethyl acetate/methanol (9:1) in hexanes) to give 45 mg of pure product; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H, exchange with D2O), 7.58 (d, J=7.0 Hz, 2H), 7.51 (s, 1H), 7.47-7.40 (m, 2H), 7.33 (d, J=4.3 Hz, 5H), 7.25 (dd, J=8.3, 3.8 Hz, 3H), 5 .47 (s, 1H), 3.77 (s, 2H), 3.22 (d, J=6.8 Hz, 2H), 1.03 (dd, J=11.7, 5.5 Hz, 1H), 0.56-0.39 (m, 2H), 0.22-0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73, -122.98; MS (ESI+) 539.2 (M+1), 537.2 (M-1), 573.1 (M+Cl);

2. (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (37b) (55 mg, ee=37.8%), Rt=14.433 [68.9002%, (-)-isomer], Rt=15.793 [31.0998, (+)-isomer]. The resulting material was purified again by flash column chromatography (silica gel, 4 g, eluted with chloroform/methanol (1:0 to 9:1)) to give 12.3 mg of pure product, [a]D=-3.90 [CH ₃ OH, 0.615].

Scheme 38

38s

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (38d).

Step 1. Preparation of X-(5-(chloro(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (38a).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (34a) (0.462 g, 0.962 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (0.211 ml, 2.89 mmol) and leave to warm to room temperature for 3 hours. Concentrate the reaction mixture to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give N-(5-(chloro(phen)

- 106 045731 nil)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (38a) (0.208 g, 0.417 mmol, 43.4% yield) as a pale yellow oily solid; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (t, J=1.6 Hz, 1H), 8.02 (d, J=1.8 Hz, 2H), 7.88 (dd, J =7.2, 2.3 Hz, 1H), 7.83 - 7.78 (m, 3H), 7.77 - 7.73 (m, 1H), 7.64 (ddd, J=8.9 , 4.9, 2.3 Hz, 1H), 7.48 (dd, J=10.0, 8.7 Hz, 1H), 7.32 (dt, J=4.3, 1.1 Hz, 4H), 6.57 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -61.09, -121.678; MS (IER+) 534.2 (M+1); (IER-) 533.2 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 3 8b).

In a solution of N-(5-(chloro(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (38a) (0.17 g, 0.341 mmol ) cyclopropylmethanamine (0.591 mL, 6.82 mmol) was added to THF (10 mL) and heated at reflux temperature overnight. Additional cyclopropylmethanamine (0.591 ml, 6.82 mmol) was added and heated at reflux temperature for 48 hours. The reaction was quenched with water (10 ml) and the mixture was extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with brine (10 ml), dried, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-M-(5-(((cyclopropylmethyl)amino)(phenyl)methyl) -2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (38b) (0.12 g, 0.225 mmol, 66.0% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.15-8.10 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz , 1H), 7.94 - 7.86 (m, 1H), 7.77 - 7.69 (m, 2H), 7.57 (d, J=7.0 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.36 - 7.15 (m, 6H), 4.84 (s, 1H), 2.26 (d, J=6.3 Hz, 2H), 0.98 - 0.83 (m, 1H), 0.43 0.31 (m, 2H), 0.04 (dd, J=5.3, 3.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -61.06, -123.36; MS (IER+) 534.2 (M+1); (IER-) 533.2 (M-1).

Step 3. Preparation of tert-butyl-3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (38c).

Into a stirred solution of 1-(3-cyanophenyl)-M-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (38b) (0 .12 g, 0.225 mmol) in anhydrous methanol (10 ml), cooled to 0°C, added di-tert-butyl dicarbonate [(Boc) ₂ O] (0.196 g, 0.900 mmol), nickel (II) chloride hexahydrate (0.013 g, 0.056 mmol). Sodium borohydride (0.051 g, 1.350 mmol) was added to the reaction mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.126 mL, 1.163 mmol) and stirred for 30 min, after which the solvent was evaporated in vacuo. The residue was treated with water (15 ml) and extracted with ethyl acetate (2x25 ml). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 12 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give tert-butyl-3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (38c) (0.12 g, 0.188 mmol, 32.4% yield) as a colorless oily liquid; 1H NMR (300 MHz, DMSO^) δ 10.55 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, J=12.6, 6.1 Hz, 1H), 7.45 - 7.25 (m, 10H), 7.22 - 7.15 (m, 2H), 4.84 (s, 1H), 4 .19 (d, J=6.2 Hz, 2H), 2.26 (d, J=6.5 Hz, 2H), 1.39 (s, 9H), 0.92 (dd, J=13, 7, 5.7 Hz, 1H), 0.43 - 0.31 (m, 2H), 0.04 (td, J=5.6, 4.9, 2.1 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, -123.76; MC (IER+) 638.3 (M+1); (IER-) 636.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 38d).

Into a solution of tert-butyl-3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (38c) (0.12 g, 0.188 mmol) in methanol (5 ml) was added HCl (0.286 ml, 9.41 mmol) and stirred at reflux temperature for 2 hours. The reaction mixture was concentrated to dryness in vacuo. Trace amounts of HCl and water were removed by vacuum distillation as an azeotrope with ethanol (10 mL) and toluene (10 mL). The residue was dried using a vacuum pump and purified by flash column chromatography (silica gel, 8 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-M-(5(((cyclopropylmethyl )amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (38d) (0.044 g, 0.082 mmol, 43.5% yield) as a light yellow solid ; 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.71 (s, 1H), 7.70 - 7.58 (m, 2H), 7.60 - 7.48 ( m, 3H), 7.47 - 7.33 (m, 3H), 7.34 7.25 (m, 3H), 7.20 (dd, J=8.4, 5.7 Hz, 2H), 4.94 (s, 1H), 4.12 (s, 2H), 2.32 (d, J=6.7 Hz, 2H), 1.01 - 0.86 (m, 1H), 0.45 - 0.34 (m, 2H), 0.13 - 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.83; -123.36; MS (IER+) 538.3 (M+1); (IER-) 536.1 (M-1), 572.2 (M+Cl); analysis, calculation for C ₂ 9H ₂ 7F ₄ N ₅ O 1.25HCl-H2O: C, 57.94; H, 5.07; Cl, 7.37; N, 11.65; experiment: C, 58.12; H, 4.99; Cl, 7.40; N, 11.34.

- 107 045731

Scheme 39

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(2-cyano-1-phenylethyl)phenyl)-3-trifluoromethyl)1H-pyrazole-5-carboxamide (39e).

Step 1. Preparation of (E/Z)-3-(3-aminophenyl)-3-phenylacrylonitrile (39b).

To a suspension of NaH (0.507 g, 12.68 mmol) in DME (10 ml) was added diethyl cyanomethylphosphonate (39a) (1.835 ml, 11.66 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. A solution of (3-aminophenyl)(phenyl)methanone (18a) (1 g, 5.07 mmol) in DME (10.00 ml) was added to the reaction mixture at 0° C and stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 ml) at 0°C, and the mixture was extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with water (2x50 ml), brine (50 ml), dry, filter and concentrate in vacuo. The residue was purified by flash column chromatography (silica gel, 40 g) to give (E/Z)-3-(3-aminophenyl)-3-phenylacrylonitrile (39b) (1.1 g, 98%); MS (ESI+) 243.1 (M+Na); (IER-) 219.1 (M-1).

Step 2. Preparation of 3-(3-aminophenyl)-3-phenylpropanenitrile (39c).

To a suspension of Pd/C (10%) (0.012 g, 0.113 mmol) in methanol (30 ml) was added (E/Z)-3-(3aminophenyl)-3-phenylacrylonitrile (39b) (0.25 g, 1.135 mmol) and hydrogenated at 60 psi (414 kPa) for 14 hours. The reaction mixture was filtered through a pad of Celite and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give 3-(3-aminophenyl)-3phenylpropanenitrile (39c) (180 mg, 71.3%); MS (ESI+) 245.1 (M+Na); (IER-) 221.1 (M-1).

Step 3. Preparation of tert-butyl-3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3-(trifluoromethyl)1I-pyrazol-1-yl)benzylcarbamate (39d).

A solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (144 mg, 0.375 mmol) in N,N-dimethylformamide (2.5 ml) 3-(3aminophenyl)-3-phenylpropanenitrile (39c) (100 mg, 0.45 mmol), N-ethyl-N-isopropylpropan-2-amine (0.522 ml, 3.00 mmol) and bromo-tris hexafluorophosphate were added -pyrrolidinophosphonium (PyBroP, 192 mg, 0.412 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (100 ml, 50 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of ethyl acetate in hexane, 0-100%) to give tert-butyl-3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)- 3-(trifluoromethyl)-1I-pyrazol-1-yl)benzylcarbamate (39d) (180 mg, 81% yield) as a colorless solid; MS (IER+) 612.2 (M+Na); (IER-) 588.8 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(2-cyano-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1 N-pyrazole-5-carboxamide (39e).

Into a stirred solution of tert-butyl 3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3(trifluoromethyl)-1I-pyrazol-1-yl)benzylcarbamate (39d) (0.090 g, 0.153 mmol ) in acetonitrile (4 ml) was added 4N. hydrochloric acid in 1,4-dioxane (0.763 ml, 3.05 mmol), stirred at room temperature for 3 hours and concentrated to dryness in vacuo. The residue was suspended in diethyl ether (30 ml) and the isolated solid was collected by filtration, dried in vacuo to give 1-(3-(aminomethyl)phenyl)-N-(3-(2-cyano-1-phenylethyl)phenyl)- 3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (39e) (70 mg, 94% yield); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 8.38 (s, 3H, exchange with D2O), 7.72 (t, J=1.7 Hz, 1H), 7.66 (s, 1H), 7.64 -7.47 (m, 5H), 7.33 (d, J=4.1 Hz, 5H), 7.26 - 7.19 (m, 2H) , 4.42 (t, J=8.0 Hz, 1H), 4.12 (q, J=5.8 Hz, 2H), 3.31 (d, J=8.0 Hz, 2H); MS (IER+) 490.3 (M+1), (IER) 488.2 (M-1), 524.2 (M+35).

- 108 045731

Scheme 40

An example of the preparation of N-(3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (40b).

Step 1. Preparation of tert-butyl-3-(5-((3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-carbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (40a).

Into a stirred solution of tert-butyl 3-(5-(3-(2-cyano-1-phenylethyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (39d) (0.07 g, 0.119 mmol) in MeOH (4 ml), cooled to 0°C, added conc. NH ₄ OH (0.826 ml, 5.94 mmol), 35% hydrogen peroxide solution (1.559 ml, 17.81 mmol) and stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with mixtures of 0-100% (9:1) ethyl acetate and methanol in hexanes] to give tert-butyl3-(5-(3- (3-amino-3-oxo-1-phenylpropyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (40a) (47 mg, yield: 65.2%); MS (ESI+) 630.3 (M+Na); (IER-) 606.3 (M-1).

Step 2. Preparation of N-(3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (40b ).

Into a stirred solution of tert-butyl 3-(5-(3-(3-amino-3-oxo-1-phenylpropyl)phenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (40a) (0.040 g, 0.066 mmol) in methanol (3 ml) was added conc. HCl (0.110 mL, 1.317 mmol) and heated at reflux temperature for 30 min. The reaction mixture was concentrated to dryness in vacuo. The residue was suspended in diethyl ether and the isolated solid was collected by filtration and dried in vacuo. The solid was purified by flash column chromatography (silica gel, 4 g, eluted with 0 to 20% methanol/chloroform mixtures to give N-(3-(3-amino-3-oxo-1-phenylpropyl)phenyl)-1 -(3(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (40b) (15 mg, 44.9% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.72 (s, 1H, exchange with D2O), 7.67 (s, 1H), 7.62 (s, 1H), 7.60 - 7.43 (m, 5H), 7.39 (s, 1H), 7.30 - 7.21 (m, 5H), 7.17 (d, J=6.7 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.77 (s, 1H), 4.42 (s, 1H), 4.05 (s, 2H), 2.78 (dd, J=7.9, 3 ,6 Hz, 2H); MS (IER+) 508.3 (M+1), (IER-) 542.2 (M+35).

Scheme 41

- 109 045731

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41e) .

Step 1. Preparation of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41a).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (5.42 g, 19.27 mmol) in DMF (100 ml) at room temperature was added (3 -aminophenyl)(phenyl)methanone (18a) (3.8 g, 19.27 mmol), N-ethyl-N-isopropylpropan-2-amine (27 ml, 155 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop) (9 .42 g, 19.42 mmol). The resulting reaction mixture was stirred at room temperature for 39 hours under a nitrogen atmosphere and diluted with ethyl acetate (600 ml). The reaction mixture was washed with water (2x300 ml), brine (200 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give N(3-benzoylphenyl)-1(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (41a) (4.704 g, 53%) as a white solid containing (3-aminophenyl)(phenyl)methanone; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 8.20 (t, J=1.9 Hz, 1H), 8.07 - 7.98 (m, 3H), 7.93 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 - 7.71 (m, 4H), 7.62 -7.57 (m, 2H), 7.56 (d, J=3.2 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 7.50 (dt, J=7.7, 1.5 Hz, 1H ); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.98.

Step 2. Preparation of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (41b).

Into a stirred solution of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (41a) (4.704 g, 10.22 mmol) in anhydrous methanol (100 ml), cooled to 0°C, di-tert-butyl dicarbonate [(Boc) ₂ O] (6.76 g, 30.7 mmol), nickel (II) chloride hexahydrate (0.5 g, 2.103 mmol) was added. Sodium borohydride (2.367 g, 61.3 mmol) was added portionwise to the reaction mixture over 45 minutes. The reaction mixture was stirred for 15 min at room temperature and the reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (2.3 mL, 21.08 mmol). The mixture was stirred for 30 minutes and concentrated to dryness in vacuo. The resulting residue was treated with water (200 ml) and extracted with ethyl acetate (400 and 150 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography [(silica gel, 120 g, eluted with ethyl acetate/hexanes, 0 to 100%)] to give N(3-benzoylphenyl)-1-(3-cyanophenyl)3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (41b) (2.71 g, 46.8%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.59 - 7.39 (m, 5H), 7 ,38 - 7.17 (m, 8H), 7.13 (dt, J=7.6, 1.3 Hz, 1H), 5.94 (d, J=3.8 Hz, 1H), 5, 66 (d, J=3.9 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 1.37 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.81; MS (ESI+) 589.26 (M+Na).

Step 3. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (41d).

A solution of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41b) (0.142 g, 0.25 mmol) in dichloromethane (2.5 ml ) at 0°C, add thionyl chloride (0.073 ml, 0.999 mmol) and leave to warm to room temperature for 3 hours. To the reaction mixture containing tert-butyl-3-(5-((3-(chloro(phenyl)methyl)phenyl )carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (41c), cyclopropylmethanamine (0.217 mL, 2.500 mmol) was added and stirred at room temperature overnight. TLC analysis indicated the presence of tert-butyl 3-(5-((3(chloro(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (41c) only. Dichloromethane (5 mL) and additional cyclopropylmethanamine (0.217 mL, 2.5 mmol) were added to the reaction mixture and heated at reflux temperature overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml), washed with water (10 ml), dried, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl) -1H-pyrazol1-yl)benzylcarbamate (41d) (0.07 g, 0.113 mmol, 45.2% yield), which was of sufficient purity to be used as such in the next step; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.48 (m, 2H), 7.44 - 7.33 (m, 7H), 7.31 - 7.23 (m, 2H), 7.22 -7.16 (m, 2H), 4, 81 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.24 (d, J=6.6 Hz, 2H), 1.36 (d, J=2.1 Hz, 9H), 0.94 (d, J=10.3 Hz, 1H), 0.41 - 0.34 (m, 2H), 0.09 - 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.80; MS (IER+) 620.4 (M+1); (IER-) 618.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41e ).

In a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (41d) (0.07 g, 0.113 mmol) in methanol (5 ml) was added conc. HCl (0.069 ml, 2.259 mmol) and stirred at room temperature overnight, then heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo. Trace amounts of HCl and water were removed by vacuum distillation as an azeotrope with

- 110 045731 ethanol (10 ml) and toluene (10 ml). The residue was dried using a vacuum pump and purified by flash column chromatography (silica gel, 8 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-((( cyclopropylmethyl)amino)(phenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (41e) (0.031 g, 0.060 mmol, 52.8% yield) as a yellow hygroscopic solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.59 - 7.48 (m, 3H), 7.47 - 7.36 (m, 4H), 7.36 - 7.23 (m, 4H), 7.23 -7.14 (m, 2H), 4.81 (s, 1H), 3, 79 (s, 2H), 2.38 (d, J=6.7 Hz, 2H), 0.99 - 0.86 (m, 1H), 0.42 - 0.34 (m, 2H), 0 .04 (td, J=5.5, 3.9 Hz, 2H); ¹⁹ F NMR (282 MHz,

DMSO-d ₆ ) δ -60.72; MC (IER+) 520.3 (M+1); (IER-) 518.2 (M-1). Scheme 42

An example of the preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (42a) and (-)-1-(3-(aminomethyl)phenyl)-N-(5(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (42b).

An example of the preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (42a) and (-)-1-(3-(aminomethyl)phenyl)-N5(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (42b).

1-(3-(Aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (38d) (1.09 g) was purified using the preparative SFC method under the following conditions.

Column 3.0 x 25.0 cm, ChiralPak AD-H from Chiral Technologies (West

Chester, PA)

Co-solvent CCh (solvent B) methanol:acetonitrile (1:1) with 1%

isopropylamine Isocratic method System pressure Column temperature Sample diluent Purification resulted in: 30% cosolvent, flow rate 80 ml/min 200 bar (20 MPa) 40°C methanol:acetonitrile (~2:1)

1. (-)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5 -carboxamide (42b) (463 mg, ee 99.9%); 1H NMR (300 MHz, methanol-d^δ

7.74 (d, J=7.3 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J=4.9 Hz, 2H), 7.43 - 7.26 (m , 6H), 7.24 - 7.17 (m, 1H), 7.12 (t,

J=9.4 Hz, 1H), 3.85 (s, 2H), 3.21 (s, 1H), 2.37 (d, J=6.9 Hz, 2H), 1.04 - 0, 90 (m, 1H), 0.51 - 0.42 (m, 2H), 0.11 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, methanol^) δ -63.73, -127.27; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s,

1H), 7.61 (d, J=7.4 Hz, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.47 - 7.36 (m, 4H), 7.35- 7.25 (m, 4H), 7.19 (tt, J=7.3,

2.7 Hz, 2H), 4.83 (s, 1H), 3.77 (s, 2H), 2.26 (d, J=6.6 Hz, 2H), 1.03 - 0.72 ( m, 1H), 0.46 - 0.25 (m, 2H), 0.12 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73, -123.86; MS (IER+) 538.3 (M+1); (IER-) 536.3 (M1); optical rotation -4.95 (MeOH, 1.415).

Into a solution of the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (42b) (0.44 mg, 0.82 mmol) in methanol (4 ml) was added 2N. a solution of HCl in methanol (4 ml, prepared from methanol and conc. HCl, 4 mmol). The mixture was left to settle for 15 minutes at room temperature, concentrated to dryness in vacuo to obtain (-)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)- dihydrochloride 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (42b) (0.46 g); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.84 (s, 1H, 10.30 (d, J=16.0 Hz, 2H), 8.52 (s, 3H), 7.95 (dd , J=7.2, 2.3 Hz, 1H), 7.80 7.69 (m, 5H), 7.64 (dt, J=7.2, 1.7 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.47 - 7.33 (m, 4H), 5.74 - 5.59 (m, 1H), 4.12 (d,

J=5.0 Hz, 2H), 2.69 (d, J=6.6 Hz, 2H), 1.24 - 1.09 (m, 1H), 0.61 - 0.50 (m, 2H ), 0.36 - 0.23 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81, -120.59; MS (IER+) 538.3 (M+1); (IER-) 536.2 (M-1); analysis, calculation for

C29H27FзN5O 2HCl H2O: C, 55.42; H, 4.97; Cl, 11.28; N, 11.14; experiment: C, 55.45; H, 5.13; Cl, 11,12; N,

- 111 045731

11.15.

2. (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5 -carboxamide (42a) (461 mg, ee 95.1%), containing an impurity of isopropylamine; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.59 (d, J=7.3 Hz, 1H), 7.51 (s, 1H), 7.45-7.09 (m, 11H), 4.81 (d, J=3.2 Hz, 1H), 3.76 (s, 2H), 2.26 (d, J=6.6 Hz, 2H), 0.92 (d, J=7 .7 Hz, 1H), 0.44 - 0.31 (m, 2H), 0.04 (td, J=5.5, 5.0, 1.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.68, -124.17; ¹ H NMR (300 MHz, methanol-d4) δ 7.65 (d, J=7.3 Hz, 1H), 7.51 (s, 1H), 7.45-7.39 (m, 3H), 7.34 (d, J=7.2 Hz, 2H), 7.29 - 7.23 (m, 4H), 7.19 - 7.14 (m, 1H), 7.11 - 7.02 ( m, 1H), 4.84 (s, 1H), 3.81 (s, 2H), 2.33 (d, J=6.9 Hz, 2H), 1.02 - 0.85 (m, 1H ), 0.49 - 0.38 (m, 2H), 0.09 - -0.00 (m, 2H); ¹⁹ F NMR (282 MHz, methanol-d^ δ -63.71, -127.26; MS (ESI+) 538.2 (M+1); (ESI-) 536.2 (M-1); optical spin +2.77 (MeOH, 1.95).

Into a solution of the free base obtained above (+)-1-(3-(aminomethyl)phenyl)-N(5(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (42a) (0.44 mg, 0.82 mmol) in methanol (4 ml) was added 2N. a solution of HCl in methanol (4 ml, prepared from methanol and conc. HCl, 4 mmol). The mixture was left to settle for 15 minutes at room temperature, concentrated to dryness in vacuo to obtain (+)-1-(3-(aminomethyl)phenyl)-N(5(((cyclopropylmethyl)amino)(phenyl)methyl)-2- dihydrochloride fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (42a) (0.46 g); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.84 (s, 1H), 10.24 (d, J=20.4 Hz, 2H), 8.52 (s, 3H), 7.95 ( dd, J=7.1, 2.3 Hz, 1H), 7.79 - 7.69 (m, 5H), 7.64 (dt, J=7.2, 1.8 Hz, 1H), 7 .59 - 7.48 (m, 2H), 7.47 - 7.33 (m, 4H), 5.66 (t, J=6.3 Hz, 1H), 4.12 (q, J=5 ,7 Hz, 2H), 2.68 (d, J=10.8 Hz, 2H), 2.12 (s, 1H), 1.24 - 1.12 (m, 1H), 0.63 0, 48 (m, 2H), 0.36 - 0.24 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.81, -120.62; MS (IER+) 538.3 (M+1);

(IER-) 536.2 (M-1); analysis, calculation for C29H27F3N5O-2.25HCH,25H2O-0.5C3H9N: C, 54.54; H, 5.44; Cl,

11.88; N, 11.47; experiment: C, 54.34; H, 5.64; Cl, 12.12; N, 11.78.

The following analytical SFC method was used to verify the purity of compounds 42a and 42b:

Column

Co-solvent CO2 (solvent B)

Isocratic way

System pressure Column temperature Sample diluent

4.6 x 100 mm ChiralPak AD-H from Chiral Technologies (West Chester, PA) methanol:acetonitrile (1:1) with 0.1% isopropylamine

20% cosolvent, flow rate 4 ml/min

150 bar (15 MPa)

40°C methanol

Fraction 1 (42b) 1.6 min (Rt) 463 mg

Fraction 2 (42a) 2.9 min (Rt) 461 mg

99.9% (e.i.) 97.1% (purity)

95.1% (e.i.) 96.5% (purity)

Scheme 43

DIPEA

NaBH ₄ NiCI ₂ 6H ₂ O

HCl

43g = (-)-isomer 43h = (+)-isomer

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43f); (-)-1-(3-(aminomethyl)phenyl)-N-(3((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43g )

- 112 045731 and (+)-1 -(3 -(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3 -(trifluoromethyl)- 1 H-pyrazole -5-carboxamide (43h)

Step 1. Preparation of (3-nitrophenyl)(pyridin-2-yl)methanol (43b).

To a solution of 2-bromopyridine (43a) (2.9 ml, 29.8 mmol) in diethyl ether (20 ml) at -78°C, n-BuLi (19.00 ml, 30.4 mmol) was added dropwise and stirred for 30 min at -78°C. A solution of 3-nitrobenzaldehyde (31a) (4.50 g, 29.8 mmol) in THF (30 ml) was added dropwise to the 2-lithium-containing pyridine at -78°C and stirred at -78°C for 2 hours and at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (75 ml). Combine the organic layers, wash with brine (60 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-nitrophenyl)(pyridin-2-yl)methanol (43b) (1.246 g, 18%) in as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.27 (t, J=2.0 Hz, 1H ), 8.10 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.92 - 7.76 (m, 2H), 7.68 - 7.59 (m, 2H ), 7.26 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 6.48 (d, J=4.5 Hz, 1H), 5.89 (d, J= 4.2 Hz, 1H); MS (IER+): 231.1 (M+1).

Step 2. Preparation of (3-aminophenyl)(pyridin-2-yl)methanol (43c).

To a solution of (3-nitrophenyl)(pyridin-2-yl)methanol (43b) (1.152 g, 5.00 mmol) in methanol (30 ml), cooled to 0°C, was added nickel (II) chloride hexahydrate (0.297 g , 1.251 mmol), then sodium borohydride (0.773 g, 20.02 mmol) in parts over 30 minutes. The reaction mixture was stirred at room temperature for 30 min, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.100 mL, 10.18 mmol), stirred for another 30 min and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (150 ml), washed with water (75 ml). The aqueous phase was again extracted with ethyl acetate (75 ml). The combined extracts were washed with brine (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 0:1)] to give (3aminophenyl)(pyridin-2-yl)methanol (43c) (746 mg, 75%) as light yellow viscous substance. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.43 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 7.75 (td, J=7.7, 1, 8 Hz, 1H), 7.50 (dt, J=8.0, 1.1 Hz, 1H), 7.21 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 6.90 (t, J=7.7 Hz, 1H), 6.60 (dd, J=2.3, 1.6 Hz, 1H), 6.56 -6.50 (m, 1H), 6 .37 (ddd, J=7.9, 2.4, 1.1 Hz, 1H), 5.88 (d, J=4.0 Hz, 1H), 5.51 (d, J=4.0 Hz, 1H), 5.00 (s, 2H); MS (IER+): 223.1 (M+23).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43d).

To a solution of (3-aminophenyl)(pyridin-2-yl)methanol (43c) (0.983 g, 3.50 mmol) in N,Ndimethylformamide (30 ml) was added 1-(3-cyanophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxylic acid (9i) (0.983 g, 3.50 mmol), N-ethyl-N-isopropylpropan-2-amine (4.90 ml, 28.1 mmol) and bromo-hexafluorophosphate (V) tripyrrolidin-1-ylphosphonium (1.676 g, 3.52 mmol) at room temperature. The reaction mixture was stirred at 25°C for 13 hours and diluted with ethyl acetate (200 ml). The reaction mixture was washed with water (2x100 ml), brine (75 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 0:1)] to give 1 -(3 -cyanophenyl)-N-(3 -(hydroxy(pyridinium- 2-yl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-5 carboxamide (43d) (1.049 g, 65%) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.44 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.16 (dd , J=2.1, 1.4 Hz, 1H), 8.01 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2 , 1.1 Hz, 1H), 7.81 - 7.65 (m, 4H), 7.59 - 7.52 (m, 2H), 7.30 - 7.15 (m, 3H), 6, 16 (d, J=4.0 Hz, 1H), 5.68 (d, J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.95; MS (IER+): 464.2 (M+1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (43e).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (43d) (0.48 g, 1.036 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.240 ml, 3.29 mmol) and leave to warm to room temperature for 2 hours. The reaction is quenched with triethylamine (1.3 ml, 9.33 mmol) and the mixture is stirred at room temperature for 1 hour. Cyclopropylmethanol (8.00 mL, 97 mmol), triethylamine (1.300 mL, 9.33 mmol) was added to the chlorine compound and concentrated in vacuo to remove most of the dichloromethane. Triethylamine (1.3 mL, 9.33 mmol) was added to the reaction mixture and heated at 70°C for 14 hours and at 100°C for 6 hours. The reaction mixture was diluted with ethyl acetate and filtered. Concentrate the filtrate in vacuo and purify the residue by flash column chromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to 2:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy) (pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43e) (231 mg, 43%) as a light brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.29 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 8.00 (t , J=1.8 Hz, 1H), 7.89 - 6.95 (m, 11H), 5.30 (s, 1H), 3.11 (d, J=6.8 Hz, 2H), 0 .98 - 0.80 (m, 1H), 0.38 - 0.21 (m, 2H), 0.08 - -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.97; MS (IER+): 540.2

- 113 045731 (M+23).

Step 5. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy)(pyridin-2yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43f ).

In a solution of 1-(3-cyanophenyl)-M-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43e) (30 mg , 0.058 mmol) in MeOH (2 mL), cooled in ice/water, nickel(II) chloride hexahydrate (3.0 mg, 0.013 mmol) was added, then sodium borohydride (14.00 mg, 0.363 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 1 hour, quenched with N-(2-aminoethyl)ethane-1,2-diamine (0.015 ml, 0.133 mmol), stirred at room temperature for 0.5 hour and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (100 ml), washed with water (50 ml). The aqueous phase was again extracted with ethyl acetate (50 ml). The organic extracts were combined, washed with brine (50 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/methanol (1:0 to 9:1)] to give the racemate 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy )(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43f) (14 mg, 46%) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.48-8.44 (m, 1H), 7.93 - 7.04 (m, 12H), 5.46 ( s, 1H), 3.77 (s, 2H), 1.14 0.99 (m, 1H), 0.53 - 0.41 (m, 2H), 0.20 - 0.11 (m, 2H ); ¹ H NMR (300 MHz, DMSO-d6, exchange with D ₂ O) δ 8.48 8.43 (m, 1H), 7.91 - 7.03 (m, 12H), 5.46 (s, 1H ), 3.77 (s, 2H), 3.28 (d, J=6.8 Hz, 2H), 1.14-0.96 (m, 1H), 0.53 0.43 (m, 2H ), 0.22 - 0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-46) δ -60.73; MS (IER+): 522.3 (M+1).

Into a solution of 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (43f) ( 193 mg, 0.37 mmol) in acetone (10 ml) added conc. HCl (0.123 ml, 1.480 mmol) and concentrated to dryness in vacuo. The residue was dried in vacuo to remove excess HCl and dissolved in IPA (2 ml) and heated until dissolved. Diethyl ether (40 ml) was added to the homogeneous solution and heated at reverse condensation temperature for 30 min. After cooling to room temperature, the resulting solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 1-(3-(aminomethyl)phenyl)N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl) dihydrochloride phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (43f) (0.227 g, 0.382 mmol, 103% yield) as a white solid; 1H NMR (300 MHz, deuterium oxide) δ 8.54 - 8.48 (m, 1H), 8.25 (td, J=8.0, 1.6 Hz, 1H), 7.72 (ddd, J =7.6, 5.8, 1.3 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.44 (t, J=2.5 Hz, 4H), 7 .42 - 7.35 (m, 1H), 7.34 - 7.24 (m, 3H), 7.14 (dt, J=7.0, 1.8 Hz, 1H), 5.82 (s , 1H), 4.07 (s, 2H), 3.46 - 3.31 (m, 1H), 3.28 (m, 1H), 0.99 - 0.88 (m, 1H), 0, 41 - 0.25 (m, 2H), 0.07 - -0.07 (m, 2H); ¹⁹ F NMR (282 MHz, D2O) δ -62.34; MS (IER-) 520.3 (M-1); analysis, calculation for C ₂ 8Н^з^О ₂ -1.9НС1-Н ₂ О: C, 55.24; H, 4.95; Cl, 11.06; N, 11.50; experiment: C, 55.59; H, 5.19; Cl, 10.91; N, 10.83.

Step 6. Preparation of (-)-1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy)(pyridin-2yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (43g) and (+)-1-(3-(aminomethyl)phenyl)-N(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (43h).

1-(3-(Aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (43f) (158 mg) were separated by chiral preparative HPLC using a CHIRALPAK AD-H chiral column, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 90% hexane/10% EtOH/0.1% DEA, UV=254 nm , with receiving:

1. (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (43g) (0.066 g, ee 98.2%, Rt=10.432 min). The resulting product was purified again by flash column chromatography (silica gel, 12 g, eluted with 025% methanol/chloroform mixtures for 13 minutes) to give 50 mg of pure (-)-1-(3(aminomethyl)phenyl)-N-(3 -((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (43g); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 8.50 - 8.43 (m, 1H), 7.81 (td, J=7.7, 1.8 Hz , 1H), 7.65 (t, J=1.8 Hz, 1H), 7.61 - 7.49 (m, 4H), 7.47 - 7.38 (m, 2H), 7.34 - 7.23 (m, 3H), 7.19 7.10 (m, 1H), 5.46 (s, 1H), 3.78 (s, 2H), 3.28 (dd, J=6.8 , 1.2 Hz, 2H), 2.37 - 2.09 (m, 2H), 1.15 - 0.98 (m, 1H), 0.56 - 0.33 (m, 2H), 0, 27 - 0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.71; MS (IER+) 522.3 (M+1); (IER-) 556.3 (M+Cl); optical rotation -11.04 (MeOH, 2.5); analysis, calculation for C ₂₈ H ₂₆ F ₃ N ₅ O ₂ -0.5H ₂ O: C, 63.39; H, 5.13; N, 13.20; experiment: C, 63.18; H, 5.13; N, 12.83; chiral purity was confirmed by chiral HPLC using CHIRALPAK AD-H, 5 µm, 25 cm, 0.8 ml/min, solvent: 75% hexane/24% EtOH/0.1% TEA, UV=260 nm, cycle 14 min , Rt=6.157 min (1 peak, 43g, 100%) 9.32 (2 peak, 43h, 0%);

2. (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (43h) (0.071 g, ee 98.8%, Rt=18.373 min). The resulting product was purified again by flash column chromatography (silica gel, 12 g, eluted with 025% methanol/chloroform mixtures for 13 minutes) to give 40 mg of pure (+)-1-(3(aminomethyl)phenyl)-N-(3 -((cyclopropylmethoxy)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (43h); 1H NMR (300 MHz, DMSO- _d6 ) δ 10.56 (s, 1H), 8.37 - 8.24 (m, 1H), 7.64 (td,

- 114 045731

J=7.7, 1.8 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.44 - 7.32 (m, 4H), 7.31 - 7.21 (m, 2H), 7.19 - 7.05 (m, 3H), 6.98 (d, J=7.6 Hz, 1H), 5.29 (s, 1H), 3.61 (s, 2H), 1.00 - 0.79 (m, 1H), 0.44 - 0.18 (m, 2H), 0.13 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.71; MS (IER+) 522.3 (M+1); (IER-) 556.3 (M+Cl); analysis, calculation for C ₂₈ H ₂₆ F ₃ N ₅ O ₂ -0.75H ₂ O: C, 62.85; H, 5.18; N, 13.09; experiment: C, 63.17; H, 5.24; N, 12.70; optical rotation +11.51 (MeOH, 2.05); chiral purity was confirmed by chiral HPLC using CHIRALPAK AD-H, 5 µm, 25 cm, 0.8 ml/min, solvent: 75% hexane/24% EtOH/0.1% TEA, UV=260 nm, cycle 14 min , Rt=6.157 min (1 peak, 43g, 0% e.i.) 9.313 (2 peak, 43h, 100% e.i.).

Scheme 44

Example preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)-pyridin-3yl)methyl)phenyl-3-(trifluoromethyl)-N-pyrazole-5-carboxamide racemate (44c); (+)-1-(3-(aminomethyl)phenyl)-N-(3((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44d) and (-)-1 -(3 -(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44e) .

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44a).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.463 g, 1.648 mmol) in DMF (10 ml) was added (3-aminophenyl)(pyridine-3 -yl)methanol (31d) (0.33 g, 1.648 mmol), N-ethyl-N-isopropylpropan-2-amine (1.435 ml, 8.24 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop) (0.922 g, 1.978 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl )phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (44a) (0.653 g, 1.409 mmol, 86% yield) as a yellow oily liquid; ¹ H NMR (300 MHz, DMSO) δ 10.67 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1.7 Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8 ,3, 2.2, 1.1 Hz, 1H), 7.77 -7.64 (m, 4H), 7.62 - 7.52 (m, 1H), 7.37 - 7.25 (m , 2H), 7.21 - 7.14 (m, 1H), 6.15 (d, J=3.9 Hz, 1H), 5.77 (d, J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98; MS (IER-) 462.2 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (44b).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (44a) (0.24 g, 0.518 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (0.12 ml, 1.647 mmol) and leave to warm to room temperature for 3 hours. The reaction is quenched with triethylamine (0.22 ml, 1.58 mmol), the mixture is stirred at room temperature for 1 hour, add cyclopropylmethanol (5.00 ml, 60.4 mmol), triethylamine (0.5 ml, 3.59 mmol), concentrate to remove most of the dichloromethane, then add additional triethylamine (0. 5 ml, 3.59 mmol). The reaction mixture was heated at 70°C for 2 hours, at 100°C for 6 hours and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3cyanophenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (44b) (124 mg, 46%) as a light yellow viscous substance; 1H NMR (300 MHz, DMSO-th ₆ ) δ 10.70 (s, 1H), 8.60 - 8.55 (m, 1H), 8.46 (dd, J=4.8, 1.7 Hz , 1H), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.8, 1.3 Hz, 1H), 7.91 (ddd, J=8, 2, 2.2, 1.1 Hz, 1H), 7.78 - 7.58 (m, 5H), 7.42 - 7.28 (m, 2H), 7.20 - 7.13 (m, 1H), 5.56(s,

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1H), 3.28 - 3.24 (m, 2H), 1.13 - 0.97 (m, 1H), 0.54 - 0.41 (m, 2H), 0.20-0.12 ( m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.97; MS (IER+): 518.3 (M+1).

Step 3. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethoxy)-pyridin-3yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44c) .

In a solution of 1-(3-cyanophenyl)-N-(3 -((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44b) (108 mg , 0.209 mmol) in MeOH (6 mL), cooled in ice/water, nickel(II) chloride hexahydrate (11.00 mg, 0.046 mmol) was added, then sodium borohydride (50 mg, 1.296 mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour and quenched with N-(2-aminoethyl)ethane-1,2-diamine (0.05 ml, 1.296 mmol), then stirred for an additional 0.5 hour. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was dissolved in ethyl acetate (150 ml) and water (75 ml). The aqueous layer was separated and extracted with ethyl acetate (75 ml). The combined extracts were washed with brine (75 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 2x4 g, eluted with chloroform/methanol (1:0 to 9:1)] to give the racemate 1 -(3 -(aminomethyl)phenyl)-N-(3 -( (cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (44c) (0.042 g, 39%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 1 .7 Hz, 1H), 7.75- 7.13 (m, 11H), 5.55 (s, 1H), 3.80 (s, 2H), 3.26 (dd, J=6.8, 2.5 Hz, 2H), 1.12-1.00 (m, 1H), 0.53 - 0.35 (m, 2H), 0.22 - 0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d;) δ -60.74; MS (IER+): 522.3 (M+1).

Step 4. Preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (44d) and (-)-1-(3-(aminomethyl)phenyl)-M-(3((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (44e).

Racemate 1 -(3 -(aminomethyl)phenyl)-N-(3 -((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44c) (231 mg ) were separated by chiral preparative HPLC using CHIRALPAK AD-H, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 80% hexane/20% EtOH/0.1% DEA, UV=254 nm, giving :

1. (+)-1 -(3 -(aminomethyl)phenyl)-N-(3 -((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (44d) (0.0791 g, Rt=6.28 min, 99.8% ee). The resulting product was purified again by flash column chromatography (silica gel, 12 g, eluted with 025% methanol/chloroform mixtures for 13 min at a flow rate of 50 ml/min) to give pure (+)-1-(3(aminomethyl)phenyl)- N-(3-((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (44d) (60 mg) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.46 (dd, J=4.8, 1 .7 Hz, 1H), 7.75-7.26 (m, 11H), 7.21 - 7.11 (m, 1H), 5.55 (s, 1H), 3.77 (s, 2H) , 3.26 (dd, J=6.8, 2.3 Hz, 2H), 1.16 - 0.96 (m, 1H), 0.56 - 0.37 (m, 2H), 0.27 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.71; MS (IER+) 522.3 (M+1); (IER-) 520.3 (M+1); optical rotation = +10.86 (methanol, 3.0). Chiral purity was confirmed by chiral HPLC using an AD-H column (76/24/0.1 hexane/ethanol/TEA) 0.8 ml/min, UV 260 nm, cycle 14 min (temperature 25°C), Rt=6.817 (100%, 1 peak, 44d), Rt=10.043 (0%, 2 peak, 44e); analysis, calculation for C ₂₈ H2 ₆ F ₃ N ₅ O2-0.75H2O: C, 62.85; H, 5.18; N, 13.09; experiment: C, 62.90; H, 5.11; N, 12.73;

2. (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 44e) (0.083 g, Rt=8.961 min, 99.0% e.i.). The resulting product was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-25% methanol in chloroform for 13 min at a flow rate of 50 ml/min) to give (-)-1-(3(aminomethyl)phenyl) -N-(3-((cyclopropylmethoxy)pyridin-3-yl)methyl)phenyl-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (44e) (60 mg) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.46 (dd, J=4.8, 1 .7 Hz, 1H), 7.70 (dt, J=8.0, 2.0 Hz, 1H), 7.64 (t, J=1.8 Hz, 1H), 7.61 - 7.50 (m, 3H), 7.43 (d, J=2.7 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.37 - 7.28 (m, 3H) , 7.16 (d, J=7.6 Hz, 1H), 5.55 (s, 1H), 3.77 (s, 2H), 3.25 (dd, J=6.9, 2.4 Hz, 2H), 1.16 - 0.96 (m, 1H), 0.56 - 0.34 (m, 2H), 0.27 - 0.04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.71; MS (IER+) 522.3 (M+1); (IER-) 520.3 (M+1); optical rotation = -11.33 (methanol, 3.0); chiral purity was confirmed by chiral HPLC on an AD-H column (76/24/0.1 hexane/ethanol/TEA) 0.8 ml/min, UV 260 nm, cycle 14 (temperature 25°C), Rt=6.817 (0 % e.i., 1 peak, 44d), Rt=9.943 (100%, 2 peak, 44e); analysis, calculation for C ₂₈ H2 ₆ F ₃ N ₅ O2-0.75H2O: C, 62.85; H, 5.18; N, 13.09; experiment: C, 62.88; H, 5.12; N, 12.70.

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Scheme 45

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5 -carboxamide (45g).

Step 1. Preparation of (E)-3-cyclopropyl-1-(pyridin-2-yl)prop-2-en-1-one (45b).

To a stirred solution of 1-(pyridin-2-yl)ethanone (45a) (1.516 ml, 13.27 mmol) in methanol (100 ml), cooled to 0°C, was added cyclopropanecarboxaldehyde (1.5 ml, 19.90 mmol ) and aqueous potassium hydroxide (1N, 2.65 ml, 2.65 mmol). The reaction mixture was left to warm to room temperature overnight. The reaction mixture was acidified with 1N. hydrochloric acid and concentrated in vacuo to remove methanol. The crude residue was dissolved in ethyl acetate (100 ml), washed with sodium carbonate solution, water (2x50 ml), brine (50 ml), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give pure (E)-3cyclopropyl-1-(pyridin-2-yl)prop-2-ene- 1-one (45b) (479 mg, 20.85%), which was of sufficient purity to be used as such in the next step. MS (IER+) 174.1 (M+1).

Step 2. Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45c).

To Pd/C (10%, 0.230 g, 0.216 mmol) in methanol (50 ml) was added (E)-3-cyclopropyl-1-(pyridin-2yl)prop-2-en-1-one (45b) (1 .5 g, 8.66 mmol) and hydrogenated at 60 psi (414 kPa) for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45c) ( 1.02 g, 66.5%) as an oily liquid. ¹ H NMR (300 MHz, DMSOC) δ 8.46 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.76 (td, J=7.7, 1.8 Hz , 1H), 7.46 (dt, J=8.1, 1.2 Hz, 1H), 7.22 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 5, 29 (d, J=5.0 Hz, 1H), 4.58 (dt, J=8.2, 4.8 Hz, 1H), 1.83 (dddd, J=13.6, 9.2, 7.2, 4.6 Hz, 1H), 1.66 (dtd, J=13.3, 8.1, 6.7 Hz, 1H), 1.22 (dt, J=8.1, 6, 5 Hz, 2H), 0.73 - 0.58 (m, 1H), 0.41 -0.29 (m, 2H), 0.03 - -0.06 (m, 2H); MS (IER+) 200.1 (M+23).

Step 3. Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (45d).

NaHCO ₃ (1.422 g, 16.93 mmol) and Dess-Martin periodinane (4.79 g, 11.28 mmol). The reaction mixture was stirred at 0°C for 30 min and warmed to room temperature for 15 min. The reaction mixture was stirred at room temperature for 1 hour and quenched by adding saturated aqueous sodium bicarbonate (25 ml), extracted with dichloromethane (2x50 ml). Combine the organic layers, wash with water (2x25 ml), brine (25 ml), dry, filter and concentrate in vacuo. The crude residue was purified by column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (45d) (836 mg, 85 %) in the form of an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (ddd, J=4.8, 1.7, 1.0 Hz, 1H), 8.13 - 7.87 (m, 2H), 7 .77 - 7.56 (m, 1H), 3.26 (t, J=7.3 Hz, 2H), 1.54 (q, J=7.2 Hz, 2H), 0.83 - 0, 67 (m, 1H), 0.45-0.32 (m, 2H), 0.08 - 0.01 (m, 2H); MS (IER+) 176.1 (M+1).

Step 4. Preparation of 1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45e).

To a stirred solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (45d) (400 mg, 2.283 mmol) in tetrahydrofuran (15 ml) was added (3-(bis(trimethylsilyl)amino)phenyl bromide )magnesium (49c) (2.283 ml, 2.283 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and

- 117 045731 was stirred for 2 hours. The reaction was quenched with ammonium chloride solution (25 ml), the mixture was extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with water (2x25 ml), brine (25 ml), dry, filter and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0100%) to give 1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1 -ol (45e) (365 mg, 59.6%), which was of sufficient purity to be used as such in the next step; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.70 (ddd, J=8.0, 7.3 , 1.8 Hz, 1H), 7.58 (dt, J=8.0, 1.1 Hz, 1H), 7.17 (ddd, J=7.4, 4.8, 1.2 Hz, 1H), 6.86 (t, J=7.8 Hz, 1H), 6.75 (t, J=1.9 Hz, 1H), 6.64 (ddd, J=7.7, 1.8 , 1.1 Hz, 1H), 6.31 (ddd, J=7.8, 2.2, 1.0 Hz, 1H), 5.51 (s, 1H), 4.93 (s, 2H) , 2.36 (ddd, J=13.3, 11.1, 5.2 Hz, 2H), 1.17 - 0.89 (m, 2H), 0.60 (dqd, J=11.9, 7.0, 3.9 Hz, 1H), 0.39-0.26 (m, 2H), -0.04- -0.17 (m, 2H); MS (IER+) 291.2 (M+23).

Step 5. Preparation of 1-(3-cyanophenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (45f).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (297 mg, 1.056 mmol) in DMF (6 ml) was added 1-(3-aminophenyl)-3 -cyclopropyl-1-(pyridin-2-yl)propan-1-ol (45e) (340 mg, 1.267 mmol), K-ethyl-K-isopropylpropan-2-amine (1.471 ml, 8.45 mmol) and hexafluorophosphate bromo-tris-pyrrolidinophosphonium (PyBroP, 541 mg, 1.161 mmol) at room temperature and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml, 50 ml). The organic layers were combined and dried over anhydrous MgSO ₄ , filtered, concentrated under reduced pressure to dryness. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1 -(3-cyanophenyl)-K-(3-(3-cyclopropyl-1-hydroxy- 1 -(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (45f) (328 mg, 58.4%); MS (IER+) 532.2 (M+1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (45g).

Into a stirred solution of 1-(3-cyanophenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (45f) (300 mg, 0.564 mmol) in methanol (25 ml) at 0°C was added nickel (II) chloride hexahydrate (29.2 mg, 0.123 mmol). Sodium tetrahydroborate (133 mg, 3.53 mmol) was added to the resulting mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min, quenched by adding K1-(2-aminoethyl)ethane-1,2diamine (0.135 ml, 1.298 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated in vacuo to remove methanol. The residue was loaded onto silica gel and purified twice by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, from 0 to 100%) and (silica gel, 2x4 g, eluted with mixtures of methanol in chloroform, from 0 to 30%) to give 1-(3-(aminomethyl)phenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (70 mg, 0.131 mmol, 23.16% yield) as a colorless solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.75 (s, 1H, exchange with D2O), 8.68 - 8.48 (m, 1H), 7.87 - 7.77 (m, 2H) , 7.73 - 7.68 (m, 1H), 7.67 (s, 1H), 7.65- 7.60 (m, 2H), 7.54 - 7.47 (m, 2H), 7 .40 (ddd, J=7.5, 3.9, 1.9 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.31 - 7.25 (m, 2H), 5 .84 (s, 1H, exchange with D2O), 3.87 (s, 2H), 2.56 2.44 (m, 2H), 2.33 (s, 2H, exchange with D2O), 1.12 ( m, 2H), 0.78 - 0.56 (m, 1H), 0.49 - 0.32 (m, 2H), -0.01 (m, 2H); MS (IER+) 536.3 (M+1), (IER-) 534.1 (M-1), 570.0 (M+23).

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Scheme 46

ManSOz, Dess-Martin periodinan

chiral separation

46h (+)-isomer 46i (-)-isomer

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopronyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (46g ), (+)-1-(3-(aminomethyl)phenyl)-K-(3(3-cyclopropyl-1 -hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5- carboxamide (46h) and (-)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopronyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (46i).

Step 1. Preparation of (E)-3-cyclopropyl-1-phenylprop-2-en-1-one (46b).

To a stirred solution of diethyl 2-oxo-2-phenylethylphosphonate (46a) (1.8 g, 7.02 mmol) in acetonitrile (50 ml) was added LiBr (0.610 g, 7.02 mmol) and diisopropylethylamine (DIPEA, 2.454 ml , 14.05 mmol), add cyclopropanecarboxaldehyde (0.529 mL, 7.02 mmol) dropwise at room temperature and stir the reaction mixture at room temperature for 16 hours. Filter the reaction mixture through Celite and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 24 g, eluted with ethyl acetate in hexanes, 0100%) to give (E)-3-cyclopropyl-1-phenylprop-2-en-1-one (46b) (315 mg , 26.0%) in the form of an oily liquid; Ή NMR (300 MHz, chloroform-d) δ 8.00 - 7.87 (m, 2H), 7.63 - 7.42 (m, 3H), 7.03 (d, J=15.1 Hz, 1H), 6.56 (dd, J=15.1, 10.3 Hz, 1H), 1.83 - 1.59 (m, 1H), 1.14 - 0.94 (m, 2H), 0 .84 - 0.65 (m, 2H); MS (IER+): 173.1 (M+1).

Step 2. Preparation of 3-cyclopropyl-1-phenylpropan-1-ol (46c).

To a suspension of Pd/C (10%, 97 mg, 0.091 mmol) in ethyl acetate (35 ml) was added (E)-3-cyclopropyl-1phenylprop-2-en-1-one (46b) (315 mg, 1.829 mmol) and hydrogenated at 60 psi (414 kPa) for 1 hour. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 24 g, eluted with ethyl acetate in hexanes, 0-30%) to give (46c) (260 mg, 81%) as an oil; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.40 - 7.14 (m, 5H), 5.10 (d, J=4.4 Hz, 1H), 4.52 (ddd, J=7 ,3, 5.7, 4.4 Hz, 1H), 1.76 - 1.55 (m, 2H), 1.35- 1.08 (m, 2H), 0.72 - 0.59 (m , 1H), 0.43 - 0.28 (m, 2H), -0.04 (ddt, J=5.2, 4.2, 2.0 Hz, 2H); MS (ESI+): 199.1 (M+Na).

Step 3. Preparation of 3-cyclopropyl-1-phenylpropan-1-one (46d).

Sodium bicarbonate (0.336 g, 4.00 mmol), DessaMartin periodinane ( 1.191 g, 2.67 mmol) and stirred for 30 minutes. The reaction mixture was warmed to room temperature for 15 min, filtered through a pad of Celite and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%) to give 3-cyclopropyl-1-phenylpropan-1-one (46d) (150 mg, 60.7%) in the form of an oily liquid; 1H NMR (300 MHz, DMSO-d^ δ 7.98 - 7.87 (m, 2H), 7.63 7.53 (m, 1H), 7.47 (ddt, J=8.2, 6, 6, 1.2 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H), 1.46 (q, J=7.1 Hz, 2H), 0.81 - 0.59 ( m, 1H), 0.41 - 0.24 (m, 2H), 0.04 - -0.05 (m, 2H); MS (ESI+): 197.1 (M+Na).

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Step 4. Preparation of 1-(3-aminophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (46e).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (1.722 ml, 1.722 mmol) at 0°C. The reaction mixture was left stirring for 2 hours at 0°C, quenched with saturated aqueous ammonium chloride (25 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with water (2x25 ml), brine (25 ml), dry, filter and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% ethyl acetate in hexanes) to give 1-(3-aminophenyl)3-cyclopropyl-1-phenylpropan-1-ol (46e) (180 mg, 78%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.44 - 7.33 (m, 2H), 7.30 - 7.18 (m, 2H), 7.17 - 7.07 (m, 1H) , 6.88 (t, J=7.8 Hz, 1H), 6.68 (t, J=1.9 Hz, 1H), 6.55 (dt, J=7.7, 1.3 Hz, 1H), 6.32 (ddd, J=7.8, 2.2, 0.9 Hz, 1H), 5.21 (s, 1H), 4.93 (s, 2H), 2.23 (t , J=8.2 Hz, 2H), 1.07 (ddd, J=28.3, 13.6, 6.4 Hz, 2H), 0.61 (dd, J=11.7, 6.1 Hz, 1H), 0.40 - 0.26 (m, 2H), -0.09 (td, J=5.2, 3.5 Hz, 2H); MS (IER+): 290.2 (M+Na), MS (IER-): 266.1 (M-1).

Step 5. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (46f).

1-( 3-Aminophenyl)-3-cyclopropyl-1-phenylpropan-1ol (46e) (1.15 g, 4.30 mmol), N-ethyl-N-isopropan-2-amine (5.01 ml, 28.7 mmol ) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 1.838 g, 3.94 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours, quenched with water (100 ml) and extracted with ethyl acetate (2x150 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with hexanes in ethyl acetate/hexanes, 0-40 to 100%) to give 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy -1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (46f) (1.6 g, 84%), which was used as such in the next step; 1H NMR (300 MHz, DMSO^) δ 10.61 (s, 1H), 8.21 - 8.13 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H ), 7.90 (ddd, J=8.3, 2.3, 1.2 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.62 - 7.54 (m, 1H ), 7.46 - 7.36 (m, 2H), 7.29 - 7.23 (m, 3H), 7.19 -7.14 (m, 2H), 5.49 (s, 1H), 2.36 - 2.24 (m, 2H), 1.08 (d, J=8.7 Hz, 2H), 0.63 (s, 1H), 0.43 - 0.26 (m, 2H) , 0.04 - -0.14 (m, 2H); MS (IER-) 529.2 (M-1).

Step 6. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (46g ).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (46f) (0 .77 g, 1.451 mmol) in methanol (75 ml) at 0°C, nickel (II) chloride hexahydrate (0.075 g, 0.316 mmol) was added, then sodium tetrahydroborate (0.549 g, 14.51 mmol) was added in small portions over 15 min. . The reaction mixture was stirred for 15 min, quenched by adding N-(2-aminoethyl)ethane-1,2-diamine (0.076 mL, 0.737 mmol), stirred for an additional 30 min at room temperature and concentrated in vacuo to remove methanol. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3x50 ml). Combine the organic layers, wash with water (2x20 mL), brine (20 mL), dry and concentrate. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give the racemate 1-(3-(aminomethyl)phenyl)N-(3-(3-cyclopropyl-1 -hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (46g) as a colorless solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.65 (s, 1H, exchange with D2O), 7.71 - 7.66 (m, 1H), 7.60 - 7.50 (m, 3H) , 7.45-7.38 (m, 4H), 7.34 -7.11 (m, 6H), 5.48 (s, 1H, exchange with D2O), 3.78 (s, 2H), 2 .30 (dd, J=10.5, 5.8 Hz, 4H, 2H exchange with D2O), 1.06 (dd, J=10.7, 5.7 Hz, 2H), 0.62 (q, J=9.4, 7.3 Hz, 1H), 0.41 - 0.25 (m, 2H), -0.08 (tt, J=5.4, 2.8 Hz, 2H); mass spectrum (ESI+) 535.3 (M+1), 557.3 (M+23), (ESI-) 533.3 (M-1), 569.3 (M+35).

Step 7. Preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (46h) and (-)-1 -(3 -(αmunomethyl)phenyl)-N-(3-(3 cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (46i).

Racemate 1 -(3 -(aminomethyl)phenyl)-N-(3 -(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (46g) (367 mg) were separated by chiral preparative HPLC on CHIRALPAK IC, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 50% hexane/49% DCM/1% EtOH/0.1% DEA, UV=280 nm, 25°C, obtaining:

1. 1 peak corresponding to (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (46h) (101.9 mg, 97.1% ee); chiral HPLC (Rt=8.975 min, 98.5689%, 1 peak, compound 46h), (Rt=10.075 min, 1.4311%, 2 peak, compound 46i). The resulting compound was purified again by flash column chromatography (silica gel, 4 g, eluted with mixtures of 0-25-100% CMA-80 in chloroform for 25 minutes) to give (+)-1-(3(aminomethyl)phenyl)-N -(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (46h) (84 mg, ee 91.49%); optical rotation: [a]D=+1.674 [CH3OH]; 1H NMR

- 120 045731 (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H, exchange with D2O), 7.68 (s, 1H), 7.60 - 7.50 (m, 3H), 7, 48 - 7.37 (m, 4H), 7.35-7.21 (m, 4H), 7.16 (q, J=7.1 Hz, 2H), 5.48 (s, 1H, exchange with D ₂ O), 3.78 (s, 2H), 2.39 - 2.21 (m, 2H), 1.14 1.00 (m, 2H), 0.61 (h, J=6.4 Hz, 1H), 0.34 (dq, J=8.1, 4.0 Hz, 2H), -0.08 (t, J=4.8 Hz, 2H); MS (IER+) 535.3 (M+1), (IER-) 533.3 (M-1); analysis, calculation for C ₃₀ H ₂₉ F ₃ N ₄ O ₂ -0.75H ₂ O: C, 65.74; H, 5.61; N, 10.22; experiment C, 66.10; H, 5.82; N, 9.78;

2. 2 peaks corresponding to (-)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (46i) (98.8 mg, 97.5% ee); chiral HPLC (Rt=9.039 min, 1.2741% peak 1, compound 46h) (Rt=10.052, 98.7259% peak 2, compound 46i). The resulting compound was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-30% MeOH in chloroform for 25 minutes) to give (-)-1-(3(aminomethyl)phenyl)-N-(3- (3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (46i) (45 mg, 87.3% ee) as a white solid; optical rotation: [a] _D = -2.00 [CH3OH, 0.505]; ^1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H, exchange with D2O), 7.72 - 7.66 (m, 1H), 7.61 - 7.50 (m, 3H) , 7.47 - 7.37 (m, 4H), 7.35 - 7.11 (m, 6H), 5.48 (s, 1H, exchange with D2O), 3.78 (s, 2H), 2 .38 - 2.23 (m, 2H), 1.36 - 1.00 (m, 3H), 0.62 (ddt, J=10.5, 7.3, 3.7 Hz, 1H), 0 .47 - 0.30 (m, 2H), -0.08 (td, J=5.4, 3.8 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.70; MS (ESI+) 557.3 (M+Na); analysis, calculation for C30H29F3N4O2-0.25H2O: C, 66.84; H, 5.52; N, 10.39; experiment: C, 66.90; H, 5.74; N, 10.04.

Scheme 47

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (47f); (-)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole -5-carboxamide (47g) and (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47h).

Step 1. Preparation of (E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one (47b).

To a stirred solution of 3-acetylpyridine (47a) (9.07 ml, 83 mmol) in methanol (200 ml), cooled to 0°C, was added cyclopropanecarboxaldehyde (9.95 ml, 132 mmol) and aqueous potassium hydroxide (1N solution , 16.51 ml, 16.51 mmol). The reaction mixture was left to warm to room temperature overnight. The reaction mixture was acidified with 1N. hydrochloric acid and concentrated in vacuo to remove methanol. The crude residue was dissolved in ethyl acetate (300 ml), washed with sodium carbonate solution, water (2x100 ml), brine (50 ml), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give (E)-3cyclopropyl-1-(pyridin-3-yl)prop-2-en-1 -ona (47b) (5.99 g, 41.9%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.14 (td, J=2.7, 0.9 Hz, 1H), 8.80 (ddd, J=4.9, 3.3, 1, 7 Hz, 1H), 8.36 - 8.27 (m, 1H), 7.57 (ddt, J=8.0, 4.8, 1.2 Hz, 1H), 7.28 (d, J =15.1 Hz, 1H), 6.58 (dd, J=15.1, 10.3 Hz, 1H), 1.80 (dddd, J=12.5, 10.4, 7.8, 4 .5 Hz, 1H), 1.08 - 0.99 (m, 2H), 0.85 - 0.76 (m, 2H); MS (ESI+) 196.1 (M+Na).

Step 2. Preparation of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c).

To a stirred solution of (E)-3-cyclopropyl-1-(pyridin-3-yl)prop-2-en-1-one (47b) (5.93 g, 34.2 mmol) in benzene (150 ml) was added tributylstannane (18.42 ml, 68.5 mmol) and heated to reflux temperature. The reaction mixture was stirred at reflux temperature for 5 hours and cooled to room temperature. Benzene was evaporated and the residue was purified by colo

- 121 045731 overnight flash chromatography (silica gel, 80 g, eluted with mixtures of ethyl acetate in hexanes, from 0 to 100%) to obtain 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c) (5 .29 g, 88%); 1H NMR (300 MHz, DMSO-d6) δ 9.07 (dd, J=2.3, 0.9 Hz, 1H), 8.72 (dd, J=4.8, 1.7 Hz, 1H) , 8.24 (ddd, J=8.0, 2.4, 1.8 Hz, 1H), 7.50 (ddd, J=8.0, 4.9, 0.9 Hz, 1H), 3 .09 (t, J=7.2 Hz, 2H), 1.47 (q, J=7.1 Hz, 2H), 0.70 (dddd, J=12.0, 8.1, 5.1 , 2.2 Hz, 1H), 0.40 - 0.21 (m, 2H), 0.06 - -0.05 (m, 2H).

Step 3. Preparation of 1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol (47d).

To a stirred solution of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c) (2 g, 11.41 mmol) in tetrahydrofuran (20 ml) was added (3-(bis(trimethylsilyl)amino) chloride )phenyl)magnesium (49c) (4.23 g, 14.27 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature for 12 hours, the reaction was quenched by adding a solution of ammonium chloride (25 ml) and ethyl acetate (50 ml). The reaction mixture was acidified with hydrochloric acid (10 ml, 3N) and stirred for 15 min, made basic with saturated potassium carbonate solution (20 ml), extracted with ethyl acetate (3x100 ml). Combine the organic layers, wash with water (2x50 ml), brine (25 ml), dry and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of CMA 80 in chloroform) to give 1-(3-aminophenyl)-3cyclopropyl-1-(pyridin-3-yl)propan-1-ol (47d) (3.0 g, 11.18 mmol, 98% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (dd, J=2.4, 0.9 Hz, 1H), 8.38 - 8.31 (m, 1H), 7.74 (ddd , J=8.0, 2.4, 1.7 Hz, 1H), 7.27 (ddd, J=8.0, 4.7, 0.8 Hz, 1H), 6.91 (t, J =7.8 Hz, 1H), 6.69 (t, J=2.0 Hz, 1H), 6.61 - 6.51 (m, 1H), 6.35 (ddd, J=7.9, 2.2, 0.9 Hz, 1H), 5.46 (s, 1H, exchange with D ₂ O), 4.98 (s, 2H, exchange with D ₂ O), 2.35-2.18 ( m, 2H), 1.21 - 0.94 (m, 2H), 0.62 (qt, J=7.2, 3.8 Hz, 1H), 0.41 - 0.28 (m, 2H) , -0.07 (td, J=5.3, 3.7 Hz, 2H).

Step 4. Preparation of 1-(3-cyanophenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (47e).

In a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.148 g, 7.64 mmol) in K,K-dimethylformamide (46.1 ml, 596 mmol ) added 1-(3-aminophenyl)-3-cyclopropyl-1(pyridin-3-yl)propan-1-ol (47d) (2.46 g, 9.17 mmol), K-ethyl-K-isopropylpropan- 2-amine (10.64 mL, 61.1 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3.92 g, 8.40 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were washed with water (2x100 ml), brine (100 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1 -(3-cyanophenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1 -(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47e) (3.63 g, 89%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.37 (dd, J=4.7, 1 .6 Hz, 1H), 8.16 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J =8.2, 2.3, 1.1 Hz, 1H), 7.82 - 7.66 (m, 4H), 7.65 - 7.55 (m, 1H), 7.38 - 7.06 (m, 3H), 5.74 (s, 1H), 2.34 (t, J=8.1 Hz, 2H), 1.10 (t, J=6.1 Hz, 2H), 0.64 (s, 1H), 0.41 - 0.27 (m, 2H), -0.06 (dd, J=5.8, 4.1 Hz, 2H); MS (IER-) 530.2 (M-1).

Step 5. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-C-(3-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (47f).

Into a stirred solution of 1-(3-cyanophenyl)-K-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47e) (2.038 g, 3.83 mmol) in methanol (100 ml) at 0°C, nickel (II) chloride hexahydrate (1.139 g, 4.79 mmol) was added, followed by small portions of sodium tetrahydroborate (1.451 g, 38. 3 mmol) for 15 min. The reaction mixture was stirred for 30 min, quenched with K1-(2-aminoethyl)ethane-1,2-diamine (3.18 mL, 30.7 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated to remove methanol, diluted with water (200 ml) and stirred for 30 minutes. The isolated solid was collected by filtration. The solid was suspended in ethanol (100 ml) and concentrated to remove water. The residue was dissolved in methanol and purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of CMA 80 in chloroform, 0-50%) to give the racemate 1-(3(aminomethyl)phenyl)-K-(3-(3- cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47f) (575 mg, 1.074 mmol, 28.0% yield) in form of a colorless solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H, exchange with D2O), 8.62 (dd, J=2.4, 0.9 Hz, 1H), 8.37 (dd , J=4.7, 1.6 Hz, 1H), 7.77 (dt, J=8.0, 2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H) , 7.56 (d, J=6.6 Hz, 2H), 7.54 - 7.49 (m, 1H), 7.47 - 7.37 (m, 2H), 7.34 - 7.27 (m, 2H), 7.24 (d, J=7.7 Hz, 1H), 7.19 (dt, J=8.0, 1.5 Hz, 1H), 5.73 (s, 1H, exchange with D2O), 3.77 (s, 2H), 2.42 - 2.27 (m, 2H), 2.04 (s, 2H, exchange with D2O), 1.09 (h, J=6, 7, 6.3 Hz, 2H), 0.73 0.54 (m, 1H), 0.44 - 0.28 (m, 2H), -0.07 (dd, J=4.8, 1, 6 Hz, 2H); mass spectrum (ESI+) 536.3 (M+1), (ESI-) 534.3 (M-1), 570.4 (M+35).

Step 6. Preparation of (-)-1-(3-(aminomethyl)phenyl)-C-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3yl)propyl)phenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (47g) and (+)-1-(3-(aminomethyl)phenyl)

- 122 045731

N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5carboxamide (47b).

Racemate 1 -(3 -(aminomethyl)phenyl)-N-(3 -(3 -cyclopropyl-1 -hydroxy-1 -(pyridin-3 -yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-Carboxamide (47f) (317 mg) was separated by chiral preparative HPLC using CHTRALPAK AD-H, 5 µm, 4.6 x 250 mm, flow rate 1 ml/min, solvent: 85% hexane/15% EtOH/0.1% DEA, UV=254 nm, 25°C, obtaining:

1. 1 peak corresponding to (-)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (47g) (0.139 g, 98.9% ee); chiral HPLC (Rt=9.426 min, 99.4471% peak 1, corresponding to 47g), (Rt=11.592, 0.5529% peak 2, corresponding to 47h); 1 peak or compound 47g was re-purified by flash column chromatography (silica gel, 12 g, eluted with 0-100% CMA-80 in chloroform for 13 minutes) to give (-)-1-(3-(aminomethyl)phenyl)-N -(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47g) (124 mg net 1 peak) ; optical rotation: -4.87 (MeOH, 0.945); ¹ H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.62 (dd, J=2.5, 0.9 Hz, 1H), 8.37 (dd, J=4 ,7, 1.6 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.70 (t, J=1.9 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.51 (t, J=1.6 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.33 - 7.27 (m, 2H), 7.24 (d , J=7.8 Hz, 1H), 7.19 (dt, J=7.9, 1.5 Hz, 1H), 5.72 (s, 1H), 3.77 (s, 2H), 2 .41 - 2.27 (m, 2H), 1.94 (s, 2H), 1.13 - 1.06 (m, 2H), 0.63 (dt, J=8.4, 5.4 Hz , 1H), 0.40 - 0.30 (m, 2H), -0.03 - -0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.71. Free base 47g was dissolved in methanol and 0.05 ml of 2N was added. HCl in methanol. Concentrate the mixture to dryness in vacuo to give (-)-1 -(3 -(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47g) (105 mg, 98.93% ee) as HCl salt; 1H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.38 (dd, J=4.7, 1, 6 Hz, 1H), 7.77 (dt, J=8.0, 2.0 Hz, 1H), 7.71 (t, J=1.9 Hz, 1H), 7.64 - 7.55 ( m, 3H), 7.54 - 7.44 (m, 2H), 7.40 (dt, J=7.2, 2.1 Hz, 1H), 7.34 - 7.29 (m, 1H) , 7.27 (d, J=7.5 Hz, 1H), 7.24 - 7.16 (m, 1H), 5.73 (s, 1H), 3.94 (s, 2H), 2, 38 - 2.27 (m, 2H), 1.18 - 0.99 (m, 2H), 0.72 - 0.53 (m, 1H), 0.41 - 0.25 (m, 2H), -0.07 (dt, J=5.5, 2.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-ph) δ 60.75; MS (IER+) 536.3 (M+1); (IER-) 570.3 (M+Cl); purity was confirmed by chiral HPLC using ChIRALPAK AD-H, 0.8 ml/min, solvent: 85% hexane/15% EtOH/0.1% TEA, UV=260 nm, 40°C; chiral HPLC (Rt=13.443 min, 99.4653% for peak 1, corresponding to compound 47g), (Rt=16.433, 0.5347% for peak 2, corresponding to compound 47h); analysis, calculation for C ₂₉ H ₂₈ F ₃ N ₅ O ₂ -0.75HCl: C, 61.88; H, 5.15; Cl, 4.72; N, 12.44; experiment: C, 62.02; H, 5.31; Cl, 4.55; N, 12.30.

2. 2 peaks corresponding to (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (47h) (0.248 g, 94.25; ee); chiral HPLC (Rt=9.347, 2.88% peak 1, corresponding to 47g) (Rt=11.47, 97.11% peak 2, corresponding to 47h). Peak 2 or compound 47h was purified twice by flash column chromatography (silica gel, 24 g and 12 g, eluted with 0-100% mixtures of CMA-80 in chloroform for 13 min) to give (+)-1-(3-(aminomethyl )phenyl)-M-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (47h) (105 mg pure peak 2) as free base; optical rotation: +4.76 (MeOH, 0.84); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.62 (dd, J=2.4, 0.9 Hz, 1H), 8.37 (dd, J=4 ,7, 1.6 Hz, 1H), 7.77 (ddd, J=8.0, 2.4, 1.6 Hz, 1H), 7.70 (t, J=1.8 Hz, 1H) , 7.56 (d, J=6.4 Hz, 2H), 7.53 - 7.50 (m, 1H), 7.46 - 7.37 (m, 2H), 7.34 -7.27 (m, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.22 - 7.16 (m, 1H), 5.72 (s, 1H), 3.77 (s, 2H), 2.34 (t, J=8.0 Hz, 2H), 1.99 (s, 2H), 1.08 (dt, J=13.2, 6.6 Hz, 2H), 0, 72 - 0.55 (m, 1H), 0.43 -0.28 (m, 2H), -0.03 - -0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.71. The free base 47h was dissolved in methanol and 0.05 ml of 2N was added. HCl in methanol. Concentrate the mixture to dryness in vacuo to give (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3yl)propyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (47h) (95 mg, 95.39% ee) as HCl salt; 1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.44 (dd, J=4.7, 1, 6 Hz, 1H), 7.84 (dt, J=8.0, 2.0 Hz, 1H), 7.78 (t, J=1.9 Hz, 1H), 7.71 - 7.51 ( m, 5H), 7.47 (dt, J=7.6, 2.0 Hz, 1H), 7.40 - 7.24 (m, 3H), 5.80 (s, 1H), 4.02 (s, 2H), 2.46 - 2.34 (m, 2H), 1.22 -1.05 (m, 2H), 0.78 - 0.60 (m, 1H), 0.48 - 0 .30 (m, 2H), -0.01 (dt, J=5.5, 2.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.74; MS (IER+) 536.3 (M+1); (IER-) 570.3 (M+Cl); purity was confirmed by chiral HPLC using CHIRALPAK AD-H, 0.8 ml/min, solvent: 85% hexane/15% EtOH/0.1% TEA, UV=260 nm, 40°C; chiral HPLC (Rt=13.617 min, 2.3061% for peak 1, corresponding to compound 47g), (Rt=16.35, 97.6939% for peak 2, corresponding to compound 47h); analysis, calculation for C ₂₉ H ₂₈ F ₃ N ₅ O ₂ -0.65HCl-0.5H ₂ O: C, 61.29; H, 5.26; Cl, 4.06; N, 12.32; experiment: C, 61.20; H, 5.30; Cl, 4.04; N, 12.05.

- 123 045731

Scheme 48

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide ( 48f); (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (48g) and (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (48h).

Step 1. Preparation of (4-fluoro-3-nitrophenyl)(pyridin-3-yl)methanol (48b).

A solution of 4-fluoro-3-nitrobenzaldehyde (48a) (4.2 g, 24.84 mmol) in tetrahydrofuran (100 ml) was cooled to 0°C and treated with pyridin-3-ylmagnesium bromide (99 ml, 24.84 mmol, 0.25M solution in 2methyl-THF), stirred at 0°C for 3 hours and at room temperature for 14 hours. The reaction was quenched with saturated aqueous NH4C1 (60 ml) and extracted with EtOAc (2x75 ml). The organic extracts were combined, washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 50% ethyl acetate/hexanes)] to give (4-fluoro-3-nitrophenyl)(pyridin-3yl)methanol (48b) (3.104 g , yield 50%) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.64 (d, J=2.2 Hz, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 8, 20 (dd, J=7.4, 2.3 Hz, 1H), 7.79 (ddt, J=15.0, 8.0, 2.2 Hz, 2H), 7.56 (dd, J= 11.3, 8.7 Hz, 1H), 7.36 (ddd, J=7.9, 4.7, 0.9 Hz, 1H), 6.45 (d, J=4.2 Hz, 1H , exchange with D ₂ O), 5.94 (d, J=4.2 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -121.35; MS (IER+): MS (IER+) 249.1 (M+1), MS (IER-) 495.1 (2M-1).

Step 2. Preparation of (3-amino-4-fluorophenyl)(pyridin-3-yl)methanol (48c).

Nickel chloride hexahydrate was added to a stirred solution of (4-fluoro-3-nitrophenyl)(pyridin-3-yl)methanol (48b) (3.456 g, 13.92 mmol) in anhydrous methanol (120 mL), cooled to 0°C. (II) (0.827 g, 3.48 mmol), then sodium borohydride (1.054 g, 27.8 mmol) in small portions over 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 20 min at 0°C. TLC analysis (ethyl acetate/hexanes, 2/8, v/v) indicated completion of the reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (15.04 mL, 139 mmol) was added. The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (75 ml) and extracted with ethyl acetate (2x75 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 80 g, eluted with 0 to 50% ethyl acetate/hexanes)] to give (3-amino-4-fluorophenyl)(pyridin-3-yl)methanol (48c) ( 1.889 g, yield 62%) as an orange-yellow oily liquid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 - 8.50 (m, 1H), 8.42 (dd, J=4.8, 1.7 Hz, 1H), 7.74 - 7 .58 (m, 1H), 7.32 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 6.90 (dd, J=11.5, 8.3 Hz, 1H ), 6.78 (dd, J=8.9, 2.2 Hz, 1H), 6.52 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.97 ( d, J=3.9 Hz, 1H, exchange with D ₂ O), 5.61 (d, J=3.9

- 124 045731

Hz, 1H), 5.11 (s, 2H, exchange with D ₂ O); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -137.43; MS (IER ⁺ ): MS (IER+) 219.1 (M+1), 241.1 (M+Na), MS(IER+) 217.1 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (48d) .

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (2.88 g, 10.23 mmol), (3-amino-4-fluorophenyl )(pyridin-3-yl)methanol (48c) (1.861 g, 8.53 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (4.77 g, 10.23 mmol) N,N-dimethylformamide ( DMF) (52 ml) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (7.43 ml, 42.6 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-80% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(2fluoro-5-(hydroxy(pyridin-3-yl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48d) (2.707 g, 5.62 mmol, 66% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSOd ₆ ) δ 10.56 (s, 1H, exchange with D2O), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8 , 1.7 Hz, 1H), 8.17 - 8.09 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J= 8.2, 2.3, 1.2 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.56 (dd, J=7.5, 2.0 Hz, 1H), 7 .38 - 7.20 (m, 3H), 6.20 (d, J=4.0 Hz, 1H, exchange with D2O), 5.79 (d, J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ 60.98, -122.90; IR (KBr, cm ^-1 ): 2235 cm ^-1 (stretching vibrations -CN); MS (IER+): MS (IER+) 482.2 (M+1), MS (IER-) 480.2 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48e) .

Into a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (48d) (0.784 g, 1.629 mmol) in dichloromethane (20 ml) at 0°C was added thionyl chloride (0.356 ml, 4.89 mmol), the reaction mixture was left to warm to room temperature and stirred for 12 hours. The reaction was quenched with cyclopropylmethanol (0.585 ml, 8. 14 mmol), acetonitrile (20 ml) was added, the mixture was stirred for 1 hour at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanol (5.97 ml, 81 mmol), acetonitrile (20 ml), triethylamine (0.681 ml, 4.89 mmol) was added and heated at 100°C for 24 hours. The reaction mixture was cooled to room temperature and evaporated dry. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures) to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl) methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48e) (378 mg, 43% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H, exchange with D2O), 8.58 (d, J=2.1 Hz, 1H), 8.47 (dd, J=4, 8, 1.7 Hz, 1H), 8.17 - 8.10 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.95- 7.86 (m, 1H), 7.78 - 7.67 (m, 3H), 7.62 - 7.54 (m, 1H), 7.43 - 7.25 (m, 3H), 5.59 (s , 1H), 3.25 (d, J=6.8 Hz, 2H), 1.05 (dddd, J=14.8, 6.8, 5.0, 2.6 Hz, 1H), 0, 53 - 0.39 (m, 2H), 0.15 (dtd, J=5.5, 3.7, 3.3, 1.5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.99, -122.10; MS (IER+): MS (IER+) 536.2 (M+1), MS (IER-) 534.2 (M-1).

Step 5. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (48f).

Into a stirred solution of 1-(3-cyanophenyl)-M-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48e) ( 0.238 g, 0.444 mmol) in anhydrous methanol (30 ml), cooled to 0°C, add nickel (II) chloride hexahydrate (0.158 g, 0.667 mmol), add sodium borohydride (0.135 g, 3.56 mmol) in small portions to for 5 minutes The reaction mixture was stirred for 25 min, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.480 ml, 4.44 mmol), stirred for 30 min and concentrated in vacuo. The reaction mixture was treated with saturated aqueous NH ₄ Cl (60 ml) and the product was extracted with chloroform (2x60 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with methanol/chloroform, 0 to 50%)] to give the racemate 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy) (pyridin-3yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48f) (0.129 g, 0.239 mmol, 53.8% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.57 (d, J=2.2 Hz, 1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H), 7, 71 (dt, J=8.0, 2.0 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.58 (s, 1H), 7.52 (s, 1H ), 7.47 7.41 (m, 2H), 7.40 - 7.25 (m, 4H), 5.59 (s, 1H), 3.77 (s, 2H), 3.25 (d , J=6.8 Hz, 2H), 1.15-0.96 (m, 1H), 0.56 0.35 (m, 2H), 0.23 - 0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75, -122.56; MS (IER+): MS (IER+) 540.2 (M+1), MS (IER-) 538.2 (M-1), 574.1 (M+Cl); analysis, calculation for C ₂₈ H ₂₅ F ₄ N5O ₂ -0.25H ₂ O: C, 61.82; H, 4.72; N, 12.87; experiment: C, 61.89; H, 4.91; N, 12.75.

Step 6. Preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (48g) and (-)-1-(3-(aminomethyl)phenyl)N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-car

- 125 045731 boxamide (48h).

Racemate 1-(3-(aminomethyl)phenyl)-M-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 48f) (725 mg) was separated by chiral preparative HPLC using CHIRALPAK IC, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 80% hexane/20% EtOH/0.1% DEA, UV=320 nm , 25°C, obtaining:

1. (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazol- 5-carboxamide (48g) (358.5 mg) corresponding to peak 1, Rt=6.758 min, 99.2473% for peak 1 (compound 48g), Rt=9.193 min, 0.7527% for peak 2 (compound 48h) , 97.1% e.i. 48g. The resulting compound was purified again by flash column chromatography (silica gel, 25 g, eluted with methanol/chloroform mixtures for 25 minutes) to give pure (+)-1-(3(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy )(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48g) (180 mg) as a white solid; pure free base (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole -5-carboxamide (48g) was dissolved in methanol and 4 ml of 2N was added. HCl in methanol. Concentrate the mixture to dryness in vacuo to obtain pure dihydrochloride salt (+)-1-(3(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (48g) (180 mg); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H, exchange with D2O), 8.86 (d, J=2.0 Hz, 1H), 8.78 (dd, J=5 .5, 1.5 Hz, 1H), 8.53 (s, 3H, exchange with D2O), 8.37 - 8.28 (m, 1H), 7.89 (dd, J=8.1, 5 .4 Hz, 1H), 7.77 - 7.61 (m, 4H), 7.59 - 7.47 (m, 2H), 7.40 - 7.25 (m, 2H), 5.80 ( s, 1H), 4.11 (q, J=5.9 Hz, 2H), 3.31 (s, 2H), 1.06 (ddt, J=9.3, 7.5, 2.8 Hz , 1H), 0.56 - 0.33 (m, 2H), 0.26 - 0.09 (m, 2H); MS (IER+) 541.3 (M+1), (IER-) 538.3 (M-1), 574.3 (M+35); optical rotation [a]D=+10.228 [CH3OH, 1.095]; chiral purity was confirmed by chiral HPLC on a chiral AD-H column, 0.8 ml/min, solvent: 85% hexane/15% EtOH/0.1% TEA, UV=260 nM, 40°C; C (Rt=8.860 min, 99.1567% for peak 1, corresponding to compound 48g), (Rt=14.127, 0.8433% for peak 2, corresponding to compound 48h) (98.31% ee of 48g as salt HCl); analysis, calculation for C2 ₈ H25F4N ₅ O2-2.05HCl-1.75H ₂ O: C, 52.08; H, 4.77; Cl, 11.25; N, 10.84; experiment: C, 52.07; H, 4.80; Cl, 11.46; N, 10.60;

2. (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazol- 5-carboxamide (48h) (382.5 mg) corresponding to peak 2, Rt=6.861 min, 3.7692% for peak 1 (compound 48g), Rt=9.131 min, 96.2308% for peak 2 (compound 48h) , 92.4% e.i. connections 48h. The resulting compound was purified again by flash column chromatography (silica gel, 12 g, eluted with 0-30% MeOH/chloroform for 25 minutes) to give (-)1-(3-(aminomethyl)phenyl)-N-(5- ((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48h) (0.255 g) as a white solid. Pure free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (48h) (245 mg) was dissolved in methanol (8 ml) and 2N was added. HCl (in methanol, 2.25 ml, 10 eq.). The solution was stirred at room temperature for 30 minutes, evaporated to dryness to obtain the hydrochloride salt of (-)-1-(3-(aminomethyl)phenyl)-N-(5((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2 -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (48h) (238 mg) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H, exchange with D2O), 8.83 (d, J=2.0 Hz, 1H), 8.75 (dd, J=5 ,4, 1.5 Hz, 1H), 8.49 (lat.s, 3H, exchange with D2O), 8.27 (d, J=8.1 Hz, 1H), 7.85 (dd, J= 8.1, 5.4 Hz, 1H), 7.76 - 7.60 (m, 4H), 7.59 - 7.48 (m, 2H), 7.40 - 7.25 (m, 2H) , 5.78 (s, 1H), 4.11 (q, J=5.8 Hz, 2H), 3.29 (d, J=6.8 Hz, 2H), 1.17 - 0.97 ( m, 1H), 0.59 - 0.37 (m, 2H), 0.25 - 0.11 (m, 2H); ¹ H NMR (300 MHz, DMSO-d6, D2O) δ 8.81 (d, J=2.0 Hz, 1H), 8.71 (dd, J=5.5, 1.5 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 5.5 Hz, 1H), 7.70 (s, 1H), 7.67 (d , J=7.0 Hz, 1H), 7.63 (s, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.57 (s, 1H), 7.52 (td , J=4.9, 2.5 Hz, 1H), 7.41 - 7.28 (m, 2H), 5.76 (s, 1H), 4.12 (s, 2H), 3.30 ( dd, J=6.9, 2.0 Hz, 2H), 1.05 (dq, J=8.6, 5.2, 4.3 Hz, 1H), 0.57 - 0.40 (m, 2H), 0.26 - 0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 60.80 (d, J=2.5 Hz), -121.44; MS (IER+) 540.3 (M+1), MS (IER-) 538.3 (M-1), 574.2 (M+Cl); optical rotation [a] _D = -9.16 [CH3OH, 0.83].

- 126 045731

Scheme 49

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49h) , (+)-1-(3 -(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (49i) and (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49j) .

Step 1. Preparation of 2-(benzyloxy)benzaldehyde (49b).

Cesium carbonate (15.48 g, 47.5 mmol) and benzyl bromide (4.97 mL, 41.8 mmol) were added to a solution of 2-hydroxybenzaldehyde (49a) (3.98 mL, 38 mmol) in DMF (12 mL). . The reaction mixture was stirred at room temperature for 36 hours and the reaction was quenched with cold water (50 ml). The resulting solid was collected by filtration, washed with water (2x50 ml) and dried under reduced pressure over P2O5 to give 2-(benzyloxy)benzaldehyde (49b) (6.524 g, 81%) as a white solid; 1H NMR (300 MHz, DMSOL) δ 10.43 (d, J=0.8 Hz, 1H), 7.75-7.62 (m, 2H), 7.56 - 7.49 (m, 2H) , 7.46 - 7.30 (m, 4H), 7.10 (tt, J=7.5, 0.9 Hz, 1H), 5.30 (s, 2H); MS (ESI+): MS (ESI+) 235.2 (M+Na).

Step 2. Preparation of (3-aminophenyl)(2-(benzyloxy)phenyl)methanol (49d).

To a solution of 2-(benzyloxy)benzaldehyde (3 g, 14.13 mmol) in tetrahydrofuran (10 ml) was added a solution of 3-[bis(trimethylsilyl)amino]phenylmagnesium chloride (49c) (16.96 ml, 16.96 mmol, 1M solution in THF) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched at 0°C with hydrogen chloride (17.67 ml, 35.3 mmol), stirred for 6 hours. The reaction mixture was treated with sodium hydroxide (21.20 ml, 42.4 mmol ) and extracted with ethyl acetate (2x75 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (75 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(2-(benzyloxy)phenyl)methanol (49d) (4.02 g, 93%) as white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 7.47 (dd, J=7.5, 1.8 Hz, 1H), 7.41 - 7.28 (m, 5H), 7.16 (ddd , J=8.9, 7.3, 1.8 Hz, 1H), 7.03 - 6.82 (m, 3H), 6.56 (t, J=1.9 Hz, 1H), 6, 46 (dt, J=7.6, 1.3 Hz, 1H), 6.37 (ddd, J=7.9, 2.3, 1.1 Hz, 1H), 5.90 (d, J= 4.3 Hz, 1H), 5.48 (d, J=4.3 Hz, 1H, exchange with D2O), 5.09 (s, 2H), 4.93 (s, 2H, exchange with D2O); MS (IER+): MS (IER+) 328.3 (M+Na), MS (IER-) 304.16 (M-1).

Step 3. Preparation of N-(3-((2-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (49e).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1.381 g, 4.91 mmol), (3-aminophenyl)(2-(benzyloxy )phenyl)methanol (49d) (1.5 g, 4.91 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (2.75 g, 5.89 mmol), N,N-dimethylformamide (28, 5 ml, 368 mmol) and N-ethyl-N-isopropylpropan-2-amine (4.28 ml, 24.56 mmol) under positive nitrogen flow at room temperature. The resulting reaction

- 127 045731 the mixture was stirred at room temperature for 16 hours in a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (50 ml) and extracted with chloroform (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give N-(3-((2(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1- (3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49e) (2.568 g, 92% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H, exchange with D2O), 8.16 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7 ,8, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.76-7.68 (m,2H), 7, 64 (t, J=1.8 Hz, 1H), 7.50 (ddd, J=9.6, 8.1, 1.8 Hz, 2H), 7.34 - 7.29 (m, 4H) , 7.25 - 7.15 (m, 2H), 7.09 - 6.91 (m, 4H), 6.01 (d, J=4.2 Hz, 1H), 5.76 (d, J =4.2 Hz, 1H, exchange with D ₂ O), 5.09 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.95; IR (KBr, cm-1): 2235 cm-1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 591.2 (M+Na), MS (IER-) 567.2 (M-1).

Step 4. Preparation of N-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49f).

Into a solution of N-(3-((2-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49e) (2.491 g, 4.38 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.959 ml, 13.14 mmol) and leave to warm to room temperature, after 13 hours add more thionyl chloride (0.959 ml, 13.14 mmol ) and stirred for 1.5 hours. The reaction was quenched with cyclopropylmethanamine (2.63 ml, 30.7 mmol), stirred for 1 hour at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanamine (7.511 ml, 88 mmol) and acetonitrile (20 ml) and heated at 80°C for 16 hours. The reaction mixture was concentrated in vacuo and the resulting residue was treated with water (50 ml), extracted with ethyl acetate (2x50 ml). The organic layers were combined, dried over anhydrous MgSO4, filtered, and excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give N(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl )-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (49f) (1.168 g, 43% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H, exchange with D2O), 8.16 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7 ,7, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 7.76 -7.64 (m, 3H), 7, 53 (dd, J=8.3, 1.9 Hz, 1H), 7.44 (dd, J=7.6, 1.7 Hz, 1H), 7.41 7.27 (m, 5H), 7.26 - 7.07 (m, 3H), 7.01 (dd, J=8.2, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.21 (s, 1H), 5.08 (s, 2H), 2.30 (d, J=7.6 Hz, 1H), 2.24 (s, 1H), 2.22 ( s, 1H), 0.88 (q, J=6.7 Hz, 1H), 0.41 - 0.29 (m, 2H), 0.02 - 0.01 (m, 2H); MS (IER ⁺ ): MS (IER+) 622.3 (M+1), MS (IER-) 620.3 (M-1).

Step 5. Preparation of tert-butyl-3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (49g ).

Into a stirred solution of N-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49f) (1 .11 g, 1.786 mmol) in anhydrous methanol (20 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.531 g, 2.232 mmol) was added, then sodium borohydride (0.540 g, 14.28 mmol) was added in small portions ) for 5 min. The reaction mixture was stirred for 45 min at 0°C, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.929 mL, 17.86 mmol), stirred for an additional 30 min and concentrated in vacuo. The residue was treated with water (50 ml) and extracted with chloroform (2x50 ml). The organic layers were combined, dried over anhydrous MgSO4, filtered, and the excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 100%)] to give tert-butyl-3-(5-(3-((2-(benzyloxy)phenyl) (cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (49g) (525 mg, 40% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.65 (s, 1H, exchange with D2O), 7.62 (s, 2H), 7.58 - 7.28 (m, 12H), 7.07 (dd, J=50.3, 30.3 Hz, 4H), 5.21 (s, 1H), 5.09 (s, 2H), 4.18 (d, J=6.2 Hz, 2H) , 2.25 (d, J=15.2 Hz, 3H), 1.36 (s, 9H), 0.87 (s, 1H), 0.34 (s, 2H), -0.00 (s , 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77; MS (IER ⁺ ): MS (IER+) 726.5 (M+1), MS (IER-) 724.4 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49h) .

Into a solution of tert-butyl-3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (49g) ( 0.496 g, 0.683 mmol) in methanol (30 ml), hydrogen chloride (4N in dioxane) (4.27 ml, 17.08 mmol) and palladium (10% on carbon support) (0.218 g, 0.205 mmol) were added. The reaction mixture was hydrogenated at 60 psi (414 kPa) for 14 hours at room temperature. The reaction mixture was filtered through a small pad of Celite, which was washed successively with methanol (2x25 ml) and ethyl acetate (25 ml). Excess solvents were pumped out under reduced pressure. The residue was dissolved in isopropanol (15 ml), then the solution was treated with diethyl ether (30 ml), refluxed for 1 hour, and cooled to room temperature. The resulting solid was collected by filtration. The solid was dissolved in methanol, filtered through a syringe filter and the excess solvent was pumped out, so

- 128 045731 this cycle was repeated three times, after which the compound was dried under reduced pressure to obtain 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (49h) (211 mg, 58% yield) as an off-white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.36 (s, 1H, exchange with D ₂ O), 10.02 (s, 1H, exchange with D ₂ O), 9.76 (s, 1H, exchange with D2O), 8.56 (s, 3H, exchange with D2O), 7.83 (t, J=1.7 Hz, 1H), 7.77 -7.69 ( m, 3H), 7.68 - 7.47 (m, 5H), 7.40 (t, J=7.9 Hz, 1H), 7.23 - 7.12 (m, 1H), 6.97 (dd, J=8.3, 1.2 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 5.83 5.65 (m, 1H), 4.11 (q , J=5.7, 5.2 Hz, 2H), 2.83 - 2.64 (m, 2H), 1.22 - 1.07 (m, 1H), 0.54 (dt, J=7 ,9, 3.0 Hz, 2H), 0.31 (t, J=5.0 Hz, 2H); 1H NMR (300 MHz, DMSO-d;, D2O) δ 10.96 (s, 1H), 7.80 (s, 1H), 7.72 (t, J=1.8 Hz, 1H), 7. 69 - 7.38 (m, 8H), 7.27 - 7.17 (m, 1H), 6.99 - 6.86 (m, 2H), 5.71 (s, 1H), 4.13 ( s, 2H), 2.75 (d, J=7.3 Hz, 2H), 1.09 (tt, J=8.1, 4.8 Hz, 1H), 0.69 - 0.45 (m , 2H), 0.40 - 0.17 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d;) δ -60.75; MS (ESI ⁺ ): MS (ESI+) 536.3 (M+1), 534.3 (M-1), 570.3 (M+Cl); analysis, calculation for: C ₂ 9H ₂ 8F3N ₅ O ₂ -6H ₂ O-2.75HCl: C, 46.82; H, 5.79; Cl, 13.11; N, 9.41; experiment: C, 47.02; H, 5.49; Cl, 12.78; N, 9.37.

Step 7. Preparation of (+)-1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (49i) and (-)-1-(3-(aminomethyl)phenyl)N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (49j).

1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (49h) (1, 09 g) were separated by chiral preparative HPLC using CHIRALPAK AY-H, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 90% ACN/10% MeOH/0.1% DEA, UV=320 nm, with receiving:

1. (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (49i ) (0.5415 g, e.i. >99%) Rt=4.672 min (100%) (peak 1, corresponding to 49i), Rt=5.448 (0% peak 2, corresponding to 49j). The resulting product was purified again by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-25% methanol in chloroform for 13 minutes) to give pure (+)-1-(3-(aminomethyl)phenyl)-N-( 3((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49i) (0.31 g) as a white solid. Optical rotation: +52.03 (MeOH, 1.18); 1H NMR (300 MHz, DMSO- _d6 ) δ 11.64 (s, 1H), 10.73 (s, 1H), 7.67 - 7.61 (m, 1H), 7.59 - 7.50 (m, 3H), 7.46 - 7.40 (m, 2H), 7.31 (dq, J=4.9, 2.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.20 (dt, J=7.9, 1.4 Hz, 1H), 7.02 (dtd, J=7.4, 4.5, 4.0, 1.7 Hz, 2H), 6.73 - 6.64 (m, 2H), 5.00 (s, 1H), 3.77 (s, 2H), 2.47 - 2.37 (m, 1H), 2.33 - 2.21 (m, 1H), 1.00 - 0.90 (m, 1H), 0.40 (dt, J=9.0, 2.9 Hz, 2H), 0.17 - 0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.68; MS (IER+) 536.3 (M+1); (IER-) 534.3 (M-1). The free base (+)-1-(3-(aminomethyl)phenyl)-N-(3((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-carboxamide (49i) was dissolved in methanol and added 2.5 ml of 2N. HCl in methanol. Concentrate the mixture to dryness in vacuo to obtain HCl salt (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (49i) (300 mg); 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.32 (s, 1H), 9.88 (d, J=11.6 Hz, 1H), 9.63 (s , 1H), 8.44 (s, 3H), 7.81 (s, 1H), 7.72 (t, J=1.7 Hz, 1H), 7.70 - 7.59 (m, 4H) , 7.59 - 7.48 (m, 3H), 7.41 (t, J=7.9 Hz, 1H), 7.24 - 7.14 (m, 1H), 6.97 - 6.84 (m, 2H), 5.72 (d, J=6.6 Hz, 1H), 4.12 (q, J=5.8, 5.4 Hz, 2H), 2.73 (d, J= 6.4 Hz, 2H), 1.19 - 1.01 (m, 1H), 0.65-0.46 (m, 2H), 0.38 - 0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.75; MS (IER+) 536.3 (M+1); (IER-) 570.3 (M+Cl); analysis, calculation for C ₂ 9H ₂ 8F3N ₅ O ₂ -2HCl-1.25H ₂ O: C, 55.20; H, 5.19; Cl, 11.24; N, 11.10; experiment: C, 55.37; H, 5.20; Cl, 10.80; N, 10.61;

2. (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (49j ) (0.670 g, 76.341% e.i.) Rt=4.668 min (11.8295%) (peak 1, corresponding to 49i), Rt=5.447 (88.1705%, peak 2, corresponding to 49j). The resulting product was purified again by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-30% methanol in chloroform for 30 minutes) to give pure (-)-1-(3-(aminomethyl)phenyl)-M-( 3((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (49j) (0.461 g) as a yellow waxy solid. Optical rotation -40.85 (MeOH, 2.11); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H, exchange with D2O), 7.65 (d, J=2.2 Hz, 1H), 7.56 (q, J=2 .7, 1.6 Hz, 2H), 7.52 (s, 1H), 7.47 - 7.41 (m, 2H), 7.33 - 7.27 (m, 3H), 7.22 ( dd, J=10.0, 8.5 Hz, 1H), 7.03 (ddd, J=7.1, 4.2, 2.4 Hz, 2H), 6.72 - 6.65 (m, 2H), 5.00 (s, 1H), 3.78 (s, 2H), 2.46 - 2.39 (m, 1H), 2.26 (dd, J=12.3, 7.0 Hz , 1H), 0.94 (d, J=7.3 Hz, 1H), 0.40 (dt, J=8.7, 2.8 Hz, 2H), 0.17 - 0.03 (m, 2H); 1H NMR (300 MHz, DMSO-d6 D2O) δ 7.65 (d, J=2.0 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.45-7.41 (m , 2H), 7.36 - 7.27 (m, 3H), 7.26 - 7.17 (m, 1H), 7.03 (t, J=7.5 Hz, 2H), 6.71 ( d, J=1.5 Hz, 1H), 6.70 - 6.68 (m, 1H), 5.00 (s, 1H), 3.76 (s, 2H), 2.45- 2.38 (m, 1H), 2.25 (dd, J=12.2, 7.0 Hz, 1H), 0.96 (dd, J=14.1, 7.1 Hz, 1H), 0.51 - 0.29 (m, 2H), 0.08 (dt, J=5.3, 2.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.70; MC (IER+) 536.3 (M+1), 534.3 (M-1). Free base (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 49j) (0.451 g) was dissolved in methanol (15 ml) and 4.21 ml of 2N was added. HCl in methanol (10 eq.). Concentrate the mixture to dryness in vacuo to obtain

- 129 045731 HCl salts (-)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5- carboxamide (49j) (386 mg) as a whitish solid; ^1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.35 (s, 1H), 9.95 (s, 1H), 9.70 (s, 1H), 8. 50 (s, 3H), 7.82 (t, J=1.8 Hz, 1H), 7.75- 7.67 (m, 3H), 7.64 (dt, J=7.7, 1, 8 Hz, 2H), 7.60 - 7.48 (m, 3H), 7.45- 7.26 (m, 4H), 7.18 (ddd, J=8.6, 7.3, 1, 6 Hz, 1H), 6.96 (dd, J=8.2, 1.2 Hz, 1H), 6.93 -6.83 (m, 1H), 6.73 (s, 2H), 6, 10 (s, 6H), 5.72 (t, J=6.6 Hz, 1H), 4.12 (d, J=5.8 Hz, 2H), 2.73 (d, J=6.1 Hz, 2H), 1.12 (s, 1H), 0.67 - 0.47 (m, 2H), 0.30 (h, J=4.0 Hz, 2H); ¹ H NMR (300 MHz, DMSO-d6, D2O) δ 10.95 (s, 1H), 7.79 (s, 1H), 7.71 (t, J=1.8 Hz, 1H), 7, 63 (d, J=4.8 Hz, 2H), 7.60 (dd, J=3.7, 2.0 Hz, 1H), 7.56 (td, J=4.5, 2.1 Hz , 2H), 7.52 (t, J=2.0 Hz, 1H), 7.50 - 7.43 (m, 3H), 7.22 (ddd, J=8.6, 7.3, 1 .6 Hz, 1H), 7.01 - 6.85 (m, 2H), 5.71 (s, 1H), 4.13 (s, 2H), 2.75 (d, J=7.2 Hz , 2H), 1.18 - 0.99 (m, 1H), 0.71 - 0.47 (m, 2H), 0.40 -0.16 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.76; MS (ESI+) 536.3 (M+1), 534.3 (M-1), 570.3 (M+Cl).

Scheme 50

nh ₂ chiral separation iid (+)-isomer 50h (-)-isomer

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50f); (+)-1-(3-(aminomethyl)phenyl)N(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (50g) and ( -)-1-(3-(aminomethyl)phenyl)-№(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (5 0h) .

Step 1. Preparation of (3-aminophenyl)(4-nitrophenyl)methanol (50b).

To a solution of 4-nitrobenzaldehyde (50a) (5 g, 32.4 mmol) in tetrahydrofuran (60 ml) was added a solution of 3-[bis(trimethylsilyl)amino]phenylmagnesium chloride (49c) (36.0 g, 36 mmol) at 0 °C. The reaction mixture was stirred for 2 hours at 0°C and the reaction was quenched with saturated aqueous NH ₄ Cl (100 ml). The reaction mixture was extracted with ethyl acetate (2x120 ml). Combine the organic layers, wash with brine (100 ml), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography [silica gel, 120 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give (3-aminophenyl)(4-nitrophenyl)methanol (50b) (3.524 g , 45%) in the form of a dark brown viscous substance; Ή NMR (300 MHz, DMSO-d ₆ ) δ 8.22 - 8.14 (m, 2H), 7.68 - 7.57 (m, 2H), 6.94 (t, J=7.7 Hz , 1H), 6.59 -6.49 (m, 2H), 6.40 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 6.06 (d, J=3 .8 Hz, 1H), 5.65 (d, J=3.8 Hz, 1H), 5.05 (s, 2H); MS (IER+) 245.2 (M+1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50c).

In a 100 ml one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbo

- 130 045731 new acid (9i) (1.381 g, 4.91 mmol), (3-aminophenyl)(4-nitrophenyl)methanol (50b) (1.19 g, 4.91 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (6.65 g, 13.98 mmol), N,N-dimethylformamide (80 mL) and N-ethyl-N-isopropylpropan-2-amine (20.00 mL, 115 mmol) were added sequentially under positive flow nitrogen at room temperature. The resulting reaction mixture was stirred at room temperature for 14 h under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (300 ml), washed with water (2x120 ml), brine (120 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 120 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(4- nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50c) (3.8 g, 54%) as a light brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.23 - 8.14 (m, 3H), 8.00 (dt, J=7.8, 1.3 Hz , 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 - 7.61 (m, 5H), 7.57 (dt, J=8 ,1, 1.4 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.21 -7.15 (m, 1H), 6.31 (d, J=3, 9 Hz, 1H), 5.85 (d, J=3.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.97; MS (IER+) 530.3 (M+23).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50d).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (50c) (1.9 g, 3. 74 mmol) in dichloromethane (60 ml) at 0°C, add thionyl chloride (0.790 ml, 10.67 mmol) and warm to room temperature for 2 hours. The reaction is quenched with triethylamine (4.60 ml, 33.0 mmol), stirred mixture at room temperature for 1 hour, then treated with cyclopropylmethanamine (5.49 g, 74.9 mmol), concentrated to remove most of the dichloromethane, then added acetonitrile (45 ml), stirred at 70°C for 19 hours and concentrated dry in a vacuum. The residue was treated with chloroform (200 ml), washed with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give 1-(3-cyanophenyl)-M-(3-((cyclopropylmethylamino)(4-nitrophenyl )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50d) (466 mg) as a brown viscous substance which was of sufficient purity for use in the next step; MS (IER+) 561.3 (M+1).

Step 4. Preparation of tert-butyl-3-(5-((3-((4-tert-butyloxycarbonylaminophenyl)-((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1 -yl)benzylcarbamate (50e).

In a stirred solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50d) (458 mg, 0.817 mmol) in anhydrous methanol (12 ml), cooled to 0°C, di-tert-butyl dicarbonate (540 mg, 2.451 mmol) and nickel (II) chloride hexahydrate (105 mg, 0.442 mmol) were added and then borohydride was added in small portions sodium (0.540 g, 14.28 mmol) for 5 minutes. The reaction mixture was stirred for 45 min at 0°C, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.410 ml, 3.75 mmol), stirred for another 30 min and concentrated in vacuo. The residue was treated with ethyl acetate (120 ml), washed with water (60 ml). The aqueous layer was again extracted with ethyl acetate (80 ml). Combine the organic layers, wash with brine, dry over anhydrous MgSO4, filter and concentrate in vacuo. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-((3-((4-tert- butyloxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-N-pyrazol-1yl)benzylcarbamate (50e) (81 mg, 3% in 2 steps) as a white solid; MS (IER+) 735.5 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-M-(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50f) .

Into a solution of tert-butyl-3-(5-((3-((4-tert-butyloxycarbonylaminophenyl)-((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )benzylcarbamate (50e) (79 mg, 0.108 mmol) in 1,4-dioxane (8 ml), hydrogen chloride (1.2 ml, 4.8 mmol, 4 M in 1,4 dioxane) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was diluted with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-(3-((4 -aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50f) (41 mg) as a light yellow viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.56 (s, 1H), 7.54 - 7.46 (m, 2H), 7.46 - 7.38 (m, 2H), 7.31 (dt, J=6.5, 2.5 Hz, 1H), 7.22 (t, J= 7.8 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.03 - 6.96 (m, 2H), 6.51 - 6.41 (m, 2H), 4.90 (s, 2H), 4.61 (s, 1H), 2.26 (d, J=6.7 Hz, 2H), 2.05 (s, 2H), 0.90 (p, J=7, 0 Hz, 1H), 0.44 - 0.22 (m, 2H), 0.09 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.70; MS (IER+) 535.3 (M+1), (IER-) 533.3 (M-1); ICS (KBr tablet, ^cm'1 ): 3441, 3005, 1616, 1558, 1243; analysis, calculation for C ₂₉ H ₂₉ F ₃ N ₆ O-1.0H ₂ O: C, 63.03; H, 5.65; N, 15.21; experiment: C, 63.42; H, 5.41; N, 14.83.

Step 6. Preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 -carboxamide (50g) and (-)-1 -(3 -(aminomethyl)phenyl)

- 131 045731 No. (3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5carboxamide (50h).

1-(3-(Aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (50f) (0.201 g) separated by chiral preparative HPLC on a CHIRALPAK IC column, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 70% hexane/30% EtOH/0.1% DEA, UV=254 nm, obtaining:

1. (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (50g ) (0.091 g, Rt=7.73 min (100%), e.i. >99.9%). Optical rotation +10.37 (MeOH, 0.54); ¹ H NMR (300 MHz, methanol) δ 7.55-7.50 (m, 2H), 7.48 - 7.42 (m, 3H), 7.45-7.34 (m, 1H), 7 .32 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.18 (dt, J=7.7, 1.4 Hz, 1H), 7.13 - 7, 06 (m, 2H), 6.70 6.62 (m, 2H), 4.75 (s, 1H), 3.83 (s, 2H), 2.36 (d, J=6.9 Hz, 2H), 1.03 - 0.88 (m, 1H), 0.52 - 0.40 (m, 2H), 0.06 (qd, J=4.5, 2.9 Hz, 2H); ¹ H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.54 - 7.40 (m, 4H), 7.31 (dt, J=6.2, 2.4 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.16 - 7 .10 (m, 1H), 7.04 - 6.95 (m, 2H), 6.49 - 6.42 (m, 2H), 4.91 (s, 2H), 4.61 (s, 1H ), 3.78 (s, 2H), 2.26 (d, J=6.7 Hz, 2H), 0.97 - 0.84 (m, 1H), 0.40 0.31 (m, 2H ), 0.09 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, MeOD) δ -63.72; ¹⁹ F NMR (282 MHz, DMSO) δ 60.71; MC (IER+) 557.3 (M+Na); (IER-) 533.3 (M-1). Free base (+)-1-(3-(aminomethyl)phenyl)N-(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50g ) (0.085 g, 0.159 mmol) was dissolved in methanol (5 ml) and HCl (0.133 ml, 1.590 mmol) was added. The reaction mixture was concentrated to dryness in vacuum and distilled twice with chloroform, dried in vacuum to obtain trihydrochloride (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4aminophenyl)(cyclopropylmethylamino)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50g) (0.07 g, 0.109 mmol) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.08 (s, 2H), 8.50 (s, 3H), 7.91 - 7.81 (m, 1H) , 7.73 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.66 - 7.57 (m, 5H), 7.56 - 7.49 (m, 2H ), 7.44 (t, J=7.9 Hz, 1H), 7.15 (d, J=7.9 Hz, 2H), 5.54 (t, J=6.2 Hz, 1H), 4.12 (q, J=5.8 Hz, 2H), 2.88 - 2.59 (m, 2H), 1.21-1.09 (m, 1H), 0.65-0.45 ( m, 2H), 0.40 - 0.19 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.78; MS (IER+) 535.4 (M+1), 557.3 (M+Na); (IER-) 533.3 (M-1), 569.3 (M+Cl); analysis, calculation for C29H29F ₃ N6O-3HCl-1.75H2O: C, 51.56; H, 5.30; N, 12.44; experiment: C, 51.68; H, 5.61; N, 11.54;

2. (-)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (50h ) (0.132 g, Rt=10.449 min (99.6604%), e.i. >99.4%); 1H NMR (300 MHz, methanol-d4) δ 7.72 (t, J=1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.55 (ddq, J =13.2, 6.1, 1.6 Hz, 4H), 7.44 - 7.34 (m, 2H), 7.28 (dt, J=7.9, 1.4 Hz, 1H), 7.21 - 7.13 (m, 2H), 6.75 - 6.60 (m, 2H), 5.14 (s, 1H), 4.14 (s, 2H), 2.65 (d, J=7.2 Hz, 2H), 1.12 - 0.98 (m, 1H), 0.67 - 0.52 (m, 2H), 0.27 - 0.14 (m, 2H); ¹⁹ F NMR (282 MHz, methanol-d4) δ -63.80; MS (IER+) 535.4 (M+1); 557.3 (M+Na); (IER-) 569.3 (M+Cl). The resulting product was purified again by flash column chromatography (silica gel, 4 g, eluted with mixtures of 0-100% CMA-80 in chloroform) to give pure free base (-)-1-(3(aminomethyl)phenyl)-N-(3 -((4-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (50h) (36 mg) as a white solid. Optical rotation: -11.5 (MeOH, 1.8). The free base obtained above is (-)-1-(3-(aminomethyl)phenyl)-N-(3-((4aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 50h) (0.036 g, 0.067 mmol) was dissolved in methanol (5 ml) and HCl (0.056 ml, 0.673 mmol) was added. The reaction mixture was concentrated to dryness in vacuo and distilled twice together with chloroform, dried in vacuo to obtain trihydrochloride (-)-1-(3-(aminomethyl)phenyl)-N-(3-((4aminophenyl)(cyclopropylmethylamino)methyl)phenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (50h) (0.04 g) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.12 - 9.91 (m, 2H), 8.47 (s, 3H), 7.88 - 7.81 ( m, 1H), 7.74 -7.71 (m, 1H), 7.70 (s, 1H), 7.66 - 7.48 (m, 7H), 7.44 (t, J=7, 9 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 5.51 (d, J=6.6 Hz, 1H), 4.12 (q, J=5.7 Hz , 2H), 2.69 (q, J=6.4 Hz, 2H), 1.23 1.05 (m, 1H), 0.65- 0.44 (m, 2H), 0.39 - 0 .20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.78; MS (IER+) 535.4 (M+1); 557.4 (M+Na); (IER-) 569.3 (M+Cl); analysis, calculation for C ₂₉ H ₂₉ F ₃ N ₆ O-3HCl-3H ₂ OC, 49.90; H, 5.49; N, 12.04; experiment: C, 49.85; H, 5.49; N, 11.45.

- 132 045731

Scheme 51

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-H-(3-((cyclopropylmethylamino)(2-methoxynaphthalin-1 -yl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazol-5- carboxamide (51f); (-)-1-(3 -(aminomethyl)phenyl)-No(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide ( 51g) and (+)-1-(3-(aminomethyl)phenyl)-I-(3-((cyclopropylmethylamino)(2methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (51h).

Step 1. Preparation of (3-aminophenyl)(2-methoxynaphthalene-1-yl)methanol (51b).

To a stirred solution of 2-methoxynaphthalene-1-carbaldehyde (51a) (1.2 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was neutralized

2n. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). The organic layers were combined, washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(2methoxynaphthalene-1-yl)methanol (51b) (1.7 g, yield 94%) as a white solid; ^1H NMR (300

MHz, DMSO-d ₆ ) δ 8.26 - 8.18 (m, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.48 (d, J=9.1 Hz, 1H), 7.29 - 7.16 (m, 2H), 6.86 (t, J=7.7 Hz, 1H), 6.67 - 6 ,60 (m, 1H), 6.56 (dt, J=2.3, 1.2 Hz, 1H), 6.49 (dq, J=7.7, 1.1 Hz, 1H), 6, 31 (ddt, J=7.8, 2.0, 0.9 Hz, 1H), 5.82 (d, J=4.6 Hz, 1H), 4.90 (s, 2H), 3.96 (s, 3H); MS (IER+) 302.2 (M+Na), MS (IER-) 557.2 (2M-1).

Step 2. Preparation of {3-[hydroxy-(2-methoxynaphthalen-1-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (51c).

(3-Aminophenyl) (2 -methoxynaphthalen-1-yl)methanol (51b) (1.7 g, 6.085 mmol), N-ethyl-N-isopropylpropan-2-amine (8.5 ml, 48.68 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP , 2.836 g, 6.085 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (40 ml), washed with water (2x40 ml), brine (100 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%) to give {3-[hydroxy-(2methoxynaphthalene-1-yl)methyl]phenyl}amide 2-(3- cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (51c) (1.8 g, 54.5% yield) as a pale sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.21 - 8.11 (m, 2H), 7.99 (dt, J=7.8, 1.3 Hz , 1H), 7.93 - 7.86 (m, 2H), 7.83 - 7.77 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.69 ( s, 1H), 7.65-7.60 (m, 1H), 7.53 (dd, J=11.8, 8.1 Hz, 2H), 7.29 -7.17 (m, 3H) , 7.11 - 7.04 (m, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.10 (d, J=4.6 Hz, 1H), 3.98 ( s, 3H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (51d).

In a solution of {3-[hydroxy-(2-methoxynaphthalene-1-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-tri

- 133 045731 fluoromethyl-2H-pyrazole-3-carboxylic acid (51c) (1.8 g, 3.317 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (0.74 g, 6.635 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (3.54 g, 49.77 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give {3-[(cyclopropylmethylamino)(2-methoxynaphthalene-1-yl)methyl]phenyl}amide 2-( 3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (51d) (1.05 g, 53%) as a pale liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.44 - 8.36 (m, 1H), 8.24 (t, J=1.8 Hz, 1H), 8.09 (dt, J=7.7, 1.4 Hz, 1H), 7.96 (dd, J=11.7, 8.1 Hz, 3H), 7.83 (d, J=7, 9 Hz, 1H), 7.76 (d, J=7.4 Hz, 2H), 7.63 (d, J=8.2 Hz, 1H), 7.57 (d, J=9.0 Hz , 1H), 7.52 - 7.34 (m, 2H), 7.29 (t, J=7.8 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 5 .99 (s, 1H), 3.96 (s, 3H), 2.72 - 2.62 (m, 2H), 2.29 - 2.13 (m, 1H), 1.11 - 0.85 (m, 1H), 0.51 - 0.37 (m, 2H), 0.20 - 0.06 (m, 1H), 0.05 - 0.07 (m, 1H).

Step 4. Preparation of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(2- methoxynaphthalene-1-yl)methyl)(cyclopropylmethyl)carbamate (51e).

In a solution of {3-[(cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl]phenyl}amide 2-(3cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (51d) (1.0 g, 1.678 mmol) in MeOH (20 mL), cooled in ice/water, nickel(II) chloride hexahydrate (0.48 g, 2.01 mmol) and Boc anhydride (1.1 g, 5.036 mmol) were added, then sodium borohydride (0.38 g, 10.073 mmol) was added portionwise over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N-(2-aminoethyl)ethane-1,2-diamine (0.5 ml, 4.197 mmol), then stirred for an additional 0.5 hours. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(2-methoxynaphthalene-1-yl)methyl)(cyclopropylmethyl)carbamate (51e) (0.8 g, 68.13%) as white solid matter; ¹ H NMR (300 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.99 (d, J=9.1 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.62 - 7.54 (m, 1H), 7.55-7.40 (m, 3H), 7.43 - 7.37 (m, 3H), 7.35-7.24 (m, 4H ), 7.15 (s, 1H), 6.91 - 6.81 (m, 1H), 4.17 (d, J=6.2 Hz, 2H), 3.42 (s, 3H), 3 .07 (dd, J=14.6, 6.8 Hz, 1H), 1.38 (d, J=5.3 Hz, 18H), 0.34 (p, J=6.7 Hz, 1H) , 0.00 (td, J=8.8, 4.5 Hz, 1H), -0.08 - -0.25 (m, 1H), -0.21 - -0.39 (m, 1H) , -0.65- -0.87 (m, 1H).

Step 5. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (51f).

Into a solution of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamido)phenyl)(2-methoxynaphthalene-1 -yl)methyl)(cyclopropylmethyl)carbamate (51 e) (0.8 g, 1.143 mmol) in methanol (16 ml) was added conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. The product was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-15% methanol in dichloromethane) to give the free base 1-(3-(aminomethyl)phenyl)-N(3-((cyclopropylmethylamino)(2-methoxynaphthalene -1-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (51f) (170 mg, 24.8%) as a white solid; 1H NMR (300 MHz, DMSO-Y6) δ 10.82 (s, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H ), 7.90 (d, J=8.1 Hz, 1H), 7.82 - 7.68 (m, 2H), 7.66 - 7.43 (m, 6H), 7.42 - 7, 24 (m, 3H), 6.12 (s, 1H), 4.11 (s, 2H), 3.95 (s, 3H), 2.78 2.70 (m, 1H), 2.66 ( d, J=7.4 Hz, 2H), 0.92 - 0.69 (m, 1H), 0.48 - 0.35 (m, 2H), 0.10 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77; MS (IER+) 600.4 (M+1); (IER-) 634.3 (M+Cl); 1-(3-(aminomethyl)phenyl)-N3(((cyclopropylmethyl)amino)(2-methoxynaphthalene-1 -yl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 carboxamide (51f) ( 160 mg) was converted to the hydrochloride salt by dissolving the free base in methanol (5 ml) and treating with 10 equivalents of conc. HCl. The resulting solution was concentrated to dryness in vacuo, dried in vacuo to obtain the racemate of 1-(3-(aminomethyl)phenyl)N-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalene-1 -yl)methyl)phenyl)- dihydrochloride 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (51f) (100 mg, 53%) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.87 (s, 1H), 9.27 (d, J=10.4 Hz, 1H), 8.58 (s , 3H), 8.20 (d, J=8.7 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.95 (dd, J=8.3, 1, 4 Hz, 1H), 7.91 (s, 1H), 7.72 (t, J=1.8 Hz, 1H), 7.69 - 7.36 (m, 10H), 6.35 (t, J=6.4 Hz, 1H), 4.10 (q, J=5.9 Hz, 2H), 4.03 (s, 3H), 2.89 (dt, J=7.5, 4.4 Hz, 1H), 2.80 - 2.64 (m, 1H), 1.12 (ddd, J=12.4, 8.1, 4.9 Hz, 1H), 0.51 (dtt, J= 17.5, 9.3, 4.6 Hz, 2H), 0.34 - 0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77; MS (IER+) 600.4 (M+1); (IER-) 634.3 (M+Cl); analysis, calculation for Сз4Нз2Рз№О2-2НС1-1.75Н2О:

- 134 045731

C, 58.00; H, 5.37; Cl, 10.07; N, 9.95; experiment: C, 58.06; H, 5.45; Cl, 9.93; N, 9.74.

Step 6. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (51g) and (+)-1-(3(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (51h).

Racemate 1 -(3 -(aminomethyl)phenyl)-M-(3-(((cyclopropylmethyl)amino)(2-methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (51f) (2 g) was separated by chiral preparative HPLC on a CHIRALPAK AD-H column, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 80% hexane/20% IPA/0.1% DEA, UV=320 nm, 25°C, obtaining:

1. 1 peak corresponding to (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (51g) (904 mg, Rt=5.191 min, peak 1 corresponding to compound 51g, 99.4822%, Rt=8.194, peak 2 corresponding to compound 51h, 0.5178, 98.96% e.g. And.). The resulting compound was purified again by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-30% MeOH in chloroform for 25 minutes) to give the free base (-)-1-(3-(αminomethyl)phenyl)-N- (3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (51g) (730 mg, 99.38% ee. ); optical rotation: -137.78 (MeOH, 1.645). Free base (-)-1-(3(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5- carboxamide (51g) (720 mg) was dissolved in methanol (8 ml) and 2N was added. HCl (in methanol, 2.25 ml, 10 eq.). The solution was stirred at room temperature for 30 minutes, evaporated to dryness to obtain (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl hydrochloride salt )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (51g) (780 mg) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.86 (dd, J=11.1, 8 ,1 Hz, 2H), 7.63 (s, 1H), 7.52 (q, J=3.1, 1.6 Hz, 3H), 7.47 (d, J=9.1 Hz, 1H ), 7.43 - 7.26 (m, 5H), 7.18 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.89 (s, 1H), 3.86 (s, 3H), 3.76 (s, 2H), 2.11 (t, J=9.5 Hz, 1H), 0.92 (d, J=7, 3 Hz, 1H), 0.42 - 0.27 (m, 2H), 0.08 - 0.02 (m, 1H), -0.04 - -0.16 (m, 1H); analysis, calculation for C ₃₄ H ₃ 2F ₃ N ₅ O2-2HCl-2.5H ₂ O: C, 56.91; H, 5.48; Cl, 9.88; N, 9.76; experiment; C, 57.14; H, 5.42; Cl, 9.47; N, 9.98;

2. 2 peaks corresponding to (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (51h) (922 mg, Rt=5.271 min, 1 peak corresponding to compound 51g, 0.25785%, Rt=8.049, 2 peak corresponding to compound 51h, 99.4215%, 97.67% e .And.). The resulting compound was purified again by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-30% MeOH in chloroform for 25 min) to give the free base (+)-1-(3-(aminomethyl)phenyl)-N- (3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (51h) (0.753 g) as a white solid; optical rotation: +131.32 (MeOH, 2.695). To the free base (+)-1 -(3 -(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalene-1 -yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (51h) (770 mg) in methanol (25 ml) was added 2N. HCl (in methanol, 6.5 mL, 10 eq.), stirred at room temperature for 30 min and concentrated to dryness in vacuo to give (+)-1-(3-(aminomethyl)phenyl)-M-(3) hydrochloride ((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (51h) (753 mg) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.98 (s, 1H, exchange with _D2O ), 9.88 (s, 1H, exchange with _D2O ), 9.25 (s, 1H, exchange with D ₂ O), 8.58 (s, 3H, exchange with D ₂ O), 8.20 (d, J=8.7 Hz, 1H), 8.07 (d, J=9.2 Hz , 1H), 7.99 - 7.87 (m, 2H), 7.72 (t, J=1.8 Hz, 1H), 7.70 - 7.54 (m, 6H), 7.53 7 .39 (m, 3H), 6.50 - 6.19 (m, 1H), 4.10 (d, J=5.4 Hz, 2H), 4.03 (s, 3H), 2.89 ( d, J=11.1 Hz, 1H), 2.73 (s, 1H), 1.13 (h, J=7.3, 6.8 Hz, 1H), 0.50 (ttd, J=13 ,2, 8.9, 4.3 Hz, 2H), 0.23 (ddq, J=18.4, 9.2, 4.6 Hz, 2H); 1H NMR (300 MHz, DMSO-d6 D ₃ O) δ 8.19 (d, J=8.8 Hz, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.96 ( dd, J=8.3, 1.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.71 (t, J=1.8 Hz, 1H), 7, 66 - 7.55 (m, 6H), 7.54 - 7.38 (m, 4H), 6.34 (s, 1H), 4.12 (s, 2H), 4.03 (s, 3H) , 2.91 (dd, J=12.9, 6.8 Hz, 1H), 2.73 (dd, J=13.0, 7.6 Hz, 1H), 1.08 (q, J=6 ,1, 5.0 Hz, 1H), 0.53 (dtd, J=17.3, 9.4, 8.9, 4.7 Hz, 2H), 0.23 (d.hept., J= 18.0, 4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.74; MS (IER+) 600.3 (M+1), MS (IER-) 598.3 (M-1), 634.3 (M+Cl); analysis, calculation for

C34H ₃ 2F ₃ N ₅ O2-2HCl-2.75H2O: C, 56.55; H, 5.51; Cl, 9.82; N, 9.70; experiment; C, 56.42; H, 5.40; Cl, 10.26; N, 9.66.

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Scheme 52

Receiving example

1-(3-(aminomethyl)phenyl)-N(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (52h).

Step 1. Preparation of N(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-N(trimethylsilyl)silanamine (52b)

To a stirred solution of 5-bromo-2-fluoroaniline (52a) (225 g, 1184 mmol) in triethylamine (3301 mL, 20 eq.) was added trimethylsilyl trifluoromethanesulfonate (481 mL, 2664 mmol) at room temperature. [Note: Heat was generated during the addition, but it was not necessary to cool the flask.] The mixture was heated at the reverse condensation temperature for 16 hours and cooled to room temperature. The two layers were separated. [Note: Do not expose the solution to air or moisture during separation.] The dark lower solution was discarded and the upper layer was concentrated in vacuo to remove excess triethylamine. The oily residue was transferred to a 1000 ml flask and distilled under high vacuum. The compound began to distill off at 100°C, 0.5 mmHg. The first fraction (approximately 15 ml) was discarded and the second fraction was collected continuously at 100°C, 0.5 mmHg, to give Na(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-Na( trimethylsilyl)silanamine (52b) (364 g, 1089 mmol, 92% yield). The said compound was in all cases used freshly prepared in the next step; ¹ H NMR (300 MHz, chloroform-d) δ 7.17 - 7.11 (m, 1H), 7.09 (dd, J=7.5, 2.5 Hz, 1H), 6.89 (d , J=0.9 Hz, 1H), 0.08 (d, J=0.6 Hz, 18H).

Step 2. Preparation of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c).

To magnesium turnings (33.1 g, 1361 mmol) in tetrahydrofuran (15 ml) was added iodine (1.381 g, 5.44 mmol), then N-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl -N-(trimethylsilyl)-silanamine (52b) (4 g) to activate the reaction for approximately 5 min (discoloration of the iodine occurred). The remaining solution of K-(5-bromo-2-fluorophenyl)-1,1,1-trimethyl-K-(trimethylsilyl)silanamine (52b) (364 g, 1089 mmol) in tetrahydrofuran (1000 ml) was then added slowly over 3 hours (reaction temperature during addition was approximately 60°C). The resulting dark gray solution was stirred overnight to give (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (397 g, 1107 mmol, 102% yield, approximately 1M solution), which was used freshly at the next stage.

Step 3. Preparation of 4-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (52e).

To a solution of 4-formylbenzonitrile (52d) (6.56 g, 50 mmol) in tetrahydrofuran (50 ml), cooled to 0°C, was added Grignard reagent (52c) (63.0 ml, 50.4 mmol, ~0. 8M in THF), stirred at 0°C for 1 hour and at room temperature for 17 hours. The reaction was quenched with 1N. HCl (aq, 100 ml), stirred for 3 hours, neutralized with NaOH (2N, aq) to pH = ~8. The reaction mixture was extracted with ethyl acetate (200, 150 ml). The combined extracts were washed with brine (120 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)] to give 4-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (52e) (6.37 g) as a brown viscous substance, which was used as such in the next step. MS (IER+): 265.2 (M+23).

Step 4. Preparation of tert-butyl-3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52f) .

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To a solution of 4-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (52e) (3 g, 12.38 mmol) in DMF (80 ml) was added 1-(3-((tert-butoxycarbonylamino) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (4.77 g, 12.38 mmol), N-ethyl-N-isopropylpropan-2-amine (18.00 ml, 103 mmol), bromo-tri-pyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBrOP, 5.94 g, 12.48 mmol) and stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate (400 ml), washed with water (200, 150 ml), brine (150 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 120 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3(5-(5-((4-cyanophenyl)- (hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (52f) (1.998 g) as a light yellow solid, which was used as such in the next step; MS (IER+): 632.3 (M+23).

Step 5. Preparation of tert-butyl-3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52g ).

Into a solution of tert-butyl-3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52f) ( 1.007 g, 1.652 mmol) in dichloromethane (32 ml) at 0°C, add thionyl chloride (0.260 ml, 3.52 mmol) and warm to room temperature over 2 hours. The reaction is quenched with triethylamine (1.5 ml, 10.76 mmol ), stirred the mixture at room temperature for 1 hour, then treated with cyclopropylmethanamine (3.20 ml, 35.8 mmol), concentrated to remove most of the dichloromethane, then added acetonitrile (24 ml), stirred at 70°C for 19 h and concentrated to dryness in vacuo. The residue was treated with chloroform (200 ml), washed with water (100 ml), dried over MgSO4, then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino) methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52g) (244 mg, 3% in three steps) as a yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.56 (s, 1H), 7.80 - 7.73 (m, 2H), 7.67 - 7.29 (m, 10H), 7.26 - 7.17 (m, 1H), 4.95 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.25 (d, J=6.9 Hz, 2H) , 1.37 (s, 9H), 0.98 - 0.79 (m, 1H), 0.43 - 0.27 (m, 2H), 0.09 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.81, -123.20; MS (IER+): 663.4 (M+1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-M-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (52N)e

Into a solution of tert-butyl-3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52g) ( 85 mg, 0.128 mmol) in 1,4-dioxane (9 ml), hydrogen chloride (1.400 ml, 5.60 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 18 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-M-(5-((4 -cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (52h) (40 mg, 55%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.82 (s, 1H), 10.43 (s, 2H), 8.42 (s, 3H), 7.95 (s, 5H), 7. 78 - 7.66 (m, 3H), 7.62 (dt, J=7.3, 1.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.48 - 7.36 (m, 1H), 5.81 (d, J=6.9 Hz, 1H), 4.13 (d, J=5.3 Hz, 2H), 2.84 - 2.63 (m, 2H), 1.28 - 1.03 (m, 1H), 0.66 - 0.45 (m, 2H), 0.44 - 0, 14 (m, 2H); ¹ H NMR (300 MHz, DMSO-d6, D2O, exchange NMR) δ 7.95 (d, J=8.2 Hz, 2H), 7.90 - 7.78 (m, 3H), 7.70 (s, 1H), 7.65 (s, 1H), 7.62 - 7.48 (m, 4H), 7.43 (t, J=9.4 Hz, 1H), 5.77 (s, 1H), 4.12 (s, 2H), 2.74 (d, J=7.3 Hz, 2H), 1.15-1.00 (m, 1H), 0.58 (d, J=7 .6 Hz, 2H), 0.29 (d, J=4.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.82, -120.00; MS (IER+): 563.3 (M+1).

1-(3-(aminomethyl)phenyl)-M-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (52h) (21 mg) was dissolved in methanol (10 ml) and treated with 4N. HCl (aq, 0.04 ml), then concentrated to dryness to give HCl salt 1-(3(aminomethyl)phenyl)-M-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (52h) (21 mg) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.98 - 7.91 (m, 2H), 7.90 - 7.79 (m, 3H), 7.73 - 7.49 (m, 7H) , 7.43 (dd, J=10.2, 8.6 Hz, 1H), 5.77 (s, 1H), 4.12 (s, 2H), 2.75 (d, J=7.0 Hz, 2H), 1.14-1.00 (m, 1H), 0.64-0.54 (m, 2H), 0.33 -0.23 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81, -119.99; MS (IER+): 563.3 (M+1); analysis, calculation for C ₃₀ H ₂₆ F ₄ N ₆ O-2.0HCl-2.5H ₂ O: C, 52.95; H, 4.89; N, 12.35; experiment: C, 53.21; H, 4.95; N, 11.71.

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Scheme 53

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (53f).

Step 1. Preparation of (3-aminophenyl)(3-nitrophenyl)methanol (53b).

To a stirred solution of 3-nitrobenzaldehyde (53a) (3.02 g, 20 mmol) in tetrahydrofuran (20 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (24.00 ml, 24, 00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding hydrogen chloride (12N) (4.17 ml, 50.0 mmol), stirred for 1 hour. The reaction mixture was treated with sodium hydroxide (2N) (30.0 ml, 60.0 mmol) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(3nitrophenyl)methanol (53b) (966 mg) as a brown solid; 1H NMR (300 MHz, DMSOd6) δ 8.21 (t, J=2.0 Hz, 1H), 8.08 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7 .78 (ddt, J=7.6, 1.6, 0.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 6.95 (t, J=7.7 Hz, 1H), 6.62 - 6.51 (m, 2H), 6.41 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 6.07 (d, J= 3.9 Hz, 1H), 5.68 (d, J=3.9 Hz, 1H), 5.06 (s, 2H); MS (IER+) 245.2 (M+1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (53 c).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1101 mg, 3.91 mmol), (3-aminophenyl)(3-nitrophenyl) methanol (53b) (956 mg, 3.91 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (1862 mg, 3.91 mmol), N,N-dimethylformamide (DMF) (22 ml) and N- ethyl-N-isopropylpropan-2-amine (DIPEA) (5.50 mL, 31.6 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 13 hours under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (180 ml), washed with water (2x80 ml), brine (80 ml), dried over MgSO4, filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(3- nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (53c) (1.102 g, 65%) as a brown viscous substance; Ή NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.24 (t, J=1.9 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.10 (ddd, J=8.1, 2.4, 1.1 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.83 - 7.55 (m, 6H), 7.31 (t, J=7.8 Hz, 1H), 7.20 (dt, J=7.8, 1.3 Hz, 1H), 6.32 (d, J=4.0 Hz, 1H), 5.88 (d, J=4.0 Hz, 1H ); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.98; MS (IER+) 530.2 (M+23).

Step 3. Preparation of tert-butyl-3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)-(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzylcarbamate (53d).

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A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (53c) (0.865 g, 1.705 mmol) in MeOH (30 ml) was cooled in ice/water and treated with di-tert-butyl dicarbonate (1.503 g, 6.82 mmol) and nickel (II) chloride hexahydrate (0.218 g, 0.917 mmol), then sodium borohydride (0.658 g) was added slowly , 17.05 mmol) for 5 min and stirred at room temperature for 1 h. The reaction mixture was treated with N1-(2aminoethyl)ethane-1,2-diamine (0.840 ml, 7.70 mmol), then stirred at room temperature for 0.5 h and concentrated to dryness. The residue was treated with ethyl acetate (120 ml), washed with water (80 ml). The aqueous phase was again extracted with ethyl acetate (80 ml). The combined extracts were washed with brine (80 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-((3-((3-tert-butyloxycarbonylaminophenyl) (hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (53d) (547 mg, 47%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.70 (s, 1H), 9.30 (s, 1H), 7.57 (s, 2H), 7.55-7.08 (m, 11H ), 6.93 (d, J=7.5 Hz, 1H), 5.90 (d, J=3.7 Hz, 1H), 5.57 (d, J=3.7 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.45 (s, 9H), 1.36 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.79; (IER+) 704.4 (M+23).

Step 4. Preparation of tert-butyl-3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(cyclopropylmethoxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (53e).

Into a solution of tert-butyl-3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (53d ) (531 mg, 0.779 mmol) in dichloromethane (15 ml) at 0°C was added thionyl chloride (0.110 ml, 1.511 mmol), the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with cyclopropylmethanol (5.80 ml , 70.1 mmol), stirred the mixture for 1 hour at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanol (5.80 ml, 70.1 mmol), triethylamine (0.660 ml, 4.74 mmol) was added and heated at 100°C for 13 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in ethyl acetate (150 ml) and washed with water (80 ml), brine (70 ml), dried over MgSO4, then filtered and concentrated. The residue was purified by flash column chromatography [(silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 2:1))] to give tert-butyl-3-(5-((3-((3- tert-butyloxycarbonylaminophenyl)(cyclopropylmethoxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (53e) (243 mg, 42%) as a colorless viscous substance; ¹ H NMR (300 MHz, DMSOd6) δ 10.74 (s, 1H), 9.34 (s, 1H), 7.62 - 7.25 (m, 11H), 7.19 (t, J=7 ,8 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 5.36 (s, 1H), 4, 19 (d, J=6.2 Hz, 2H), 3.27 - 3.15 (m, 2H), 1.45 (s, 9H), 1.36 (s, 9H), 1.12 - 0 .97 (m, 1H), 0.52 -0.39 (m, 2H), 0.21-0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.79; (IER+) 758.4 (M+23).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (53f) .

Into a solution of tert-butyl-3-(5-((3-((3-tert-butyloxycarbonylaminophenyl)(cyclopropylmethoxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (53e ) in methanol (20 ml) was added conc. hydrogen chloride (0.230 ml, 2.76 mmol) and stirred at room temperature for 13 hours. Concentrate the reaction mixture to dryness in vacuo (<30°C). The residue was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give the free base 1-(3-(aminomethyl)phenyl)-N-(3-((3 -aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (53f) (84 mg). The purified product was dissolved in methanol (10 ml) and treated with 4N. HCl (aq, 0.16 ml), then concentrated to dryness to give HCl salt 1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (53f) (91 mg, 55%) as a white solid; 1H NMR (D2O exchange NMR, 300 MHz, DMSO^) δ 7.56 - 7.33 (m, 7H), 7.21-7.10 (m, 2H), 6.98 (d, J=7 .6 Hz, 1H), 6.90 (broads, 2H), 6.78 (d, J=8.1 Hz, 1H), 5.26 (s, 1H), 3.97 (s, 2H ), 3.08 (dd, J=6.9, 1.3 Hz, 2H), 0.97 0.81 (m, 1H), 0.40 - 0.26 (m, 2H), 0.08 - -0.07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.77; MS (IER+) 536.3 (M+1); analysis, calculation for C2 ₉ H2 ₈ F ₃ N ₅ O2-2.0HCl-2.0H ₂ O: C, 54.04; H, 5.32; N, 10.87; experiment: C, 53.63; H, 5.19; N, 10.78.

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Scheme 54

1-(3-(aminomethyl)phenyl)-X-(5-((3-cyanophenyl)(cyclopropylmethylamide) Preparation example of but)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (54e ).

Step 1. Preparation of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b).

To a solution of 3-formylbenzonitrile (54a) (29 g, 217 mmol) in tetrahydrofuran (200 ml), cooled to 0°C, was added freshly prepared Grignard reagent (52c) (245 ml, 221 mmol, ~0.9 M in THF), stirred at 0°C for 1 hour and at room temperature for 18 hours. The reaction was quenched with 1N. HCl (aq, 440 ml), stirred for 3 hours, neutralized with NaOH (2N, aq) to pH = ~8. The reaction mixture was extracted with ethyl acetate (600, 300 ml). The combined extracts were washed with brine (120 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (36.28 g) as a brown viscous substance, which was used as such in the next step; MS (IER+) 265.3 (M+23).

Step 2. Preparation of tert-butyl-3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54c) .

To a solution of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (24.682 g, 102 mmol) in DMF (480 ml) was added 1-(3-((tert-butoxycarbonylamino)methyl) phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxylic acid (10d) (35.0 g, 91 mmol), N-ethyl-X-isopropylpropan-2-amine (132 ml, 758 mmol), hexafluorophosphate (V ) bromo-tri-pyrrolidin-1-ylphosphonium (PyBrOP, 42.8 g, 91 mmol) and stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate (1000 ml), washed with water (500, 400 ml), saline solution (400 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-(5((3-cyanophenyl)(hydroxy)methyl )-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54c) (4.583 g, 5% in two steps) as a yellow solid; 1H NMR (300 MHz, DMSOd6) δ 10.57 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.64 - 7.19 (m, 10H), 6.25 (d, J=4.0 Hz, 1H), 5.78 (d, J=4.0 Hz, 1H), 4.19 (d, J= 6.1 Hz, 2H), 1.37 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81, -123.09; MS (IER+) 632.3 (M+23).

Step 3. Preparation of tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54d) .

In a solution of tert-butyl-3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54c) ( 1.333 g, 2.187 mmol) in dichloromethane (40 ml) at 0°C, add thionyl chloride (0.340 ml, 4.59 mmol) and warm to room temperature over 2 hours. The reaction is quenched with triethylamine (2.0 ml, 14.35 mmol ), stirred the mixture at room temperature for 1 hour, then treated with cyclopropylmethanamine (4.30 ml, 48.0 mmol), concentrated to remove the bulk of the dichloromethane, then added acetonitrile (30 ml), stirred at 70°C for 14 h and concentrated to dryness in vacuo. The residue was treated with chloroform (200 ml), washed with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino) methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (54d) (184 mg,

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13%) in the form of a colorless viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.70 - 7.30 (m, 10H), 7.22 (dd, J=10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J= 6.2 Hz, 2H), 2.26 (d, J=6.6 Hz, 2H), 1.37 (s, 9H), 1.00 - 0.80 (m, 1H), 0.45- 0.28 (m, 2H), 0.12 - -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.80, -123.20; MS (IER+) 663.4 (M+1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (54e).

Into a solution of tert-butyl-3 -(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54d) ( 161 mg, 0.243 mmol) in 1,4dioxane (18 ml), hydrogen chloride (2.60 ml, 10.40 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 16 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1 -(3-(aminomethyl)phenyl)-M-(5-((3 -cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (54e). The pure product was dissolved in methanol (10 ml) and 4N was added. HCl (aq, 0.14 ml), then concentrated to dryness in vacuo to give HCl salt 1-(3-(aminomethyl)phenyl)-K-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2- fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (54e) (74 mg, 48%) as a white solid; 1H NMR (300 MHz, DMSO-d6, D2O exchange NMR) δ 8.13 (t, J=1.7 Hz, 1H), 7.98 - 7.84 (m, 3H), 7.73 - 7 .64 (m, 3H), 7.63 7.48 (m, 4H), 7.44 (dd, J=10.2, 8.6 Hz, 1H), 5.75 (s, 1H), 4 .12 (s, 2H), 2.76 (d, J=7.2 Hz, 2H), 1.17 - 0.94 (m, 1H), 0.68 - 0.47 (m, 2H), 0.34-0.24 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82, -120.02; MS (IER+): 563.3 (M+1); analysis, calculation for C ₃₀ H ₂₆ F ₄ N ₆ O-2.0HCl-3.0H ₂ O: C, 52.26; H, 4.97; N, 12.19; experiment: C, 52.26; H, 5.00; N, 11.72.

Scheme 55

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2fluorophenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (5 5b ).

Step 1. Preparation of tert-butyl-3-(5-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate ( 55 a).

In a solution of tert-butyl-3-(5-(5-((4-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52f (5 .4 g, 8.86 mmol) in dichloromethane (50 ml) and triethylamine (7.51 ml, 53.9 mmol) at 0°C, add thionyl chloride (1.254 ml, 17.19 mmol), the reaction mixture was left to warm to room temperature and stirred for 1.5 hours. The reaction was quenched with triethylamine (7.51 ml, 53.9 mmol), cyclopropylmethanol (26.4 ml, 319 mmol) and heated with stirring at 105°C for 13 hours. The reaction mixture cooled to room temperature and evaporated to dryness. To the residue was added water (100 ml) and extracted with chloroform (2x75 ml). Combine the organic layers, washed with brine (70 ml), dried over MgSO ₄ , then filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 80 g, eluted with hexanes/ethyl acetate mixtures, 0 to 100%) to give tert-butyl-3-(5-(5-((4cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (55a) (0.308 g, 5.24% yield) as a yellow solid. MS (IER+): 632.3 (M+23).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (5 5b).

Into a stirred solution of tert-butyl 3-(5-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (55 a) ( 43 mg, 0.065 mmol) in methanol (5 ml), hydrochloric acid (2M solution in methanol, 0.648 ml, 1.296 mmol) was added at room temperature and stirred for 18 hours. The reaction mixture was concentrated to

- 141 045731 removal of excess hydrochloric acid. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-50% methanol/chloroform mixtures) to give pure 1-(3(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy) )methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (55b) (18 mg, 49.3%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H, exchange with D ₂ O), 7.82 (d, J=8.3 Hz, 2H), 7.56 (dt, J =12.3, 6.2 Hz, 5H), 7.44 (d, J=7.0 Hz, 2H), 7.34 (d, J=7.2 Hz, 1H), 7.27 (d , J=7.8 Hz, 2H), 5.61 (s, 1H), 3.80 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.05 (s , 1H), 0.51 - 0.40 (m, 2H), 0.20 - 0.08 (m, 2H); MS (IER+) 564.3 (M+1), (IER-) 562.3 (M-1), 598.2 (M+Cl).

Scheme 56

Receiving example

1-(3-(aminomethyl)phenyl)-C-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (56c).

Step 1. Preparation of tert-butyl-3-(5-(5-(chloro(3-cyanophenyl)methyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (56a).

In a solution of tert-butyl-3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54c) ( 1.333 g, 2.187 mmol) in dichloromethane (40 ml) at 0°C, add thionyl chloride (0.34 ml, 4.59 mmol) and warm to room temperature over 2 hours. The reaction mixture was treated with triethylamine (2.000 ml, 14.35 mmol), stirred at room temperature for 1 hour, then treated with cyclopropylmethanamine (4.30 ml, 48.0 mmol) and concentrated to remove the bulk of the dichloromethane, after which acetonitrile (30 ml) was added, stirred at 70°C for 14 h and concentrated to dryness. The residue was treated with chloroform (200 ml), washed with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give:

1. tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (54d) (184 mg, 13%) in the form of a colorless viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.70 - 7.30 (m, 10H), 7.22 (dd, J=10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J= 6.2 Hz, 2H), 2.26 (d, J=6.6 Hz, 2H), 1.37 (s, 9H), 1.00 - 0.80 (m, 1H), 0.45- 0.28 (m, 2H), 0.12 - -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.80, -123.20; MS (IER+) 663.4 (M+1);

2. tert-butyl-3-(5-(5-(chloro(3-cyanophenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (56a) (300 mg, 22 %) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 7.95 (t, J=1.7 Hz, 1H), 7.86 - 7.74 (m, 3H), 7.67 - 7.58 (m, 2H), 7.54 - 7.28 (m, 7H), 6.64 (s, 1H), 4.19 (d, J=6.2 Hz, 2H) , 1.37 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.82, -120.97; MS (IER+) 650.3 (M+23).

Step 2. Preparation of tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (56b ).

Tert-Butyl 3-(5-(5-(chloro(3-cyanophenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate solution (56a) (0.26 g , 0.414 mmol) was treated with cyclopropylmethanol (3.10 ml, 37.5 mmol) and triethylamine (0.470 ml, 3.37 mmol), then stirred at 100°C for 15 hours. The reaction mixture was diluted with ethyl acetate (120 ml) and washed water (75 ml). The organic layer was washed with brine (60 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy) methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (56b) (243 mg, 88%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 7.82 (t, 1H), 7.74 (dt, J=7.5, 1.5 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.64 - 7.22 (m, 10H), 5.59 (s, 1H), 4.19 (d, J=6.3 Hz, 2H) , 3.24 (d, J=6.8 Hz, 2H), 1.37 (s, 9H), 1.12 - 0.99 (m, 1H), 0.54 - 0.39 (m, 2H ), 0.22 - 0.08 (m, 2H); ¹⁹ F NMR (282

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MHz, DMSO-d^ δ -60.82, -122.30; MS (IER+) 686.4 (M+23).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (56c).

Into a solution of tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (56b) ( 220 mg, 0.331 mmol) in methanol (24 ml) was added conc. hydrogen chloride (0.170 ml, 2.039 mmol) was then stirred at room temperature for 23.5 hours and concentrated in vacuo (<30°C). The resulting residue was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give the free base 1-(3-(aminomethyl)phenyl)-N-(5 -((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (56c) (133 mg, 71%) as a colorless viscous substance. The purified product (69 mg) was dissolved in methanol (10 ml) and then treated with 4N. HCl (aq, 0.12 ml) and then concentrated to dryness to give the HCl salt of the above colorless viscous substance (78 mg) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.38 (s, 3H), 7.81 (t, J=1.7 Hz, 1H), 7.76 - 7.66 (m, 4H), 7.63 - 7.47 (m, 6H), 7.37 - 7.23 (m, 2H), 5.59 (s, 1H), 4.11 (q, J=5.8 Hz, 2H), 3.29 - 3.20 (m, 2H), 1.15-0.95 (m, 1H), 0.54 - 0.37 (m, 2H), 0 .27 - 0.04 (m, 2H); 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 (t, J=1.6 Hz, 1H), 7.74 (dt, J=7.6, 1.5 Hz, 1H), 7, 72 - 7.66 (m, 2H), 7.64 (s, 1H), 7.62 - 7.49 (m, 5H), 7.36 - 7.23 (m, 2H), 5.59 ( s, 1H), 4.12 (s, 2H), 3.26 - 3.23 (m, 2H), 1.14 - 0.95 (m, 1H), 0.54 -0.39 (m, 2H), 0.18-0.11 (m, 2H), ¹⁹ F NMR (282 MHz, DMSOL) δ -60.82, -121.88; MS (IER+) 564.3 (M+1); (IER-) 562.3 (M-1); HPLC (94.54%, tR=19.943 min); analysis, calculation for C ₃₀ H ₂₅ F ₄ N ₅ O ₂ -1.0HCl-1.25H ₂ O: C, 57.88; H, 4.61; N, 11.25; experiment: C, 57.90; H, 4.57; N, 11.19.

Scheme 57

9i

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (57e) .

Step 1: (3-amino-4-fluorophenyl)(3-nitrophenyl)methanol (57a).

Freshly prepared (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (170 ml, 170 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding hydrogen chloride (2N, 213 ml, 425 mmol) at 0°C, stirred for 1 hour. TLC analysis (ethyl acetate/hexanes, 1/1, vol/ vol.) indicated the completion of the interaction. The reaction mixture was treated with sodium hydroxide (2N, 255 ml, 510 mmol) and extracted with ethyl acetate (3x750 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 1 kg, eluted with mixtures of 0-70% ethyl acetate in hexane) to give (3-amino-4-fluorophenyl)(3nitrophenyl)methanol (57a) (4.638 g, 10% yield) in the form of a dark brown thick liquid.

1H NMR (300 MHz, DMSO-d6) δ 8.21 (t, J=2.0 Hz, 1H), 8.08 (ddd, J=8.1, 2.5, 1.1 Hz, 1H) , 7.77 (dt, J=7.2,

- 143 045731

1.4 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 6.91 (dd, J=11.5, 8.3 Hz, 1H), 6.78 (dd, J=8.9, 2.2 Hz, 1H), 6.55 (ddd, J=8.4, 4.4, 2.2 Hz, 1H), 6.13 (d, J=3.9 Hz , 1H), 5.71 (d, J=3.8 Hz, 1H), 5.13 (s, 2H); MS (IER+): MS (IER+) 263.1 (M+1), MS (IER-) 523.2 (2M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-M-(2-fluoro-5-(hydroxy(3-nitrophenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (57b).

In a 500 mL one-neck flask, 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (5.91 g, 21.00 mmol), (3-amino-4-fluorophenyl )(3-nitrophenyl)methanol (57a) (4.59 g, 17.50 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 9.79 g, 21.00 mmol) was sequentially treated with N,N-dimethylformamide (102 ml) and N-ethyl-N-isopropan-2-amine (15.24 ml, 88 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The residue was diluted with ethyl acetate (250 ml) and the layers were separated with water (1 ml), aq. the layer was extracted again with ethyl acetate (500 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-nitrophenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (57b) (2.641 g, 29% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-di) δ 10.56 (s, 1H), 8.24 (t, J=2.0 Hz, 1H), 8.15-8.06 (m, 2H), 7 .99 (dt, J=7.8, 1.3 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.80 (d, J=7.7 Hz, 1H), 7. 77 - 7.68 (m, 2H), 7.67 - 7.54 (m, 2H), 7.39 - 7.19 (m, 2H), 6.36 (d, J=4.1 Hz, 1H), 5.90 (d, J=4.0 Hz, 1H); MS (IER ⁺ ): MS (IER+) 548.2 (M+Na), MS (IER-) 524.7 (M-1); 560.3 (M+Cl).

Step 3. Preparation of tert-butyl-3-(5-((5-((3-tert-butyloxycarbonylaminophenyl)-(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1 -yl)benzylcarbamate (57c).

Into a stirred solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-nitrophenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (57b) (2, 25 g, 4.28 mmol) in anhydrous methanol (60 ml), cooled to 0°C, di-tert-butyl dicarbonate (3.74 g, 17.13 mmol) was added and stirred for 10 min. Then nickel (II) chloride hexahydrate (0.763 g, 3.21 mmol), sodium borohydride (1.620 g, 42.8 mmol) were added in small portions over 4 hours. The reaction occurred with the release of heat and gas. The reaction mixture was stirred for 45 min at 0°C, after which N1-(2-aminoethyl)ethane-1,2-diamine (4.63 ml, 42.8 mmol) was added. The mixture was left to stir for another 30 minutes, after which the solvent was evaporated. The residue was treated with water (75 ml) and extracted with chloroform (2x100 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, and excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 50%)] to give tert-butyl-3-(5-((5-((3-tert-butyloxycarbonylaminophenyl)(hydroxy )methyl)-2-fluorophenyl)carbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (57c) (0.963 g, 1.376 mmol, 32.1% yield) as a light red solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.55 (s, 1H), 9.30 (s, 1H), 7.61 - 7.31 (m, 7H), 7.29 - 7.12 (m, 4H), 6.92 (d, J=7.6 Hz, 1H), 5.96 (d, J=3.8 Hz, 1H), 5.60 (d, J=3.9 Hz , 1H), 4.19 (d, J=6.2 Hz, 2H), 1.45 (s, 9H), 1.38 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.79, -123.57; MS (ESI ⁺ ): MS (ESI+) 722.3 (M+Na).

Step 4. Preparation of tert-butyl-3-(5-((5-((tert-butoxycarbonyl-3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (57d).

Solution of tert-butyl 3-(5-((5-((3-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)-2fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (57c ) (1.1 g, 1.572 mmol) in dichloromethane (20 ml) at 0°C was treated with thionyl chloride (0.222 ml, 3.05 mmol) and allowed to warm to room temperature and stirred for 2.5 hours. The solution was treated with triethylamine ( 1.332 ml, 9.56 mmol), then stirred at room temperature for 30 min, added cyclopropylmethanol (11.70 ml, 141 mmol) and triethylamine (1.332 ml, 9.56 mmol), concentrated to remove most of the dichloromethane, then whereupon additional triethylamine (1.332 mL, 9.56 mmol) was added and stirred at 115°C for 11 hours. The reaction mixture was cooled and concentrated to dryness. The resulting residue was treated with water (25 ml) and extracted with chloroform (2x30 ml). The combined organic layers were dried over MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%)] to give tert-butyl-3-(5-((5-((tert-butoxycarbonyl-3aminophenyl) (cyclopropylmethoxy)methyl)-2-fluorophenyl)-carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (57d) (0.521 g, 0.691 mmol, 44.0% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.58 (s, 1H, exchange with D2O), 9.35 (s, 1H), 7.58 (s, 1H), 7.56 - 7.45 (m, 3H), 7.42 (d, J=7.4 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.23 (dq, J=20.3, 7.8 Hz, 4H), 6.92 (d, J=7.4 Hz, 1H), 5.39 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.21 ( dd, J=6.8, 3.1 Hz, 2H), 1.45 (s, 9H), 1.37 (s, 9H), 1.03 (d, J=7.8 Hz, 1H), 0.45 (dt, J=8.7, 2.9 Hz, 2H), 0.16 (dd, J=5.6, 3.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.81, -122.72; MS (IER ⁺ ): MS (IER+) 776.4 (M+Na), MS (IER-) 752.3 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)

- 144 045731

2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (57e).

Into a solution of tert-butyl-3-(5-((5-((tert-butoxycarbonyl-3-aminophenyl)(cyclopropylmethoxy)methyl)2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )benzylcarbamate (57d) (0.511 g, 0.678 mmol) in methanol (20 ml) was added dropwise with conc. hydrogen chloride (12N HCl) (1.412 ml, 16.95 mmol), then stirred at room temperature for 14 hours. Excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 50% CMA 80 in chloroform)] to give 1-(3-(aminomethyl)phenyl)-N-(5((3-aminophenyl )(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (57e) (0.261 g, 70% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H, exchange with D ₂ O), 7.59 (d, J=8.8 Hz, 2H), 7.55-7.45 (m, 3H), 7.44 - 7.35 (m, 1H), 7.30 - 7.15 (m, 2H), 6.94 (t, J=7.7 Hz, 1H), 6, 52 (t, J=1.9 Hz, 1H), 6.50 - 6.36 (m, 2H), 5.26 (s, 1H), 5.08 (s, 2H, exchange with D2O), 3 .89 (s, 2H), 3.19 (dd, J=6.8, 2.7 Hz, 2H), 1.11 - 0.94 (m, 1H), 0.54 - 0.38 (m , 2H), 0.23 - 0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.76, -123.05; MS (IER ⁺ ): MS (IER+) 554.3 (M+1), 588.2 (M-1).

A solution of the free base 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 57e) (20 mg, 0.036 mmol) in methanol (2 ml) was treated with hydrogen chloride (0.217 ml, 0.434 mmol), then stirred at room temperature for 10 min. The excess solvent was pumped off under reduced pressure to obtain the hydrochloride salt of 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (57e) (22 mg, 97%) as a colorless solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.68 (s, 1H), 8.35 (s, 4H), 7.72 (s, 1H), 7.68 (s, 1H), 7. 64 - 7.47 (m, 5H), 7.36 - 7.21 (m, 3H), 7.10 (s, 2H), 7.00 (s, 2H), 5.47 (s, 1H) , 4.12 (s, 2H), 3.22 (d, J=6.8 Hz, 2H), 1.15-0.97 (m, 1H), 0.55-0.35 (m, 2H ), 0.23 - 0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82, -122.33; MS (ESI ⁺ ): MS (ESI+) 554.3 (M+1), 576.3 (M+Na), 552.3 (M-1), 588.2 (M+Cl); analysis, calculation for: C29H27F4N5O2-1.75H2O-2HCl: C, 53.30; H, 4.94; N, 10.72; experiment: C, 53.37; H, 4.79; N, 10.67.

Scheme 58

An example of the preparation of 1-(3 -(aminomethyl)phenyl)-N-(5 -(3 -cyclopropyl-1 -hydroxy-1 -(pyridin-3 yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -nirazole-5-carboxamide (58c).

Step 1. Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propan-1-ol (58a)

Freshly prepared bromide (3-(bis(trimethylsilyl) amino)-4fluorophenyl)magnesium (52c) (88 ml, 79 mmol) at 0°C.

The reaction mixture was allowed to warm to room temperature for 12 hours, quenched by adding hydrogen chloride (2N, 100 ml, 200 mmol) at 0°C, stirred for 1 hour. TLC analysis (ethyl acetate/hexanes, 1/1, vol/ vol.) indicated the completion of the interaction. The reaction mixture was treated with sodium hydroxide (2N, 105 ml, 210 mmol) and extracted with ethyl acetate (3x150 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 120 g, eluted with 0100% ethyl acetate in hexanes) to give 1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3yl)propane-1 -ol (58a) (15.3 g, 78%) as a brown semi-solid; MS (IER+) 309.2 (M+Na), (IER-) 285.2 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)2-fluorophenyl)-3-(trifluoromethyl)-1 P -pyrazole-5-carboxamide (5 8b).

A solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (11.99 g, 42.6 mmol) in N,N-dimethylformamide (257 ml, 3326 mmol ) added 1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-(pyridin-3-yl)propan-1-ol (58a) (14.65 g, 51.2 mmol), N-ethyl-N -isopropylpropane-2

- 145 045731 amine (59.4 ml, 341 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP) (21.86 g, 46.9 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (1000 ml) and extracted with ethyl acetate (3x1000 ml), washed with water (2x500 ml), brine (300 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography [silica gel, 80 g, eluted with 9:1 ethyl acetate:methanol in hexanes, 0 to 50%] to give 1-(3-cyanophenyl)-N(5-(3-cyclopropyl -1-hydroxy-1(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (58b) (19.9 g, 85% yield) as yellow solid matter; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.38 (dd, J=4.7, 1 .6 Hz, 1H), 8.12 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.95- 7.86 (m, 1H), 7.82 7.69 (m, 3H), 7.61 (dd, J=7.6, 2.3 Hz, 1H), 7.40 - 7.27 (m, 2H) , 7.21 (dd, J=10.2, 8.7 Hz, 1H), 5.81 (s, 1H), 2.34 (t, J=8.0 Hz, 2H), 1.05 ( d, J=13.9 Hz, 2H), 0.64 (h, J=6.6 Hz, 1H), 0.40 - 0.28 (m, 2H), -0.07 (dd, J= 4.9, 1.6 Hz, 2H); MS (IER+): 550.3 (M+1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-I-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (58c).

Into a stirred solution of 1-(3-cyanophenyl)-N(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (58b) (10 g, 18.20 mmol) in methanol (300 ml) at 0°C was added nickel (II) chloride hexahydrate (5.41 g, 22.75 mmol). Sodium tetrahydroborate (6.88 g, 182 mmol) was added to the resulting mixture in small portions over 15 minutes. The reaction mixture was stirred for 30 min and quenched by adding N-(2-aminoethyl)ethane1,2-diamine (15.09 mL, 146 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated to remove methanol. The reaction mixture was diluted with water (200 ml) and stirred for 30 minutes. The isolated solid was collected by filtration. The solid was suspended in ethanol (100 ml) and concentrated to dryness to remove water. The residue was dissolved in methanol and purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give pure 1-(3-(aminomethyl)phenyl)-N(5-(3cyclopropyl- 1-Hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (58c) (2.56 g, 25.4% yield) as a colorless solid. 1H NMR (300 MHz, DMSOd ₆ ) δ 10.54 (s, 1H, exchange with D2O), 8.62 (dd, J=2.4, 0.9 Hz, 1H), 8.38 (dd, J =4.7, 1.6 Hz, 1H), 7.77 (dt, J=8.1, 1.9 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.57 ( s, 1H), 7.51 (s, 1H), 7.48 - 7.38 (m, 2H), 7.39 - 7.27 (m, 3H), 7.25 - 7.15 (m, 1H), 5.80 (s, 1H, exchange with D ₂ O), 3.78 (s, 2H), 2.33 (t, J=7.9 Hz, 2H), 1.13 - 1.02 (m, 2H), 0.63 (p, J=7.3, 6.5 Hz, 1H), 0.39 - 0.28 (m, 2H), -0.07 (dt, J=5, 5, 2.8 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.73, -123.95; MS (IER+): 554.3 (M+1); analysis, calculation for C ₂ 9H^4^O ₂ 4.5H ₂ O: C, 59.99; H, 5.21; N, 12.06; experiment: C, 60.07; H, 4.86; N, 11.68.

Scheme 59

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (59c).

Step 1. Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (59a).

(3-(bis(trimethylsilyl) bromide )amino)-4-fluorophenyl)magnesium (52c) (93 ml, 93 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours at the indicated temperature. The reaction was quenched by adding ammonium chloride solution (25 ml) and diluting the mixture with ethyl acetate (50 ml). The mixture was acidified with hydrochloric acid (10 ml, 3N) and stirred for 15 minutes and made basic with saturated potassium carbonate solution (20 ml). The mixture was extracted with ethyl acetate (3x100 ml), washed with water (2x50 ml), brine (25 ml), dried and concentrated. The crude residue was purified by

- 146 045731 Combiflash system (silica gel, 80 g), eluted with mixtures of CMA 80 in chloroform to obtain pure 1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-2-yl)propan-1- ol (59a) (9.95 g, 46.5%) as a colorless solid; MS (IER+): 309.2 (M+23).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (59b).

A solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (7.32 g, 26.0 mmol) in N,N-dimethylformamide (157 ml, 2032 mmol ) added 1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-(pyridin-2-yl)propan-1-ol (59a) (8.951 g, 31.3 mmol), N-ethyl-N-isopropylpropane -2amine (36.3 mL, 208 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP) (13.36 g, 28.7 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (1000 ml) and extracted with ethyl acetate (3x1000 ml), washed with water (2x500 ml), saline (300 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography [silica gel, 80 g, eluted with 9:1 ethyl acetate:methanol in hexanes, 0 to 50%] to give 1-(3-cyanophenyl)-N-(5-(3- Cyclopropyl-1-hydroxy-1(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (59b) (9.42 g,

65.8%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H, exchange with D ₂ O), 8.49 (ddd, J=4.8, 1.8, 0.9 Hz, 1H) , 8.12 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.79 - 7.61 (m, 5H), 7.42 (ddd, J=8.8, 4.8, 2.3 Hz, 1H), 7.24 - 7.12 (m, 2H), 5.84 (s, 1H, exchange with D ₂ O), 2.47 - 2.29 (m, 2H), 1.02 (qt, J=13.7, 7.4 Hz, 2H), 0. 59 (ddt, J=10.3, 7.0, 3.7 Hz, 1H), 0.39 - 0.26 (m, 2H), -0.05- -0.17 (m, 2H); MS (IER+): 572.3 (M+23).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (59c).

Into a stirred solution of 1-(3-cyanophenyl)-M-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (59b) (8.9 g, 16.20 mmol) in methanol (300 ml) was added nickel (II) chloride hexahydrate (4.81 g, 20.24 mmol) at 0°C. Sodium tetrahydroborate (6.13 g, 162 mmol) was added to the resulting mixture in small portions over 15 minutes. The reaction mixture was stirred for 30 min and quenched by adding K1-(2-aminoethyl)ethane1,2-diamine (13.43 ml, 130 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated to remove methanol. The reaction mixture was diluted with water (800 ml) and stirred for 30 minutes. The isolated solid was collected by filtration. The solid was dissolved in chloroform (500 ml), washed with water (2x200 ml). The aqueous layer was extracted with chloroform (2x200 ml). The combined chloroform extracts were washed with brine (2x200 ml), dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1(3-(aminomethyl)phenyl)-M-(5-(3-cyclopropyl-1-hydroxy-1 -(pyridin-2-yl)propyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (59c) (4.56 g, 50.9% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H, exchange with D2O), 8.49 (dt, J=4.6, 1.4 Hz, 1H), 7.72 (ddt, J=7.8, 5.5, 2.7 Hz, 2H), 7.63 (d, J=7.9 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H ), 7.48 - 7.37 (m, 3H), 7.36 - 7.30 (m, 1H), 7.24 - 7.11 (m, 2H), 5.83 (s, 1H, exchange with D2O), 3.78 (s, 2H), 3.342 (s, 2H, exchange with D2O), 2.42 - 2.26 (m, 2H), 1.00 (ddd, J=25.9, 14 ,0, 7.2 Hz, 2H), 0.68 - 0.49 (m, 1H), 0.40 - 0.24 (m, 2H), -0.10 (dd, J=5.5, 3.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.71, -124.32; MS (IER+): 554.3 (M+1); analysis, calculation for C ₂₉ H ₂₇ F ₄ N ₅ O ₂ (H ₂ O) ₀ , ₂₅ : C, 62.39; H, 4.96; N, 12.55; experiment: C, 62.09; H, 5.05; N, 12.51.

- 147 045731

Scheme 60

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-I-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60e ).

Step 1: (3-amino-4-fluorophenyl)(2-(benzyloxy)phenyl)methanol (60a).

(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (150 ml, 150 mmol) at 0°C for 30 min. The reaction mixture was stirred for 14 hours at room temperature and quenched with 2N. HCl (188 ml, 375 mmol) for 30 min, stirred for 1 h. TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated completion of the reaction. The reaction mixture was treated with 2N. NaOH (225 ml, 450 mmol) and extracted with ethyl acetate (2x750 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 1 kg, eluted with mixtures of 0-70% ethyl acetate in hexanes) to give (3-amino-4-fluorophenyl)(2-(benzyloxy)phenyl)methanol (60a) (19.54 g, yield 40%) in the form of a yellow oily liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.48 (dd, J=7.6, 1.7 Hz, 1H), 7.41 7.27 (m, 5H), 7.17 (ddd , J=8.1, 7.2, 1.8 Hz, 1H), 7.04 - 6.91 (m, 2H), 6.88 - 6.71 (m, 2H), 6.43 (ddd , J=8.3, 4.5, 2.1 Hz, 1H), 5.90 (d, J=4.2 Hz, 1H), 5.56 (d, J=4.3 Hz, 1H, exchange with D ₂ O), 5.09 (s, 2H), 5.01 (s, 2H, exchange with D2O); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.98; MS (IER ⁺ ): MS (IER+) 346.2 (M+Na), MS (IER-) 322.1 (M-1).

Step 2. Preparation of N-(5-((2-(benzyloxy)phenyl)(hydroxy)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60b).

In a 1 L one-neck flask, 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (12.67 g, 45.1 mmol), (3-amino-4-fluorophenyl )(2-(benzyloxy)phenyl)methanol (60a) (12.14 g, 37.5 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (21.00 g, 45.1 mmol) were treated sequentially with N,N -dimethylformamide (218 ml, 2816 mmol) and N-ethyl-N-isopropylpropan-2-amine (32.7 ml, 188 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The residue was diluted with ethyl acetate (750 ml) and the layers were separated with water (2 L), aq. the layer was extracted again with ethyl acetate (2x400 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 1 kg, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give N-(5-((2-(benzyloxy)phenyl)(hydroxy)methyl)-2-fluorophenyl )-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60b) (15.16 g, 25.8 mmol, 68.8% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.17 - 8.09 (m, 1H), 7.99 (dt, J=7.7, 1.3 Hz , 1H), 7.88 (dt, J=8.1, 1.3 Hz, 1H), 7.79 - 7.66 (m, 2H), 7.56 - 7.44 (m, 2H), 7.30 (s, 5H), 7.16 (dd, J=7.4, 1.4 Hz, 3H), 7.06 - 6.92 (m, 2H), 5.98 (d, J= 4.3 Hz, 1H), 5.83 (d, J=4.3 Hz, 1H), 5.08 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.97, -123.49; MS (IER ⁺ ): MS (IER+) 609.3 (M+Na); MS (IER+) 585.2 (M-1).

Step 3. Preparation of N-(5-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)1 -(3-cyanophenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (60c).

In a solution of N-(5-((2-(benzyloxy)phenyl)(hydroxy)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(tri

- 148 045731 fluoromethyl)-1H-pyrazole-5-carboxamide (60b) (14.91 g, 25.4 mmol) in dichloromethane (120 ml) at 0°C added thionyl chloride (3.71 ml, 50.8 mmol) , the reaction mixture was stirred for 6 hours while maintaining 0°C. TLC analysis indicated that the reaction was incomplete, then an additional equivalent of thionyl chloride (3.02 g, 25.4 mmol) was added at 0°C and stirred for 1 hour. The reaction was quenched with triethylamine (11.35 ml, 81 mmol) and the solution was stirred in for 30 min at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanamine (22.05 ml, 254 mmol) and acetonitrile (120 ml) and stirred at 80°C for 16 h, after which TLC analysis (ethyl acetate/hexanes, 1/1, v/v) indicated For maximum conversion, the reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 1 kg, eluted with mixtures of methanol in chloroform, 0-100%) to give N(5-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-1- (3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60c) (9.25 g, 57% yield) as a pale yellow solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 8.15-8.10 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz , 1H), 7.94 - 7.86 (m, 1H), 7.76 - 7.67 (m, 2H), 7.56 - 7.43 (m, 2H), 7.32 (tdd, J =7.4, 5.0, 2.3 Hz, 5H), 7.23 - 7.14 (m, 3H), 7.056.90 (m, 2H), 5.19 (s, 1H), 5, 08 (s, 2H), 2.24 (qd, J=12.0, 6.7 Hz, 2H), 0.85 (d, J=11.2 Hz, 1H), 0.32 (dq, J =7.8, 1.7 Hz, 2H), -0.00 - -0.05 (m, 2H); MS (IER+) 640.3 (M+1); MS (IER+) 638.3 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60d).

In a solution of N-(5-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60c ) (7.59 g, 11.87 mmol) in dichloromethane (150 ml), cooled to -78°C, tribromoborane (1M solution in dichloromethane) (13.05 ml, 13.05 mmol) was added dropwise under nitrogen. . The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 15 hours. The reaction mixture was treated with methanol (3x100 ml) and evaporated, then quenched with water (100 ml) and extracted with chloroform (3x100 ml). The combined organic layers were dried over anhydrous MgSO ₄ and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 120 g, eluted with 0-50% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2hydroxyphenyl)methyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60d) (7.407 g) as a yellow thick liquid, which was used as such in the next step; MS (IER ^- ): 548.3 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60e).

Solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (CVR-008-141 ) (7.35 g, 13.38 mmol) in anhydrous methanol (120 ml), cooled to 0°C, stirred for 10 min, then nickel (II) chloride hexahydrate (2.384 g, 10.03 mmol) was added in small portions ), sodium borohydride (5.06 g, 134 mmol) for 4 hours. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 45 min at 0°C, after which N1-(2-aminoethyl)ethane-1,2-diamine (14.45 ml, 134 mmol) was added. The mixture was left stirring for 1 hour, after which the solvent was evaporated. The residue was treated with water (400 ml) and extracted with chloroform (2x300 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 120 g, then two separate 80 g columns, eluted with methanol/chloroform mixtures, 0 to 50%)] to give 1-(3(aminomethyl)phenyl)-N-( 5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60e) (0.840 g, 1.517 mmol, 11.35% yield) as yellow solid; 1H NMR (300 MHz, DMSO-d^) δ 10.58 (s, 1H, exchange with D2O), 7.65- 7.55 (m, 2H), 7.51 (s, 1H), 7.47 - 7.40 (m, 2H), 7.33 (dtt, J=6.8, 4.6, 2.5 Hz, 2H), 7.28 - 7.13 (m, 1H), 7.03 (ddt, J=8.5, 5.1, 1.7 Hz, 2H), 6.76 -6.65 (m, 2H), 5.03 (s, 1H), 3.78 (s, 2H ), 2.45 - 2.37 (m, 1H), 2.25 (dd, J=12.2, 7.0 Hz, 1H), 0.97 - 0.83 (m, 1H), 0, 42 - 0.38 (m, 2H), 0.07 (d, J=5.1 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.75, -123.06; MS (IER+) 554.3 (M+1), 576.2 (M+Na), 552.2 (M-1), 588.2 (M+Cl).

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Scheme 61

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2methoxynaphthalin-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- dihydrochloride carboxamide (61e).

Step 1. Preparation of (3-amino-4-fluorophenyl)(2-methoxynaphthalene-1-yl)methanol (61a).

(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) ( 130 ml, 130 mmol) at 0°C. The reaction mixture was stirred for 20 hours at room temperature and quenched by adding hydrogen chloride (2N) (163 ml, 325 mmol), stirred for 1 hour. TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated the end of the interaction. The reaction mixture was treated with sodium hydroxide (2N) (195 ml, 390 mmol) and extracted with ethyl acetate (2x750 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 1.3 kg, eluted with mixtures of 0-70% ethyl acetate in hexanes) to give (3-amino-4-fluorophenyl)(2-methoxynaphthalene-1yl)methanol (61a) (24 .84 g, 84 mmol, 64.3% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.28 - 8.10 (m, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.84 - 7.72 (m , 1H), 7.48 (d, J=9.1 Hz, 1H), 7.35- 7.17 (m, 2H), 6.91 - 6.70 (m, 2H), 6.66 - 6.57 (m, 1H), 6.46 (dddd, J=8.2, 4.6, 2.2, 1.0 Hz, 1H), 5.91 (d, J=4.6 Hz, 1H, exchange with D2O), 4.98 (s, 2H, exchange with D2O), 3.96 (s, 3H); ¹⁹ F NMR (282 MHz, DMSOL ₆ ) δ -139.08; MS (IER ⁺ ): MS (IER+) 320.2 (M+Na), MS (IER-) 296.0 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(2-methoxynaphthalene-1-yl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 - carboxamide (61b).

1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (16.04 g, 57.0 mmol), (3-amino-4- fluorophenyl)(2-methoxynaphthalen-1-yl)methanol (61a) (14.13 g, 47.5 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (26.6 g, 57.0 mmol) and treated sequentially N,N-dimethylformamide (276 ml, 3564 mmol) and N-ethyl-N-isopropylpropan2-amine (41.4 ml, 238 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The residue was diluted with ethyl acetate (750 ml) and the layers were separated with water (2 L), aq. the layer was extracted again with ethyl acetate (500 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 800 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N(2-fluoro-5-(hydroxy(2-methoxynaphthalene- 1 -yl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (61b) (11.819 g, 44% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H, exchange with D ₂ O), 8.20 - 8.08 (m, 2H), 8.00 (dt, J=7, 7, 1.3 Hz, 1H), 7.95- 7.85 (m, 2H), 7.85- 7.78 (m, 1H), 7.75- 7.65 (m, 2H), 7 .56 - 7.43 (m, 2H), 7.30 - 7.13 (m, 4H), 6.72 (d, J=4.6 Hz, 1H), 6.19 (d, J=4 .6 Hz, 1H, exchange with D ₂ O), 3.97 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.98, -124.01; IR (KBr, ^cm'1 ): 2235 ^cm'1 (stretching vibrations -CN); MS (IER+): MS (IER+) 583.2 (m+Na), MS (IER-) 559.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalene-1yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 61c).

- 150 045731

Into a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(2-methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (61b ) (11.61 g, 20.71 mmol) in dichloromethane (120 ml) at 0°C was added thionyl chloride (3.02 ml, 41.4 mmol), the reaction mixture was stirred for 4.5 hours, during which time the temperature increased from 0°C to room temperature. The reaction was quenched with triethylamine (9.25 mL, 66.3 mmol) and the solution was stirred for 30 min at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanamine (14.37 ml, 166 mmol) and acetonitrile (120 ml) and stirred at 80°C for 16 h, after which TLC analysis (ethyl acetate/hexanes, 1/1, v/v) indicated For maximum conversion, the reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by flash column chromatography (two separate 120 g silica gel columns, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1-(3cyanophenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalene) -1-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (61c) (10.828 g, 85% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H, exchange with D2O), 8.29 (d, J=8.5 Hz, 1H), 8.16 - 8.09 (m , 1H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.94 - 7.81 (m, 3H), 7.76 -7.65 (m, 2H), 7.53 (d, J=7.4 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.34 (dt, J=14.5, 7.5 Hz, 2H ), 7.27 - 7.10 (m, 2H), 5.87 (s, 1H), 3.85 (s, 3H), 2.12 (s, 1H), 0.90 (s, 1H) , 0.45-0.24 (m, 2H), 0.06 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.97, -123.98; IR (KBr, ^cm'1 ): 2234 ^cm'1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 614.3 (M+1), MS (IER-) 612.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalene-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (61d).

Into a stirred solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylaminoX2-methoxynaphthalin-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (61c) (9.61 g, 15.66 mmol) in anhydrous methanol (180 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.931 g, 3.92 mmol) was added, then sodium borohydride (4 .74 g, 125 mmol) for 1 hour. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 3 hours at 0°C, TLC analysis (methanol/chloroform, 9/1) indicated that the reaction was incomplete (about 10-20%), nickel (II) chloride hexahydrate (0.931 g) was added again , 3.92 mmol) and small portions of NaBH ₄ (1.5 g) for 20 min and stirred the solution for 30 min, after which N1-(2-aminoethyl)ethane-1,2-diamine (16.92 ml, 157 mmol). The mixture was left stirring for another 4 hours, after which the solvent was evaporated. The residue was treated with water (200 ml) and extracted with chloroform (2x300 ml). The combined organic layers were dried over anhydrous MgSO ₄ and filtered, and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, two separate 120 g columns (divided into two parts), eluted with methanol/chloroform mixtures, 0 to 40%)] to give 1-(3-(aminomethyl)phenyl) -N-(5((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (61d) (3.28 g, 34% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H, exchange with D2O), 8.29 (d, J=8.4 Hz, 1H), 7.87 (dd, J=11, 5, 8.1 Hz, 2H), 7.55 (t, J=9.6 Hz, 3H), 7.49 (s, 1H), 7.47 - 7.41 (m, 2H), 7, 41 - 7.29 (m, 3H), 7.16 (dt, J=18.7, 9.7 Hz, 2H), 5.86 (s, 1H), 3.84 (s, 3H), 3 .80 (s, 2H), 2.11 (dd, J=11.8, 7.3 Hz, 1H), 1.02 - 0.79 (m, 1H), 0.34 (dq, J=8 ,1, 1.7 Hz, 2H), 0.10 -0.24 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.74, -124.35; MS (ESI ⁺ ): MS (ESI+) 618.3 (M+1), 652.3 (M+Cl).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2methoxynaphthalene-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- dihydrochloride 5-carboxamide (61e).

Stirred solution of 1-(3-(aminomethyl)phenyl)-M-(5-((cyclopropylmethylamino)(2methoxynaphthalin-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (61d) (0.250 g, 0.405 mmol) in anhydrous methanol (15 ml) was treated with 2N. HCl (in methanol) (1.012 mL, 2.024 mmol) and stirred for 10 min and evaporated to dryness to give 1-(3(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalene-1- yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (61e) (253 mg, 91% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.91 (s, 1H), 9.24 (s, 1H), 8.51 (s, 3H), 8.24 (d, J=8.7 Hz, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.95 (dd, J=8.3, 1.4 Hz, 1H), 7 .89 (dd, J=7.4, 2.3 Hz, 1H), 7.77 - 7.54 (m, 5H), 7.53 - 7.31 (m, 4H), 6.39 (t , J=6.4 Hz, 1H), 4.11 (q, J=5.9 Hz, 2H), 4.03 (s, 3H), 2.98 - 2.78 (m, 1H), 2 .72 (d, J=7.8 Hz, 1H), 1.20 - 1.01 (m, 1H), 0.51 (ddt, J=16.9, 9.3, 4.7 Hz, 2H ), 0.22 (ddt, J=17.7, 9.0, 4.8 Hz, 2H); 1H NMR (300 MHz, DMSO-d ₆ D ₂ O) δ 8.20 (d, J=8.8 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 7.96 (dd, J=8.3, 1.4 Hz, 1H), 7.88 (dd, J=7.3, 2.5 Hz, 1H), 7.75- 7.31 (m, 10H), 6.35 (s, 1H), 4.11 (s, 2H), 4.03 (s, 3H), 2.89 (dd, J=12.9, 6.9 Hz, 1H), 2.72 (dd, J=12.9, 7.7 Hz, 1H), 1.08 (d, J=8.3 Hz, 1H), 0.54 (dd, J=13.1, 6.3 Hz, 2H), 0.23 (ddd, J=19.1, 9.3, 5.0 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.79, -120.01; MS (IER ⁺ ): MS (IER+) 618.3 (M+1), 616.3 (M-1), 652.3 (M+Cl); analysis, calculation for: C ₃₄ H ₃₁ F ₄ N5O ₂ -1.75H ₂ O-2HCl: C, 56.55; H, 5.09; Cl, 9.82; N, 9.70; experiment: C, 56.64; H, 5.06; Cl, 9.62; N, 9.56.

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Scheme 63

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-X-(5-((cyclopropylmethylamino)(2-methoxynaphthalin-1 -yl)methyl)-2-fluorophenyl)-3 -(trifluoromethyl)-1 N-pyrazole-5-carboxamide (63 a), (+)-1-(3(aminomethyl)phenyl)-X-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl )-3(trifluoromethyl)-1H-pyrazole-5-carboxamide(63b).

Racemate 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (61e) (2.0 g) was separated using the preparative SFC method, column: 2.1x25 cm, ChiralPak IC SFC from Chiral Technologies; CO2 co-solvent (solvent B) acetonitrile:isopropanol (4:1) with 1% isopropylamine; isocratic method: 40% cosolvent, flow rate 80 ml/min; system pressure 100 bar (10 MPa), column temperature 25°C; sample diluent methanol, obtaining:

. 1 peak corresponding to (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2methoxynaphthalene-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (63a) (136 mg, >95% ee); The resulting product (112 mg) was purified by flash column chromatography (silica gel, 12 kg, eluted with mixtures of 0-60% methanol in chloroform) to give (-)-1-(3(aminomethyl)phenyl)-N-(5-( (cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (63a) (0.069 g, 50.7%, >95% ee .) as a white solid; Ή NMR (300 MHz, DMSO) δ 10.48 (s, 1H, exchange with D2O), 8.29 (d, J=8.4 Hz, 1H), 7.87 (dd, J=11.9, 8.5 Hz, 2H), 7.61 - 7.53 (m, 2H), 7.50 (d, J=5.9 Hz, 1H), 7.47 - 7.28 (m, 5H), 7.19 (s, 2H), 7.17 -7.09 (m, 1H), 5.86 (s, 1H), 3.84 (s, 3H), 3.78 (s, 2H), 2 .13 (d, J=8.0 Hz, 1H), 0.89 (d, J=8.5 Hz, 1H), 0.34 (dt, J=8.1, 1.9 Hz, 2H) , -0.11 (dd, J=9.7, 4.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.73, -124.39; MS (ESI+) 618.3 (M+1), 652.3 (M+Cl). Optical rotation: [a]D=(-) 88.88 [CH3OH, 0.75]; free base (-)-1-(3(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole -5-carboxamide (63a) (69 mg) was dissolved in methanol (15 ml) and 2N was added. HCl (0.28 ml, 5 eq.) and stirred at room temperature for 10 min. The solution was evaporated to dryness to obtain the hydrochloride salt (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalin-1 -yl)methyl)-2-fluorophenyl)-3 - (trifluoromethyl)-1H-pyrazole-5-carboxamide (63a) (0.069 g) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H, exchange with D2O), 9.89 (s, 1H, exchange with D2O), 9.22 (s, 1H, exchange with D2O), 8.49 (s, 3H, exchange with D2O), 8.24 (d, J=8.7 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.95 (dd , J=8.3, 1.4 Hz, 1H), 7.89 (dd, J=7.5, 2.3 Hz, 1H), 7.75- 7.53 (m, 7H), 7, 53 - 7.32 (m, 4H), 6.37 (d, J=7.0 Hz, 1H), 4.11 (q, J=5.9 Hz, 2H), 4.03 (s, 3H ), 2.88 (d, J=11.9 Hz, 1H), 2.72 (d, J=9.6 Hz, 1H), 1.11 (s, 1H), 0.63 -0.39 (m, 2H), 0.23 (ddq, J=17.8, 9.4, 4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d^ δ -60.81, -120.03; MS (IER ⁺ ): MS (IER+) 618.3 (M+1), MS (IER-) 652.2 (M+Cl); analysis, calculation for C34H ₃₁ F ₄ N ₅ O ₂ -2H ₂ O-2HCl: C, 56.20; H, 5.13; Cl, 9.76; N, 9.64; experiment : C, 56.64; H, 5.14; Cl, 9.35; N, 9.59;

peak corresponding to (+)-1-(3-(aminomethyl)phenyl)-X-(5-((cyclopropylmethylamino)(2methoxynaphthalene-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (63b) (107 mg, >95% ee); The resulting product (107 mg) was purified by flash column chromatography (silica gel, 12 g, eluted with 0-60% methanol/chloroform mixtures) to give 83 mg of BCX-7362 free base. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H, exchange with D ₂ O), 8.29 (d, J=8.5 Hz, 1H), 7.96 7.79 ( m, 2H), 7.61 - 7.48 (m, 4H), 7.46 (s, 1H), 7.44 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 7.24 - 7.08 (m, 2H), 5.86 (s, 1H), 3.84 (s, 3H), 3.79 (s, 2H), 2.19 - 2.04 (m, 1H), 0.89 (q, J=6.7 Hz, 1H), 0.34 (dt, J=8.0, 2.0 Hz, 2H), -0.11 (td, J =8.8, 7.6, 4.2 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.74, -124.37; MS (ESI+) 618.3 (M+1), 616.2 (M-1), 652.3 (M+Cl); optical rotation: [a] _D =(+) 103.11 [CH3OH, 0.9]; into a solution of the free base (+)-1-(3-(aminomethyl)phenyl)-X-(5-((cyclopropylmethylamino)(2-methoxynaphthalin-1-yl)methyl)2-fluorophenyl)-3-(trifluoromethyl)- 1H-πyrazole-5-carboxamide (63b) (63 mg) in methanol (15 ml) was added with hydrogen chloride (0.336 ml, 0.672 mmol) and stirred at room temperature for 10 min. The solution was evaporated to dryness to obtain the hydrochloride salt of (+)-1-(3-(aminomethyl)phenyl)-X-(5((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (63b) (49 mg) as an off-white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.74 (s, 1H, exchange with D2O), 9.81 (s, 1H, exchange with D2O), 9.21 (s, 1H, exchange with D2O) , 8.43 (s, 3H, exchange with D2O),

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8.24 (d, J=8.7 Hz, 1H), 8.13 - 8.05 (m, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.88 (d , J=7.0 Hz, 1H), 7.75 - 7.54 (m, 5H), 7.53 - 7.32 (m, 3H), 6.39 (s, 1H), 4.11 ( d, J=5.7 Hz, 2H), 4.03 (d, J=1.5 Hz, 3H), 2.87 (s, 1H), 2.72 (s, 1H), 1.10 ( s, 1H), 0.50 (d, J=9.4 Hz, 2H), 0.22 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-06) δ -60.82, -120.05; MS (IER ⁺ ): MS (IER+) 618.3 (M+1), MS (IER-) 652.2 (M+Cl). Analysis, calculation for C ₃₄ H ₃₁ F ₄ N ₅ O ₂ -2H ₂ O-2HCl: C, 56.20; H, 5.13; Cl, 9.76; N, 9.64; experiment: C, 56.67; H, 5.18; Cl, 9.34; N, 9.58.

To confirm the chiral purity of compounds 63a and 63b, the following analytical method was used:

Analytical SFC method

Column 4.6 x 100 mm ChiralPak IC SFC manufactured by Chiral Technologies

_CO2 co-solvent (solvent B) acetonitrile:isopropanol (4:1) with 0.1% isopropylamine

Isocratic method 35% cosolvent, flow rate 4 ml/min

System pressure 150 bar (15 MPa)

Column temperature 40°C

Sample diluent methanol

Scheme 64

⁰⁰¹ 64a (-)-isomer

64b(+)-isomer

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 64a) and (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (64b )

1-(3-(Aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (53f (660 mg) was purified by preparative chiral HPLC using CHIRALPAK AD-H, 5 µm, 4.6x250 mm, flow rate 1 ml/min, solvent: 80% hexane/20% EtOH/0.1% DEA, UV=320 nm, obtaining:

1. 1 peak corresponding to (-)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (64a) [0.304 g, Rt=7.401 min, 99.6953% peak 1 (64a), Rt=9.479, 0.3047% peak 2 (64b), 99.4% ee]. The resulting product was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-25% methanol in chloroform for 13 min) to give (-)-1-(3-(aminomethyl)phenyl)-N-(3- ((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (64a) (0.270 g) as a white solid. Optical rotation -6.30 (MeOH, 1.46); ^1H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.61 7.52 (m, 4H), 7.48 - 7.40 (m, 2H), 7.33 ( dt, J=6.4, 2.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.09 (dd, J=7.6, 1.6 Hz, 1H ), 6.93 (t, J=7.7 Hz, 1H), 6.53 (t, J=1.9 Hz, 1H), 6.50 - 6.44 (m, 1H), 6.40 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.23 (s, 1H), 5.06 (s, 2H), 3.80 (s, 2H), 3, 20 (dd, J=6.8, 1.5 Hz, 2H), 1.05-0.98 (m, 1H), 0.51 - 0.41 (m, 2H), 0.19 0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.71; MS (IER+) 536.3 (M+1); (IER-) 570.3 (M+Cl). Free base (-)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 64a) was dissolved in methanol and 2.5 ml of 2N was added. HCl in methanol. The mixture was concentrated to dryness in vacuo to obtain the hydrochloride salt of (-)-1-(3(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazol- 5-carboxamide (64a) (270 mg); 1H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 9.80 (s, 3H), 8.46 (s, 3H), 7.74 - 7.57 (m, 6H), 7 .56 - 7.50 (m, 2H), 7.42 - 7.22 (m, 4H), 7.17 - 7.11 (m, 2H), 5.48 (s, 1H), 4.19 - 4.00 (m, 2H), 3.24 (d, J=6.7 Hz, 2H), 1.15- 1.00 (m, 1H), 0.57 -0.40 (m, 2H ), 0.17 (ddd, J=5.7, 4.7, 3.6 Hz, 2H); ¹ H NMR (300 MHz, DMSO-d6/D2O) δ 10.84 (s, 1H), 7.73 - 7.65 (m, 3H), 7.64 - 7.49 (m, 4H), 7 ,45- 7.26 (m, 4H), 7.15 (dd, J=7.9, 5.2 Hz, 2H), 5.49 (s, 1H), 4.13 (s, 2H), 3.25 (d, J=6.8 Hz, 2H), 1.14 - 0.95 (m, 1H), 0.58 - 0.38 (m, 2H), 0.29 - 0.05 ( m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (IER+) 536.3 (M+1); (IER-) 534.3 (M-1), 570.3 (M+Cl); chiral purity was confirmed by chiral HPLC on an AD-H column; isocratic method (85/15/0.1 hexane/ethanol/TEA), 0.5 ml/min, UV 260 nm, cycle 40 min, temperature 5°C) [Rt=20.22 (100% peak 1, corresponding 64a), Rt=27.323 (0%, peak 2, corresponding to 64b, >99% e.i.); analysis, calculation for C29H ₂₈ F ₃ N ₅ O ₂ -2.1HCl-H ₂ O: C, 55.27; H, 5.13; Cl, 11.81; N, 11.11; experiment: C, 55.18; H, 5.20; Cl, 11.74; N, 10.93.

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2. 2 peaks corresponding to (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazol- 5-carboxamide (64b) (0.308 g), which was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-30% MeOH in chloroform for 25 minutes) to give the free base (+)-1-(3 -(aminomethyl)phenyl)-N-(3-((3aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (64b) (0.251 g, 92.67% e.g. And.). Optical rotation: [a] _D =(+) 6.66 [CH3OH, 1.38]. ¹ H NMR (300 MHz, DMSO-66) δ 10.72 (s, 1H, exchange with D2O), 7.56 (dd, J=11.1, 7.1 Hz, 4H), 7.47 - 7 .39 (m, 2H), 7.35- 7.22 (m, 2H), 7.09 (d, J=7.7 Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.58 - 6.37 (m, 3H), 5.23 (s, 1H), 5.06 (s, 2H), 3.77 (s, 2H), 3.20 (dd, J =6.8, 1.5 Hz, 2H), 1.04 (s, 1H), 0.61 - 0.30 (m, 2H), 0.23 - 0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 60.70; MS (IER+) 536.3 (M+1), 534.3 (M-1). Into a solution of the free base (+)-1-(3(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (64b ) (245 mg) in methanol (8 ml) was added 2N. HCl (in methanol, 2.3 ml, 10 eq.) and stirred at room temperature for 30 minutes. The solution was evaporated to dryness to obtain the hydrochloride salt (+)-1-(3-(aminomethyl)phenyl)-N(3-((3-aminophenyl)(cyclopropylmethoxy)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (64b) (239 mg, 98%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.84 (s, 1H, exchange with _D2O ), 9.66 (s, 2H, exchange with D2O), 8.43 (s, 4H, exchange with D ₂ O), 7.75-7.48 (m, 8H), 7.35 (dt, J=19.9, 7.8 Hz, 2H), 7.24 (s, 2H), 7.13 (d, J=7.7 Hz, 3H), 5.48 (s, 1H), 4.12 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.16 - 0.98 (m, 1H), 0.59 - 0.36 (m, 2H), 0.17 (h, J=3.8 Hz, 2H); ¹ H NMR (300 MHz, DMSO-d6 D2O) δ 7.71 (d, J=1.9 Hz, 1H), 7.68 (t, J=2.0 Hz, 1H), 7.65 (s , 1H), 7.61 - 7.55 (m, 3H), 7.52 (td, J=5.2, 2.5 Hz, 1H), 7.45 - 7.23 (m, 4H), 7.14 (dd, J=6.9, 3.0 Hz, 2H), 5.48 (s, 1H), 4.13 (s, 2H), 3.25 (d, J=6.8 Hz , 2H), 1.17 - 0.97 (m, 1H), 0.61 - 0.36 (m, 2H), 0.27 - 0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77; MS (ESI ⁺ ): MS (ESI+) 536.3 (M+1), 534.3 (M-1), 570.3 (M+Cl); analysis, calculation for C29H ₂₈ F ₃ N ₅ O ₂ -1.5H ₂ O-2HCl: C, 54.81; H, 5.23; Cl, 11.16; N, 11.02; experiment: C, 55.01; H, 5.21; Cl, 11.05; N, 11.01; chiral purity was confirmed by chiral HPLC on an AD-H column; isocratic method (85/15/0.1 hexane/ethanol/TEA), 0.5 ml/min, UV 260 nm, cycle 40 min, temperature 5°C), Rt=20.427 (3.6638% peak 1, corresponding 64a), Rt=27.260 (96.3362% peak 2, corresponding to 64b, 92.67% e.i.);

analysis, calculation for C ₂ 9H28F3N5O ₂ 1.5H ₂ O-2HCl: C, 54.81; H, 5.23; Cl, 11.16; N, 11.02; experiment: C, 55.01; H, 5.21; Cl, 11.05; N, 11.01.

Scheme 65

isomer-1 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cycloExample of preparation of chiral propylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (65 a) and chiral isomer-2 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H -pyrazole-5-carboxamide (65b).

1-(3-(Aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide racemate (57e) (240 mg) were separated into chiral pure isomers by preparative chiral HPLC. The following conditions were used:

Column

Solvent

Isocratic method System pressure Column temperature Sample diluent

3.0 x 25.0 cm RegisPack from Regis Technologies (Morton Grove, IL) hexane:ethanol:diethylamine (80:20:0.1) 50 ml/min

100 bar (10 MPa)

25°C methanol

1. 1 peak was designated as chiral isomer-1 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (65a). The compound was repurified by flash column chromatography (silica gel, 4 g, eluted with 0 to 25% methanol/chloroform mixtures) to give pure chiral isomer-1 1-(3(aminomethyl)phenyl)-N-(5-(( 3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (65a) (17 mg, 62.35% ee); 1H NMR (300 MHz, DMSO^) δ 10.58 (s, 1H), 7.58 (s, 1H), 7.52 (d, J=5.7 Hz, 2H), 7.48 - 7, 39 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.94 (t,

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J=7.7 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 6.50 - 6.37 (m, 2H), 5.26 (s, 1H), 5, 08 (s, 2H), 3.80 (s, 2H), 3.19 (dd, J=6.9, 3.1 Hz, 2H), 1.04 (dd, J=12.3, 6, 3 Hz, 1H), 0.45 (dt, J=9.0, 2.8 Hz, 2H), 0.14 (q, J=4.8 Hz, 2H); mass spectrum (IER+) 554.3 (M+1), (IER-) 552.2 (M-1); chiral purity was confirmed by chiral HPLC on a chiral AD-H column; isocratic mode, solvent (85/15/0.1 hexane/ethanol/TEA); flow rate 0.8 ml/min; UV 243 nm, cycle 25 min (temperature 30°C), Rt=18.247 (peak 1, corresponding to 65a, 81.1746%); Rt=20.287 (peak 2, corresponding to 65b, 18.83%).

2. Peak 2 was designated as chiral isomer-2 1-(3-(αminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (65b). The compound was repurified by flash column chromatography (silica gel, 4 g, eluted with 0 to 25% methanol/chloroform mixtures) to give pure chiral isomer-2 1-(3(aminomethyl)phenyl)-N-(5-(( 3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (65b) (6 mg, 57.4% ee); ^1H NMR (300 MHz, DMSO- _dg ) δ 10.60 (s, 1H), 7.67 - 7.37 (m, 5H), 7.28 - 7.17 (m, 2H), 6, 99 - 6.90 (m, 1H), 6.52 (t, J=1.9 Hz, 2H), 6.43 (dddd, J=10.3, 7.9, 2.6, 1.1 Hz, 2H), 5.25 (d, J=5.2 Hz, 1H), 5.07 (s, 2H), 3.19 (dd, J=6.7, 2.5 Hz, 2H), 1.10 - 0.96 (m, 1H), 0.44 (m, 2H), 0.19 - 0.02 (m, 2H);

¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.79, -123.04. Chiral purity was confirmed by chiral HPLC on a chiral AD-H column; isocratic mode, solvent (85/15/0.1 hexane/ethanol/TEA); flow rate 0.8 ml/min; UV 243 nm, cycle 25 min (temperature 30°C), Rt=18.41 (peak 1, corresponding to 65a, 21.30%), Rt=20.31 (peak 2, corresponding to 65b, 78.70%).

Scheme 66

^ie 66a (-)-isomer

66b(+)-isomer

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (66a) and (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)1H- pyrazole-5-carboxamide (66b).

Racemate isomers 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylαamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (60e ) (335 mg) was separated by chiral preparative SFC; method: column: 3.0 x 25 cm RegisPack from Regis Technologies (Morton Glove, IL); solvent hexane:ethanol (9:1) with 0.1% diethylamine; isocratic method: 60 g/min; system pressure 100 bar (10 MPa); column temperature 25°C; sample diluent ethanol, obtaining:

1. 1 peak, which was designated as (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (66a) (37 mg). The resulting material was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-30% methanol in chloroform) to give (-)-1-(3-(aminomethyl)phenyl)-N-(5((cyclopropylmethylamino) (2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (66a) (2 mg, 44% ee). 1H NMR (300 MHz, DMSO-dg) δ 10.58 (s, 1H), 7.58 (d, J=12.0 Hz, 3H), 7.52 - 7.19 (m, 5H), 7 .10 - 6.96 (m, 2H), 6.78 - 6.62 (m, 2H), 5.03 (s, 1H), 3.87 (s, 2H), 2.44 - 2.32 (m, 1H), 2.31 - 2.19 (m, 1H), 1.00 - 0.82 (m, 1H), 0.46 - 0.33 (m, 2H), 0.15 - 0 .03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ 60.77, -122.98; MS (IER+) 554.2 (M+1);

2. 2 peaks, which was designated as (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (66b) (44 mg, 92% ee). The resulting compound was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-30% methanol in chloroform) to give the free base (+)-1-(3(aminomethyl)phenyl)-N-(5-(( cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (66b) (40 mg); optical rotation: [a] _D =(+) 61.86 [CH ₃ OH, 0.86]; 1H NMR (300 MHz, DMSO-dg) δ 10.57 (s, 1H, exchange with D2O), 7.64-7.54 (m, 2H), 7.51 (s, 1H), 7.47- 7.40 (m, 2H), 7.32 (dq, J=6.8, 2.3 Hz, 2H), 7.23 (dd, J=10.3, 8.5 Hz, 1H), 7 .03 (td, J=6.3, 2.4 Hz, 2H), 6.75-6.64 (m, 2H), 5.03 (s, 1H), 3.77 (s, 2H), 2.45-2.35 (m, 2H), 2.31-2.18 (m, 1H), 1.02-0.86 (m, 1H), 0.52-0.29 (m, 2H ), 0.14-0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.73 (d, J=5.3 Hz), -123.06; MS (IER+) 554.4 (M+1), 552.4 (M-1). Into a solution of the free base (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (66b)

- 155 045731 (29 mg) in methanol (4 ml) was added 2N. HCl (0.131 mL, 5 eq.), stirred for 30 min and evaporated to dryness to give (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl) hydrochloride salt )methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (66b) (20 mg) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H, exchange with D ₂ O), 10.39 (s, 1H, exchange with D ₂ O), 10.08 (s, 1H, exchange with D ₂ O), 9.77 (s, 1H, exchange with D ₂ O), 8.51 (d, J=7.3 Hz, 3H, exchange with D2O), 7.92 - 7.46 ( m, 8H), 7.37 (dd, J=10.3, 8.5 Hz, 1H), 7.18 (td, J=7.7, 1.6 Hz, 1H), 7.01 - 6 .81 (m, 2H), 5.88 - 5.58 (m, 1H), 4.12 (q, J=5.8 Hz, 2H), 2.72 (q, J=5.9 Hz, 2H), 1.13 (ddd, J=12.9, 8.7, 3.8 Hz, 1H), 0.64 0.45 (m, 2H), 0.38 - 0.18 (m, 2H ); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81, -120.50; MS (ESI+) 554.3 (M+1), 552.3 (M-1), 588.3 (M+Cl); calculation for CsH^NsO^IHCM^O: C, 53.00; H, 4.92; Cl, 11.33; N, 10.66; experiment: C, 52.90; H, 4.90; Cl, 11.46; N, 10.28.

Scheme 67

67a (-)-isomer

67b(+)-isomer

An example of the preparation of (-)-1 -(3 -(aminomethyl)phenyl)-K-(5-(3-cyclopropyl-1-hydroxy-1 -(pyridin-3 yl)propyl)-2-fluorophenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (67a) and (+)-1-(3-(aminomethyl)phenyl)-K-(5-(3-cyclopropyl-1-hydroxy-1-(pyridine-3- yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (67b).

Racemate isomers 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- Pyrazole-5-carboxamide (58c) (2.0 g) was separated using the preparative SFC method under the following conditions to obtain:

Column: 2.1x25 cm, ChiralPak IC SFC manufactured

Chiral Technologies (West Chester, PA)

Co-solvent CO2 (solvent B) acetonitrile:methanol (3:1) with 1% isopropylamine

Isocratic way 35% cosolvent, flow rate 80 ml/min System pressure 200 bar (20 MPa) Column temperature 25°С Sample diluent MeOH:ACN (2:1) with a small amount

DXM

1. 1 peak, which was designated as (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (67a) (755 mg, >95% ee); optical rotation: [α%=(-) 3.10 [CH3OH, 2.19]; 1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 8.67 - 8.57 (m, 1H), 8.38 (dd, J=4.8, 1.6 Hz, 1H) , 7.77 (dt, J=8.2, 2.0 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.57 (s, 1H), 7.51 (s, 1H ), 7.47 - 7.38 (m, 2H), 7.37 - 7.27 (m, 3H), 7.25 - 7.15 (m, 1H), 5.80 (s, 1H), 3.77 (s, 2H), 2.33 (t, J=7.9 Hz, 2H), 1.99 (s, 2H), 1.06 (q, J=9.4, 6.3 Hz , 2H), 0.63 (t, J=7.2 Hz, 1H), 0.41 -0.26 (m, 2H), -0.07 (dd, J=4.8, 1.6 Hz , 2H); Into a solution of the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (67a) (700 mg) in methanol (10 ml) add hydrochloric acid in methanol (2M, 6.5 ml), stir for 30 min and concentrate to remove excess hydrochloric acid . The residue was dried in vacuo to give (-)-1-(3-(aminomethyl)phenyl)-C-(5-(3-cyclopropyl-1hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl hydrochloride salt )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (67a); 1H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H, exchange with D ₂ O), 8.85 (d, J=2.1 Hz, 1H), 8.72 (dd, J= 5.4, 1.4 Hz, 1H), 8.44 (t, J=7.4 Hz, 4H, 3H, exchange with D ₂ O), 7.87 (dd, J=8.2, 5, 4 Hz, 1H), 7.72 (t, J=8.4 Hz, 3H), 7.63 (dt, J=7.2, 1.8 Hz, 1H), 7.59 - 7.47 ( m, 2H), 7.40 (ddd, J=8.8, 4.5, 2.3 Hz, 1H), 7.25 (dd, J=10.2, 8.7 Hz, 1H), 6 .28 (s, 1H, exchange with D ₂ O), 4.11 (q, J=5.8 Hz, 2H), 2.43 (dd, J=10.6, 5.8 Hz, 2H), 1.06 (td, J=15.4, 14.2, 6.9 Hz, 2H), 0.71 - 0.56 (m, 1H), 0.41 - 0.31 (m, 2H), -0.06 (dd, J=4.1, 1.5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -57.73 - -63.18 (m), -122.87 (s); mass spectrum (ESI+) 554.3 (M+1); (IER-) 552.2 (M-1), 588.2 (M+Cl); analysis, race

- 156 045731 even for Cz^F^Oz^HCl-HO: C, 54.10; H, 4.85; Cl, 10.87; N, 10.88; experiment: C, 53.97; H, 4.88; Cl, 11.19; N, 10.65;

2. 2 peaks, which was designated as (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1(pyridin-3-yl)propyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (67b) (816 mg, 97.6% ee) as free base; optical rotation: [a] _D =(+) 3.23 [CH ₃ OH, 2.04]; 1H NMR (300 MHz, DMSO-dg) δ 10.53 (s, 1H, exchange with D2O), 8.62 (dd, J=2.4, 0.9 Hz, 1H), 8.38 (dd, J=4.7, 1.6 Hz, 1H), 7.78 (dt, J=8.0, 2.1 Hz, 1H), 7.65 (dd, J=7.5, 2.4 Hz , 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.47 - 7.38 (m, 2H), 7.32 (dddd, J=8.8, 7.9 , 4.7, 1.6 Hz, 3H), 7.20 (dd, J=10.3, 8.6 Hz, 1H), 5.80 (s, 1H, exchange with D2O), 3.77 ( s, 2H), 2.34 (t, J=7.8 Hz, 2H), 1.17 - 0.99 (m, J=6.8 Hz, 2H), 0.61 (dt, J=12 ,8, 6.9 Hz, 1H), 0.41 - 0.25 (m, 2H), -0.07 (dd, J=4.8, 1.6 Hz, 2H); MS (IER+) 554.3 (M+1), 576.3 (M+Na); 552.3 (M-1), 588.2 (M+Cl). Into a solution of the free base (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (67b) (700 mg) in methanol (10 ml), add hydrochloric acid in methanol (2M, 6.5 ml), stir for 30 min and concentrate in vacuo to removing excess hydrochloric acid. The residue was dried to obtain the hydrochloride salt of (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (67b) (730 mg) as a white solid; 1H NMR (300 MHz, DMSO-de) δ 10.70 (s, 1H, exchange with D2O), 8.86 (s, 1H), 8.73 (d, J=5.0 Hz, 1H), 8 .45 (d, J=9.5 Hz, 4H, 3H exchange with D2O), 7.99 - 7.84 (m, 1H), 7.71 (d, J=10.0 Hz, 3H), 7 .63 (d, J=7.0 Hz, 1H), 7.59 7.47 (m, 2H), 7.45- 7.36 (m, 1H), 7.26 (dd, J=10, 2, 8.6 Hz, 1H), 6.30 (s, 1H, exchange with D2O), 4.11 (q, J=5.8 Hz, 2H), 2.43 (t, J=8.5 Hz, 2H), 1.06 (dq, J=13.8, 7.8, 6.7 Hz, 2H), 0.70 -0.56 (m, 1H), 0.40 - 0.29 ( m, 2H), -0.02 - 0.09 (m, 2H); mass spectrum (ESI+) 554.3 (M+1), (ESI-) 552.1 (M-1), 588.2 (M+Cl); analysis, calculation for C ₂₉ H ₂₇ F ₄ N ₅ O ₂ -2HCl-H ₂ O: C, 54.10; H, 4.85; Cl, 10.87; N, 10.88; experiment: C, 53.94; H, 5.00; Cl, 11.09; N, 10.74.

Scheme 68

An example of the preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 68c); (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (68d) and (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (68e).

Step 1. Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropan-1-ol (68a).

To a stirred solution of 3-cyclopropyl-1-phenylpropan-1-one (46d) (12 g, 68.9 mmol) in tetrahydrofuran (10 ml) was added freshly prepared (3-(bis(trimethylsilyl)amino)-4fluorophenyl)magnesium bromide ( 52c) (88 ml, 79 mmol, 0.9 M solution in THF) at 0°C. The reaction mixture was left stirring for 2 hours at 0°C, quenched with saturated aqueous ammonium chloride (100 ml), stirred for 2 hours and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with water (2x100 ml), brine (100 ml), dry, filter and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give 1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-phenylpropan-1-ol (68a ) (15.6 mg, 79%) as an oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.42 - 7.35 (m, 2H), 7.25 (ddd, J=7.7, 6.9, 1.2 Hz, 2H), 7, 17 - 7.09 (m, 1H), 6.92 - 6.77 (m, 2H), 6.54 (ddd, J=8.5, 4.5, 2.3 Hz, 1H), 5, 29 (s, 1H), 4.99 (s, 2H), 2.31 - 2.17 (m, 2H), 1.14 - 0.95 (m, 2H), 0.72 - 0.53 ( m, 1H), 0.39 - 0.27 (m, 2H), -0.09 (td, J=5.3, 3.7 Hz, 2H).

- 157 045731

Step 2. Preparation of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 68b).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (12.32 g, 43.8 mmol) in N,N-dimethylformamide (265 ml) was added 1 -(3-amino-4-fluorophenyl)-3-cyclopropyl-1phenylpropan-1-ol (68a) (15 g, 52.6 mmol), N-ethyl-N-isopropan-2-amine (61.0 ml, 350 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 22.46 g, 48.2 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours, quenched with water (200 ml) and extracted with ethyl acetate (3x300 ml). Combine the organic layers, wash with water (2x100 ml), brine (100 ml), dry over anhydrous MgSO ₄ , filter and concentrate to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 120 g, eluted with hexanes in ethyl acetate/hexanes, 0-40 to 100%) to give 1-(3-cyanophenyl)-N-(5(3-cyclopropyl-1- hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (68b) (18.715 g, 34.1 mmol, 78% yield); ¹ H NMR (300 MHz, DMSO^) δ 10.52 (s, 1H, exchange with D2O), 8.12 (t, J=2.0 Hz, 1H), 8.00 (dt, J=7, 8, 1.3 Hz, 1H), 7.96 - 7.85 (m, 1H), 7.78 - 7.67 (m, 2H), 7.57 (dd, J=7.6, 2, 3 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.35 - 7.23 (m, 3H), 7.21 - 7.16 (m, 1H), 7.16 - 7 .11 (m, 1H), 5.57 (s, 1H, exchange with D2O), 2.35-2.24 (m, 2H), 1.06 (q, J=7.1 Hz, 2H), 0.60 (dt, J=12.1, 7.2 Hz, 1H), 0.40 - 0.27 (m, 2H), 0.09 (td, J=5.2, 3.6 Hz, 2H).

Step 3. Preparation of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1phenylpronyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (68c).

Into a stirred solution of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (68b) ( 10 g, 18.23 mmol) in methanol (300 ml) at 0°C, nickel (II) chloride hexahydrate (1.083 g, 4.56 mmol) was added, then sodium tetrahydroborate (6.90 g, 182 mmol) was added in small portions for 15 minutes. The reaction mixture was stirred for 15 min, quenched by adding N1-(2-aminoethyl)ethane-1,2-diamine (4.73 mL, 45.6 mmol), stirred for an additional 30 min at room temperature and concentrated in vacuo to remove methanol. The reaction mixture was diluted with water (500 ml) and stirred for 2 hours. The isolated solid was collected by filtration. The solid was dissolved in dichloromethane (500 ml), washed with water (2x200 ml), extracted with dichloromethane (2x200 ml). Combine the layers in chloroform, wash with brine (2x200 ml), dry and concentrate in vacuo. The residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give the racemate 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1 -hydroxy-1phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (68c) (6.1 g, 11.04 mmol, 60.6% yield) as a colorless solid.

Step 4. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (68d) and (+)-1-(3-(aminomethyl)phenyl)N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (68e).

Isomers of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 68c) (240 mg) was separated using the preparative SFC method under the following conditions to obtain:

Preparative SFC method

Column 2.1x25 cm ChiralPak IC SFC manufactured

Chiral Technologies (West Chester, PA)

Co-solvent CO ₂ (solvent B) methanol with 1% isopropylamine

Isocratic method 25% cosolvent, flow rate 80 ml/min

System pressure 100 bar (10 MPa)

Column temperature 25°C

Sample diluent MeOH:dichloromethane (3:1)

1. 1 peak, which was designated as (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (68d) (59 mg, >95% ee); optical rotation: [a] _D =(-) 0.987 [CH3OH, 0.081]; ¹ H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 7.62 (dd, J=7.5, 2.4 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.46 - 7.38 (m, 4H), 7.29 (dt, J=15.0, 7.6 Hz, 4H), 7.21 - 7.11 ( m, 2H), 5.57 (s, 1H), 3.77 (s, 2H), 2.28 (d, J=8.2 Hz, 2H), 1.05 (dd, J=10.4 , 5.9 Hz, 2H), 0.62 (dq, J=12.5, 6.0, 5.4 Hz, 1H), 0.41 - 0.28 (m, 2H), -0.09 (t, J=4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.71, -124.35- -124.46 (m); MC (IER+) 553.3 (M+1), 575.3 (M+Na), (IER-) 551.2 (M-1); analysis, calculation for C ₃₀ H ₂₈ F ₄ N ₄ O ₂ : C, 65.19; H, 5.11; N, 10.14; experiment: C, 65.33; H, 5.37; N, 9.88;

2. 2 peaks, which was designated as (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1

- 158 045731 phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (68e) (124 mg, >95% ee); The resulting compound was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform) to give pure (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3cyclopropyl-1- hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (68e) (77 mg) as a white solid; optical rotation: [a]D=(+) 1.558 [CH3OH, 0.77]; ¹ H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 7.62 (dd, J=7.5, 2.3 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.45-7.38 (m, 4H), 7.35-7.30 (m, 1H), 7.29 (d, J=2.6 Hz, 1H) , 7.26 (d, J=7.7 Hz, 2H), 7.20 - 7.12 (m, 2H), 5.57 (s, 1H), 3.78 (s, 2H), 2, 29 (t, J=8.1 Hz, 2H), 1.11 - 1.02 (m, 2H), 0.69 - 0.54 (m, 1H), 0.33 (dt, J=8, 5, 2.8 Hz, 2H), -0.08 (q, J=4.8 Hz, 2H); MS (IER+) 553.3 (M+1), (IER-) 551.2 (M-1).

Scheme 69

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (69a) and (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl )propyl)-2-fluorophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (69b).

Racemate isomers 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- Pyrazole-5-carboxamide (59c) (2.0 g) was separated using the preparative SFC method under the following conditions to obtain:

Preparative SFC method used:

Column 2.1x25 cm ChiralPak IC SFC manufactured

Chiral Technologies (West Chester, PA)

Co-solvent CO2 (solvent B) dichloromethane:methanol (9:1) with 1% isopropylamine Isocratic way 60% cosolvent, flow rate 80 ml/min System pressure 100 bar (10 MPa) Column temperature 25°С

Sample diluent methanol

The chiral purity of the peaks was determined using the following analytical SFC method:

Column 4.6x100cm ChiralPak IC SFC from Chiral Technologies (West Chester, PA)

Co-solvent CO ₂ (solvent B) dichloro methane: methanol (9:1) with 0.1%

isopropylamine Gradient method 5-65% cosolvent, flow rate 4 ml/min System pressure 100 bar (10 MPa) Column temperature 25°С Sample diluent methanol Peak 1 (69a) Rt = 2.8 min Peak 2 (69b) Rt = 3.7 min 265 mg >95% e.i. (UV 254) purity 95.3% (UV 254) 464 mg >95% e.i. (UV 254) purity 98.0% (UV 254)

1. 1 peak, which was designated as the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2 -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (69a) (265 mg, >95% ee), as a white solid. Optical rotation: [a]D=(-) 0.95 [CH3OH, 2.105]; ¹ H NMR (300 MHz, DMSO^) δ 10.54 (s, 1H), 8.67 - 8.57 (m, 1H), 8.38 (dd, J=4.8, 1.6 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H, exchange with D ₂ O), 8.52 - 8.46 (m, 1H), 7.77 - 7.68 (m, 2H ), 7.61 (t,

- 159 045731

J=8.2 Hz, 3H), 7.50 - 7.46 (m, 2H), 7.40 (ddd, J=7.4, 5.0, 2.2 Hz, 2H), 7.23 - 7.12 (m, 2H), 5.83 (s, 1H, exchange with D ₂ O), 5.00 (s, 2H, exchange with D ₂ O), 3.91 (s, 2H), 2 .42 -2.22 (m, 2H), 1.01 (s, 2H), 0.67 - 0.51 (m, 1H), 0.37 - 0.27 (m, 2H), -0, 10 (p, J=4.8 Hz, 2H); MS (IER+) 554.3 (M+1), 576.3 (M+Na); (IER-) 552.3 (M-1), 588.3 (M+Cl). Into a solution of the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1(pyridin-2-yl)propyl)-2-fluorophenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (69a) (250 mg) in methanol (10 ml), add hydrochloric acid in methanol (2M, 2.305 ml), stir for 30 min and concentrate in vacuo to remove excess hydrochloric acid acids. The residue was dried to obtain (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1(pyridin-2-yl)propyl)-2-fluorophenyl)- hydrochloride 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (69d) (250 mg, 87% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H, exchange with D ₂ O), 8.60 (d, J=5.3 Hz, 1H), 8.46 (s, 3H , exchange with D2O), 8.11 (s, 1H), 7.89 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.73 (d, J=2, 2 Hz, 1H), 7.70 (s, 1H), 7.63 (dt, J=7.2, 1.7 Hz, 1H), 7.59 - 7.42 (m, 4H), 7, 23 (t, J=9.5 Hz, 1H), 4.11 (q, J=5.8 Hz, 2H), 2.47 - 2.35 (m, 2H), 1.20 - 1.04 (m, 1H), 1.04 - 0.86 (m, 1H), 0.60 (q, J=7.3, 6.8 Hz, 1H), 0.33 (dt, J=8.4 , 2.8 Hz, 2H), -0.07 (d, J=4.5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.80, -123.19; MS (IER+) 554.3 (M+10), (IER-) 552.2 (M-1), 588.3 (M+Cl). Analysis, calculation for C29H27F4N5O2-2HCl-1.75H2O: C, 52.99; H, 4.98; Cl, 10.65; N, 10.66; experiment: C, 53.07; H, 5.06; Cl, 10.88; N, 10.45;

2. 2 peaks, which was designated as (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1(pyridin-2-yl)propyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (69e) (464 mg 90% ee), which was purified by flash column chromatography (silica gel, 12 g, eluted with 0-30% MeOH in chloroform for 15 minutes) to obtain 345 mg of free base 69e. 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H, exchange with D2O), 8.54 - 8.45 (m, 1H), 7.77 - 7.68 (m, 2H), 7.67 -7.61 (m, 3H), 7.59 - 7.52 (m, 1H), 7.51 - 7.37 (m, 3H), 7.25 - 7.11 (m, 2H ), 5.84 (s, 1H, exchange with D ₂ O), 4.01 (s, 2H), 2.44 2.27 (m, 2H), 1.02 (s, 2H), 0.68 - 0.50 (m, 1H), 0.41 -0.23 (m, 2H), -0.11 (q, J=4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.78, -124.06; MS (IER+): MS (IER+) 554.3 (M+1), MS (IER-) 552.2 (M-1), 588.2 (M+Cl); optical rotation: [a] _D =(+) 1.81 [CH3OH, 1.1]. To a stirred solution of 69e (303 mg) in methanol (10 ml) was added 2N. HCl (2.74 mL, 5.47 mmol) and stirred for 10 min and evaporated to dryness to give HCl salt (S)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl- 1-Hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (69e) (0.269 g, 89% yield) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.74 (s, 1H), 8.73 - 8.44 (m, 4H), 8.24 (s, 1H), 7.99 (s, 1H ), 7.87 - 7.43 (m, 8H), 7.25 (dd, J=10.2, 8.7 Hz, 1H), 4.11 (q, J=5.8 Hz, 2H) , 2.50 (d, J=1.9 Hz, 2H), 1.14 (s, 1H), 0.95 (td, J=12.5, 6.0 Hz, 1H), 0.72 - 0.53 (m, 1H), 0.33 (dt, J=8.4, 2.7 Hz, 2H), -0.06 (h, J=3.6 Hz, 2H); 1H NMR (300 MHz, DMSO-d ₆ , D ₂ O) δ 8.65 (dd, J=5.5, 1.6 Hz, 1H), 8.33 (td, J=7.9, 1, 7 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.83 - 7.68 (m, 3H), 7.65 - 7.57 (m, 3H), 7, 56 - 7.44 (m, 2H), 7.35-7.22 (m, 1H), 4.12 (s, 2H), 2.54 - 2.40 (m, 2H), 1.16 ( ddd, J=17.6, 14.4, 8.1 Hz, 1H), 0.96 (tt, J=12.5, 5.7 Hz, 1H), 0.63 (td, J=7, 6, 4.0 Hz, 1H), 0.36 (ddt, J=8.6, 5.6, 2.8 Hz, 2H), -0.05 (dd, J=5.7, 3.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ 60.80, -122.61; MS (IER+): MS (IER+) 554.3 (M+1), MS (IER-) 552.3 (M-1), 588.2 (M+Cl); HPLC: chiral purity 90% ee; chiral HPLC: AD-H column (90/10/0.2 hexane/ethanol/TEA) 0.8 ml/min, UV 260 nm, cycle 45 min (temperature 40°C), Rt=16.88 (peak 1 , 95.03%); Rt=19.99 (peak 2 4.96%) 90% e.i.; reverse phase HPLC, Rt=6.97 (95.01%); analysis, calculation for C29H27F4N5O2 2HCl 2H2O: C, 52.57; H, 5.02; Cl, 10.70; N, 10.57; experiment; C, 52.95; H, 5.01; Cl, 10.85; N, 10.50.

Scheme 70

70a (+)-isomer

70b (-)-isomer

An example of the preparation of (+)-1 -(3 -(aminomethyl)phenyl)-N-(5 -((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (70a) and (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole -5-carboxamide (70b).

Isomers of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (54e ) (0.4 g) was separated using the preparative SFC method under the following conditions to obtain:

Preparative SFC method used:

- 160 045731

Column 20mm x 25.0cm ChromegaChiral CSS from Regis Technologies (Morton Grove, IL)

Co-solvent CO2 (solvent B) methanol:isopropanol (1:1) with 1% isopropylamine Isocratic way 20% cosolvent, flow rate 80 ml/min System pressure 200 bar (20 MPa) Column temperature 25°С

Sample diluent methanol:isopropanol

The chiral purity of the peaks was determined using the following analytical SFC method:

Column 4.6x100 cm ChiralPak AS from Chiral Technologies (West Chester, PA) Co-solvent CO2 (solvent B) methanol:isopropanol (1:1) with 0.1% isopropylamine Gradient method gradient 5-65% co-solvent, consumption 4 ml/min

System pressure 100 bar (10 MPa) Column temperature 25°С

Sample diluent methanol

Peak 1 (70a)

Peak 2 (70b)

Κϊ = 2.1μηη 144 mg >95% e.i. (UV 254) purity 98.6% (UV 254)

Rt~ 2.4 min 172 mg 95.5% e.i. (UV 254) purity 96.5% (UV 254)

1. 1 peak, which was designated as the free base (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5carboxamide (70a) (144 mg, >95% ee), as a white solid; optical rotation: [a]D=(+) 6.83 [CH ₃ OH, 1.2]; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H, exchange with D ₂ O), 7.88 (t, J=1.7 Hz, 1H), 7.77 7.71 ( m, 1H), 7.67 (dt, J=7.7, 1.4 Hz, 1H), 7.63 (dd, J=7.5, 2.1 Hz, 1H), 7.56 (s , 1H), 7.54 -7.47 (m, 2H), 7.47 7.38 (m, 2H), 7.34 (ddt, J=8.6, 5.9, 2.8 Hz, 2H), 7.22 (dd, J=10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.77 (s, 2H), 2.312.21 (m, 2H), 0.97 - 0.80 (m, 1H), 0.42 - 0.33 (m, 2H), 0.10 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 60.73, -123.20; MS (IER+) 563.3 (M+1), 561.3 (M-1). Into a solution of the free base (+)-1-(3(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (70a) (120 mg) in methanol (15 ml), add hydrogen chloride (0.969 ml, 1.938 mmol), stir at room temperature for 10 min, evaporate to dryness to obtain the hydrochloride salt (+)-1-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (70a) (100 mg) as white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.84 (s, 1H, exchange with D2O), 10.44 (s, 2H, exchange with D2O), 8.44 (s, 3H, exchange with D2O), 8.30 (s, 1H, exchange with D2O), 8.09 (d, J=7.9 Hz, 1H), 7.99 (d, J=6.8 Hz, 1H), 7.91 7, 83 (m, 1H), 7.80 - 7.50 (m, 7H), 7.42 (dd, J=10.3, 8.6 Hz, 1H), 5.78 (d, J=6, 9 Hz, 1H), 4.13 (d, J=5.7 Hz, 2H), 2.88 - 2.62 (m, 2H), 1.42 - 0.99 (m, 1H), 0, 73 - 0.46 (m, 2H), 0.32 (d, J=4.4 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.81, -119.99; MS (IER ⁺ ): MS (IER+) 563.3 (M+1), MS (IER-) 561.3 (M-1), 597.3 (M+Cl); analysis, calculation for С30Н2^6О-2НСМ,75Н2О: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; experiment: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97;

2. 2 peaks, which was designated as the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (70b) (172 mg, 95.5% ee), which was repurified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-30% MeOH in chloroform for 15 min) to obtain the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (70b) as an off-white solid; optical rotation: [a] _D =(-) 5.44 [CH ₃ OH, 1.25]; 1H NMR (300 MHz, DMSO-dg) δ 7.88 (t, J=1.6 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.57 (s, 1H), 7.54 - 7.47 (m, 2H), 7.45 - 7.41 (m, 2H), 7.34 (ddq, J=8 ,7, 6.1, 3.5, 2.8 Hz, 2H), 7.22 (dd, J=10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3, 78 (s, 2H), 2.25 (d, J=6.9 Hz, 2H), 0.90

- 161 045731 (ddd, J=9.8, 8.0, 5.2 Hz, 1H), 0.47 - 0.29 (m, 2H), 0.04 (dd, J=5.0, 1 .5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.73, -123.19; MS (IER+) 563.3 (M+1), MS (IER-), 561.3 (M-1). Into a solution of the free base (-)-1(3-(αminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (70b) (0.124 g, 0.220 mmol) in methanol (15 ml), add hydrogen chloride (1.102 ml, 2.204 mmol), stir at room temperature for 10 min, evaporate to dryness to obtain the hydrochloride salt (-)-1- (3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (70b) (0.121 g ) as a whitish solid; ^1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H, exchange with D2O), 10.36 (s, 2H, exchange with D2O), 8.38 (s, 3H, exchange with D2O) , 8.27 (s, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.98 (d, J=6.7 Hz, 1H), 7.87 (d, J= 7.7 Hz, 1H), 7.78 - 7.49 (m, 7H), 7.48 - 7.37 (m, 1H), 5.78 (s, 1H), 4.13 (d, J =5.7 Hz, 2H), 2.72 (s, 2H), 1.14 (s, 1H), 0.56 (d, J=7.7 Hz, 2H), 0.31 (d, J =5.0 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.82, 120.03; MS (IER ⁺ ): MS (IER+) 563.3 (M+1), MS (IER-), 561.3 (M-1), 597.2 (M+Cl); analysis, calculation for C30H ₂₆ F ₄ N ₆ O-2HCl-1.75H ₂ O: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; experiment: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97.

Scheme 71

An example of the preparation of chiral isomer-1 1-(3-1

71a chiral isomer-1

71b chiral isomer-2 methyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamideα (71a) and chiral isomer-2 1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 71b).

Racemate isomers 1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (52h ) (235 mg) were separated into pure chiral isomers using the preparative SFC method under the following conditions to obtain:

Preparative SFC method:

Column 20 mm x 25.0 cm Chromega Chiral CSS by Regis Technologies (Morton

Grove, IL)

Co-solvent CO ₂ (solvent B) methanol:isopropanol (1:1) with 1% isopropylamine Isocratic way 20% cosolvent, flow rate 80 ml/min System pressure 100 bar (10 MPa) Column temperature 25°С

Sample diluent methanol

The chiral purity of the peaks was determined using the following analytical SFC method:

- 162 045731

Column 4.6x100 cm ChiralPak AS from Chiral Technologies (West Chester, PA) Co-solvent CO ₂ (solvent B) methanol:isopropanol (1:1) with 0.1% isopropylamine Gradient method gradient 5-65% co-solvent, consumption 4 ml/min

System pressure 100 bar (10 MPa) Column temperature 25°С Sample diluent methanol

Peak 1 (71a)

Rt = 2.2 min mg >95% e.i. (UV 254) purity 81.9% (UV 254)

Peak 2 (71b)

Rt = 2.4 min mg

97.7% e.i. (UV 254)

1. 1 peak, which was designated as chiral isomer-1, purity 98.5% (UV 254)

1-(3-(aminomethyl)phenyl)-N-(5-((4cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (71a) (46 mg , >95% ee), which was purified again by flash column chromatography (silica gel, 4 g, eluted with mixtures of CMA 80 in chloroform, 0 to 30%) to give pure chiral isomer-1 free base 1-(3 -(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (71a) (34 mg) in as a white solid; ¹ H NMR (300 MHz, DMSO-dg) δ 7.77 (d, J=7.3 Hz, 2H), 7.66 - 7.56 (m, 4H), 7.56 (s, 1H), 7.51 (s, 1H), 7.49 -7.38 (m, 2H), 7.37 - 7.27 (m, 3H), 7.21 (dd, J=10.2, 8.5 Hz, 1H), 4.95 (s, 1H), 3.77 (s, 2H), 2.25 (d, J=6.7 Hz, 3H), 0.95-0.84 (m, 1H ), 0.43 - 0.30 (m, 2H), 0.10 - -0.01 (m, 1H); MS (IER+) 563.3 (M+1), (IER-) 561.3 (M-1). Into a solution of the free base of chiral isomer-1 1-(3(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (71a) (34 mg) in methanol (2 ml), add hydrochloric acid in methanol (2M, 0.3 ml), stir for 15 min and concentrate to remove excess hydrochloric acid. The residue was dried to obtain the hydrochloride salt of chiral isomer-1 1-(3(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (71a) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.49 (s, 2H), 8.47 (s, 3H), 8.04 - 7.90 (m, 5H) , 7.82 - 7.68 (m, 3H), 7.63 (dt, J=7.4, 1.7 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.41 (dd, J=10.2, 8.6 Hz, 1H), 5.83 (t, J=6.6 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 2 .71 (q, J=6.0, 4.6 Hz, 2H), 1.18 (td, J=13.9, 12.8, 7.3 Hz, 1H), 0.55 (dt, J =8.3, 3.1 Hz, 2H), 0.32 (t, J=5.0 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-b6) δ -60.81, -120.01; analysis, calculation for C30H26F4N6O-2HCl-2.75H2O: C, 52.65; H, 4.93; Cl, 10.22; N, 12.28; experiment: C, 52.95; H, 4.87; Cl, 11.61; N, 10.06;

2. 2 peaks, which was designated as the free base of chiral isomer-2 1-(3(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3(trifluoromethyl) -1H-pyrazole-5-carboxamide (71b) (57 mg, 97.7% ee), as a white solid; 1H NMR (300 MHz, DMSO-b ₆ ) δ 10.54 (s, 1H), 7.80 -7.74 (m, 2H), 7.61 (d, J=7.8 Hz, 3H), 7.57 (s, 1H), 7.52 (s, 1H), 7.43 (d, J=6.9 Hz, 2H), 7.35-7.30 (m, 2H), 7.22 (t, J=9.5 Hz, 1H), 4.95 (s, 1H), 3.79 (s, 2H), 2.25 (d, J=7.0 Hz, 2H), 0.90 (s, 1H), 0.41 - 0.33 (m, 2H). Into a solution of the free base of chiral isomer-2 1-(3(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-nirazol-5 -carboxamide (71b) in methanol (2 ml) was added hydrochloric acid in methanol (2M, 0.5 ml), stirred for 15 min and concentrated in vacuo to remove excess hydrochloric acid. The residue was dried to obtain the hydrochloride salt of chiral isomer-2

1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (71b) ( 50 mg) as a white solid; 1H NMR (300 MHz, DMSO-b ₆ ) δ 10.83 (d, J=5.2 Hz, 1H, exchange with D2O), 10.45 (s, 2H, exchange with D2O), 8.45 (s , 3H, exchange with D2O), 8.04 - 7.89 (m, 5H), 7.81 - 7.67 (m, 3H), 7.66 - 7.60 (m, 1H), 7.59 - 7.48 (m, 2H), 7.47 - 7.36 (m, 2H), 5.81 (d, J=6.8 Hz, 1H), 4.13 (q, J=5.7 Hz, 2H), 2.71 (q, J=6.2, 5.2 Hz, 2H), 1.15 (td, J=8.1, 5.2 Hz, 1H), 0.64 - 0 .49 (m, 2H), 0.32 (t, J=5.0 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.79, -120.01; MS (ESI+) 563.3 (M+1), 585.3 (M+Na), 561.3 (M-1), 597.3 (M+Cl); analysis, calculation for C ₃₀ H ₂₆ F ₄ N ₆ O-1.95HCl-1.75H ₂ O: C, 53.80; H, 4.81; Cl, 10.32; N, 12.55; experiment: C, 54.09; H, 4.94; Cl, 10.13; N, 11.42.

- 163 045731

Scheme 72

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (72c) and (+)-1-(3-(aminomethyl)phenyl)N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5carboxamide (72d).

Racemate isomers of tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (56b) ( 0.75 g) were separated by preparative chiral HPLC under the following conditions to obtain:

Column CHIRALPAK AD-H; 5 µm, 4.6x250 mm, flow rate 1 ml/min

Eluent hexane:ethanol-diethylamine (90:10:0.1)

Column temperature

UV detection room temperature

270 nm

Peak 1 (72a)

8,849 min

239 mg >99% e.i.

11,589 minutes indicated

Peak 2 (72b)

1. 1 peak, which

220 mg

98.0% e.i.

as (-)-tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (72a) (239 mg, >99% ee); optical rotation: No=(-) 17.11 [CH3OH, 0.83]; 1H NMR (300 MHz, DMSO-dg) δ 10.60 (s, 1H), 7.82 (s, 1H), 7.74 (dt, J=7.5, 1.4 Hz, 1H), 7 .70 - 7.65 (m, 1H), 7.64 - 7.23 (m, 10H), 5.58 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.37 (s, 9H), 1.11 - 0.95 (m, 1H), 0.52 - 0.40 (m, 2H) , 0.18-0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82, -122.29; (IER+) 686.3 (M+23). Into a solution of (-)-tert-butyl-3-(5-(5((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate ( 72a) (230 mg, 0.347 mmol) in methanol (25 ml) was added conc. hydrogen chloride (0.180 ml, 2.156 mmol) and stirred at room temperature for 19 hours (~20% conversion by TLC). The reaction mixture was concentrated to dryness in vacuo (at <30°C, ~50% conversion according to TLC). Conc. was added to the residue. HCl (0.15 mL, 1.8 mmol), stirred at room temperature for 0.5 h and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give the free base (-)-1-(3-(aminomethyl)phenyl)- N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (72c) (95 mg) as a white solid; optical rotation: [a] _D =(-) 15.92 [CH ₃ OH, 0.515]; 1H NMR (300 MHz, DMSO-dg) δ 10.59 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 7.74 (dt, J=7.6, 1, 5 Hz, 1H), 7.67 (dt, J=8.1, 1.5 Hz, 1H), 7.63 - 7.50 (m, 4H), 7.43 (q, J=1.5 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.35-7.22 (m, 3H), 5.59 (s, 1H), 3.77 (s, 2H ), 3.23 (d, J=6.8 Hz, 2H), 1.14 - 0.95 (m, 1H), 0.59 - 0.34 (m, 2H), 0.26 - 0, 04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.75, -122.42; MS (IER+) 564.2 (M+1); (IER-) 562.1 (M-1). Into a solution of the free base (-)-1-(3(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5 -carboxamide (72c) (70 mg) in methanol (10 ml) was added 4N. HCl (aq, 0.12 ml) and concentrated to dryness in vacuo to give (-)-1-(3(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)- hydrochloride salt 2-fluorophenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (72c) (78 mg) as a white solid; optical rotation: [a]D=(-) 9.72 [CH3OH, 0.535]; 1H NMR (300 MHz, DMSO-dg) δ 10.49 (s, 1H), 8.08 (s, 3H), 7.66 (t, J=1.7 Hz, 1H), 7.59 (dt , J=7.6, 1.5 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.46-7.32 (m, 5H), 7.19 - 7.06 (m , 2H), 5.43 (s, 1H), 3.96 (s, 2H), 3.08 (d, J=6.8 Hz, 2H), 0.97 - 0.80 (m, 1H) , 0.37 - 0.22 (m, 2H), 0.02 --0.04 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.83, -121.94; MS (IER+): 564.2 (M+1); analysis, calculation for

C ₃ 0H25F4N5O2-1.15HCl-1.25H2O: C, 57.38; H, 4.60; Cl, 6.49; N, 11.15; experiment C, 57.01; H, 4.63; Cl, 6.11; N, 10.82;

2. 2 peaks, which was designated as (+)-tert-butyl-3-(5-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole -1-yl)benzylcarbamate (72b) (220 mg, 98.0%

- 164 045731

e.i.); optical rotation: [afc=(+) 17.14 [CH3OH, 0.70]; 1H NMR (300 MHz, DMSO^ ₆ ) δ 10.60 (s, 1H), 7.82 (s, 1H), 7.74 (dt, J=7.6, 1.5 Hz, 1H), 7 .70 - 7.65 (m, 1H), 7.65- 7.22 (m, 10H), 5.58 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.37 (s, 9H), 1.14 - 0.90 (m, 1H), 0.54 - 0.38 (m, 2H) , 0.18-0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, -122.34; (IER+) 686.3 (M+23). Into a solution of (+)-tert-butyl-3-(5-(5-((3cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1yl)benzylcarbamate (72b) ( 210 mg, 0.316 mmol) in methanol (23 ml) was added conc. hydrogen chloride (0.160 ml, 1.914 mmol) and stirred at room temperature for 19 hours (~20% conversion by TLC). The reaction mixture was concentrated to dryness in vacuo (at <30°C, ~50% conversion according to TLC). Conc. was added to the residue. HCl (0.13 mL, 1.56 mmol), stirred at room temperature for 10 min and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give the free base (+)-1-(3-(aminomethyl)phenyl)- N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (72d) (88 mg) as a white solid; optical rotation: [a]D=(+) 19.59 [CH3OH, 0.515]; 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.82 (t, J=1.7 Hz, 1H), 7.74 (dt, J=7.6, 1, 5 Hz, 1H), 7.67 (dt, J=8.0, 1.5 Hz, 1H), 7.63-7.50 (m, 4H), 7.44 (q, J=1.4 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.36-7.22 (m, 3H), 5.59 (s, 1H), 3.78 (s, 2H ), 3.23 (d, J=6.8 Hz, 2H), 1.12-0.96 (m, 1H), 0.56-0.36 (m, 2H), 0.24-0, 07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.76, 122.38; MS (IER+) 564.2 (M+1); (IER-) 562.2 (M-1); Into a solution of the free base (+)-1-(3(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (72d) (62 mg) in methanol (10 ml) was added 4N. HCl (aq, 0.11 ml) and concentrated to dryness in vacuo to give (+)-1-(3-(aminomethyl)phenyl)-N(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)- hydrochloride salt 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (72d) (68 mg) as a white solid; optical rotation: [a]D=(+) 8.0 [CH3OH, 0.325]; ¹ H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.29 (s, 3H), 7.81 (t, J=1.7 Hz, 1H), 7.77- 7.64 (m, 4H), 7.59 (t, J=4.7 Hz, 3H), 7.55 (d, J=4.5 Hz, 1H), 7.54-7.46 (m , 1H), 7.30 (dd, J=4.7, 2.5 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 5.59 (s, 1H), 4 .12 (s, 2H), 3.23 (d, J=6.8 Hz, 2H), 1.13-0.96 (m, 1H), 0.55-0.36 (m, 2H), 0.26-0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.85, -122.03; MS (IER+) 564.2 (M+1); (IER-) 562.2 (M-1); calculation for C ₃₀ H ₂₅ F ₄ N ₅ O ₂ -HCl-1.25H ₂ O: C, 57.88; H, 4.61; Cl, 5.70; N, 11.25; experiment C, 57.80; H, 4.57; Cl, 5.94; N, 11.05.

Scheme 73

/for (+)-isomer

73b (-)-isomer

An example of the preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (73a) and (-)-1-(3-(aminomethyl)phenyl)N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (73b).

Isomers of the racemate 1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (55b) ( 400 mg) were separated into chirally pure isomers using the preparative SFC method under the following conditions to obtain:

Preparative SFC method used:

Column 3.0 x 25.0 cm CSS by ES Industries (West Berlin, NJ)

Co-solvent CO ₂ (solvent B) acetonitrile (methanol (1:1) with 1% isopropylamine Isocratic way 25% cosolvent, flow rate 80 ml/min System pressure 100 bar (10 MPa) Column temperature 25°С

Sample diluent methanol

The chiral purity of the peaks was determined using the following analytical SFC method:

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Column 4.6x100cm CCS by ES Industries (West Berlin, NJ)

Co-solvent CO ₂ (solvent B) acetonitrile: methanol (1:1) with 0.1% isopropylamine Isocratic way 20% cosolvent, flow rate 4 ml/min

System pressure 100 bar (10 MPa)

Column temperature 25°С Sample diluent methanol

Peak 1 (73a) Rt = 4.2 min 77 mg >95% e.i. (UV 254) purity 96.4% (UV 254)

Peak 2 (73b)

R1 = 4.9mhh 100 mg >95% e.i. (UV 254) purity 96.4% (UV 254)

1. 1 peak, which was designated as (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (73a) (77 mg, >95% ee) which was repurified by flash column chromatography (silica gel, 4 g, eluted with mixtures of CMA 80 in chloroform, 0 to 30 %) to obtain the free base (+)-1-(3(aminomethyl)phenyl)-X-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (73 a) (43 mg) as a white solid; optical rotation: [a]D=(+) 15.38 [CH3OH, 1.3]; ¹ H NMR (300 MHz, DMSO) δ 7.85-7.78 (m, 2H), 7.62 - 7.56 (m, 4H), 7.53 (d, J=4.7 Hz, 2H ), 7.48 - 7.41 (m, 2H), 7.35 (d, J=2.3 Hz, 1H), 7.28 (dd, J=7.0, 1.6 Hz, 2H) , 5.61 (s, 1H), 3.80 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 1.04 (q, J=4.6, 2.7 Hz, 1H), 0.54 - 0.38 (m, 2H), 0.24 - 0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.75, -122.33; MS (IER+) 564.2 (M+1), 562.2 (M-1); Into a solution of the free base (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (73a) (26 mg) in methanol (4 ml) was added 2N. HCl (0.11 mL, 5 eq.), stirred for 15 min and concentrated to dryness in vacuo to give (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-) hydrochloride salt cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (73a) (22 mg) as an off-white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.68 (s, 1H), 8.38 (s, 4H), 7.83 (d, J=1.8 Hz, 1H), 7.81 (d , J=1.8 Hz, 1H), 7.72 (t, J=1.8 Hz, 1H), 7.67 (s, 1H), 7.64 - 7.47 (m, 6H), 7 .29 (d, J=1.2 Hz, 1H), 7.29 -7.25 (m, 1H), 5.61 (s, 1H), 4.12 (s, 2H), 3.24 ( d, J=6.8 Hz, 2H), 1.12 - 0.95 (m, 1H), 0.52 - 0.36 (m, 2H), 0.22 - 0.05 (m, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.83, -121.91; MS (IER+) 564.3 (M+1), (IER-) 562.2 (M-1); analysis, calculation for C30H ₂₅ F ₄ N ₅ O ₂ -HCl-0.75H ₂ O: C, 58.73; H, 4.52; N, 11.42; experiment: C, 58.72; H, 4.72; N, 11.10;

2. 2 peaks, which was designated as (-)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (73b) (100 mg, >95% ee), which was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-30% methanol in chloroform) to give free base (-)-1-(3-(aminomethyl)phenyl)N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide ( 73b) (0.063 g) as a white solid; optical rotation: [a] _D =(-) 15.9 [CH3OH, 1.3]; 1H NMR: 1H NMR (300 MHz, DMSOL) δ 7.88 - 7.76 (m, 2H), 7.65 - 7.49 (m, 5H), 7.47 - 7.38 (m, 2H) , 7.30 (ddd, J=16.1, 5.9, 2.0 Hz, 3H), 5.61 (s, 1H), 3.77 (s, 2H), 3.24 (d, J =6.8 Hz, 2H), 1.05 (dddd, J=11.7, 8.2, 6.8, 2.7 Hz, 1H), 0.56 - 0.36 (m, 2H), 0.24 - 0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.74, -122.37; MS (IER+): MS (IER+) 564.3 (M+1), MS (IER-) 562.2 (M-1). HPLC: HPLC (modified method 5191, Zorbax SB-C3, 3.0x150mm, 5mm, using ZGC SB-C3, 2.1x12.5mm guard cartridge, buffer A = (98% 0.1M ammonium acetate in 2 % acetonitrile), buffer B = 100% acetonitrile, UV absorbance 250 nm; Rt = 19.89 min (99.33%)] into a solution of the free base (-)-1-(3(aminomethyl)phenyl)-X -(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1I-pyrazole-5-carboxamide (73b) (43 mg) in methanol (15 ml) was added 2N. HCl (0.19 ml, 5 eq.), stirred for 15 min, concentrated to dryness in vacuo to give (-)-1-(3-(aminomethyl)phenyl)-N-(5-((4-) hydrochloride salt cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (73b) (39 mg) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H, exchange with D2O), 8.31 (s, 4H, exchange with D2O), 7.70 - 7.63 (m, 2H), 7.59 - 7.51 (m, 2H ), 7.50 - 7.31 (m, 6H), 7.17 - 7.06 (m, 2H), 5.46 (s, 1H), 3.95 (q, J=5.4 Hz, 2H), 3.08 (d, J=6.8 Hz, 2H), 0.89 (dddd, J=14.8, 6.7, 3.4, 2.0 Hz, 1H), 0.41 - 0.20 (m, 2H), 0.09 - -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, -121.84; MS (IER+) 564.3 (M+1), MS (IER-) 562.3 (M-1), 598.2 (M+Cl). Analysis, calculation for: C30H ₂₅ F ₄ N5O ₂ -H ₂ O-HCl: C, 58.30; H, 4.57; Cl, 5.74; N, 11.33; experiment: C, 58.46; H, 4.71; Cl, 5.93; N, 11.22.

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Scheme 74

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethoxy)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (74a).

In a solution of tert-butyl-3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (0.2 g, 0.353 mmol) in Hydrogen chloride (3.80 mL, 15.21 mmol) (4M in 1,4-dioxane) was added to 1,4-dioxane (18 ml) and stirred at room temperature for 15 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. Chloroform (40 ml), 2-cyclopropylethanol (1.520 g, 16.94 mmol) and 2 g of silica gel were added to the insoluble crude product. The mixture was concentrated to dryness in vacuo and the resulting slurry was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give 1-(3-(aminomethyl)phenyl)-N-( 3-((2-cyclopropylethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (74a) (25 mg, 13%) as a white solid; 1H NMR (300 MHz, DMSOL) δ 10.71 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.59 - 7.50 (m, 3H), 7.46 - 7.38 (m, 2H), 7.36 - 7.20 (m, 7H), 7.14 (d, J=7.7 Hz, 1H), 5.42 (s, 1H), 3, 77 (s, 2H), 3.49 - 3.38 (m, 3H), 1.46 (q, J=6.7 Hz, 2H), 0.76 (ddt, J=10.3, 7, 4, 3.7 Hz, 1H), 0.41 - 0.32 (m, 2H), 0.05 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -60.72; MS (IER+): 535.3 (M+1).

Scheme 75

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclobutylmethoxy)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (75 a).

Into a solution of tert-butyl-3 -(5-(3 -(hydroxy(phenyl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (18c) (0.2 g, 0.353 mmol) in 1,4-dioxane (18 ml), hydrogen chloride (3.80 ml, 15.21 mmol) (4M in 1,4-dioxane) was added and stirred at room temperature for 15 hours. The reaction mixture was treated with hexanes, decanted , washed with hexanes and decanted again. Chloroform (40 ml), 2-cyclobutylmethanol (1.480 g, 17.01 mmol) and 2 g of silica gel were added to the insoluble crude product. The mixture was concentrated to dryness in vacuo and the resulting slurry was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give 1-(3-(aminomethyl)phenyl)-N-( 3-((cyclobutylmethoxy)(phenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (75a) (15 mg, 8%) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 7.61 (s, 1H), 7.55 (d, J=9.4 Hz, 3H), 7.47 - 7.41 (m, 2H), 7.33 (d, J=4.5 Hz, 5H), 7.24 (dd, J=8.8, 4.3 Hz, 2H), 7.13 (d , J=7.6 Hz, 1H), 5.39 (s, 1H), 3.80 (s, 2H), 3.37 (d, J=6.6 Hz, 2H), 2.05- 1 .89 (m, 3H), 1.88 - 1.64 (m, 4H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.72; MS (IER+): 535.3 (M+H).

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Scheme 76

Receiving example

1-(3-(aminomethyl)phenyl)-X-(3-((cyclopropylmethoxy)(phenyl)methyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (76h).

Step 1. Preparation of (5-amino-3-fluorophenyl)methanol (76b).

To a suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF (50 ml) was added dropwise at 0°C a solution of 5-amino-3-fluorobenzoic acid (76a) (5 g, 32.2 mmol) in THF ( 30 ml). The reaction mixture was stirred at room temperature overnight. The mixture was then cooled to 0°C, the reaction was quenched with ethyl acetate (30 ml) and water (10 ml). The resulting slurry was filtered through celite and washed with ethyl acetate (50 ml). The aqueous layer was separated and the organic layer was dried, filtered and concentrated to dryness in vacuo to obtain the crude product. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0-100% ethyl acetate in hexanes) to give (5-amino-3-fluorophenyl)methanol (76b) (1.17 g, 8.29 mmol, yield 25.7%) as a beige solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.76 (dd, J=10.1, 8.6 Hz, 1H), 6.65 (ddt, J=6.5, 2.9, 0, 8 Hz, 1H), 6.39 (ddd, J=8.6, 4.3, 2.9 Hz, 1H), 5.10 (t, J=5.7 Hz, 1H), 4.91 ( s, 2H), 4.41 (dt, J=5.8, 0.9 Hz, 2H); MS (IER+) 164.1 (M+23); (IER-) 140.0 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (76c).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1.992 g, 7.09 mmol), (5-amino-2-fluorophenyl)methanol (76b) (1 g, 7.09 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (3.30 g, 7.09 mmol), X,X-dimethylformamide (43 ml) and K-ethyl- N-isopropylpropan-2-amine (6.17 ml) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. TLC analysis (ethyl acetate/hexanes, v/v, 3/7) indicated completion of the reaction. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml), washed with brine (50 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give 1(3-cyanophenyl)-N-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (76c) (1.213 g, 42% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H, exchange with D ₂ O), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J =7.8, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.85-7.69 (m,

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3H), 7.56 (ddd, J=7.9, 4.6, 2.8 Hz, 1H), 7.13 (dd, J=9.8, 8.9 Hz, 1H), 5.37 (t, J=5.6 Hz, 1H, exchange with D ₂ O), 4.53 (d, J=5.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.96, -124.39; MS (IER ⁺ ): MS (IER+) 405.1 (M+1), 427.4 (M+Na), (IER-) 403.1 (M-1), 807.3 (2M-1) .

Step 3. Preparation of 1-(3-cyanophenyl)-N-(4-fluoro-3-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (76d).

In a stirred solution of 1-(3-cyanophenyl)-M-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (76c) (1.205 g, 2.98 mmol ) in dichloromethane (20 ml) was added sodium bicarbonate (1.252 g, 14.90 mmol). Dess-Martin periodinane (1.896 g, 4.47 mmol) was added to the mixture and stirred at room temperature for 5 hours. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated only moderate conversion, after After this, Dess-Martin periodinane (1.896 g, 4.47 mmol) was added and stirred for 30 minutes. The excess solvent was pumped off under reduced pressure, the residue was diluted with water (50 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give 1-(3-cyanophenyl)-N-(4fluoro-3-formylphenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (76d) (0.552 g, 46.0% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.86 (d, J=37.4 Hz, 1H, exchange with D ₂ O), 10.22 (d, J=4.9 Hz, 1H), 8.39 - 8.30 (m, 1H), 8.24 - 7.82 (m, 5H), 7.80 - 7.69 (m, 1H), 7.45 (dd, J=10.3 , 9.0 Hz, 1H); MS (IER ⁺ ): MS (IER+) 403.11 (M+1), 425.15 (M+Na), MS (IER-) 401.1 (M-1), 803.1 (2M-1 ).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (76e).

A solution of 1-(3-cyanophenyl)-N-(4-fluoro-3-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (76d) (0.528 g, 1.312 mmol) in THF (15 ml ), cooled to 0°C, phenylmagnesium bromide (2.66 mL, 2.66 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 3 hours and quenched with saturated aqueous NH ₄ Cl (100 ml). The product was extracted with ethyl acetate (100 ml, 75 ml). The combined organic extracts were washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography [(silica gel, 25 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give 1-(3-cyanophenyl)-N-(4-fluoro-3-(hydroxy( phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (76e) (0.338 g, 54% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H, exchange with D2O), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7 ,8, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.83 (dd, J=6.6, 2.8 Hz, 1H), 7.79 - 7.69 (m, 2H), 7.63 (m, 1H), 7.37 - 7.28 (m, 4H), 7.23 (m, 1H), 7 .11 (dd, J=9.9, 8.9 Hz, 1H), 6.11 (d, J=4.0 Hz, 1H, exchange with D2O), 5.92 (d, J=3.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.97, -123.11. MS (IER ⁺ ): MS (IER+) 503.2 (M+Na), MS (IER-) 479.2 (M-1).

Step 5. Preparation of tert-butyl-3-(5-(4-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (76f).

Into a stirred solution of 1-(3-cyanophenyl)-M-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (76e) (0.333 g, 0.693 mmol) in anhydrous methanol (20 ml), cooled to 0°C, added nickel (II) chloride hexahydrate (0.041 g, 0.173 mmol), (Boc) _2O (0.454 g, 2.07 mmol), then borohydride in small portions sodium (0.157 g, 4.16 mmol) for 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 1 hour at 0°C. TLC analysis (ethyl acetate/hexanes, 2/2, v/v) indicated completion of the reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.150 mL, 1.386 mmol) was added. The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%) to give tert-butyl-3-(5-(4-fluoro-3-(hydroxy(phenyl)methyl) phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (76f) (0.243 g, 60% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.81 (dd, J=6.6, 2.7 Hz, 1H), 7.61 (d, J=8, 3 Hz, 2H), 7.49 (d, J=9.0 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.38 - 7.28 (m, 6H), 7, 23 (q, J=5.7, 4.5 Hz, 1H), 7.09 (t, J=9.4 Hz, 1H), 6.09 (d, J=4.0 Hz, 1H, exchange with D2O), 5.92 (d, J=4.0 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 1.36 (s, 9H); ¹ H NMR (300 MHz, DMSO-d ₆ D ₂ O) δ 10.77 (s, 1H), 7.81 (dd, J=6.5, 2.7 Hz, 1H), 7.59 (s , 2H), 7.54 - 7.42 (m, 2H), 7.40 (s, 1H), 7.34 (dd, J=13.1, 3.1 Hz, 5H), 7.27 - 7.20 (m, 1H), 7.10 (t, J=9.4 Hz, 1H), 5.91 (s, 1H), 4.19 (d, J=6.4 Hz, 2H), 1.36(s,9H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.81, -123.19; MS (IER ⁺ ): MS (IER+) 607.2 (M+Na), MS (IER-) 583.3 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-M-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (76g).

Into a solution of tert-butyl-3-(5-(4-fluoro-3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (76f) (0.230 g, 0.393 mmol) in cyclopropylmethanol (3.39 ml, 47.2 mmol) was added ytterbium(III) trifluoromethanesulfonate (0.488 g, 0.787 mmol) and heated at 80°C overnight. TLC analysis (CMA 80/CHCl ₃ , 1/2, v/v) indicated completion of the reaction. Pumping out

- 169 045731 excess solvent was dried under reduced pressure. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1(3-(aminomethyl)phenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl) )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (76g) (139 mg, 73% yield) as a white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.75 (s, 1H, exchange with D ₂ O), 7.83 (dd, J=6.6, 2.7 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.52 (d, J=2.1 Hz, 1H), 7.48 7.40 (m, 2H), 7.32 (d, J=4.3 Hz, 5H), 7.27 - 7.18 (m, 1H), 7.10 (dd, J=9.9, 8.9 Hz, 1H), 6.09 (d, J=4.0 Hz, 1H , exchange with D ₂ O), 5.91 (d, J=3.7 Hz, 1H), 3.77 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.74, -123.20; MS (IER ⁺ ): MS (IER+) 485.2 (M+1), MS (IER-) 483.2 (M-1), 967.3 (2M-1).

Step 7. Preparation of 1-(3-(aminomethyl)phenyl)-^(3-((cyclopropylmethoxy)(phenyl)methyl)-4fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (76h).

Into a solution of 1 -(3-(aminomethyl)phenyl)-N-(4-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (76g) (0.131 g , 0.27 mmol) in cyclopropylmethanol (2.330 ml, 32.4 mmol) was added ytterbium(III) trifluoromethanesulfonate (0.503 g, 0.811 mmol) and heated at 80°C overnight. TLC analysis (CMA 80/CHCl ₃ , 1/2, v/v) indicated completion of the reaction. The excess solvent was pumped out and dried under reduced pressure. The residue was purified twice by flash column chromatography [silica gel, 25 g, eluted with mixtures of methanol in chloroform, 0-100%] to give 1(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)- 4-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (76h) (78 mg, 54% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.76 (dd, J=6.5, 2.7 Hz, 1H), 7.64 (ddd, J=9, 1, 4.7, 2.8 Hz, 1H), 7.59 (s, 1H), 7.56 - 7.51 (m, 1H), 7.43 (m, 2H), 7.39 - 7 .30 (m, 5H), 7.27 (m, 1H), 7.14 (t, J=9.4 Hz, 1H), 5.70 (s, 1H), 3.78 (s, 2H) , 3.27 (d, J=6.8 Hz, 2H), 1.05 (dddd, J=11.6, 8.1, 6.8, 2.6 Hz, 1H), 0.58 - 0 .37 (m, 2H), 0.22 - 0.08 (m, 2H); 1H NMR (300 MHz, DMSO-de D2O) δ 7.79 (dd, J=6.5, 2.7 Hz, 1H), 7.59 (ddd, J=9.1, 4.7, 2, 8 Hz, 1H), 7.55 (s, 1H), 7.54 - 7.50 (m, 1H), 7.49 - 7.44 (m, 2H), 7.41 - 7.27 (m , 6H), 7.15 (dd, J=9.9, 8.9 Hz, 1H), 5.70 (s, 1H), 3.77 (s, 2H), 3.27 (d, J= 6.8 Hz, 2H), 1.09 - 0.99 (m, 1H), 0.55-0.39 (m, 2H), 0.23 - 0.07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.74, -123.09; MS (IER ⁺ ): MS (IER+) 539.2 (M+1), MS (IER-) 537.2 (M-1), 573.2 (M+Cl); analysis, calculation for: C29H26F4N4O2-0.5H2O: C, 63.61; H, 4.97; N, 10.23; experiment: C, 63.99; H, 5.20; N, 9.89.

Scheme 77

NaOtBu 77b

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (77e).

Step 1. Preparation of 4-fluoro-3-nitro-N-phenyl-N-propylaniline (77b).

In a 250 ml one-neck flask equipped with a magnetic stirrer insert, 4-bromo-1fluoro-2-nitrobenzene (77a) (2.24 ml, 18.18 mmol), N-propylaniline (27a) (3.11 ml, 21, 82 mmol), sodium 2methylpropan-2-olate (1.747 g, 18.18 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.052 g, 1.818 mmol) and tris (dibenzylideneacetone)dipalladium (0) (0.499 g, 0.545 mmol). The flask was degassed and refilled with nitrogen, and this cycle was repeated three times. Toluene (50 ml) was injected into the solid reagents under a positive nitrogen flow. The reaction mixture was stirred at 110°C for 16 h under a positive nitrogen flow, cooled to room temperature, quenched with water (75 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over MgSO ₄ , filtered, and evaporated to dryness. The residue was purified twice by flash column chromatography [(silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give 4-fluoro-3-nitro-Nphenyl-N-propylaniline (77b) (2.377 g, 8.67 mmol, yield 47.7%) in the form of a brown-yellow oily liquid; MS (ESI ⁺ ): MS (ESI+) 297.2 (M+Na).

Step 2. Preparation of 4-fluoro-N1-phenyl-N1-propylbenzene-1,3-diamine (77c).

To a solution of 4-fluoro-3-nitro-N-phenyl-N-propylaniline (77b) (2.35 g, 8.57 mmol) in methanol (30 ml) was added palladium (10% Pd on a carbon support) (0.182 g , 1.714 mmol). The mixture was hydrogenated at 60

- 170045731 psi (414 kPa) for 2.5 hours. The reaction mixture was filtered through a Celite pad, which was washed successively with methanol (2x25 ml) and ethyl acetate (25 ml). Excess solvents were pumped out under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give 4-fluoro-N1-phenyl-N1propylbenzene-1,3-diamine (77c) (0.168 g , yield 8%) in the form of a pale yellow oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.16 (dd, J=8.7, 7.2 Hz, 2H), 6.93 (dd, J=11.4, 8.6 Hz, 1H) , 6.79 - 6.71 (m, 3H), 6.49 (dd, J=8.3, 2.7 Hz, 1H), 6.21 (ddd, J=8.6, 3.9, 2.7 Hz, 1H), 5.11 (s, 2H, exchange with D2O), 3.61 - 3.44 (m, 2H), 1.67 -1.44 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ -140.87; MS (IER ⁺ ): MS(IER+) 245.2 (M+1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (77d).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (0.215 g, 0.766 mmol), 4-fluoro-N1-phenyl-N1-propylbenzene- 1,3-Diamine (77c) (0.156 g, 0.639 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop, 0.357 g, 0.766 mmol), N,N-dimethylformamide (3.86 mL, 49.8 mmol) was added sequentially and N-ethyl-Nisopropylpropan-2-amine (0.556 ml, 3.19 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Excess DMF was removed under reduced pressure. The reaction mixture was treated with water (25 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(phenyl(propyl)amino) phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (77d) (0.149 g, 46% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H, exchange with D2O), 8.11 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7 .89 (d, J=7.9 Hz, 1H), 7.79 - 7.66 (m, 2H), 7.30 - 7.19 (m, 3H), 7.18 - 7.12 (m , 2H), 6.96 - 6.85 (m, 3H), 3.59 (t, J=7.3 Hz, 2H), 1.54 (q, J=8.4, 7.9 Hz, 2H), 0.87 (td, J=7.4, 1.7 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.99, -129.31; IR (KBr, cm ^-1 ): 2235 cm ^-1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 530.2 (M+Na), MS (IER-) 506.2 (M-1), 542.2 (M+Cl).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (77e).

Into a stirred solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(phenyl(propyl)amino)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (77d) (0.132 g, 0.260 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.062 g, 0.260 mmol) was added, followed by sodium borohydride (0.059 g, 1.561 mmol) in small portions over 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 15 minutes and TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated completion of the reaction. Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with water (30 ml) and the product was extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 2x12 g, eluted with methanol/chloroform, 0 to 100%) to give 1-(3-(aminomethyl)phenyl)-M-(2-fluoro-5(phenyl(propyl) )amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (77e) (0.039 g, 29% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.48 (s, 1H), 7.56 (s, 1H), 7.53 - 7.48 (m, 1H), 7.47 - 7.39 (m, 2H), 7.37 - 7.28 (m, 1H), 7.28 - 7.10 (m, 4H), 6.96 - 6.82 (m, 4H), 3.77 (s , 2H), 3.64 - 3.52 (m, 2H), 1.54 (h, J=7.4 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H); 1H NMR (300 MHz, DMSO-d6 D2O) δ 7.55 (s, 1H), 7.53 - 7.48 (m, 1H), 7.47 - 7.38 (m, 2H), 7.31 (dt, J=8.8, 2.4 Hz, 1H), 7.28 - 7.11 (m, 4H), 6.97 - 6.83 (m, 4H), 3.76 (d, J =4.8 Hz, 2H), 3.58 (t, J=7.5 Hz, 2H), 1.54 (h, J=7.4 Hz, 2H), 0.87 (t, J=7 ,3 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.75, -129.58; MS (IER ⁺ ): MS (IER+) 512.2 (M+1), MS (IER-) 510.2 (M-1); analysis, calculation for C27H25F ₄ N ₅ O-0.75H2O: C, 61.77; H, 5.09; N, 13.34; experiment: C, 61.71; H, 5.03; N, 12.80.

- 171 045731

Scheme 78

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (78d).

Step 1. Preparation of (E)- and ^)-3-(3-cyclopropyl-1-phenylprop-1-enyl)aniline (78a).

BF ₃ -Et2O ( 0.322 ml, 2.54 mmol) and triethylsilane (0.203 ml, 1.272 mmol). The reaction mixture was warmed to room temperature, stirred for 30 minutes, and the reaction was carefully quenched with saturated sodium bicarbonate solution. The reaction mixture was stirred for 5 min and diluted with dichloromethane (50 ml). The organic layer was separated, washed with water (2x25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 20%) to give pure (E)- and ^)-3-(3-cyclopropyl1-phenylprop-1-enyl) aniline (78a) (151 mg, 95% yield), which was used as such in the next step.

Step 2. Preparation of 3-(3-cyclopropyl-1-phenylpropyl)aniline (78b).

(E)- and (Z)-3(3-cyclopropyl-1-phenylprop-1-enyl)aniline (78a) (150 mg, 0.602 mmol) and hydrogenated at 60 psi (414 kPa) for 1 hour. The reaction mixture was filtered through celite and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0 to 30% ethyl acetate in hexanes) to give 3-(3-cyclopropyl-1-phenylpropyl)-aniline (78b) (133 mg, 88% yield) %) in the form of an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.25 (d, J=5.0 Hz, 4H), 7.19 - 7.09 (m, 1H), 6.89 (t, J=7 .7 Hz, 1H), 6.47 (t, J=1.9 Hz, 1H), 6.43 (dt, J=7.6, 1.3 Hz, 1H), 6.33 (ddd, J =8.0, 2.2, 1.0 Hz, 1H), 4.95 (s, 2H), 3.73 (t, J=7.8 Hz, 1H), 2.02 (td, J= 8.4, 6.6 Hz, 2H), 1.07 (qd, J=6.9, 1.9 Hz, 2H), 0.77 - 0.59 (m, 1H), 0.42 - 0 .30 (m, 2H), -0.03 -0.11 (m, 2H).

Step 3. Preparation of 1-(3-cyanophenyl)-M-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (78 c).

3-(3-cyclopropyl- 1-Phenylpropyl)aniline (78b) (130 mg, 0.517 mmol), N-ethyl-N-isopropylpropan-2-amine (0.655 ml, 3.76 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 241 mg, 0.517 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water (25 ml), the mixture was extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with water (25 ml), brine (25 ml), dry over anhydrous MgSO ₄ , filter and concentrate to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with hexanes in ethyl acetate/hexanes, 0-100%) to give 1-(3-cyanophenyl)-N(3-(3-cyclopropyl-1phenylpropyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (78c) (194 mg, 0.377 mmol, 80% yield) as an oily liquid; MS (ESI+) 537.3 (M+Na).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (78d).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (78c) (180 mg, 0.350 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (18.14 mg, 0.076 mmol) was added, followed by sodium borohydride (83 mg, 2.188 mmol) in small portions over 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 1 h at 0°C, TLC analysis (ethyl acetate/hexanes, 2/2, v/v) indicated completion of the reaction, after which N1-(2aminoethyl)ethane-1,2-diamine ( 0.087 ml, 0.805 mmol). The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (25 ml) and extracted with ethyl acetate (2x25 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and pumped out

- 172 045731 excess solvents under reduced pressure. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with ethyl acetate/hexanes, 0 to 50%) to give the free base 1-(3-(aminomethyl)phenyl)-C-(3-(3-cyclopropyl-1- phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (78d) (165 mg, 0.318 mmol, 91% yield) as a white semi-solid. The semi-solid was dissolved in methanol (10 ml), conc. HCl (0.043 mL, 0.513 mmol), stirred for 15 min and concentrated to dryness in vacuo to give 1-(3(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylpropyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (78d) (100 mg) as a white solid; ^1H NMR (300 MHz, DMSO- _d6 ) δ 10.71 (s, 1H), 8.34 (s, 3H), 7.72 (s, 1H), 7.68 - 7.58 (m, 2H), 7.58 - 7.48 (m, 4H), 7.34 - 6.59 (m, 5H), 7.16 (dp, J=8.6, 2.7 Hz, 1H), 7 .09 (d, J=7.7 Hz, 1H), 4.13 (d, J=5.7 Hz, 2H), 3.92 (t, J=7.8 Hz, 1H), 2.08 (q, J=7.6 Hz, 2H), 1.07 (dd, J=9.5, 6.3 Hz, 2H), 0.78 - 0.60 (m, 1H), 0.43 - 0.29 (m, 2H), -0.07 (td, J=5.4, 3.8 Hz, 2H); ¹⁹ F NMR (282 MHz,

DMSO-d6) δ -60.80; MS (IER+) 519.57 (M+1), (IER-) 517.2 (M-1); analysis, calculation for

C ₃ 0H29F3N4O-1.5HCM,25H2O: C, 60.48; H, 5.58; Cl, 8.93; N, 9.40 experiment: C, 60.12; H, 5.40; Cl, 8.65; N, 9.80.

Scheme 79

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (79f).

Step 1. Preparation of 1-(3-cyanophenyl)-X-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (79 a).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.463 g, 1.648 mmol) in DMF (10 ml) was added (3-aminophenyl)(pyridine-3 -yl)methanol (31d) (0.33 g, 1.648 mmol), P-ethyl-X-isopropylpropan-2-amine (1.435 ml, 8.24 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.922 g, 1.978 mmol ) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-(hydroxy-(pyridin-3-yl) methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (79a) (0.653 g, 1.409 mmol, 86% yield) as a yellow oily liquid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.43 (dd, J=4.8, 1 .7 Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7,1.3 Hz, 1H), 7.90 (ddd, J =8.3, 2.2, 1.1 Hz, 1H), 7.77 - 7.64 (m, 4H), 7.62 -7.52 (m, 1H), 7.37 - 7.25 (m, 2H), 7.21 - 7.14 (m, 1H), 6.15 (d, J=3.9 Hz, 1H), 5.77 (d, J=4.0 Hz, 1H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.98; MS (IER-) 462.2 (M-1).

Step 2. Preparation of (Z)-1-(3-cyanophenyl)-N-(cyclopropylmethyl)-N'-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-( trifluoromethyl)-1H-pyrazol-5-carboximidamide (79b) and 1-(3cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)- 1Hpyrazole-5-carboxamide (79c).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (79a) (0.32 g, 0.691 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (0.151 ml, 2.072 mmol), triethylamine (0.289 ml, 2.072 mmol) and leave to warm to room temperature for 3 hours. Concentrate the reaction mixture to dryness in vacuum. The residue was dissolved in acetonitrile (10.00 ml) and cyclopropylmethanamine (1.198 ml, 13.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was diluted with chloroform (25 ml), washed with water (10 ml), dried, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-100% ethyl acetate/methanol (9:1) in hexane) to give (Z)-1-(3-cyanophenyl)-N-(cyclopropylmethyl)- N'-(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboximidamide (79b) (0.05

- 173 045731 g, 0.088 mmol, yield 12.71%) in the form of a colorless oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (d, J=2.2 Hz, 1H), 8.38 (dd, J=4.8, 1.7 Hz, 1H), 7, 89 (dt, J=7.8, 1.3 Hz, 1H), 7.84 (t, J=5.4 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.41 - 7.36 (m, 1H), 7.34 (t, J=1.8 Hz, 1H), 7.30 - 7.22 ( m, 2H), 6.80 (q, J=7.7 Hz, 2H), 6.19 (s, 1H), 5.91 - 5.84 (m, 1H), 4.59 (s, 1H ), 3.20 (s, 2H), 2.32 - 2.05 (m, 3H), 0.82 (d, J=17.1 Hz, 1H), 0.56 - 0.47 (m, 2H), 0.42 - 0.33 (m, 2H), 0.27 (q, J=5.1 Hz, 2H), 0.08 - 0.01 (m, 2H); MS IER(+) 570.3 (M+1), (IER-) 568.3 (IER-). Additional elution gave 1-(3-cyanophenyl)-N(3-(((cyclopropylmethyl)amino)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-N-pyrazole-5carboxamide (79c) (0.07 g, 0.136 mmol, 19.63% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.62 (d, J=2.2 Hz, 1H), 8.44 - 8.37 (m, 1H), 8 .17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.3, 2.2 , 1.1 Hz, 1H), 7.82 - 7.66 (m, 5H), 7.57 (dt, J=7.9, 1.7 Hz, 1H), 7.39 7.18 (m , 4H), 4.90 (s, 1H), 2.29 (t, J=6.2 Hz, 2H), 0.90 (t, J=12.0 Hz, 1H), 0.38 (td , J=5.7, 3.7 Hz, 2H), 0.13 0.02 (m, 2H); MS (IER+) 517.2 (M+1); (IER-) 515.2 (M-1).

Step 3. Preparation of tert-butyl-((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamido)phenyl)(pyridin-3-yl)methyl)(cyclopropylmethyl) carbamate (79d) and tert-butyl-3-(5-(3((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (79e) .

Into a stirred solution of 1-(3-cyanophenyl)-N(3-(((cyclopropylmethyl)amino)-(pyridin-3yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (79c) ( 0.25 g, 0.484 mmol) in anhydrous methanol (5 ml), cooled to 0°C, di-tert-butyl dicarbonate (0.317 g, 1.452 mmol) and nickel (II) chloride hexahydrate (0.029 g, 0.121 mmol) were added. Sodium borohydride (0.110 g, 2.90 mmol) was added to the reaction mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min at 0°C. TLC analysis (50% 9:1 EtOAc/MeOH in hexanes) indicated the presence of starting material. An additional amount of nickel (II) chloride hexahydrate (0.029 g, 0.121 mmol) and sodium borohydride (0.110 g, 2.90 mmol) was added to the reaction mixture in parts over 15 min, and stirred for 30 min at 0°C. TLC analysis indicated no change, two major products could be observed, one of which had the same Rf as the starting material. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.105 mL, 0.968 mmol), stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (25 ml) and water (25 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 ml). Combine the organic layers, wash with water (25 mL), brine (25 mL), dry and concentrate in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give tert-butyl-((3-(1-(3-(aminomethyl)phenyl)-3(trifluoromethyl) -1H-pyrazol-5-carboxamido)phenyl)(pyridin-3-yl)methyl)(cyclopropylmethyl)carbamate (79d) (0.036 g, 11.98% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 8.62 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.13 ( d, J=7.9 Hz, 1H), 7.69 - 7.54 (m, 4H), 7.53 - 7.20 (m, 8H), 5.03 (s, 1H), 4.19 (d, J=6.3 Hz, 2H), 2.40 - 0.90 (m, 2H), 0.93 - 0.84 (m, 1H), 0.45 - 0.32 (m, 2H ), 0.11 - -0.00 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 621.3 (M+1). Additional elution gave tert-butyl-3-(5-(3-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (79e ) (0.030 g, 9.99% yield) as a white solid which had the same Rf as the starting material; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 8.61 (s, 1H), 8.40 (d, J=4.9 Hz, 1H), 7.77 ( d, J=7.9 Hz, 1H), 7.59 - 7.19 (m, 11H), 4.88 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.37 - 2.21 (m, 2H), 1.35 (s, 9H), 1.00 - 0.79 (m, 1H), 0.43 - 0.33 (m, 2H), 0, 09 - 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 332.3 (1/2M+Na), 621.3 (M+1), (IER-) 619.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)-(pyridin-3yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (79f).

Mixture of tert-butyl-((3-(1 -(3 -(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-carboxamido)phenyl)(pyridin-3-yl)methyl)(cyclopropylmethyl) carbamate (79d) (0.03 g, 0.048 mmol) and tert-butyl-3(5-(3-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole1 -yl)benzylcarbamate (79e) (0.030 g, 0.048 mmol) was dissolved separately in methanol (2.5 ml) and conc. HCl (0.073 ml, 2.42 mmol) and water (0.073 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. NMR analyzes of both residues in methanol and TLC indicated identical compounds. The products were combined, dried and purified by flash column chromatography (silica gel, 4 g, eluted with mixtures of 0-150% methanol in chloroform) to give 1(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)( pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (79f) (0.035 g, 66%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 11.00 (s, 1H), 10.42 (s, 1H), 8.81 (s, 1H), 8.52 (s, 3H), 8. 11 (s, 1H), 7.87 (s, 1H), 7.73 (s, 2H), 7.68 - 7.59 (m, 2H), 7.58 - 7.48 (m, 2H) , 7.42 (d, J=7.6 Hz, 3H), 5.59 (s, 1H), 4.11 (s, 2H), 2.81 - 2.56 (m, 2H), 1, 21 - 1.01 (m, 1H), 0.63 - 0.41 (m, 2H), 0.35 - 0.16 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 521.3 (M+1), (IER-) 555.2 (M+Cl).

- 174 045731

Scheme 80

PyBrOP

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-N-pyrazole-5-carboxamide (80h).

Step 1. Preparation of 3-amino-5-fluorobenzoic acid (80b).

Palladium (10% Pd on carbon support) (0.287 g, 2.70 mmol) was added to a solution of 3-fluoro-5-nitrobenzoic acid (80a) (2.5 g, 13.51 mmol) in methanol (30 mL). The reaction mixture was hydrogenated at 60 psi (414 kPa) for 2 hours. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated completion of the reaction. The reaction mixture was filtered through a small pad of Celite, which was washed successively with methanol (2x25 ml) and ethyl acetate (25 ml). The excess solvents were pumped off under reduced pressure to give 3-amino-5-fluorobenzoic acid (80b) (1.903 g, 91% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H, exchange with D2O), 7.06 - 6.97 (m, 1H), 6.72 (ddd, J=9.4, 2.5, 1.4 Hz, 1H), 6.52 (dt, J=11.4, 2.3 Hz, 1H), 5.71 (s, 2H, exchange with D ₂ O); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -113.44; MS (IER ⁺ ): MS (IER+) 156.0 (M+1), MS (IER-) 153.9 (M-1).

Step 2. Preparation of (3-amino-5-fluorophenyl)methanol (80c).

To a suspension of lithium aluminum hydride (1.209 g, 31.8 mmol) in THF (50 ml) was added dropwise at 0°C a solution of 3-amino-5-fluorobenzoic acid (80b) (1.9 g, 12.25 mmol) in THF (30 ml) for 30 min under a positive nitrogen flow. The reaction mixture was stirred at room temperature for 14 hours, cooled to 0°C, carefully quenched with ethyl acetate (50 ml) and stirred for 1 hour. The reaction was carefully quenched with water (50 ml) under a positive stream of nitrogen, filtered through a small pad of Celite which was washed with ethyl acetate (2x50 ml). The organic extracts were evaporated to dryness. The resulting residue was purified by flash column chromatography [(silica gel, 80 g, eluted with ethyl acetate/hexanes, 0 to 100%)] to give (3-amino-5-fluorophenyl)methanol (80c) (0.594 g, 34% yield ) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.33 (dt, J=2.0, 1.1 Hz, 1H), 6.23 - 6.11 (m, 2H), 5.36 (s , 2H, exchange with D ₂ O), 5.12 (t, J=5.8 Hz, 1H), 4.33 (d, J=5.8 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -114.63; MS (IER ⁺ ): MS (IER+) 142.02 (M+1), MS (IER-) 140.00 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (80d).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1.375 g, 4.89 mmol), (3-amino-5-fluorophenyl)methanol (80c) (0.575 g, 4.07 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 2.279 g, 4.89 mmol), X,X-dimethylformamide (24.60 mL, 318 mmol) and N- ethyl-N-isopropylpropan-2-amine (DIPEA) (3.55 mL, 20.37 mmol) under positive nitrogen flow at room temperature. The resulting reaction

- 175 045731 the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Excess DMF was pumped out under reduced pressure. The reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (2x75 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-fluoro-5(hydroxymethyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (80d) (1.416 g, 86% yield) as a white solid; 1H NMR: (300 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 8.18 (t, J=1.8 Hz, 1H), 8.02 (dt, J=7.7, 1.3 Hz, 1H), 7.92 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.81 -7.71 (m, 2H), 7.50 - 7 .36 (m, 2H), 6.90 (ddd, J=9.7, 2.4, 1.3 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H, exchange with D2O ), 4.49 (d, J=5.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98, -112.56; MS (IER ⁺ ): MS (IER+) 427.20 (M+Na), MS (IER-) 403.22 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-fluoro-5-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (80e).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80d) (1.36 g, 3. 36 mmol) in dichloromethane (20 ml), solid sodium bicarbonate (1.413 g, 16.82 mmol) was added, then Dess-Martin periodinane (2.140 g, 5.05 mmol) was added in one go and stirred at room temperature for 6 hours. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated moderate conversion. Additional Dess-Martin periodinane (2.140 g, 5.05 mmol) was added to the reaction mixture and stirred for 16 hours. Excess solvent was pumped off under reduced pressure. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and the excess solvent was evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 100%)] to give 1-(3cyanophenyl)-N-(3-fluoro-5-formylphenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (80e) (0.910 g, 67% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H, exchange with D2O), 9.97 (d, J=1.5 Hz, 1H), 8.22 (t, J=1 .8 Hz, 1H), 8.06 (t, J=1.5 Hz, 1H), 8.03 (dt, J=7.8, 1.4 Hz, 1H), 7.95 (ddd, J =8.2, 2.2, 1.1 Hz, 1H), 7.84 (dt, J=10.8, 2.3 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.53 (ddd, J=8.4, 2.6, 1.3 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.99, -110.28; IR (KBr, ^cm'1 ): 2236 ^cm'1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 425.11 (M+Na), MS (IER-) 401.06 (M-1), 803.15 (2M-1).

Step 5. Preparation of 1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80f).

A solution of 1-(3-cyanophenyl)-N-(3-fluoro-5-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80e) (0.413 g, 1.027 mmol) in THF (20 ml ), cooled to 0°C, phenylmagnesium bromide (2.084 mL, 2.084 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated completion of the reaction. The reaction was quenched with saturated aqueous NH ₄ Cl (30 ml) and the mixture was extracted with ethyl acetate (50 ml, 25 ml). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and evaporated. The resulting residue was purified by flash column chromatography [(silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%)] to give 1-(3-cyanophenyl)-N-(3-fluoro-5-(hydroxy(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (80f) (155 mg, 31% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H, exchange with D2O), 8.18 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7 ,8, 1.3 Hz, 1H), 7.95 - 7.85 (m, 1H), 7.82 - 7.65 (m, 2H), 7.53 - 7.41 (m, 2H), 7.41 - 7.28 (m, 4H), 7.27 - 7.19 (m, 1H), 7.00 (dt, J=9.8, 1.7 Hz, 1H), 6.10 ( d, J=3.8 Hz, 1H, exchange with D2O), 5.69 (d, J=3.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -61.00, -112.17; IR (KBr, ^cm'1 ): 2236 ^cm'1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 503.1 (M+Na), MS (IER-) 479.1 (M-1), 959.1 (2M-1).

Step 6. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5-fluorophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80g).

In a solution of 1 -(3-cyanophenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (80f) (0.113 g, 0.235 mmol ) in cyclopropylmethanol (1.689 ml, 23.52 mmol), ytterbium(III) trifluoromethanesulfonate (0.292 g, 0.470 mmol) was added and heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, excess solvent was pumped off under reduced pressure and treat the residue with water (30 ml), extract with chloroform (2x30 ml) and filter through a pad of Celite, removing excess solvent under reduced pressure. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5fluorophenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80g) (31 mg, 25% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H, exchange with D2O), 8.18 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7 ,8, 1.3 Hz, 1H), 7.95 - 7.87 (m, 1H), 7.79 - 7.69 (m, 2H), 7.56 - 7.47 (m, 1H), 7.43 (s, 1H), 7.39 - 7.32 (m, 4H), 7.27 (dd, J=5.4, 2.9 Hz, 1H), 7.05 - 6.94 ( m, 1H), 5.48 (s, 1H), 3.29 - 3.21 (m, 2H), 1.13 - 1.00 (m, 1H), 0.47 (dt, J=8, 4, 2.5 Hz, 2H), 0.22 - 0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.98, -111.79; MS (IER ⁺ ): MS (IER+) 557.2 (M+Na), MS (IER-) 533.2 (M-1), 569.0 (M+Cl).

- 176 045731

Step 7. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80h).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)-5fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80g) (0.026 g, 0.049 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.017 g, 0.073 mmol) was added, followed by sodium borohydride (0.022 g, 0.584 mmol) in small portions over 5 min. The reaction mixture was stirred for 10 min, the reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.053 ml, 0.486 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography [(silica gel, 2x12 g, eluted with methanol/chloroform, 0 to 50%)] to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy) (phenyl)methyl)-5-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80h) (18 mg, 69% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H, exchange with D2O), 7.60 (s, 1H), 7.50 (dt, J=11.5, 2.1 Hz , 2H), 7.45 - 7.40 (m, 3H), 7.40 - 7.22 (m, 6H), 7.09 - 6.88 (m, 1H), 5.47 (s, 1H ), 3.77 (s, 2H), 3.24 (dd, J=6.8, 4.0 Hz, 2H), 1.15 - 0.98 (m, 1H), 0.57 - 0, 38 (m, 2H), 0.16 (tq, J=4.8, 2.9, 2.5 Hz, 2H); ¹ H NMR (300 MHz, DMSO-d6 D2O) δ 7.58 (s, 1H), 7.50 (dd, J=4.1, 2.2 Hz, 2H), 7.48 - 7.40 ( m, 3H), 7.39 - 7.23 (m, 6H), 7.06 - 6.91 (m, 1H), 5.47 (s, 1H), 3.75 (s, 2H), 3 .24 (dd, J=6.8, 2.4 Hz, 2H), 1.15- 0.99 (m, 1H), 0.47 (dt, J=9.2, 2.8 Hz, 2H ), 0.15 (td, J=5.6, 4.9, 3.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.76, -111.81; MS (IER ⁺ ): MS (IER+) 539.2 (M+1), MS (IER-) 537.1 (M-1).

Scheme 81

An example of the preparation of (2S)-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamido)phenyl)(phenyl)methyl-2-amino-3-methylbutanoate ( 81c).

Step 1. Preparation of (2R)-(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl -2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (81b).

In a solution of tert-butyl-3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (18c) (132 mg, 0.233 mmol) in DMF ( 4 ml), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (81a) (101 mg, 0.466 mmol), N,N-dimethylpyridin-4amine (29.0 mg, 0.235 mmol) and N1-( (ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (90 mg, 0.468 mmol). The reaction mixture was stirred at room temperature for 14 hours, diluted with ethyl acetate (150 ml), washed with water (2x75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 4 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give (2R)-(3-(1-(3-(((tert- butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl-2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (81b) (125 mg , 70%) as a whitish solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.76 (d, J=4.2 Hz, 1H), 7.67 - 7.12 (m, 16H), 6.78 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.94 (ddd, J=8.1, 6.6, 3.7 Hz, 1H), 2.15-2.02 (m, 1H), 1.36 (d, J=1.6 Hz, 18H), 0.80 (d, J=6.8 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82; MS (IER+): 766.5 (M+1).

Step 2. Preparation of (2S)-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl-2-amino-3- methyl butanoate (81c).

A solution of (2R)-(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamido)phenyl)(phenyl)methyl-2-( (tert-butoxycarbonyl)amino)-3-methylbutanoate (81b) (60 mg, 0.078 mmol) in 1,4-dioxane (4 ml) was treated with hydrogen chloride (0.830 ml, 3.32 mmol) (4 M in 1,4 dioxane) and stirred at room temperature for 14.5 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give (28)-(3-(1-(3-(aminomethyl)phenyl)- 3-(trifluoromethyl)1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl-2-amino-3-methylbutanoate (81c) (35 mg, 79% yield, mixture of diastereomers) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.89 (d, J=3.7 Hz, 1H), 8.38 (s, 4H), 7.79 (d, J=2.0 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.67 - 7.49 (m, 4H), 7.47 - 7.32 (m, 6H), 7.29 - 7.23 ( m, 1H), 6.92 (s, 1H), 4.12 (s, 2H), 4.14 - 4.04 (m, 1H), 2.30 - 2.22 (m, 1H), 0 .94 - 0.86 (m, 6H); ¹⁹ F NMR

- 177 045731 (282 MHz, DMSO-d ₆ ) δ -60.80, -60.81; MC (IER+): 566.3 (M+1). Scheme 82

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazol-5-carboxamide (82f ).

Step 1. Preparation of (3-nitrophenyl)(thiazol-2-yl)methanol (82b).

To a solution of 2-bromothiazole (82a) (1.8 ml, 17.42 mmol) in diethyl ether (12 ml) at -78°C, n-BuLi (11.00 ml, 17.60 mmol) was added dropwise and stirred at -78°C for 2 hours. A solution of 3-nitrobenzaldehyde (31a) (2.63 g, 17.42 mmol) in THF (18 ml) was added dropwise to the 2-lithium thiazole at -78°C and stirred at -78 °C for 2 h and at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (75 ml). Combine the organic layers, wash with brine (60 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexane (1:0 to 2:1)] to give (3-nitrophenyl)(thiazol-2-yl)methanol (82b) (1 .1 g, 27%) as a brown solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (ddd, J=2.2, 1.4, 0.7 Hz, 1H), 8.16 (ddd, J=8.3, 2 ,4, 1.1 Hz, 1H), 7.93 (dddd, J=7.8, 1.7, 1.1, 0.6 Hz, 1H), 7.74 (d, J=3.2 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.67 (d, J=2.3 Hz, 1H), 7.20 (d, J=4.8 Hz, 1H), 6.17 (d, J=4.7 Hz, 1H); MS (IER+): 259.1 (M+23).

Step 2. Preparation of (3-aminophenyl)(thiazol-2-yl)methanol (82c).

To a solution of (3-nitrophenyl)(thiazol-2-yl)methanol (82b) (1.072 g, 4.54 mmol) in methanol (27 ml), cooled to 0°C, was added nickel (II) chloride hexahydrate (0.270 g , 1.134 mmol), then sodium borohydride (0.701 g, 18.15 mmol) in parts over 30 minutes. The reaction mixture was stirred at room temperature for 30 min, quenched with N-(2-aminoethyl)ethane-1,2-diamine (1.0 mL, 9.26 mmol), stirred for another 30 min and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (75 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (75 ml). The combined extracts were washed with brine (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography [silica gel, 25 g, eluted with hexanes/ethyl acetate (1:0 to 0:1)] to give (3-aminophenyl)(thiazol-2-yl)methanol (82c) (667 mg, 71%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J=3.3 Hz, 1H), 7.60 (d, J=3.3 Hz, 1H), 6.95 (t, J =7.7 Hz, 1H), 6.65-6.62 (m, 1H), 6.59 -6.53 (m, 2H), 6.43 (ddd, J=7.9, 2.3 , 1.1 Hz, 1H), 5.74 (d, J=4.0 Hz, 1H), 5.07 (s, 2H); MS (IER+): 207.1 (M+1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (82d).

To a solution of (3-aminophenyl)(thiazol-2-yl)methanol (82c) (0.983 g, 3.50 mmol) in N,N-dimethylformamide (26 ml) was added 1-(3-cyanophenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxylic acid (9i) (0.872 g, 3.10 mmol), N-ethyl-N-isopropylpropan-2-amine (4.40 ml, 25.3 mmol) and hexafluorophosphate (V) bromo-tripyrrolidin-1-ylphosphonium (1.476 g, 3.1 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours and diluted with ethyl acetate (200 ml). The reaction mixture was washed with water (2x100 ml), brine (75 ml), dried over anhydrous MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 0:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2- yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (82d) (1.113 g, 76%) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 8.17 (t, J=1.7 Hz, 1H), 8.01 (dt, J=7.7, 1 ,3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 - 7.58 (m, 6H), 7.31 (t, J=7.8 Hz, 1H), 7.21 (dt, J=7.8, 1.4 Hz, 1H), 6.86 (d, J=4.2 Hz, 1H), 5.92 ( d, J=4.2 Hz, 1H); MC (IER+): 470.1 (M+1).

- 178 045731

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (82e).

In solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (82d) (500 mg, 1.065 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.240 ml, 3.29 mmol) and leave to warm to room temperature for 2 hours. The reaction is quenched with triethylamine (1.4 ml, 10.04 mmol) and the mixture is stirred at room temperature for 1 hour. Cyclopropylmethanol (8.00 mL, 97 mmol), triethylamine (1.300 mL, 9.33 mmol) was added to the chlorine compound and concentrated in vacuo to remove most of the dichloromethane. Triethylamine (1.4 mL, 10.04 mmol) was added to the reaction mixture and heated at 70°C for 15 hours and at 120°C for 4 hours. The reaction mixture was diluted with ethyl acetate and filtered. Concentrate the filtrate in vacuo and purify the residue by flash column chromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to 2:1)] to give 1-(3-cyanophenyl)-K-(3-((cyclopropylmethoxy) (thiazol2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (82e) (296 mg, 53%) as a light brown solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 7.98 (dd, J=2.1, 1.4 Hz, 1H), 7.84 - 7.78 ( m, 1H), 7.72 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.58 - 7.38 (m, 6H), 7.15 (t, J= 7.9 Hz, 1H), 6.99 (dt, J=7.6, 1.3 Hz, 1H), 5.60 (s, 1H), 0.95-0.81 (m, 1H), 0.37 - 0.20 (m, 2H), 0.07 - -0.08 (m, 2H); MS (IER+): 524.2 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 82f).

In a solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (82e) (233 mg , 0.445 mmol) in MeOH (10 mL), cooled in ice/water, nickel(II) chloride hexahydrate (23.00 mg, 0.097 mmol) was added, then sodium borohydride (107 mg, 2.78 mmol) was added over 5 min. The reaction mixture was stirred at room temperature for 1 hour, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.912 mmol), stirred at room temperature for 0.5 hour and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (120 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 12 g, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give 1-(3-(aminomethyl)phenyl)-C-(3-((cyclopropylmethoxy )(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-Spirazol-5-carboxamide (82f) (54 mg, 23%) as a colorless viscous substance. ^1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.73 - 7.68 (m, 3H), 7.65 - 7.59 (m, 1H), 7.59 (s, 1H), 7.54 - 7.51 (m, 1H), 7.46 - 7.40 (m, 2H), 7.40 - 7.29 (m, 2H), 7.18 (dt , J=7.7, 1.3 Hz, 1H), 5.78 (s, 1H), 3.77 (s, 2H), 3.37 (d, J=6.9 Hz, 2H), 1 .10 - 1.04 (m, 1H), 0.52 - 0.45 (m, 2H), 0.22 - 0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.73; MS (IER+): 528.2 (M+H).

Scheme 83

Example of preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (83c) .

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (83a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (43d) (0.48 g, 1.036 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.240 ml, 3.29 mmol) and leave to warm to room temperature for 2 hours. The reaction is quenched with triethylamine (1.3 ml, 9.33 mmol) and the mixture is stirred at room temperature for 1 hour. To the chlorine-containing compound was added cyclopropylmethanamine (1520 mg, 20.74 mmol) and conc.

- 179 045731 tririated in vacuum to remove most of the dichloromethane. Acetonitrile (15 ml) was added to the residue and heated at reflux temperature for 16.5 hours and concentrated to dryness in vacuo. The residue was treated with chloroform (150 ml), washed with water (75 ml), dried over MgSO ₄ , then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 12 g, eluted with chloroform/CMA 80 (1:0 to 4:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(niridine -2-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (83a) (119 mg, 22%) as a white semi-solid; ¹ H NMR (300 MHz, DMSOC) δ 10.64 (s, 1H), 8.47 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.16 (t, J =1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.79 - 7.15 ( m, 9H), 4.90 (s, 1H), 2.40 -2.20 (m, 2H), 0.91 (s, 1H), 0.44 - 0.30 (m, 2H), 0 .09 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.97; MS (IER+): 517.3 (M+1).

Step 2. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (83b) .

In a solution of 1 -(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (83 a) (72 mg , 0.139 mmol) in MeOH (4 ml), cooled in ice/water, di-tert-butyl dicarbonate (92 mg, 0.418 mmol), nickel (II) chloride hexahydrate (7.0 mg, 0.029 mmol) was added, then borohydride sodium (33.0 mg, 0.856 mmol) for 5 min. The reaction mixture was stirred at room temperature for 1 hour, after which additional amounts of nickel(II) chloride hexahydrate (5 mg) and sodium borohydride (23 mg) were added and stirred at room temperature for 0.5 hours. The reaction was quenched with N1-( 2-aminoethyl)ethane-1,2-diamine (0.03 ml, 0.279 mmol), stirred at room temperature for 0.5 h and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (100 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 2x4 g, eluted with chloroform/CMA 80 (1:0 to 4:1)] to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)() pyridin-2yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-nurazol-1-yl)benzylcarbamate (83b) (13 mg, 15%); MS (IER+): 621.2 (M+H).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-πyrazole-5-carboxamide ( 83 c).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(pyridin-2-yl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-nurazol-1-yl)benzylcarbamate (83b) (13 mg , 0.021 mmol) in 1,4-dioxane (3 ml), hydrogen chloride (0.23 ml, 0.922 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 17.5 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give 1-(3(aminomethyl)phenyl)-N-(3-((cyclonronylmethylamino)(nuridine -2-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (83c) (5.3 mg, 49%) as a white semi-solid. 1H NMR (300 MHz, methanol-d4) δ 8.49 (ddd, J=4.9, 1.7, 0.9 Hz, 1H), 7.80 - 7.13 (m, 13H), 4, 97 (s, 1H), 3.86 (s, 2H), 2.46 - 2.28 (m, 2H), 1.02 - 0.81 (m, 1H), 0.54 - 0.39 ( m, 2H), 0.12 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ -63.73; MS (IER+): 521.2 (M+1).

Scheme 84

CHO

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-πurazol-4- 180 045731 yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (84h).

Step 1. Preparation of (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(3-nitrophenyl)methanol (84b).

Into a solution of 1-(1-ethoxyethyl)-4-iodo-1H-pyrazole (84a) (5 g, 18.79 mmol) (prepared according to Lin, Qiyan et al; Organic Letters 11(9): 1999-2002 (2009 )) in diethyl ether (16 ml), cooled to -78°C, a solution of n-butyllithium (12.0 ml, 19.2 mmol) in hexane was added dropwise, then stirred for 30 min at -78°C. A solution of 3-nitrobenzaldehyde (31a) (2.87 g, 18.79 mmol) in THF (24 ml) was slowly added to the resulting anion at -78°C, stirred at -78°C for 2 hours, and then at room temperature. temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (50 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (75 ml). Combine the organic layers, wash with brine (60 mL), dry over MgSO ₄ , filter and concentrate in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 80 g, eluted with hexanes/ethyl acetate (1:0 to 1:1))] to give (1-(1-ethoxyethyl)-1H-pyrazol-4-yl )(3nitrophenyl)methanol (84b) (3.537 g, 64.6%) as a yellow viscous substance; 1H NMR (300 MHz, DMSOd6) δ 8.24 (s, 1H), 8.11 (ddd, J=8.1, 2.4, 1.1 Hz, 1H), 7.82 (ddq, J= 7.8, 1.8, 1.0 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7, 37 (s, 1H), 6.04 (dd, J=4.8, 1.6 Hz, 1H), 5.85 (d, J=4.7 Hz, 1H), 5.47 (q, J =6.0 Hz, 1H), 3.43 - 3.35 (m, 1H), 3.23 - 3.05 (m, 1H), 1.54 (d, J=6.0 Hz, 3H) , 1.00 (td, J=7.0, 0.6 Hz, 3H); MS (ESI+) 314.184 (M+Na).

Step 2. Preparation of (3-aminophenyl)(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)methanol (84c).

In a solution of (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(3-nitrophenyl)methanol (84b) (3.437 g, 11.80 mmol) in methanol (70 ml), cooled to 0°C, Nickel(II) chloride hexahydrate (0.701 g, 2.95 mmol) was added. Sodium borohydride (1.822 g, 47.2 mmol) was added portionwise over 30 minutes, followed by stirring at room temperature for 30 minutes. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (2.60 mL, 24.07 mmol) and stirred at RT for 0.5 h. Concentrate the reaction mixture to dryness and dissolve the residue in ethyl acetate (240 mL ) and water (100 ml). The aqueous phase was separated and extracted with ethyl acetate (100 ml). Combine the organic layers, wash with brine (120 mL), dry over MgSO4, filter and concentrate in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 0:1)) to give (3-aminophenyl)(1-(1-ethoxyethyl)-1H-pyrazol- 4-yl)methanol (84c) (3.104 g, 100%) as a colorless oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 - 7.54 (m, 1H), 7.27 (d, J=0.7 Hz, 1H), 6.94 (t, J=7 .7 Hz, 1H), 6.60 (t, J=1.9 Hz, 1H), 6.50 (ddt, J=7.7, 1.7, 0.8 Hz, 1H), 6.45 - 6.32 (m, 1H), 5.53 - 5.39 (m, 3H), 4.99 (s, 2H), 3.42 - 3.36 (m, 1H), 3.14 (dqd , J=9.6, 7.0, 1.3 Hz, 1H), 1.59 - 1.41 (m, 3H), 1.01 (td, J=7.0, 0.8 Hz, 3H ).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((1-(1-ethoxyethyl)-1H-pyrazol-4-yl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (84d).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (3.19 g, 11.34 mmol) in DMF (90 ml) was added (3-aminophenyl) (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)methanol (84c) (3.19 g, 11.34 mmol), N-ethyl-N-isopropan-2-amine (16.0 ml, 92 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBrOP, 5.40 g, 11.34 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (300 ml), washed with water (2x120 ml), brine (120 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 80 g, eluted with hexanes/ethyl acetate (1:0 to 0:1))] to give 1-(3-cyanophenyl)-N-(3-((1 -(1ethoxyethyl)-1H-pyrazol-4-yl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (84d) (4.766 g, 80%) as a light yellow solid substances; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.7, 1 ,3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 - 7.62 (m, 4H), 7.60 - 7, 50 (m, 1H), 7.36 - 7.24 (m, 2H), 7.18 - 7.10 (m, 1H), 5.74 (dd, J=4.4, 1.9 Hz, 1H), 5.64 (d, J=4.4 Hz, 1H), 5.46 (q, J=6.0 Hz, 1H), 3.44 - 3.35 (m, 1H), 3, 21 - 3.05 (m, 1H), 1.60 - 1.45 (m, 3H), 0.99 (td, J=7.0, 1.1 Hz, 3H).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (84f ).

In solution 1 -(3-cyanophenyl)-N-(3-(( 1-(1-ethoxyethyl)-1 H-pyrazol-4-yl)(hydroxy)methyl)phenyl)-3 (trifluoromethyl)-1H-pyrazole -5-carboxamide (84d) (559 mg, 1.066 mmol) in dichloromethane (20 ml) was added with thionyl chloride (0.16 ml, 2.167 mmol) at 0°C and allowed to warm to room temperature for 2 hours. The reaction mixture was treated with triethylamine ( 0.91 ml, 6.53 mmol) and stirred at room temperature for 1 hour. The reaction was quenched with cyclopropylmethanamine (1600 mg, 21.82 mmol) and the mixture was concentrated in vacuo to remove most of the dichloromethane. Acetonitrile (15 ml), triethylamine (0.45 ml) were added to the reaction mixture, heated at reflux temperature for 17 hours and concentrated to dryness in vacuo. The resulting residue was dissolved in chloroform (150 ml), washed with water (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with chloroform/methanol (1:0 to 9:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopro

- 181 045731 pylmethylamino)(1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (84f) (264 mg, 49%) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 10.64 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 ( dt, J=7.7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.67 - 7.50 (m, 3H), 7.29 (dd, J=17.4, 9.7 Hz, 2H), 7.18 (d, J=7.6 Hz, 1H ), 4.79 (s, 1H), 2.37 - 2.09 (m, 3H), 0.86 (d, J=22.2 Hz, 1H), 0.37 (d, J=8, 1 Hz, 2H), 0.05 (t, J=5.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.97; MS (IER) 506 (IER+).

Step 5. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate ( 84g).

Into a solution of 1 -(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1 H-pyrazol-4-yl)methyl)phenyl)-3 (trifluoromethyl)-1H-pyrazol-5-carboxamide (84f) ( 236 mg, 0.467 mmol) in MeOH (8 mL), cooled in ice/water, di-tert-butyl dicarbonate (312 mg, 1.415 mmol) and nickel(II) chloride hexahydrate (60.0 mg, 0.253 mmol) were added. Sodium borohydride (181 mg, 4.69 mmol) was added slowly over 5 min and stirred at RT for 1 h. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.230 mL, 2.110 mmol). Stir the mixture at RT for 0.5 h and concentrate to dryness in vacuo. The resulting residue was dissolved in ethyl acetate (120 ml) and water (60 ml). The aqueous phase was separated and extracted with ethyl acetate (60 ml). Combine the organic layers, wash with brine (60 mL), dry over MgSO ₄ , filter and concentrate in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with chloroform/methanol (1:0 to 9:1)] to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)(1H -pyrazol-4-yl)methyl)phenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (84g) (154 mg, 54%) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.68 (s, 1H), 7.65-7.56 (m, 2H), 7.56 - 7.38 ( m, 5H), 7.38 - 7.31 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.77 (s, 1H), 4.24 - 4.14 (m, 2H), 2.33 - 2.19 (m, 2H), 1.37 (s, 9H), 0.95-0.80 (m, 1H), 0.44 - 0.28 (m, 2H), 0.10 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81.

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (84h).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(1H-pyrazol-4-yl)methyl)phenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (84g) ( 0.134 g, 0.22 mmol) in 1,4-dioxane (15 ml), a 4 M solution of hydrogen chloride in dioxane (2.4 ml, 9.60 mmol) was slowly added and stirred at RT for 15 hours. The reaction mixture was diluted with hexanes and decanted to remove solvent. The residue was treated with hexanes and decanted again. The white residue was concentrated to dryness in vacuo and purified by flash column chromatography [silica gel, 8 g, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give 1-(3-(aminomethyl)phenyl free base) -M-(3(((cyclopropylmethyl)amino)(1 H-pyrazol-4-yl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazol-5-carboxamide (84h) (73 mg, 65% ) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 12.60 (br s, 1H), 10.68 (s, 1H), 7.62 (t, J=1.8 Hz, 1H), 7, 60 - 7.55 (m, 2H), 7.54 - 7.33 (m, 6H), 7.26 (t, J=7.8 Hz, 1H), 7.20 7.14 (m, 1H ), 4.77 (s, 1H), 4.12 (s, 2H), 3.85 (s, 2H), 2.26 (dd, J=6.7, 3.9 Hz, 2H), 0 .96 - 0.82 (m, 1H), 0.42 0.32 (m, 2H), 0.07 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.74; MS (IER-) 507.9 (M-1). Into a solution of the free base 1 -(3 -(aminomethyl)phenyl)-N-(3 -(((cyclopropylmethyl)amino)(1 H-pyrazol-4yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (84h) in methanol (5 ml) was added with HCl (0.055 ml, 0.656 mmol) and concentrated to dryness in vacuo. The resulting residue was dissolved in IPA (1 ml) with heating. Diethyl ether (10 ml) was added to the clear solution and heated at reflux temperature for 15 min. The resulting white solid was collected by filtration, washed with diethyl ether, dried in vacuo to give 1-(3(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(1H-pyrazol-4-yl hydrochloride salt) )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (84h) (0.062 g, 0.100 mmol, 76% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.82 (s, 1H), 9.64 (s, 1H), 8.44 (s, 3H), 7.91 (t, J=1.8 Hz, 1H), 7.84 - 7.70 (m, 4H), 7.66 - 7.49 (m, 5H), 7.45 (t, J=7.9 Hz, 1H), 5.51 (t, J=6.3 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 2.75-2.58 (m, 2H), 1.14 -1.00 (m, 1H), 0.59 - 0.48 (m, 2H), 0.30 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ 60.79; MS (IER+) 510.3 (M+1); (IER-) 508.3 (M-1); analysis, calculation for C26H26F ₃ N7O-2.25HCl-2.25H2O: C, 49.40; H, 5.22; Cl, 12.62; N, 15.51; experiment: C, 49.09; H, 5.18; Cl, 12.99; N, 15.10.

- 182 045731

Scheme 85

85b 85c

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (85c).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (85 a).

In solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (82d) (500 mg, 1.065 mmol) in dichloromethane (20 ml) at 0°C, thionyl chloride (0.240 ml, 3.25 mmol) was added and left to warm to room temperature for 2 hours. The reaction mixture was treated with triethylamine (1.350 ml, 9.69 mmol), stirred at room temperature temperature for 1 hour, cyclopropylmethanamine (1600 mg, 21.82 mmol) was added and concentrated in vacuo to remove most of the dichloromethane. Acetonitrile (15 ml) and triethylamine (0.7 ml) were added to the reaction mixture. The reaction mixture was refluxed for 15 hours and concentrated to dryness in vacuo. The residue was dissolved in chloroform (150 ml), washed with water (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 2x12 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)( thiazol-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide (85a) (181 mg) as a brown solid. MS (IER+): 523.2 (M+1).

Step 2. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (85b ).

In a solution of 1 -(3-cyanophenyl)-K-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (85a) (170 mg, 0.325 mmol) in MeOH (6 mL), cooled in ice/water, di-tert-butyl dicarbonate (217 mg, 0.986 mmol), nickel (II) chloride hexahydrate (42.0 mg, 0.177 mmol) was added, then slowly added sodium borohydride (126 mg, 3.26 mmol) for 5 min. The reaction mixture was stirred at room temperature, quenched with N1-(2-aminoethyl)ethane-1,2diamine (0.160 mL, 1.464 mmol), stirred for 30 min and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (120 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (60 ml). The combined organic extracts were washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 2x4 g, eluted with chloroform/CMA 80 (1:0 to 4:1)] to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)() thiazol-2-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (85b) (35 mg, 17%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.75 (br s, 1H), 7.67 (s, 1H), 7.66 (d, J=3.3 Hz, 1H), 7, 63 - 7.18 (m, 10H), 5.15 (d, J=3.1 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.45- 2.28 (m, 2H), 1.36 (s, 9H), 1.04 - 0.78 (m, 1H), 0.46 - 0.32 (m, 2H), 0.11-0.04 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.81; MS (IER+): 627.2 (M+1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-K-(3-(((cyclopropylmethyl)amino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (85c).

In a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(thiazol-2-yl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (85b) (33 mg , 0.053 mmol) in 1,4-dioxane (4 ml), hydrogen chloride (0.570 ml, 2.280 mmol) (4 M in 1,4-dioxane) was added and stirred at room temperature for 20.5 hours. The reaction mixture was treated with hexanes, decanted , washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 3:1)] to give the free base 1-(3-(aminomethyl)phenyl)-N-(3-( ((cyclopropylmethyl)amino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (85c) (24 mg, 87%) as a white solid

- 183 045731 society. 1H NMR (300 MHz, DMSO^) δ 10.73 (s, 1H), 7.69 (t, J=1.8 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H) , 7.61 (d, J=3.3 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.47 - 7.41 (m, 2H), 7.35 - 7.31 (m, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.20 (dt, J=7.8, 1.4 Hz, 1H), 5.15 (s, 1H) , 3.79 (s, 2H), 2.88 (s, 2H), 2.38 (t, J=6.9 Hz, 2H), 1.02 - 0.83 (m, 1H), 0, 45 - 0.32 (m, 2H), 0.14 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.74; MC (IER+) 527.3 (M+1). Into a solution of the free base 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (85c) (0.3 g, 0.570 mmol) in IPA (10 ml) was added conc. HCl (0.176 ml, 2.117 mmol) and concentrated to dryness in vacuo. The residue was dried in vacuo to remove excess HCl and dissolved in IPA (5 ml) with heating to accelerate dissolution. Diethyl ether (50 ml) was added to the homogeneous solution and heated at reverse condensation temperature for 30 min. After cooling to room temperature, the resulting solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 1(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(thiazol-2-yl hydrochloride )methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (85c) (0.27 g, 0.425 mmol, 74.5% yield) as a white solid.

1H NMR (300 MHz, deuterium oxide) δ 7.61 (d, J=3.3 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J=3.3 Hz, 1H) , 7.38 7.31 (m, 3H), 7.34 - 7.22 (m, 3H), 7.21 - 7.12 (m, 2H), 5.76 (s, 1H), 3, 97 (s, 2H), 2.80 - 2.60 (m, 2H), 0.88 - 0.72 (m, 1H), 0.44 - 0.32 (m, 2H), 0.11 - -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, D2O) δ -62.31; MS (IER+) 527.3 (M+1); (IER-) 525.2 (M-1); analysis, calculation for C ₂₆ H ₂ 5РзК^-2.25НС1-2.5Н ₂ О: C, 47.77; H, 4.97; Cl, 12.20; N, 12.86; S, 4.91; experiment: C, 48.01; H, 5.26; Cl, 11.94; N, 12.34; S, 4.85.

Scheme 86

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmetulamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (86g) .

Step 1. Preparation of (3-nitrophenyl)(pyridin-4-yl)methanol (86b).

A solution of 4-bromopyridine hydrochloride (4.8 g) in water (50 ml) was neutralized with 6N. drive NaOH, then extracted with ethyl acetate (100 ml, 50 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ , then filtered and concentrated to give 4-bromopyridine (light brown oily liquid, 1.65 g, low yield due to low boiling point, slight loss on concentration) . To a solution of 4-bromopyridine (1.58 g, 10.00 mmol) in diethyl ether (8 ml), cooled to -78°C, n-butyllithium (6.30 ml, 10.08 mmol) was added dropwise and stirred for 30 min at -78°C. A solution of 3-nitrobenzaldehyde (31a) (1.511 g, 10.00 mmol) in THF (12 ml) was added to the reaction mixture at -78°C, stirred at -78°C for 2 hours, and then at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (40 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (60 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 40 g, eluted with chloroform/methanol (1:0 to 19:1)] to give (3-nitrophenyl)(pyridin-4-yl)methanol (86b) (1.005 g, 44%) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.54 - 8.50 (m, 2H), 8.29 (t, J=2.0 Hz, 1H), 8.12 (ddd, J=8 ,2, 2.4, 1.1 Hz, 1H), 7.86 (dt, J=7.8, 1.4 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H) , 7.44 (ddd, J=4.6, 1.6, 0.7 Hz, 2H), 6.49 (d, J=4.2 Hz, 1H), 5.93 (d, J=4 ,1 Hz, 1H); MS (IER+): 231.1 (M+1).

Step 2. Preparation of (3-aminophenyl)(pyridin-4-yl)methanol (86c).

To a solution of (3-nitrophenyl)(pyridin-4-yl)methanol (86b) (953 mg, 4.14 mmol) in methanol (25 ml), cooled to 0°C, was added nickel (II) chloride hexahydrate (246 mg , 1.035 mmol), then sodium borohydride (639 mg, 16.56 mmol) in parts over 30 minutes. The reaction mixture was stirred at room temperature for 30 min, quenched with P-(2-aminoethyl)ethane-1,2-diamine (0.900 ml, 8.33 mmol), stirred for 30 min at room temperature and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (120 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (75 ml). The combined organic extracts were washed with brine (75 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 25 g, eluted with chloroform/methanol mixtures (1:0 to

- 184 045731

9:1)] to give (3-aminophenyl)-(pyridin-4-yl)methanol (86c) (655 mg, 79%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.50 - 8.44 (m, 2H), 7.33 (ddd, J=4.4, 1.6, 0.7 Hz, 2H), 6.93 (t, J=7.7 Hz, 1H), 6.60 - 6.48 (m, 2H), 6.40 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.95 (d, J=3.9 Hz, 1H), 5.51 (d, J=3.9 Hz, 1H), 5.04 (s, 2H); MS (IER+): 201.1 (M+1).

Step 3. Preparation of 1-(3-cyanophenyl)-N(3-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (86d).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (892 mg, 3.17 mmol) in DMF (26 ml) was added (3-aminophenyl)(pyridine -4-yl)methanol (86c) (634 mg, 3.17 mmol), Nethyl-N-isopropylpropan-2-amine (4.50 ml, 25.8 mmol) and bromo-tripyrrolidin-1ylphosphonium hexafluorophosphate (V) ( PyBrOP, 1509 mg, 3.17 mmol) and stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x100 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, 40 g, eluted with chloroform/methanol (1:0 to 9:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridine- 4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (86d) (1.09 g, 74%) as a light yellow solid; % NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.52 - 8.46 (m, 2H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 - 7, 54 (m, 4H), 7.35 (ddd, J=4.5, 1.6, 0.6 Hz, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.17 (dt, J=7.8, 1.3 Hz, 1H), 6.21 (d, J=3.9 Hz, 1H), 5.70 (d, J=3.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98; MS (IER+): 464.1 (M+1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (86e).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (86d) (0.4 g, 0.863 mmol) in dichloromethane (18 ml) at 0°C, add thionyl chloride (0.2 ml, 2.70 mmol) and leave to warm to room temperature for 2 hours. The reaction mixture was treated with triethylamine (1.1 ml, 7.89 mmol) , stirred at room temperature for 1 hour, added cyclopropylmethanamine (1.3 g, 17.73 mmol) and concentrated in vacuo to remove most of the dichloromethane. Acetonitrile (14 ml) and triethylamine (0.5 ml) were added to the reaction mixture. The reaction mixture was refluxed for 17.5 hours and concentrated to dryness in vacuo. The residue was dissolved in chloroform (120 ml), washed with water (60 ml), dried over MgSO4, filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 2x12 g, eluted with chloroform/methanol (1:0 to 19:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)( pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (86e) (26 mg, 5.8%) as a brown solid; % NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.49 - 8.44 (m, 2H), 8.18 -8.15 (m, 1H), 8.01 ( dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 - 7.62 (m, 3H), 7.56 (dt, J=8.1, 1.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.28 (t, J=7.8 Hz, 1H ), 7.21 (dt, J=7.8, 1.4 Hz, 1H), 4.84 (s, 1H), 2.35- 2.22 (m, 2H), 0.1.00- 0.80 m, 1H), 0.43 0.33 (m, 2H), 0.10 -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98; MS (IER+): 517.3 (M+1).

Step 5. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (86f) .

In a solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (86e) (24 mg, 0.046 mmol) in MeOH (3 ml), cooled in ice/water, di-tert-butyl dicarbonate (31.0 mg, 0.141 mmol), nickel (II) chloride hexahydrate (6.0 mg, 0.025 mmol) was added, after to which sodium borohydride (18 mg, 0.466 mmol) was slowly added over 5 minutes. The reaction mixture was stirred at room temperature, quenched with N1-(2-aminoethyl)ethane1,2-diamine (0.022 mL, 0.203 mmol), stirred for 30 min and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (120 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (60 ml). The combined organic extracts were washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 4:1)] to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)() pyridin-4yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (86f) (12 mg, 42%) as a colorless viscous substance. % NMR (300 MHz, methanol-d4) δ 8.47 - 8.40 (m, 2H), 7.65 (t, J=1.9 Hz, 1H), 7.52 - 7.19 (m, 10H), 4.92 (s, 1H), 4.28 (s, 2H), 2.38 (dd, J=6.9, 3.0 Hz, 2H), 1.39 (s, 9H), 1.05-0.90 (m, 1H), 0.51 - 0.42 (m, 2H), 0.08 (td, J=5.3, 4.8, 3.6 Hz, 2H); ¹⁹ F NMR (282 MHz, methanol-d4) δ -63.71; MS (IER+): 621.2 (M+H).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 86g).

In a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (86f) (12 mg , 0.019 mmol) in 1,4-dioxane (3 ml), hydrogen chloride (0.210 ml, 0.841 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 14 hours.

- 185 045731

The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, 2x4 g, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-(3- ((cyclopropylmethylamino)(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (86g) (4.1 mg, 41%) as a colorless viscous substance; 1H NMR (300 MHz, methanol-d ₄ ) δ 8.46 - 8.41 (m, 2H), 7.64 (t, J=1.9 Hz, 1H), 7.56 (s, 1H), 7.52 - 7.47 (m, 4H), 7.46 - 7.40 (m, 2H), 7.35 (s, 1H), 7.30 (t, J=7.8 Hz, 1H) , 7.22 (dt, J=7.7, 1.5 Hz, 1H), 4.92 (s, 1H), 3.93 (s, 2H), 2.38 (dd, J=6.9 , 3.1 Hz, 2H), 1.04 0.91 (m, 1H), 0.55-0.42 (m, 2H), 0.12 - 0.04 (m, 2H); ¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ -63.75; MS (IER+): 521.3 (M+1).

Scheme 87

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (84f).

Step 1. Preparation of X-(2-cyclopropylethyl)aniline (87b).

Sodium 2-methylpropan-2-olate (0.673 g, 7.01 mmol), biphenyl-2-yl-di-tert-butylphosphine (0.209 g, 0.701 mmol) and Tris were placed in a 50 ml one-neck flask equipped with a magnetic stirrer insert. (dibenzylideneacetone)dipalladium (0) (0.321 g, 0.350 mmol), after which the flask was degassed and refilled with nitrogen, 2cyclopropylethanamine (87a) (0.662 ml, 7.01 mmol), bromobenzene (0.738 ml, 7 .01 mmol) and toluene (10 ml) in a positive nitrogen flow. The reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. TLC analysis (ethyl acetate/hexanes, 5/95, v/v) indicated completion of the reaction. The reaction mixture was filtered through a small pad of Celite, which was then washed with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 20% ethyl acetate in hexanes)] to give X-(2-cyclopropylethyl)aniline (87b) (198 mg, 18% yield) as yellow oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 6.97 (dd, J=8.5, 7.2 Hz, 2H), 6.59 - 6.31 (m, 3H), 5.44 (t, J=5.6 Hz, 1H, exchange with D ₂ O), 2.97 (td, J=7.2, 5.6 Hz, 2H), 1.36 (q, J=7.0 Hz, 2H ), 0.83 - 0.61 (m, 1H), 0.44 - 0.24 (m, 2H), 0.06 - -0.05 (m, 2H).

Step 2. Preparation of X-cyclopropylethyl-3-nitro-N-phenylaniline (87c).

In a 50 ml one-neck flask equipped with a magnetic stirrer insert, 1-bromo-3nitrobenzene (27a) (0.245 g, 1.213 mmol) and K-(2-cyclopropylethyl)aniline (87b) (0.163 g, 1.011 mmol) were placed and dissolved in toluene (15 ml) and added sodium 2-methylpropan-2-olate (0.078 g, 0.809 mmol), (9,9dimethyl-9H-xanthene-4,5-diyl)-bis(diphenylphosphine) (0.058 g, 0.101 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.028 g, 0.030 mmol). The reaction mixture was stirred at 110°C for 16 h under a positive nitrogen flow, cooled to room temperature, and excess solvent was evaporated to dryness. The reaction was quenched with water (25 ml), the mixture was extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%)] to give X-(2-cyclopropylethyl)-3-nitro-P-phenylaniline (87c) (280 mg , yield 98%) in the form of a brown-yellow oily liquid, which was used in this form in the next step.

Step 3. Preparation of X1-(2-cyclopropylethyl)-X1-phenylbenzene-1,3-diamine (87d).

A solution of K-(2-cyclopropylethyl)-3-nitro-I-phenylaniline (87c) (0.261 g, 0.924 mmol) in methanol (20 ml) was treated with palladium (10% Pd on a carbon support) (0.039 g, 0.370 mmol). The reaction mixture was hydrogenated at 60 psi (414 kPa) for 3 hours at room temperature. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated completion of the reaction. The reaction mixture was filtered through a small pad of Celite, which was washed successively with methanol (2x25 ml) and ethyl acetate.

- 186 045731 tatome (25 ml). Excess solvents were pumped out under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give N1-(2-cyclopropylethyl)-N1-phenylbenzene-1,3-diamine (87d) ( 0.066 g, 0.262 mmol, 28.3% yield) as a brown waxy solid, which was used as such in the next step; MS (IER+) 253.2 (M+1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (87e).

Into an oven-dried 100 mL round bottom flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (105 mg, 0.374 mmol), N1-(2-cyclopropylethyl) -N1phenylbenzene-1,3-diamine (87d) (63 mg, 0.250 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.140 g, 0.300 mmol), N,N-dimethylformamide (1.508 ml, 19.47 mmol) was added sequentially ) and X-ethyl-K-isopropylpropan-2-amine (0.217 ml, 1.248 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Excess DMF was pumped out under reduced pressure. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (87e) (93 mg, 72% yield) as a pale yellow solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1 .4 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.34 - 7 .15 (m, 5H), 7.07 - 7.01 (m, 2H), 6.96 (t, J=7.3 Hz, 1H), 6.76 - 6.66 (m, 1H), 3.75 (t, J=7.5 Hz, 2H), 1.45 (q, J=7.3 Hz, 2H), 0.68 (dd, J=12.8, 6.9 Hz, 1H ), 0.44 - 0.33 (m, 2H), 0.07 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.95; MS (IER ⁺ ): MS (IER+) 516.22 (M+1), 538.15 (M+Na), MS (IER-) 514.2 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (84f) .

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-((2-cyclopropylethyl)(phenyl)amino)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (87e) (81 mg, 0.157 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.056 g, 0.236 mmol) was added, followed by sodium borohydride (0.071 g, 1.885 mmol) in small portions over 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 5 minutes. TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated completion of the reaction, after which N1-(2aminoethyl)ethane-1,2-diamine (0.170 mL, 1.571 mmol) was added. Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (50 ml) and the product was extracted with chloroform (2x50 ml). The organic layers were combined, dried over MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with 0 to 50% methanol/chloroform mixtures)] to give 1-(3-(aminomethyl)phenyl)-N-(3-((2cyclopropylethyl)( phenyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (84f) (32 mg, 39% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.59 (s, 1H), 7.56 - 7.49 (m, 2H), 7.46 - 7.40 (m, 2H), 7.34 - 7.16 (m, 6H), 7.07 - 6.92 (m, 3H), 6.70 (dt, J=7.4, 2.0 Hz, 1H), 3.76 (d, J =7.9 Hz, 4H), 1.45 (q, J=7.1 Hz, 2H), 0.70 (ddt, J=9.6, 7.5, 4.6 Hz, 1H), 0 .47 - 0.31 (m, 2H), 0.04 (dd, J=4.9, 1.5 Hz, 2H); 1H NMR (300 MHz, DMSO D ₂ O) δ 7.50 (d, J=2.3 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.37 - 7.22 (m , 4H), 7.19 (dd, J=4.8, 2.3 Hz, 2H), 7.10 - 6.93 (m, 3H), 6.70 (dt, J=6.7, 2 .5 Hz, 1H), 3.75 (d, J=3.3 Hz, 4H), 1.45 (q, J=7.2 Hz, 2H), 0.69 (tt, J=7.4 , 4.8 Hz, 1H), 0.45-0.35 (m, 2H), 0.08 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.71; MS (IER ⁺ ): MS (IER+) 520.3 (M+1), MS (IER-) 518.3 (M-1); analysis, calculation for: C29H28F3N5O-0.5H2O: C, 65.90; H, 5.53; N, 13.25; experiment: C, 66.12; H, 5.56; N, 12.85.

Scheme 88

- 187 045731

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (88b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (88a).

In a solution of 1-(3-cyanophenyl)-A2-fluoro-3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-Spirazole-5-carboxamide (36b) (0.15 g, 0.312 mmol) in Thionyl chloride (0.046 ml, 0.624 mmol) was added to dichloromethane (10 ml) at 0°C and allowed to warm to room temperature and stirred for 3 hours. Concentrate the reaction mixture to dryness in vacuo. The residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (0.542 ml, 6.24 mmol) was added. The reaction mixture was heated at reflux temperature overnight. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give 1-(3-cyanophenyl)N-(3-((cyclopropylmethylamino)(phenyl)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (88a) (96 mg, 58% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.47 (s, 1H, exchange with D2O), 8.12 (s, 1H), 7.99 (dt, J=7.7, 1.3 Hz , 1H), 7.93 - 7.86 (m, 1H), 7.77 - 7.67 (m, 2H), 7.55 (t, J=7.1 Hz, 1H), 7.48 - 7.34 (m, 3H), 7.29 (dd, J=8.4, 6.6 Hz, 2H), 7.24 - 7.14 (m, 2H), 5.14 (s, 1H) , 2.30 (t, J=6.3 Hz, 2H), 0.91 (s, 1H), 0.47 - 0.31 (m, 2H), 0.05 (dd, J=5.7 , 4.1 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.99, -127.84; MS (IER ⁺ ): MS (IER+) 534.2 (M+1), MS (IER-) 532.14 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-^-(3-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (88b).

Into a stirred solution of 1-(3-cyanophenyl)-A3-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (88a) (0.121 g, 0.227 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.081 g, 0.340 mmol) was added, followed by sodium borohydride (0.103 g, 2.72 mmol) in small portions over 5 min. The reaction mixture was stirred for 5 min, TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated completion of the reaction, after which M-(2-aminoethyl)ethane-1,2-diamine (0.245 ml) was added , 2.268 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The organic layers were combined, dried over MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with methanol/chloroform, 0 to 50%)] to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)( phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (88b) (35 mg, 29% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.48 (s, 1H, exchange with D ₂ O), 7.60 - 7.40 (m, 6H), 7.40 - 7.26 (m, 5H), 7.19 (tdd, J=7.9, 4.7, 3.2 Hz, 2H), 5.14 (s, 1H), 3.78 (s, 2H), 2.30 (d , J=6.7 Hz, 2H), 1.03 - 0.78 (m, 1H), 0.45- 0.33 (m, 2H), 0.04 (td, J=5.4, 3 ,8 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75, -128.07; MS (IER ⁺ ): MS (IER+) 538.3 (M+1), 560.2 (M+Na), MS (IER-) 536.2 (M-1), 572.2 (M+Cl ); analysis, calculation for C29H27F4N5O-0.25H2O: C, 64.26; H, 5.11; N, 12.92; experiment: C, 64.26; H, 5.22; N, 12.58.

Scheme 89

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phen

- 188 045731 nyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (89g).

Step 1. Preparation of 3-cyclopropyl-N-methoxy-N-methylpropanamide (89b).

To a solution of 3-cyclopropylpropanoic acid (89a) (1 g, 8.76 mmol) in dichloromethane (10 ml) was added thionyl chloride (1.279 ml, 17.52 mmol) at 0°C, one drop of DMF and stirred at room temperature for 3 hours. N,O-Dimethylhydroxylamine hydrochloride (1.282 g, 13.14 mmol), triethylamine (12.21 ml, 88 mmol) was added to the reaction mixture at room temperature and stirred for 16 hours. The reaction was quenched with water (75 ml) and the mixture was extracted with dichloromethane (75 ml, 50 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%)] to give 3-cyclopropyl-N-methoxy-N-methylpropanamide (89b) (0.795 g, 5.06 mmol , yield 57.7%) in the form of a light yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 3.63 (s, 3H), 3.05 (s, 3H), 2.42 (t, J=7.5 Hz, 2H), 0.76 - 0.61 (m, 1H), 0.38 - 0.30 (m, 2H), 0.04 - -0.05 (m, 2H).

Step 2. Preparation of 1-(3-aminophenyl)-3-cyclopropylpropan-1-one (89c).

To a stirred solution of 3-cyclopropyl-N-methoxy-N-methylpropanamide (89b) (0.75 g, 4.77 mmol) in tetrahydrofuran (10 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide ( 47c) (7.16 ml, 7.16 mmol) at 0°C. The reaction mixture was stirred for 3 hours at the indicated temperature and the reaction was quenched by adding ammonium chloride solution (10 ml). The reaction mixture was extracted with ethyl acetate (2x25 ml). Combine the organic layers, wash with brine (25 mL), dry and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-20% ethyl acetate in hexanes) to give 1-(3-aminophenyl)-3-cyclopropylpropan-1-one (89c) (0.758 g, 84% yield) as colorless oily liquid; 1H NMR (300 MHz, DMSO^) δ 7.20 - 7.06 (m, 3H), 6.84 - 6.74 (m, 1H), 5.33 (s, 2H), 2.98 (t , J=7.3 Hz, 2H), 1.49 (q, J=7.2 Hz, 2H), 0.74 (dddd, J=13.9, 10.0, 5.1, 2.2 Hz, 1H), 0.42 - 0.33 (m, 2H), 0.10 0.01 (m, 2H); MS (ESI+) 212.2 (M+Na); (IER-) 188.1 (M-1).

Step 3. Preparation of 1-(3-aminophenyl)-3-cyclopropylpropan-1-ol (89d).

To a stirred solution of 1-(3-aminophenyl)-3-cyclopropylpropan-1-one (89c) (0.671 g, 3.55 mmol) in methanol (20 ml) was added sodium borohydride (0.295 g, 7.80 mmol) at 0 °C and stirred the reaction mixture for 1 hour at 0°C. TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated completion of the reaction. Excess methanol was pumped out under reduced pressure. The reaction was quenched with saturated aqueous sodium carbonate (20 ml) and the mixture was extracted with ethyl acetate (2x30 ml). Combine the organic layers, wash with brine (25 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with 0 to 50% ethyl acetate in hexanes)] to give 1-(3-aminophenyl)-3-cyclopropylpropan-1-ol (89d) (431 mg, yield 67%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 6.92 (t, J=7.7 Hz, 1H), 6.53 (t, J=1.8 Hz, 1H), 6.47 - 6.34 (m, 2H), 4.95 (s, 2H, exchange with D2O), 4.90 (d, J=4.2 Hz, 1H, exchange with D2O), 4.35 (m, 1H), 1, 74-1.51 (m, 2H), 1.31-1.04 (m, 2H), 0.59 0.69 (m, 1H), 0.43 - 0.29 (m, 2H), - 0.05 (dq, J=3.6, 2.4, 1.8 Hz, 2H); MS (IER+): MS (IER+) 192.1 (M+1), MS(IER-) 190.1 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (89e).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (0.922 g, 3.28 mmol), 1-(3-aminophenyl)-3- cyclopropylpropan-1-ol (89d) (0.418 g, 2.185 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (1.223 g, 2.62 mmol), N,N-dimethylformamide (DMF) (14 ml) was added sequentially and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (1.903 mL, 10.93 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (30 ml) and extracted with ethyl acetate (2x30 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N(3-(3-cyclopropyl-1-hydroxypropyl)phenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (89e) (918 mg, 92% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H, exchange with D2O), 8.17 (t, J=1.9 Hz, 1H), 8.01 (dt, J=7 ,8, 1.3 Hz, 1H), 7.92 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.81 - 7.69 (m, 2H), 7, 61 (t, J=1.9 Hz, 1H), 7.53 (dt, J=8.2, 1.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.07 (dt, J=7.8, 1.3 Hz, 1H), 5.18 (d, J=4.6 Hz, 1H, exchange with D ₂ O), 4.50 (d, J= 7.8 Hz, 1H), 1.64 (ddd, J=8.9, 6.4, 3.2 Hz, 2H), 1.18 (td, J=7.0, 2.1 Hz, 2H ), 0.73 - 0.57 (m, 1H), 0.42 - 0.27 (m, 2H), -0.02 - -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.96; IR (KBr, cm ^-1 ): 2236 cm ^-1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 455.2 (M+1), 477.19 (M+Na), MS (IER-) 453.02 (M-1), 488.8 (M+Cl ).

Step 5. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (89f).

In solution 1 -(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1H

- 189 045731 pyrazole-5-carboxamide (89e) (0.406 g, 0.893 mmol) in dichloromethane (20 ml) at 0°C add thionyl chloride (0.196 ml, 2.68 mmol), leave to warm to room temperature and stir for 3 h. The reaction mixture was treated with 1H-imidazole (0.608 g, 8.93 mmol), then stirred at room temperature for 5 hours. The reaction mixture was evaporated to dryness. The resulting residue was dissolved in N,N-dimethylacetamide (20 ml), 1H-imidazole (0.608 g, 8.93 mmol) was added and heated to 130°C for 36 hours. TLC analysis indicated completion of the reaction. Excess solvent was pumped out under reduced pressure. The residue was diluted with water (30 ml) and extracted with ethyl acetate (2x30 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%, then mixtures of methanol in chloroform, 0-100%] to give 1-(3cyanophenyl)-N-(3 -(3 -cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (89f (44 mg, 10% yield) as a waxy solid. ^1H NMR (300 MHz, DMSO-06) δ 10.71 (s, 1H, exchange with D2O), 8.18 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.7 , 1.3 Hz, 1H), 7.91 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.84 - 7.68 (m, 3H), 7.63 - 7.55 (m, 2H), 7.40 - 7.30 (m, 1H), 7.27 (t, J=1.2 Hz, 1H), 7.15 (dt, J=7.7, 1.4 Hz, 1H), 6.90 (t, J=1.1 Hz, 1H), 5.35 (dd, J=9.2, 6.5 Hz, 1H), 2.38 - 2, 11 (m, 2H), 1.07 (ddq, J=29.2, 15.0, 7.6, 7.1 Hz, 2H), 0.71 (p, J=6.0 Hz, 1H) , 0.44 - 0.33 (m, 2H), -0.04 (ddd, J=6.5, 4.6, 3.3 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.96; MS (IER ⁺ ): MS (IER+) 505.2 (M+1), MS (IER-) 503.2 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-imidαzol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (89g).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (89f) (0.039 g, 0.077 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.028 g, 0.116 mmol) was added, then sodium borohydride (0.035 g, 0.928 mmol) was added in small portions ) for 5 min. The reaction mixture was stirred for 5 minutes. TLC analysis (methanol/chloroform, 2/8, v/v) indicated the reaction was complete, after which M-(2-aminoethyl)ethane-1,2-diamine (0.084 mL, 0.773 mmol) was added. Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The organic layers were combined, dried over MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 2x12 g, eluted with methanol/chloroform, 0 to 50%)] to give 1 -(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1- (1H-imidazol-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (89g) (15 mg, 38% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H, exchange with D ₂ O), 7.80 (t, J=1.1 Hz, 1H), 7.62 - 7.51 (m, 4H), 7.48 - 7.41 (m, 2H), 7.37 - 7.29 (m, 2H), 7.27 (t, J=1.3 Hz, 1H), 7, 13 (dt, J=7.7, 1.3 Hz, 1H), 6.89 (t, J=1.1 Hz, 1H), 5.34 (dd, J=9.2, 6.4 Hz , 1H), 3.80 (s, 2H), 2.38 - 2.08 (m, 2H), 1.19 - 0.89 (m, 2H), 0.70 (ddt, J=10.4 , 7.3, 4.0 Hz, 1H), 0.45-0.29 (m, 2H), -0.04 (td, J=5.2, 3.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.73; MS (IER ⁺ ): MS (IER+) 509.2 (M+1), MS (IER-) 507.22 (M-1).

Scheme 90

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxαmideα (90f).

- 190 045731

Step 1. Preparation of (2-amino-3-fluorophenyl)methanol (90b).

To a suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF (20 ml) a solution of methyl 2-amino-3-fluorobenzoate (90a) (5 g, 32.2 mmol) in THF was added dropwise at 0°C (20 ml). The reaction mixture was stirred at room temperature overnight. The mixture was then cooled to 0°C, the reaction was quenched with ethyl acetate (30 ml) and water (10 ml). The resulting slurry was filtered through celite and washed with ethyl acetate (50 ml). The aqueous layer was separated and the organic layer was dried, filtered and concentrated to dryness in vacuo to obtain the crude product. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (2-amino-3-fluorophenyl)methanol (90b) (2.958 g, 65% yield) as beige solid matter; ¹ H NMR (300 MHz, DMSO-d6) δ 6.98 - 6.86 (m, 2H), 6.52 (td, J=7.8, 5.2 Hz, 1H), 5.15 (t , J=5.5 Hz, 1H), 4.88 (s, 2H), 4.43 (d, J=5.5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -136.17 (dd, J=11.3, 5.2 Hz); MS (IER+) 165 (M+Na); (IER-) 140.0 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (90c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (4 g, 14.23 mmol) in DMF (86 ml) was added fluorophenyl)methanol (90b) (2.008 g, 14.23 mmol), N-ethyl-Nisopropylpropan-2-amine (DIPEA) (12.39 ml, 71.1 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 6 .63 g, 14.23 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The residue was purified by flash column chromatography [silica gel, 80 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxymethyl)phenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (90c) (0.709 g, 12% yield) as a white solid; MS (IER-) 403.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-6-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (90d).

Into a stirred suspension of 1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (90c) (0.879 g, 2.174 mmol) in dichloromethane (20 ml) containing sodium bicarbonate (0.913 g, 10.87 mmol), added Dess-Martin periodinane (1.383 g, 3.26 mmol) and stirred at room temperature for 3 hours, TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated good conversion. The reaction mixture was filtered through a Celite pad, which was washed with ethyl acetate, and the filtrate was concentrated to dryness in vacuo. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give 1-(3-cyanophenyl)-N-(2-fluoro-6-formylphenyl)-3 -(trifluoromethyl)-1H-pyrazole-5carboxamide (90d) (154 mg, 18% yield) as a white solid; MS (IER+) 425.08 (M+1), MS (IER-) 401.1 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(90e).

A solution of 1-(3-cyanophenyl)-N-(2-fluoro-6-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (90d) (0.148 g, 0.368 mmol) in THF (4 ml ), cooled to 0°C, phenylmagnesium bromide (0.747 ml, 0.747 mmol) was added and stirred at room temperature for 14 hours. The reaction was quenched with saturated aqueous NH4Cl (25 ml), the mixture was extracted with ethyl acetate (2x25 ml). The combined extracts were dried over MgSO ₄ , filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 50%)] to give 1-(3-cyanophenyl)-N-(2-fluoro-6-(hydroxy(phenyl) )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (90e) (92 mg, 52% yield) as a pale yellow oily liquid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H, exchange with D2O), 7.97 (dt, J=6.9, 1.7 Hz, 1H), 7.90 (d , J=1.9 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.62 (s, 1H), 7.46 - 7.34 (m, 2H), 7.28 - 7.18 (m, 6H), 6.04 (s, 1H, exchange with D2O), 5.97 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.9, -119.75; MS (IER+): MS (IER+) 503.1 (M+Na), MS (IER-) 479.1 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-M-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (90f).

Into a stirred solution of 1-(3-cyanophenyl)-M-(2-fluoro-6-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (90e) (0.051 g, 0.106 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel(II) chloride hexahydrate (0.038 g, 0.159 mmol) was added, followed by sodium borohydride (0.048 g, 1.274 mmol) in small portions over 5 min. TLC analysis (methanol/chloroform, 2/8, v/v) indicated the reaction was complete, after which N1-(2-α-aminoethyl)ethane-1,2diamine (0.115 mL, 1.062 mmol) was added. Excess methanol was pumped out under reduced pressure.

The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml), the combined organic layers were dried over MgSO ₄ , filtered, evaporated

- 191 045731 dry. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with methanol/chloroform, 0 to 50%)] to give 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-6-( hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (90f) (43 mg, 84% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.47 - 7.40 (m, 3H), 7.40 - 7.33 (m, 3H), 7.31 7.13 (m, 7H), 5.96 (s, 1H), 3.75 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.74, -119.59; MS (IER ⁺ ): MS (IER+) 485.1 (M+1), 969.2 (2M+1), MS (IER-) 483.1 (M-1), 967.2 (2M-1 ); analysis, calculation for: C25H20F4N4O2: C, 61.98; H, 4.16; N, 11.57; experiment: C, 61.91; H, 4.43; N, 11.61.

Scheme 91

46g 91a

An example of the preparation of (E/Z)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-phenylprop-1-enyl)phenyl)-3-(trifluoromethyl)-1 H- hydrochloride pyrazole-5-carboxamide (91a).

Into a stirred solution of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (46g ) (0.33 g, 0.617 mmol) in acetone (10 ml) was added conc. HCl (0.154 ml, 1.852 mmol) and stirred with heating for 15 min. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in IP A (2.0 ml) and heated to reflux temperature, diethyl ether (40 ml) was added to the hot solution and continued stirring at reflux temperature for 15 minutes. The reaction mixture was cooled to room temperature and the resulting solid was collected by filtration, dried in vacuo to give (E/Z)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl1-phenylprop-1) hydrochloride -enyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (91a) (0.251 g, 0.454 mmol, 73.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (d, J=13.2 Hz, 1H), 8.38 (s, 3H), 7.74 - 7.68 (m, 2H), 7.67 - 7.47 (m, 4H), 7.46 - 7.22 (m, 5H), 7.15 (ddt, J=16.5, 6.0, 1.6 Hz, 2H), 6.93 (ddt, J=7.6, 2.8, 1.3 Hz, 1H), 6.17 (dt, J=12.0, 7.4 Hz, 1H), 4.12 (s, 2H), 2.00 - 1.89 (m, 2H), 0.86 - 0.70 (m, 1H), 0.48 - 0.36 (m, 2H), 0.06 (td, J= 5.0, 1.4 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.81, -60.82; MS (IER-) 515.3 (M-1); analysis, calculation for C ₃₀ H ₂₇ F ₃ N ₄ O-HCl: C, 65.16; H, 5.10; Cl, 6.41; N, 10.13; experiment: C, 64.75; H, 5.30; Cl, 6.21; N, 9.85.

Scheme 92

An example of the preparation of 1 -(3 -(aminomethyl)phenyl)-N-(3 -(3 -cyclopropyl-1 -hydroxy-1 -(pyridin-4yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (92g).

Step 1. Preparation of (E)-3-cyclopropyl-1-(pyridin-4-yl)prop-2-en-1-one (92b).

To a stirred solution of 1-(pyridin-4-yl)ethanone (92a) (1.516 ml, 13.27 mmol) in methanol (100 ml), cooled to 0°C, was added cyclopropanecarboxaldehyde (1.5 ml, 19.90 mmol ) and water guide

- 192 045731 potassium oxide (1N, 2.65 ml, 2.65 mmol). The reaction mixture was left to warm to room temperature overnight. The reaction mixture was acidified with 1N. hydrochloric acid and concentrated in vacuo to remove methanol. The crude residue was dissolved in ethyl acetate (100 ml), washed with sodium carbonate solution, water (2x50 ml), brine (50 ml), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give pure (E)-3cyclopropyl-1-(pyridin-4-yl)prop-2-ene- 1-one (92b) (479 mg, 20.85%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.89 - 8.59 (m, 2H), 7.91 - 7.71 (m, 2H), 7.19 (d, J=15.1 Hz , 1H), 6.58 (dd, J=15.1, 10.4 Hz, 1H), 1.88 - 1.71 (m, 1H), 1.10 - 0.96 (m, 2H), 0.87 - 0.72 (m, 2H).

Step 2. Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (92c).

To Pd/C (138 mg, 0.130 mmol) in methanol (50 ml) was added (E)-3-cyclopropyl-1-(pyridin-4yl)prop-2-en-1-one (92b) (450 mg, 2 .60 mmol) and hydrogenated at 60 psi (414 kPa) for 1 hour. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-100% ethyl acetate/hexane mixtures) to give 3-cyclopropyl-1-(pyridin-2-yl)propan-1-ol (92c) (323 mg, 70.1%) as an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 - 8.37 (m, 2H), 7.31 (ddd, J=4.5, 1.6, 0.6 Hz, 2H), 5 .36 (d, J=4.7 Hz, 1H), 4.67 - 4.41 (m, 1H), 1.66 (tdd, J=7.7, 5.7, 3.0 Hz, 2H ), 1.28 - 1.16 (m, 2H), 0.73 0.56 (m, 1H), 0.43 - 0.25 (m, 2H), 0.06 - -0.12 (m , 2H).

Step 3. Preparation of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (92d).

NaHCO ₃ (0.427 g, 5.08 mmol) and Dess-Martin periodinane (1.436 g, 3.39 mmol). The reaction mixture was stirred at 0°C for 30 min and warmed to room temperature for 15 min. The reaction mixture was stirred at room temperature for 1 hour and quenched by adding saturated aqueous sodium bicarbonate (25 ml), extracted with dichloromethane (2x50 ml). Combine the organic layers, wash with water (2x25 ml), brine (25 ml), dry, filter and concentrate in vacuo. The crude residue was purified by column chromatography (silica gel, 12 g, eluted with mixtures of 0-30% ethyl acetate in hexanes) to give 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (92d) (290 mg, 98 %) in the form of an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 3.14 (t, J=7.2 Hz, 2H), 1.52 (q, J=7.1 Hz, 2H), 0.75 (dddd, J=12.0, 8.1, 7.0, 2.8 Hz, 1H), 0.47 - 0.28 (m, 2H), 0.14 - 0.02 (m, 2H).

Step 4. Preparation of 1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92e).

To a stirred solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (92d) (250 mg, 1.427 mmol) in tetrahydrofuran (20 ml) was added (3-(bis(trimethylsilyl)amino)phenyl bromide )magnesium (49c) (2.2853 ml, 2.2853 mmol) at 0°C. The reaction mixture was left to warm to room temperature and stirred for 2 hours. The reaction was quenched with ammonium chloride solution (25 ml), extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with water (2x25 ml), brine (25 ml), dry, filter and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0100%) to give 1-(3-aminophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propan-1 -ol (92e) (430 mg, 1.602 mmol, 112% yield). The resulting product was of sufficient purity to be used as such in the next step; MS (IER+) 269.2 (M+1).

Step 5. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (92f).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (178 mg, 0.633 mmol) in DMF (5 ml) was added 1-(3-aminophenyl)-3 -cyclopropyl-1-(pyridin-4-yl)propan-1-ol (92e) (204 mg, 0.760 mmol), N-ethyl-N-isopropylpropan-2-amine (0.883 ml, 5.07 mmol) and hexafluorophosphate bromo-tris-pyrrolidinophosphonium (PyBrOP, 325 mg, 0.697 mmol) at room temperature and stirred at 25°C for 16 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml, 50 ml). The organic layers were combined and dried over anhydrous MgSO ₄ , filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1 -(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy- 1 -(pyridin-4-yl)propyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (92f) (320 mg, 95% yield) as an oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.48 - 8.42 (m, 2H), 8.16 (d, J=2.2 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.94 7.87 (m, 1H), 7.78 - 7.68 (m, 3H), 7.59 (d, J=7 .7 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.31 - 7.15 (m, 2H), 5.76 (s, 1H), 2.31 (t, J= 8.2 Hz, 2H), 1.07 (dq, J=15.1, 7.5 Hz, 2H), 0.62 (q, J=6.8 Hz, 1H), 0.42 - 0, 22 (m, 2H), -0.07 (q, J=4.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.95.

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (92g).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-4yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (92f) (300 mg, 0.564 mmol) in methanol

- 193 045731 (25 ml) Nickel (II) chloride hexahydrate (29.2 mg, 0.123 mmol) was added at 0°C. Sodium tetrahydroborate (133 mg, 3.53 mmol) was added to the resulting mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min, quenched by adding N-(2-aminoethyl)ethane-1,2diamine (0.135 mL, 1.298 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated in vacuo to remove methanol. The residue was loaded onto silica gel and purified twice by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0 to 100%) and (silica gel, 2x4 g, eluted with mixtures of methanol in chloroform, 0 to 30% ) to obtain 1-(3 -(aminomethyl)phenyl)-N-(3 -(3-cyclopropyl-1-hydroxy-1 -(pyridin-4-yl)propyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (92g) (20 mg, 6.62% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d^δ 10.67 (s, 1H, exchange with D2O), 8.52 - 8.41 (m, 2H), 7.70 (s, 1H), 7.54 ( d, J=15.9 Hz, 3H), 7.49 - 7.35 (m, 4H), 7.26 (ddd, J=20.1, 11.6, 7.3 Hz, 3H), 5 .76 (s, 1H, exchange with D ₂ O), 3.77 (s, 2H), 2.31 (t, J=8.3 Hz, 2H), 2.08 (s, 2H, exchange with D ₂ O), 1.06 (dq, J=21.4, 7.4 Hz, 2H), 0.63 (t, J=6.7 Hz, 1H), 0.40 -0.28 (m, 2H), -0.07 (q, J=4.7 Hz, 2H); MS (IER+) 536.2 (M+1), (IER-) 534.2 (M-1); analysis, calculation for C29H28F3N5O5: C: 65.02, H: 5.27, N: 13.08; experiment: C, 64.69; H, 5.40: N, 13.08.

Scheme 93

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (93b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (93a).

In a solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopronyl-1-hydroxysupronyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (89e) (0.2 g, 0.440 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.096 ml, 1.320 mmol) and leave to warm to room temperature for 3 hours. The reaction mixture was treated with morpholine (1.518 ml, 17.60 mmol) and evaporated to dryness. The residue was dissolved in N,N-dimethylformamide (20 ml), morpholine (1.518 ml, 17.60 mmol) was added and heated to reflux temperature for 18 hours. Excess solvent was pumped off under reduced pressure. The residue was diluted with water (30 ml) and extracted with ethyl acetate (2x30 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl) -3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (93a) (200 mg, 87% yield) as a dark yellow waxy solid; MS (IER ⁺ ): MS (IER+) 524.3 (M+1), MS (IER-) 522.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (93b).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-morpholinopropyl)phenyl)-3(trifluoromethyl)-1H-nirazole-5-carboxamide (93a) (0.192 g, 0.367 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.131 g, 0.550 mmol) was added, followed by sodium borohydride (0.166 g, 4.40 mmol) in small portions over 5 min. The reaction mixture was stirred for 34 minutes, TLC analysis (methanol/chloroform, 2/8, v/v) indicated completion of the reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.396 ml) was added , 3.67 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 50%)] to give 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1- morpholinopropyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (93b) (39 mg, 20% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (d, J=10.1 Hz, 1H, exchange with D2O), 7.59 (d, J=7.8 Hz, 2H), 7, 56 - 7.52 (m, 1H), 7.45 (ddt, J=5.7, 4.0, 2.1 Hz, 3H), 7.41 - 7.33 (m, 1H), 7, 29 (t, J=7.8 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 3.79 (s, 2H), 3.52 (t, J=4.7 Hz, 4H), 3.27 (dd, J=8.6, 5.3 Hz, 1H), 2.29 (h, J=7.2, 6.6 Hz, 4H), 2.02 - 1 .88 (m, 1H), 1.70 (dtd, J=13.7, 9.3, 5.2 Hz, 1H), 1.07 (ddt, J=12.7, 9.7, 6, 2 Hz, 1H), 0.99 - 0.81 (m, 1H), 0.69 - 0.54 (m, 1H), 0.42 - 0.24 (m, 2H), -0.09 ( td, J=5.4, 3.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73; MS (IER ⁺ ): MS (IER+) 528.3 (M+1), MS (IER-) 526.1 (M-1), 562.3 (M+Cl); analysis, calculation for C28H32FaN5O2-0.25H2O: C, 63.20; H, 6.16; N, 13.16; experiment: C, 63.23; H, 6.18; N, 12.73.

- 194 045731

Scheme 94

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (94b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (94a) .

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (48d) (1.433 g, 2.98 mmol) in dichloromethane (20 ml) at 0°C was added thionyl chloride (0.651 ml, 8.93 mmol), left to warm to room temperature and stirred for 12 hours. The reaction was quenched with cyclopropylmethylamine (1.275 ml, 14, 88 mmol), the mixture was stirred for 1 hour at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethylamine (5.10 ml, 59.5 mmol), acetonitrile (20 ml) and heated at 100°C for 18 hours. TLC analysis (CHCl ₃ /MeOH, 9/1, v/v) indicated the completion of the reaction, the reaction mixture was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3-yl)methyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (94a) (0.841 g, 53% yield) as an orange-red solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H, exchange with D2O), 8.61 (d, J=2.1 Hz, 1H), 8.40 (dd, J= 4.8, 1.7 Hz, 1H), 8.13 (t, J=1.7 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7, 95- 7.86 (m, 1H), 7.80 - 7.69 (m, 3H), 7.60 (dd, J=7.7, 2.2 Hz, 1H), 7.42 - 7, 19 (m, 3H), 4.92 (s, 1H), 2.69 (s, 1H, exchange with D2O), 2.27 (dd, J=6.7, 2.3 Hz, 2H), 0 .90 (ddt, J=7.7, 5.9, 4.6 Hz, 1H), 0.44 - 0.31 (m, 2H), 0.04 (tt, J=5.7, 2, 9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.99, -122.96; IR (KBr, cm ^-1 ): 2234 cm ^-1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 535.2 (M+1), 557.2 (M+Na), MC (IER-) 533.2 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (94b).

Into a stirred solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-3yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (94a) ( 0.612 g, 1.145 mmol) in anhydrous methanol (30 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.408 g, 1.717 mmol) was added, then sodium borohydride (0.347 g, 9.16 mmol) was added in small portions to for 5 minutes The reaction mixture was stirred for 10 minutes. TLC analysis (methanol/chloroform, 1/9, v/v) indicated complete reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (1.237 mL, 11.45 mmol) was added. Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (50 ml) and the product was extracted with chloroform (2x50 ml). The organic layers were combined, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 50%)] to give 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)( pyridin-3-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (94b) (258 mg, 42% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H, exchange with D2O), 8.60 (d, J=2.2 Hz, 1H), 8.40 (dd, J=4 ,7, 1.7 Hz, 1H), 7.77 (dt, J=7.9, 2.0 Hz, 1H), 7.65 (dd, J=7.5, 2.2 Hz, 1H) , 7.57 (s, 1H), 7.52 (s, 1H), 7.47 - 7.41 (m, 2H), 7.39 - 7.29 (m, 3H), 7.23 (dd , J=10.3, 8.5 Hz, 2H, 1H exchange with D ₂ O), 4.91 (s, 1H), 3.78 (s, 2H), 2.27 (dd, J=6, 5, 2.5 Hz, 2H), 0.97 - 0.84 (m, 1H), 0.44 - 0.32 (m, 2H), 0.08 - 0.01 (m, 2H); 1H NMR (300 MHz, DMSO-d ₆ D2O) δ 8.59 (d, J=2.2 Hz, 1H), 8.40 (dd, J=4.8, 1.6 Hz, 1H), 7 .79 (dt, J=8.1, 2.0 Hz, 1H), 7.65 (dd, J=7.4, 2.2 Hz, 1H), 7.55 (s, 1H), 7. 51 (d, J=2.1 Hz, 1H), 7.45 (dd, J=4.7, 2.5 Hz, 2H), 7.34 (tt, J=4.8, 2.8 Hz , 3H), 7.23 (dd, J=10.3, 8.6 Hz, 1H), 4.92 (s, 1H), 3.76 (s, 2H), 2.26 (dd, J= 6.9, 1.7 Hz, 2H), 1.03 - 0.76 (m, 1H), 0.48 0.30 (m, 2H), 0.07 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.76, -123.40; MS (IER ⁺ ): MS (IER+) 539.2 (M+1), MS (IER-) 537.2 (M-1); analysis, calculation for: C28H ₂₆ F ₄ N ₆ O-0.25H ₂ O: C, 61.93; H, 4.92; N, 15.48; experiment: C, 61.73; H, 5.06; N, 15,16.

- 195 045731

Scheme 95

Example of preparation of 1 -(3 -(aminomethyl)phenyl)-N-(3-cyclopropyl-5 -((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (95i) .

Step 1. Preparation of 3-bromo-N-methoxy-N-methyl-5-nitrobenzamide (95b).

To a solution of 3-bromo-5-nitrobenzoic acid (95a) (5 g, 20.32 mmol) in toluene (40 ml) was added thionyl chloride (14.83 ml, 203 mmol) and heated at reflux temperature for 1 h. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in CH ₂ Cl ₂ (40.0 ml) and N,O-dimethylhydroxylamine hydrochloride (2.97 g, 30.5 mmol) was added, followed by triethylamine (14.16 ml, 102 mmol). The reaction mixture was stirred at room temperature overnight, washed with 1N. HCl (40 ml), 1N. NaOH (40 ml), water (40 ml), brine (40 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 3-bromo-N-methoxyN-methyl-5-nitrobenzamide (95b) (4.5 g, 15, 57 mmol, yield 77%) in the form of a yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.51 (t, J=2.0 Hz, 1H), 8.37 (dd, J=2.1, 1.4 Hz, 1H), 8, 23 (dd, J=1.8, 1.4 Hz, 1H), 3.57 (s, 3H), 3.31 (s, 3H).

Step 2. Preparation of 3-cyclopropyl-N-methoxy-N-methyl-5-nitrobenzamide (95c).

In a 250 ml one-neck flask equipped with a magnetic stirrer insert, 3-6pom-Nmethoxy-N-methyl-5-nitrobenzamide (95b) (2.394 g, 8.28 mmol), cyclopropylboronic acid (1.423 g, 16.56 mmol), potassium phosphate monohydrate (4.77 g, 20.70 mmol), tricyclohexylphosphine (0.697 g, 2.484 mmol) and palladium(II) acetate trimer (0.837 g, 1.242 mmol). The flask was degassed and purged with nitrogen, this cycle was repeated twice, and then the reaction mixture was diluted with toluene (30 ml) and water (10 ml). The reaction mixture was again degassed twice and purged with nitrogen, and then purged with nitrogen for 5 min and started to heat to reflux at 120°C and stirred for 50 h, TLC analysis (ethyl acetate/hexanes, 3/7, v/v .) indicated the end of the interaction. The reaction mixture was cooled to room temperature, quenched with water (50 ml) and extracted with ethyl acetate (3x75 ml). Combine the organic layers, wash with brine (50 ml), dry over anhydrous MgSO ₄ (10 g), filter and remove excess solvent under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel, eluted with mixtures of ethyl acetate in hexanes, 0-50%) to give 3-cyclopropyl-N-methoxy-N-methyl-5-nitrobenzamide (95c) (1.523 g, 73% yield ) in the form of a pale yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 (dd, J=2.2, 1.4 Hz, 1H), 8.03 (t, J=2.0 Hz, 1H), 7, 71 (t, J=1.6 Hz, 1H), 3.56 (s, 3H), 3.29 (s, 3H), 2.20 (tt, J=8.3, 5.0 Hz, 1H ), 1.14 - 1.03 (m, 2H), 0.85 (dt, J=6.9, 4.6 Hz, 2H); MS (IER ⁺ ): MS (IER+) 251.1 (M+1), 273.1 (M+Na).

Step 3. Preparation of 3-amino-5-cyclopropyl-N-methoxy-N-methylbenzamide (95d).

- 196 045731

Nickel chloride hexahydrate was added to a stirred solution of 3-cyclopropyl-M-methoxy-M-methyl-5-nitrobenzamide (95c) (1.2 g, 4.80 mmol) in anhydrous methanol (25 ml), cooled to 0°C. (II) (285 mg, 1.199 mmol), then sodium borohydride (499 mg, 13.19 mmol) in parts over 30 minutes. The reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (1.036 mL, 9.59 mmol), the mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (25 ml), washed with water (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% ethyl acetate/hexanes) to give 3-amino-5-cyclopropyl-N-methoxy-N-methylbenzamide (95d) (0.875 g, 3.97 mmol, 83% yield) as a yellow semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.50 (dd, J=2.2, 1.5 Hz, 1H), 6.38 (t, J=1.6 Hz, 1H), 6, 34 (t, J=1.9 Hz, 1H), 5.15 (s, 2H), 3.54 (s, 3H), 3.18 (s, 3H), 1.78 (tt, J=8 ,4, 5.0 Hz, 1H), 0.95-0.82 (m, 2H), 0.67 - 0.48 (m, 2H); MS (IER+) 221.1 (M+1), 243.1 (M+Na).

Step 4. Preparation of (3-amino-5-cyclopropylphenyl)(phenyl)methanone (95e).

Phenylmagnesium bromide ( 8.94 ml, 8.94 mmol). The reaction mixture was stirred at room temperature for 3 hours, the reaction was quenched with saturated aqueous NH ₄ Cl (25 ml). The reaction mixture was extracted with ethyl acetate (2x25 ml). Combine the organic layers, wash with brine (25 mL), dry, filter and concentrate in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% ethyl acetate/hexanes) to give (3-amino-5cyclopropylphenyl)(phenyl)methanone (95e) (0.15 g, 15. 91%) in the form of a yellow oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.73 - 7.61 (m, 3H), 7.58 -7.51 (m, 2H), 6.70 (dd, J=2.2, 1 ,5 Hz, 1H), 6.58 (t, J=1.6 Hz, 1H), 6.52 (t, J=1.9 Hz, 1H), 5.31 (s, 2H), 1, 84 (tt, J=8.3, 5.0 Hz, 1H), 0.96 - 0.82 (m, 2H), 0.69 - 0.52 (m, 2H); MS (IER+) 238.2 (M+1), 260.1 (M+Na); (IER-) 306.1 (M-1).

Step 5. Preparation of (3-amino-5-cyclopropylphenyl)(phenyl)methanol (95f).

Sodium borohydride (120 mg, 3.16 mmol) for 10 min. The reaction mixture was stirred for 5 min at room temperature and concentrated in vacuo.

The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 9:1 ethyl acetate/methanol in hexanes, 0 to 100%) to give (3-amino-5-cyclopropylphenyl)(phenyl)methanol (95f) ( 0.099 g, 0.414 mmol, yield 65.4%) as a colorless oily liquid; 1H NMR (300 MHz, DMSO^) δ 7.35-7.23 (m, 4H), 7.23 - 7.14 (m, 1H), 6.33 (t, J=1.8 Hz, 1H ), 6.31 (d, J=1.6 Hz, 1H), 6.06 (t, J=1.9 Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 5.44 (d, J=3.9 Hz, 1H), 4.88 (s, 2H), 1.70 (tt, J=8.4, 5.1 Hz, 1H), 0.89 - 0 .77 (m, 2H), 0.58 - 0.39 (m, 2H); MS (IER+) 240.2 (M+1); (IER-) 238.1 (M-1).

Step 6. Preparation of 1-(3-cyanophenyl)-N-(3-cyclopropyl-5-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (95g).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.134 g, 0.476 mmol) in DMF (5 ml) was added (3-amino-5-cyclopropylphenyl) (phenyl)methanol (95f) (0.095 g, 0.397 mmol), N-ethyl-N-isopropylpropan-2-amine (0.346 mL, 1.985 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop, 0.222 g, 0.476 mmol) at room temperature . The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x25 ml). The combined organic layers were washed with brine (25 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 24 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-cyclopropyl-5-(hydroxy(phenyl)methyl )phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (95g) (0.184 g, 0.366 mmol, 92% yield) as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 10.53 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.70 (d , J=2.6 Hz, 1H), 7.41 (t, J=1.8 Hz, 1H), 7.36 - 7.25 (m, 4H), 7.25- 7.15 (m, 2H), 6.92 (t, J=1.5 Hz, 1H), 5.89 (d, J=3.8 Hz, 1H), 5.61 (d, J=3.7 Hz, 1H) , 1.93 - 1.80 (m, 1H), 0.99 - 0.82 (m, 2H), 0.63 -0.51 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.99; MS (IER+) 525.2 (M+Na), (IER-) 501.1 (M-1).

Step 7. Preparation of 1-(3-cyanophenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95h).

In a solution of 1-(3-cyanophenyl)-N-(3-cyclopropyl-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95g) (0.18 g , 0.358 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (0.065 ml, 0.896 mmol) and leave to warm to room temperature for 3 hours. The reaction was quenched with cyclopropylmethanamine (0.078 ml, 0.896 mmol), the mixture was stirred for 2 hours at room temperature and concentrated to dryness in vacuo. The residue was dissolved in acetonitrile (2.5 ml) and cyclopropylmethanamine (0.777 ml, 8.96 mmol) was added. The reaction mixture was heated at temperature

- 197 045731 round of reverse condensation overnight, cooled to room temperature, concentrated to dryness in vacuo. The resulting residue was dissolved in chloroform (25 ml), washed with water (10 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-cyclopronyl-5-((cyclopropylmethylamino)(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95h) (0.122 g, 0.220 mmol, 61.3% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.8, 1 ,3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.45 (t, J=1.7 Hz, 1H), 7.42 7.35 (m, 2H), 7.28 (t, J=7 .5 Hz, 2H), 7.23 - 7.13 (m, 2H), 7.00 - 6.94 (m, 1H), 4.76 (s, 1H), 2.27 (s, 2H) , 1.85 (td, J=8.4, 4.3 Hz, 1H), 0.97 - 0.87 (m, 3H), 0.60 - 0.54 (m, 2H), 0.42 - 0.33 (m, 2H), 0.08 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.98; MS (IER+) 556.2 (M+1); (IER-) 554.3 (M-1).

Step 8. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylαamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 95i).

In a stirred solution of 1-(3-cyanophenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95h) (0 .12 g, 0.216 mmol) in anhydrous methanol (10 ml), cooled to 0°C, was added nickel (II) chloride hexahydrate (0.064 g, 0.270 mmol). Sodium borohydride (0.065 g, 1.728 mmol) was added to the reaction mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min at 0°C and quenched with N1-(2-aminoethyl)ethane1,2-diamine (0.07 ml, 0.648 mmol), stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (25 ml) and water (25 ml). The organic layer was separated, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-cyclopropyl-5-((cyclopropylmethylamino) (phenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (95i) (0.044 g, 0.079 mmol, 36.4% yield) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.57 (s, 1H), 7.55 (s, 1H), 7.51 (d, J=2.2 Hz, 1H), 7.47 7.36 (m, 5H), 7.33 - 7.23 (m, 3H), 7.22 - 7.14 (m, 2H), 6.99 - 6.93 (m, 1H), 4.76 (s , 1H), 3.78 (s, 2H), 2.25 (t, J=8.7 Hz, 4H), 1.85 (tt, J=8.4, 5.0 Hz, 1H), 0 .99 - 0.83 (m, 3H), 0.63 - 0.51 (m, 2H), 0.48 - 0.31 (m, 2H), 0.10 - 0.01 (m, 2H) ; MC (IER-) 558.3 (M-1).

Scheme 96

96f

An example of the preparation of 1-(3-(αminomethyl)phenyl)-N-(2-chloro-5-((cyclopropylmethylamino)-(pyridin-3yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideα (96f).

Step 1. Preparation of (4-chloro-3-nitrophenyl)(pyridin-3-yl)methanol (96b).

To a solution of 3-bromopyridine (2.60 ml, 26.9 mmol) in diethyl ether (20 ml) at -78°C, n-BuLi (14.31 ml, 22.90 mmol) was added dropwise and stirred for 30 min at -78°C. A solution of 4-chloro-3-nitrobenzaldehyde (96a) (5.00 g, 26.9 mmol) in THF (30 mL) was added dropwise to the 3-lithium-containing pyridine at -78°C and stirred at -78°C for 2 hours and at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (50 ml). The organic layer was separated, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0-100% ethyl acetate in hexane)

- 198 045731 by the preparation of (4-chloro-3-nitrophenyl)(pyridin-3-yl)methanol (96b) (1.5 g, 5.67 mmol, 21.03% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.66 - 8.62 (m, 1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H), 8.17 - 8 .11 (m, 1H), 7.79 - 7.70 (m, 3H), 7.36 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 6.47 (d , J=4.1 Hz, 1H), 5.93 (d, J=4.1 Hz, 1H); MS (IER+) 265.1 (M+1), (IER-) 263.1 (M-1).

Step 2. Preparation of (3-amino-4-chlorophenyl)(pyridin-3-yl)methanol (96c).

To a stirred solution of (4-chloro-3-nitrophenyl)(pyridin-3-yl)methanol (96b) (1.5 g, 5.67 mmol) in anhydrous methanol (25 ml), cooled to 0°C, the hexahydrate was added nickel (II) chloride (0.337 g, 1.417 mmol), then sodium borohydride (0.643 g, 17 mmol) in parts for 30 minutes. The reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (1.225 mL, 11.34 mmol), the mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (25 ml), washed with water (25 ml), brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0 to 100% ethyl acetate/hexanes) to give (3-amino-4-chlorophenyl)(pyridin-3-yl)methanol (96c) (0.119 g, 0.507 mmol, 8.95% yield) as an oily liquid, which was of sufficient purity for use in the next step; MS (IER+) 235.1 (M+1).

Step 3. Preparation of N-(2-chloro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (96d) .

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.463 g, 1.648 mmol) in DMF (10 ml) was added (3-amino-4-chlorophenyl) (pyridin-3-yl)methanol (96c) (0.826 g, 3.52 mmol), N-ethyl-N-isopropylpropan-2-amine (3.07 ml, 17.6 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP , 1.969 g, 4.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give N-(2-chloro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)- 1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (96d) (0.328 g, 0.659 mmol, 18.72% yield) as a white solid; 1H NMR (300 MHz, DMSO-d;) δ 10.54 (s, 1H), 8.61 - 8.56 (m, 1H), 8.44 (dd, J=4.7, 1.7 Hz , 1H), 8.12 (s, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.95-7.88 (m, 1H), 7.75 ( d, J=8.0 Hz, 1H), 7.70 (d, J=3.6 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.37 - 7.34 (m, 1H), 7.34 - 7.31 (m, 1H), 6.26 (d, J=4.1 Hz, 1H), 5.81 (d , J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.98; MS (IER+) 498.1 (M+1); (IER-) 496.0 (M-1).

Step 4. Preparation of N-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (96e ).

In a solution of N-(2-chloro-5-(hydroxy(pyridin-3-yl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (96d) (0.328 g, 0.659 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (0.144 ml, 1.976 mmol) and leave to warm to room temperature for 3 hours. The reaction was quenched with cyclopropylmethanamine (0.171 ml, 1.976 mmol), the mixture was stirred for 2 h at room temperature and concentrated to dryness in vacuo. The residue was dissolved in acetonitrile (5 ml) and cyclopropylmethanamine (1.429 ml, 16.47 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature, and concentrated to dryness in vacuo. The resulting residue was dissolved in chloroform (25 ml), washed with water (10 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% ethyl acetate/methanol (9:1) in hexane) to give N-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl) )methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (96e) (0.2 g, 0.363 mmol, 55.1% yield) as a yellow solid ; 1H NMR (300 MHz, DMSO-d,) δ 10.54 (s, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.45-8.37 (m, 1H), 8.11 (d, J=2.1 Hz, 1H), 8.01 (dt, J=7.7, 1.3 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H ), 7.75 (dd, J=15.6, 7.6 Hz, 3H), 7.60 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.41 (dd, J=8.4, 2.0 Hz, 1H), 7.32 (dd, J=7.8, 4.8 Hz, 1H), 4.94 (s, 1H), 2.27 ( d, J=6.3 Hz, 2H), 0.97 - 0.82 (m, 1H), 0.43 - 0.32 (m, 2H), 0.15 - -0.05 (m, 2H ); ¹⁹ F NMR (282 MHz, DMSO) δ -60.98; MS (IER+) 551.2 (M+1); (IER-) 549.2 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-((cyclopropylmethylamino)-(pyridin3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (96f).

Into a stirred solution of N-(2-chloro-5-((cyclopropylmethylamino)(pyridin-3-yl)methyl)phenyl)-1(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (96e ) (0.2 g, 0.363 mmol) in anhydrous methanol (10 ml), cooled to 0°C, was added nickel (II) chloride hexahydrate (0.108 g, 0.454 mmol). Sodium borohydride (0.11 g, 2.9 mmol) was added to the reaction mixture in small portions over 15 minutes. The reaction mixture was stirred for 15 min at 0°C and quenched with N1-(2-aminoethyl)ethane-1,2diamine (0.12 ml, 1.1 mmol), stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (25 ml) and water (25 ml). The organic layer was separated, dried, filtered and concentrated in vacuo. The resulting residue was purified by column

- 199 045731 flash chromatography (silica gel, 12 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(2-chloro-5-((cyclopropylmethylamino)(pyridine -3-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (96f (0.040 g, 0.072 mmol, 19.85% yield) as a white solid; 1H NMR (300 MHz, DMSO ^) δ 10.38 (s, 1H), 8.67 - 8.55 (m, 1H), 8.41 (dd, J=4.8, 1.6 Hz, 1H), 7.77 (dt , J=8.0, 1.9 Hz, 1H), 7.66 - 7.54 (m, 3H), 7.51 - 7.36 (m, 5H), 7.35 - 7.28 (m , 1H), 4.93 (s, 1H), 3.87 (s, 2H), 2.27 (d, J=6.6 Hz, 2H), 0.97 - 0.81 (m, 1H) , 0.42 - 0.31 (m, 2H), 0.11 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (ESI+) 555, 2 (M+1); 553.2 (M-1).

Scheme 97

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-M-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamideα (97f).

Step 1. Preparation of 3-fluoro-K-methoxy-X-methyl-5-nitrobenzamide (97a).

To a suspension of 3-fluoro-5-nitrobenzoic acid (80a) (2.5 g, 13.51 mmol) in toluene (10 ml) was added thionyl chloride (9.86 ml, 135 mmol), three drops of DMF, heated at reverse temperature condensation for 1 hour and evaporated to dryness in vacuum. To the resulting residue was added dichloromethane (10 ml), N,O-dimethylhydroxylamine hydrochloride (1.976 g, 20.26 mmol) and cooled to 0°C. Triethylamine (TEA) (9.41 mL, 67.5 mmol) was added to the solution and stirred at room temperature for 16 hours. Excess solvent was pumped off under reduced pressure. The residue was treated with water (75 ml), extracted with ethyl acetate (100 ml, 75 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with ethyl acetate in hexanes, 0-100%)] to give (97a) (2.039 g, 66% yield) as a light yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.31 - 8.23 (m, 2H), 7.97 (ddd, J=8.6, 2.4, 1.4 Hz, 1H), 3 .58 (s, 3H), 3.31 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ -109.15; MS (IER ⁺ ): MS (IER+) 229.10 (M+1), 251.1 (M+Na).

Step 2. Preparation of 3-amino-5-fluoro-N-methoxy-N-methylbenzamide (97b).

Palladium (10% Pd on carbon support) (0.187 g, 1.753 mmol). The reaction mixture was hydrogenated at 60 psi (414 kPa) for 3 hours. TLC analysis (ethyl acetate/hexanes, 1:1, v/v) indicated completion of the reaction. The reaction mixture was filtered through a small pad of Celite!!!, which was washed successively with methanol (2x25 ml) and ethyl acetate (25 ml). Excess solvents were pumped out under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 80 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%)] to give 3-amino-5fluoro-N-methoxy-N-methylbenzamideα (97b) (1.624 g, yield 93%) in the form of a colorless oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.60 - 6.54 (m, 1H), 6.46 - 6.42 (m, 1H), 6.41 - 6.37 (m, 1H) , 5.63 (s, 2H, exchange with D2O), 3.56 (s, 3H), 3.21 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -113.68; MS (IER+): MS (IER+) 199.1 (M+1), 221.1 (M+Na), MS (IER-) 197.1 (M-1).

Step 3. Preparation of (3-amino-5-fluorophenyl)(phenyl)methanone (97c).

Phenylmagnesium bromide was carefully added dropwise to a solution of 3-amino-5-fluoro-N-methoxy-N-methylbenzamideα (97b) (1.6 g, 8.07 mmol) in THF (30 ml), cooled to 0°C. (16.39 ml, 16.39 mmol) under a positive nitrogen flow. The reaction mixture was warmed to room temperature for 16 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (60 ml), the product was extracted with ethyl acetate (100 ml, 75

- 200 045731 ml). The combined extracts were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 80 g, eluted with 0 to 100% ethyl acetate in hexanes)] to give (3-amino-5-fluorophenyl)(phenyl)methanone (97c) (0.338 g, yield 19%) as a pale yellow solid; 1H NMR (300 MHz, DMSOL6) δ 7.77 - 7.70 (m, 2H), 7.69 7.64 (m, 1H), 7.56 (tt, J=6.7, 1.5 Hz , 2H), 6.74 (t, J=1.7 Hz, 1H), 6.63 - 6.51 (m, 2H), 5.79 (s, 2H, exchange with D ₂ O); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -112.89; MS (IER ⁺ ): MS (IER+) 216.1 (M+1), MS (IER-) 214.1 (M-1).

Step 4. Preparation of N-(3-benzoyl-5-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (97d).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (0.510 g, 1.812 mmol), (3-amino-5-fluorophenyl)(phenyl) methanone (97c) (0.325 g, 1.510 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (0.845 g, 1.812 mmol), N,N-dimethylformamide (9 ml) and N-ethyl-N-isopropylpropane-2 were added sequentially -amine (1.315 ml, 7.55 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Excess DMF was pumped out under reduced pressure. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2x50 ml); the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give N(3-benzoyl-5-fluorophenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)- 1H-pyrazole-5-carboxamide (97d) (0.584 g, 1.221 mmol, 81% yield) as a white solid; 1H NMR (300 MHz, DMSO^) δ 11.04 (s, 1H, exchange with D2O), 8.21 (t, J=1.9 Hz, 1H), 8.02 (dt, J=7.7 , 1.3 Hz, 1H), 7.98 - 7.89 (m, 2H), 7.83 - 7.69 (m, 6H), 7.64 - 7.55 (m, 2H), 7, 31 (ddd, J=8.7,2.5, 1.3 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -61.00, -110.34; MS (IER ⁺ ): MS (IER+) 479.2 (M+1), MS (IER-) 512.8 (M+Cl), 955.2 (2M-1).

Step 5. Preparation of tert-butyl-3-(5-(3-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (97e).

Into a stirred solution of N-(3-benzoyl-5-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (97d) (0.558 g, 1.166 mmol) in anhydrous methanol (20 ml ), cooled to 0°C, di-tert-butyl dicarbonate (0.764 g, 3.50 mmol), nickel (II) chloride hexahydrate (0.069 g, 0.292 mmol) were added, then sodium borohydride (0.265 g, 7.00 mmol) for 5 min. The reaction mixture was stirred for an additional 15 min, TLC analysis (ethyl acetate/hexanes, 3/7, v/v) indicated completion of the reaction, after which K1-(2-aminoethyl)ethane-1,2-diamine (0.252 ml, 2.333 mmol). The mixture was left stirring for 30 minutes and the solvent was evaporated in vacuo. The residue was treated with water (25 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over MgSO4, filtered and the solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 100%)] to give tert-butyl-3-(5-(3-fluoro-5-(hydroxy(phenyl) methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (97e) (0.317 g, 46.5% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.87 (s, 1H, exchange with D2O), 7.60 (s, 1H), 7.56 - 7.44 (m, 2H), 7.43 - 7.27 (m, 9H), 7.27-7.19 (m, 1H), 6.99 (dt, J=9.6, 1.8 Hz, 1H), 6.08 (d, J =3.9 Hz, 1H, exchange with D2O), 5.68 (d, J=3.8 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 1.35 (s , 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.84, -112.19; MS (IER ⁺ ): MS (IER+) 607.2 (M+Na), MS (IER-) 583.2 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-fluoro-5-(hydroxy(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (97f).

Into a solution of tert-butyl-3-(5-(3-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (97e) (301 mg, 0.515 mmol) in 1,4-dioxane (5 ml), hydrogen chloride (4M in 1,4-dioxane, 7.47 ml, 29.9 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture was concentrated to dryness in vacuo and purify the residue by flash column chromatography [(silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0-100%)] to give 1-(3-(aminomethyl)phenyl)-N-(3-fluoro-5-(hydroxy( phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (97f) (0.177 g, 71% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.88 (s, 1H, exchange with D2O), 7.63 (s, 1H), 7.60 (s, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.40 (m, 2H), 7.39 - 7.28 (m, 5H), 7.26 - 7.19 (m, 1H), 6.99 (d , J=9.5 Hz, 1H), 6.09 (s, 1H, exchange with D2O), 5.68 (s, 1H), 3.94 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.80, -112.18; MS (IER ⁺ ): MS (IER+) 485.2 (M+1), 969.3 (2M+1), MS (IER-) 483.1 (M-1), 519.2 (M+Cl ), 967.3 (2M-1).

- 201 045731

Scheme 98

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (98b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (98a ).

In a solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (89e) (0.261 g, 0.574 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.126 ml, 1.723 mmol) and leave to warm to room temperature for 3 hours. Concentrate the reaction mixture in vacuo. The residue was dissolved in N,N-dimethylformamide (20 ml) and pyrrolidine (1.918 ml, 22.97 mmol) was added. The reaction mixture was heated at reflux temperature for 18 hours. TLC analysis indicated completion of the reaction. Excess solvent was pumped out under reduced pressure. The residue was diluted with water (30 ml) and extracted with ethyl acetate (2x30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1yl) )propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (98a) (97 mg, 33% yield) as a white waxy solid. MS (IER ⁺ ): MS (IER+) 508.2 (M+1), MS (IER-) 542.2 (M+Na); ^19F NMR (282 MHz, DMSO- _dg ) δ -60.96.

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (98b).

Into a stirred solution of 1-(3-cyanophenyl)-N(3-(3-cyclopropyl-1-(pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (98a) (0.091 g, 0.179 mmol) in anhydrous methanol (20 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.064 g, 0.269 mmol) was added, then sodium borohydride (0.054 g, 1.434 mmol) was added in small portions over 5 minutes. The reaction mixture was stirred for 10 min, TLC analysis (methanol/chloroform, 1/9, v/v) indicated complete reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.194 ml) was added , 1.793 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with methanol/chloroform, 0 to 50%)] to give 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1- (pyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (98b) (52 mg, 57% yield) as a white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.65 (s, 1H, exchange with D ₂ O), 7.65-7.49 (m, 4H), 7.48 - 7.42 (m, 2H ), 7.34 (dt, J=6.2, 2.5 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz , 1H), 3.79 (s, 2H), 3.07 (dd, J=9.4, 3.9 Hz, 1H), 2.27 (s, 3H), 1.92 (s, 1H) , 1.64 (d, J=6.1 Hz, 6H), 0.97 (d, J=10.5 Hz, 1H), 0.79 (s, 1H), 0.58 (s, 1H) , 0.32 (dd, J=8.2, 1.5 Hz, 2H), 0.08 - -0.18 (m, 2H); 1H NMR (300 MHz, DMSO-dg D ₂ O) δ 7.63 - 7.41 (m, 6H), 7.34 (dt, J=5.3, 2.5 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.03 (dt, J=7.7, 1.3 Hz, 1H), 3.77 (s, 2H), 3.07 (dd, J= 9.7, 4.0 Hz, 1H), 2.28 (d, J=7.7 Hz, 2H), 1.94 (t, J=12.0 Hz, 1H), 1.64 (q, J=6.4, 5.4 Hz, 5H), 0.98 (dt, J=16.5, 6.8 Hz, 1H), 0.77 (s, 1H), 0.58 (p, J =5.9 Hz, 1H), 0.43 - 0.24 (m, 2H), -0.05- -0.22 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.73 (d, J=4.5 Hz); MS (IER ⁺ ): MS (IER+) 512.3 (M+1), MS (IER-) 510.2 (M-1); analysis, calculation for: C28H ₃₂ F ₃ N ₅ O-0.25H ₂ O: C, 65.16; H, 6.35; N, 13.57; experiment: C, 64.92; H, 6.24; N, 13.21.

- 202 045731

Scheme 99

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3 -(2-(cyclopropylamino)-1 -hydroxy-1-phenylethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 99g).

Step 1. Preparation of 2-(cyclopropylamino)-1-phenylethanone (99b).

To a stirred solution of 2-bromo-1-phenylethanone (99a) (4 g, 20.10 mmol) in acetonitrile (50 ml) was added cyclopropylamine (2.83 ml, 40.2 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The crude reaction mixture was used as such in the next step.

Step 2. Preparation of tert-butyl-cyclopropyl(2-oxo-2-phenylethyl)carbamate (99c).

To a solution of 2-(cyclopropylamino)-1-phenylethanone (99b) (3.50 g, 20 mmol) in acetonitrile obtained in step 1, triethylamine (11.15 ml, 80 mmol) and (Boc) were added at 0°C. ₂ O (4.64 ml, 20.00 mmol). The reaction mixture was stirred for 2 hours at room temperature and diluted with water (100 ml). The reaction mixture was extracted with dichloromethane (2x150 ml). The combined organic layers were washed with water (2x50 ml), brine (50 ml), dried and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0 to 50 to 100% ethyl acetate in hexanes) to give tert-butyl-cyclopropyl(2-oxo-2phenylethyl)carbamate (99c) (5.5 g, 100%) as a white semi-solid; MS (ESI+) 298.2 (M+Na).

Step 3. Preparation of tert-butyl-2-(3-aminophenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate (99d).

Bromide (3-(bis) (trimethylsilyl)amino)phenyl)magnesium (49c) (4.0 ml, 4.0 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and quenched by adding ammonium chloride solution (50 ml). The reaction mixture was stirred for 1 hour and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with water (2x50 ml), brine (50 ml), dried and filtered, concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 40% to 100%) to give tert-butyl-2-(3-aminophenyl)-2-hydroxy-2-phenylethyl (cyclopropyl)carbamate (99d) (460 mg, 34.4%) as a white semi-solid; MS (ESI+) 391.2 (M+Na), (759.4) (2M+Na).

Step 4. Preparation of tert-butyl-2-(3-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate (99e).

In a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.268 g, 0.954 mmol) in N,N-dimethylformamide (5.76 ml, 74.4 mmol ) added tert-butyl-2-(3-aminophenyl)-2hydroxy-2-phenylethyl(cyclopropyl)carbamate (99d) (0.422 g, 1.145 mmol), N-ethyl-N-isopropylpropan2-amine (1.334 ml, 7.64 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.489 g, 1.05 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (50 ml). The isolated solid was collected by filtration, dried in vacuo and purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give tert-butyl-2-(3-(1-( 3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopro

- 203 045731 pyl)carbamate (99e) (507 mg, 0.803 mmol, 84% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.14 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1 ,3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (d, J=3.0 Hz, 2H), 7.62 (dd, J=7.7, 1.9 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7 .33 - 7.25 (m, 3H), 7.24 - 7.18 (m, 2H), 5.76 (s, 1H), 4.13 - 4.00 (m, 2H), 2.27 (s, 1H), 1.21 (s, 9H), 0.50 (d, J=7.2 Hz, 2H), 0.44 (d, J=4.1 Hz, 2H); MS (IER+) 632.3 (M+1), (IER-) 630.2 (M-1).

Step 5. Preparation of tert-butyl-2-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl) carbamate (99f).

Into a stirred solution of tert-butyl 2-(3-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamido)phenyl)-2-hydroxy-2-phenylethyl(cyclopropyl)carbamate (99e) (460 mg, 0.728 mmol) in methanol (50 ml), cooled to 0°C, nickel (II) chloride hexahydrate (43.3 mg, 0.182 mmol) was added, then sodium borohydride (220 mg, 5.83 mmol) was added in small portions ) for 15 minutes. The reaction mixture was stirred at 0°C for an additional 15 min, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.787 mL, 7.28 mmol) and stirred for 30 min. The reaction mixture was concentrated to dryness in vacuo and diluted with ethyl acetate (50 ml). The ethyl acetate layer was washed with water (50 ml), brine (20 ml), dried and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform) to give tert-butyl-2-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-III- pyrazole-5-carboxamido)phenyl)-2-hydroxy2-phenylethyl(cyclopropyl)carbamate (99f) (0.1 g, 21%) as a white foam; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.69 (s, 1H), 7.68 (s, 1H), 7.62 - 7.57 (m, 1H), 7.54 (s, 1H ), 7.51 (s, 1H), 7.46 - 7.39 (m, 4H), 7.34 - 7.23 (m, 4H), 7.23 - 7.17 (m, 2H), 5.74 (s, 1H), 4.04 (q, J=14.1 Hz, 2H), 2.26 - 2.04 (m, 1H), 1.21 (s, 9H), 0.47 (m, 4H); MS (IER+) 636.3 (M+1); (IER-) 634.2 (M-1).

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(2-(cyclopropylamino)-1-hydroxy-1-phenylethyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 -carboxamide (99g).

Into a stirred solution of tert-butyl-2-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamido)phenyl)-2-hydroxy-2-phenylethyl-(cyclopropyl) carbamate (99f) (125 mg, 0.197 mmol) in 1,4-dioxane (5 ml), add hydrochloric acid (4N in 1,4-dioxane, 2.655 ml, 10.62 mmol) at room temperature and stir overnight at room temperature. Concentrate the reaction mixture and purify by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-25%) to give compound (99g), which is purified again by flash column chromatography (silica gel, 2x4 g, eluted mixtures of CMA 80 in chloroform, 0-100%) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(2-(cyclopropylamino)-1-hydroxy-1phenylethyl)phenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (99g) (80 mg, 70.3%) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H, exchange with D2O), 7.68 (t, J=2.0 Hz, 1H), 7.53 (dd, J=11 .7, 3.1 Hz, 3H), 7.45-7.38 (m, 4H), 7.34 - 7.21 (m, 4H), 7.17 (q, J=7.2, 5 .8 Hz, 2H), 5.50 (s, 1H, exchange with D2O), 3.77 (s, 2H), 3.31 (s, 2H), 2.04 (tt, J=6.7, 3.6 Hz, 1H), 0.31 (td, J=6.3, 3.8 Hz, 2H), 0.18 (p, J=3.8 Hz, 2H); MS (IER+) 536.2 (M+1); analysis, calculation for C ₂₉ H ₂₈ F ₃ N ₅ O ₂ : C, 65.02; H, 5.27; N, 13.08; experiment: C, 64.85; H, 5.37; N, 12.74.

Scheme 100

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (100e).

- 204 045731

Step 1. Preparation of (4-fluoro-3-nitrophenyl)(pyridin-2-yl)methanol (100a).

Pyridin-2-ylmagnesium bromide (2.264 g, 12.42 mmol), stirred at 0°C for 3 h and at room temperature for 14 h, TLC analysis (ethyl acetate/hexanes, 1/1, v/v) indicated completion of the reaction. The reaction was quenched with saturated aqueous NH ₄ Cl (60 ml), extracted with a mixture of EtOAc (2x75 ml). The combined extracts were washed with brine (50 ml), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 50% ethyl acetate/hexanes)] to give (4-fluoro-3-nitrophenyl)(pyridin-2-yl)methanol (100a) ( 0.366 g, 12% yield as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 8.49 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.18 (ddd, J=7.4, 2.3, 0.7 Hz, 1H), 7.87 - 7.77 (m, 2H), 7.66 - 7.48 (m, 2H), 7.27 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 6.50 (d, J=4.5 Hz, 1H), 5.85 (d, J=4.5 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -121.56; MS (IER ⁺ ): MS (IER+) 271.0 (M+Na), MS (IER-) 247.1 (M-1), 495.1 (2M-1).

Step 2. Preparation of (3-amino-4-fluorophenyl)(pyridin-2-yl)methanol (100b).

Nickel chloride hexahydrate was added to a stirred solution of (4-fluoro-3-nitrophenyl)(pyridin-2-yl)methanol (100a) (1.345 g, 5.42 mmol) in anhydrous methanol (30 mL), cooled to 0°C. (II) (0.322 g, 1.355 mmol), then sodium borohydride (0.615 g, 16.26 mmol) in small portions over 5 min. The reaction mixture was stirred for 20 min at 0°C. TLC analysis (methanol/chloroform, 2/8, v/v) indicated the reaction was complete, after which N1-(2-α-aminoethyl)ethane-1,2diamine (5.85 mL, 54.2 mmol) was added. The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (50 ml) and extracted with ethyl acetate (2x50 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give (3-amino-4-fluorophenyl)(pyridin2-yl)methanol (100b) (1.008 g , yield 85%) in the form of a yellow oily liquid; ¹ H NMR (300 MHz, DMSO-d6) δ 8.43 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 7.76 (td, J=7.7, 1, 8 Hz, 1H), 7.50 (dt, J=8.0, 1.1 Hz, 1H), 7.22 (ddd, J=7.5, 4.8, 1.2 Hz, 1H), 6.97 - 6.71 (m, 2H), 6.53 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.95 (d, J=4.0 Hz, 1H), 5.53 (d, J=4.0 Hz, 1H), 5.07 (s, 2H, exchange with D2O); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.67; MS (IER ⁺ ): MS (IER+) 241.1 (M+Na), MS (IER+) 217.1 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-2-yl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (100c ).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1.489 g, 5.3 mmol), (3-amino-4-fluorophenyl)( pyridin-2-yl)methanol (100b) (0.963 g, 4.41 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (2.469 g, 5.30 mmol), N,N-dimethylformamide (DMF, 27) was added sequentially ml) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (3.84 ml, 22.06 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (30 ml) and extracted with chloroform (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(2fluoro-5-(hydroxy(pyridin-2-yl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100c) (1.114 g, 52% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H, exchange with D2O), 8.45 (ddd, J=4.8, 1.9, 0.9 Hz, 1H), 8 .19 - 8.08 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.83 - 7 .68 (m, 3H), 7.55 (d, J=7.7 Hz, 2H), 7.35-7.17 (m, 3H), 6.22 (d, J=4.2 Hz, 1H, exchange with D2O), 5.69 (d, J=4.2 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.98, -123.06; IR (KBr, ^cm'1 ): 2236 ^cm'1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 482.1 (M+1), MS (IER-) 480.25 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100d ).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-2-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (100c) (0.814 g, 1.691 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.370 ml, 5.07 mmol), warm to room temperature and stir for 12 hours. The reaction is quenched with cyclopropylmethanamine (0.724 ml), stir the mixture for 1 h at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanamine (2.90 ml, 33.8 mmol) and acetonitrile (20 ml) and the reaction mixture was heated at 100°C for 16 hours. TLC analysis (CHCl ₃ /MeOH, 9/1, v/v .) indicated the completion of the reaction, the reaction mixture was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% methanol in chloroform, 0-100%) to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(pyridin- 2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100d) (696 mg, 77% yield) as a yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.54 (s, 1H, exchange with D2O), 8.55-8.41 (m, 1H), 8.18 - 8.08 (m, 1H) , 8.00 (dt, J=7.7, 1.4 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.80

- 205 045731

7.69 (m, 3H), 7.57 (dd, J=7.5, 2.2 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.32 (ddd , J=8.5, 4.9, 2.1 Hz, 1H), 7.27 - 7.14 (m, 2H), 4.93 (s, 1H), 3.01 - 2.68 (m , 1H, exchange with D ₂ O), 2.29 (qd, J=12.1, 6.6 Hz, 2H), 1.03 - 0.76 (m, 1H), 0.48 - 0.30 (m, 2H), 0.03 (dt, J=7.6, 4.4 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98, -123.05; IR (KBr, cm 1): 2235 cm ^-1 (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 535.2 (M+1), MS (IER-) 533.2 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100e).

Into a stirred solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)-(pyridin-2yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100d) (0.651 g, 1.218 mmol) in anhydrous methanol (30 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.434 g, 1.827 mmol) was added, then sodium borohydride (0.369 g, 9.74 mmol) was added in small portions. within 5 min. The reaction mixture was stirred for 10 min, TLC analysis (methanol/chloroform, 1/9, v/v) indicated complete reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (1.316 ml) was added , 12.18 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 50%)] to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino )(pyridin-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100e) (267 mg, 41% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H, exchange with D2O), 8.47 (dt, J=4.6, 1.5 Hz, 1H), 7.74 (td , J=7.7, 1.8 Hz, 1H), 7.60 (d, J=9.2 Hz, 2H), 7.54 (s, 1H), 7.49 - 7.40 (m, 3H), 7.39 - 7.26 (m, 2H), 7.26 - 7.16 (m, 2H), 4.91 (s, 1H), 3.82 (s, 2H), 2.39 - 2.19 (m, 2H), 0.99 - 0.79 (m, 1H), 0.51 - 0.22 (m, 2H), 0.04 (dd, J=5.4, 3, 5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.76, -123.48; MS (IER ⁺ ): MS (IER+) 539.2 (M+1), MS (IER-) 573.2 (M+Cl), 537.2 (M-1); analysis, calculation for:

_{C28H26F4N6O - 0.75H2O} : C _{, 60.92} ; H, 5.02; N, 15.22; experiment: C, 60.84; H, 4.99; N, 14.93. Into a solution of the free base 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-ul)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (100e) (0.228 g, 0.423 mmol) in IPA (10 ml) was added conc. HCl (0.176 ml, 2.117 mmol) and concentrated to dryness in vacuo. The residue was dried in vacuo to remove excess HCl and dissolved in IPA (2 ml) with heating to accelerate dissolution. Diethyl ether (40 ml) was added to the homogeneous solution and heated at the reverse condensation temperature for 30 min. After cooling to room temperature, the resulting solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(pyridin-2-yl) hydrochloride salt methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (0.23 g, 84% yield) as a white solid; Ή NMR (300 MHz, deuterium oxide) δ 8.65 (d, J=4.9 Hz, 1H), 7.84 (t, J=7.4 Hz, 1H), 7.77 (d, J= 6.4 Hz, 1H), 7.67 - 7.56 (m, 4H), 7.50 - 7.29 (m, 5H), 5.71 (s, 1H), 4.27 (s, 2H ), 2.93 (d, J=7.4 Hz, 2H), 1.15 - 1.02 (m, 1H), 0.73 - 0.56 (m, 2H), 0.37 - 0, 17 (m, 2H); ¹⁹ F NMR (282 MHz, D2O) δ -62.36, -121.61; MS (IER+)

539.3 (M+1); (IER-) 537.2 (M-1); analysis, calculation for C ₂₈ H ₂₆ F ₄ N ₆ O-2.4HCl-2H ₂ O: C, 50.79; H, 4.93; Cl, 12.85; N, 12.69; experiment: C, 50.79; H, 5.05; Cl, 12.82; N, 12.33.

Scheme 101

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)- 206 045731

2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (101e).

Step 1. Preparation of (4-fluoro-3-nitrophenyl)(thiazol-2-yl)methanol (101a).

To a solution of 2-bromothiazole (4.8 ml, 52.2 mmol) in diethyl ether (36 ml) at -78°C, n-BuLi (33.0 ml, 52.9 mmol) was added dropwise and stirred for 30 min at -78°C. A solution of 4-fluoro-3-nitrobenzaldehyde (48a) (8.83 g, 52.2 mmol) in THF (54 ml) was added dropwise to the 2-lithium thiazole anion at -78°C and stirred at -78°C for 2 h and at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride (80 ml). The organic layer was separated, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give (4-fluoro-3-nitrophenyl)(thiazol-2-yl)methanol (101a) (3.5 g, 26%) as a brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 -8.19 (m, 1H), 7.89 (dddd, J=8.7, 4.4, 2.3, 0.6 Hz, 1H), 7.75 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.59 (dd, J=11.3, 8.6 Hz, 1H), 7.22 (d, J=4.9 Hz, 1H), 6.14 (dd, J=4.8, 0.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -120.63; MS (IER+) 277.0 (M+Na), (IER-) 253.0 (M-1).

Step 2. Preparation of (3-amino-4-fluorophenyl)(thiazol-2-yl)methanol (101b).

To a stirred solution of (4-fluoro-3-nitrophenyl)(thiazol-2-yl)methanol (101a) (2.8 g, 11.01 mmol) in anhydrous methanol (150 ml), cooled to 0°C, the hexahydrate was added nickel (II) chloride (3.27 g, 13.77 mmol), then sodium borohydride (1.25 g, 33 mmol) in parts over 30 minutes. The reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (3.57 mL, 33 mmol), the mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, washed with brine (25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0 to 100% ethyl acetate/hexanes) to give (3-amino-4-fluorophenyl)(thiazol-2-yl)methanol (101b) (1.234 g, 5.50 mmol, 50.0% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.68 (d, J=3.2 Hz, 1H), 7.61 (d, J=3.2 Hz, 1H), 6.91 (dd, J=11.5, 8.3 Hz, 1H), 6.83 (dd, J=8.9, 2.2 Hz, 1H), 6.63 (d, J=4.1 Hz, 1H), 6.60 - 6.52 (m, 1H), 5.77 (d, J=4.1 Hz, 1H), 5.14 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -136.87; MS (ESI+) 247.1 (M+Na); (IER-) 223.0 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide ( 101c).

(3-Amino- 4-fluorophenyl)(thiazol-2-yl)methanol (101b) (1.234 g, 5.50 mmol), N-ethyl-N-isopropylpropan-2-amine (4.79 ml, 27.5 mmol) and bromine hexafluorophosphate -trispyrrolidinophosphonium (PyBrOP, 3.08 g, 6.60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours, quenched with water (100 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with water (2x50 ml), brine (50 ml), dry, filter and evaporate to dryness. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(thiazol-2 -yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (101c) (1.01 g, 2.072 mmol, 37.7% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.13 (s, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.76 - 7.69 (m, 3H), 7.66 - 7.58 (m, 2H), 7.39 - 7.21 (m, 2H ), 6.92 (d, J=4.4 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H); MS (IER+) 488.1 (M+1); 510.1 (M+Na).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (101d ).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(thiazol-2-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (101c) (0 .75 g, 1.539 mmol) in dichloromethane (25 ml) at 0°C, add thionyl chloride (0.337 ml, 4.62 mmol) and stir at room temperature for 2 hours. The reaction was quenched with cyclopropylmethanamine (0.4 ml, 4.62 mmol) and stirred the mixture at room temperature for another 5 hours. Concentrated the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (2.67 ml, 30.8 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl) methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (101d) (0.22 g, 0.407 mmol, 26.5% yield) as a light yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.00 (dt, J=7.8, 1 .3 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.77 -7.70 (m, 2H), 7.66 (d, J=3.2 Hz, 1H), 7 .61 (d, J=3.3 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.41 - 7.30 (m, 1H), 7.26 (dd, J=10 ,3, 8.5 Hz, 1H), 5.19 (s, 1H), 2.98 (s, 1H), 2.37 (d, J=6.0 Hz, 3H), 0.98 - 0 .82 (m, 1H), 0.43 - 0.34 (m, 2H), 0.11 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.98, - 207 045731

122.16; MS (IER+) 541.2 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (101e).

In a solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2-yl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (101d) ( 0.2 g, 0.370 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.110 g, 0.463 mmol) was added, then sodium borohydride (0.07 g, 1 .85 mmol) for 15 min. The reaction mixture was stirred at room temperature for 1 hour and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.120 mL, 1.110 mmol), then stirred for an additional 0.5 hour. Concentrate the reaction mixture to dryness in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give 1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(thiazol-2 -yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (101e) (0.07 g, 0.129 mmol, 34.7% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.63 - 7.48 (m, 4H), 7.45 (s, 1H), 7.42 - 7.23 ( m, 5H), 7.25-7.12 (m, 1H), 5.11 (s, 1H), 3.73 (s, 2H), 2.94 (s, 2H), 2.29 (dd , J=6.7, 2.3 Hz, 2H), 0.93 - 0.77 (m, 1H), 0.37 - 0.27 (m, 2H), 0.04 - -0.05 ( m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.75, -122.60; MS (IER+) 545.3 (M+1); (IER-) 543.2 (M-1); analysis, calculation for C ₂₆ H ₂₄ F ₄ N ₆ OS-0.25H ₂ O: C, 56.87; H, 4.50; N, 15.31; S, 5.84; experiment: C, 57.04; H, 4.74; N, 14.65; S, 4.86.

Scheme 102

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (102b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (102a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (53c) (0.6 g, 1.182 mmol ) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.250 ml, 3.38 mmol) and stir at room temperature for 2 hours. The reaction is quenched with triethylamine (1.450 ml, 10.41 mmol), stir the mixture at room temperature over 1 hour, cyclopropylmethanamine (1.751 g, 23.89 mmol) was added and stirred at room temperature for an additional 5 hours. The reaction mixture was concentrated in vacuo to remove dichloromethane. Acetonitrile (10 ml) and cyclopropylmethanamine (1.751 g, 23.89 mmol) were added to the reaction mixture. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (120 ml), washed with water (60 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with hexanes/ethyl acetate, 1:0 to 2:1) to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3 -nitrophenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (102a) (132 mg, 20%) as a yellow viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.31 (t, J=2.0 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.07 (ddd, J=8.2, 2.4, 1.0 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.88-7.83 (m, 1H), 7.78 - 7.66 (m, 3H), 7.60 (t, J=8.0 Hz, 2H), 7.33 - 7.20 (m, 2H), 5.02 (s, 1H), 2.36 - 2.22 (m, 2H), 1, 01 - 0.87 (m, 1H), 0.450.32 (m, 2H), 0.09-0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.97; MS (IER+) 561.3 (M+1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (102b ).

Into a solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-nitrophenyl)methyl)phenyl)-3-(tri

- 208 045731 fluoromethyl)-1H-pyrazole-5-carboxamide (102a) (123 mg, 0.219 mmol) in MeOH (5 ml), cooled in ice/water, added nickel (II) chloride (66.0 mg, 0.278 mmol), then sodium borohydride (51.0 mg, 1.321 mmol) was added portionwise over 5 min and stirred at room temperature for 1 h. The reaction mixture was treated with N1-(2-aminoethyl)ethane-1,2-diamine ( 0.08 ml, 0.733 mmol), stirred at room temperature for 0.5 h and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (100 ml), washed with water (60 ml). The aqueous phase was again extracted with ethyl acetate (60 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give 1-(3(aminomethyl)phenyl)-N-(3-((3-aminophenyl)( cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (102b) (47 mg, 40%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.49 - 7.09 (m, 7H) , 6.86 (t, J=7.7 Hz, 1H), 6.57 - 6.52 (m, 1H), 6.49 (d, J=7.8 Hz, 1H), 6.32 ( dd, J=7.9, 2.2 Hz, 1H), 4.95 (s, 2H), 4.57 (s, 1H), 3.73 (s, 2H), 2.23 (d, J =6.7 Hz, 2H), 2.06 (broads, 2H), 0.95-0.77 (m, 1H), 0.40-0.25 (m, 2H), 0.04- -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.71; MS (IER+): 535.29 (M+1).

Scheme 103

NiCI ₂ 6H ₂ O NaBH ₄

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-nirrol-3-yl)nropyl)phenyl)-3 -(trifluoromethyl)-1 I-pyrazol- 5-carboxamide (103b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (103a).

In a solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxypropyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (89e) (0.602 g, 1.325 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.290 ml, 3.97 mmol) and stir at room temperature for 3 hours. Evaporate the reaction mixture to dryness and dissolve the residue in N,N-dimethylformamide (20 ml). N-pyrrole (3.68 mL, 53.0 mmol) was added to the solution and heated to reflux temperature for 18 hours. Additional N-pyrrole (3.68 mL, 53.0 mmol) was added and the reaction mixture was heated at temperature of reverse condensation for 54 hours. Excess solvent was pumped out under reduced pressure. The residue was diluted with water (50 ml) and extracted with chloroform (2x50 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrole -3-yl)propyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (103a) (0.063 g, 0.125 mmol, 9.45% yield) as a white waxy solid; MS (IER+) 504.34 (M+1), MS (IER-) 526.30 (M+Na), MS (IER-) 502.03 (M-1); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.94.

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(1H-pyrrol-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (103b).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(1H-nirrol-3-yl)nropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (103a) (55 mg, 0.109 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel(II) chloride hexahydrate (0.039 g, 0.164 mmol) was added followed by sodium borohydride (0.033 g, 0.874 mmol) in small portions ) for 5 min. The reaction mixture was stirred for 10 min, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.118 mL, 1.092 mmol), stirred for 30 min and concentrated to dryness in vacuo. The reaction mixture was treated with saturated aqueous NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml). The combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The residue was purified by

- 209 045731 flash column chromatography (silica gel, 25 g, eluted with methanol/chloroform mixtures, from 0 to 100%) to give 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1- (1H-pyrrol-3-yl)propyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (103b) (21 mg, 38% yield) as an off-white solid.

Ή NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H, exchange with D2O), 10.53 - 10.42 (m, 1H, exchange with D2O), 7.56 (s, 1H), 7.54 - 7.51 (m, 1H), 7.49 - 7.41 (m, 4H), 7.32 (dt, J=6.2, 2.6 Hz, 1H), 7.20 ( t, J=8.1 Hz, 1H), 7.00 (dt, J=7.8, 1.3 Hz, 1H), 6.61 (q, J=2.4 Hz, 1H), 6, 51 (q, J=2.0 Hz, 1H), 5.86 (q, J=2.3 Hz, 1H), 3.78 (s, 2H), 3.72 (t, J=7.7 Hz, 1H), 2.09 - 1.80 (m, 2H), 1.08 (tdd, J=16.9, 13.8, 7.2 Hz, 2H), 0.65 (ddt, J= 10.1, 7.2, 3.7 Hz, 1H), 0.45-0.25 (m, 2H), -0.02 - -0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.71; MS (IER+) 508.3 (M+1), MS (IER-) 506.0 (M-1).

Scheme 104

An example of the preparation of 1-(3 -(aminomethyl)phenyl)-N-(3 -((cyclopropylmethylamino)( 1 -methyl-1 H-pyrazol4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (104f).

Step 1. Preparation of (3-aminophenyl)(1-methyl-1H-pyrazol-4-yl)methanol (104b).

(3-(bis( trimethylsilyl)amino)phenyl)magnesium (49c) (49.0 ml, 49.0 mmol) and stirred at 0°C for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (120 ml) and the mixture was extracted with ethyl acetate (2x120 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO ₄ then filtered and concentrated. The residue was dissolved in diethyl ether (200 ml), treated with 4N. HCl in 1,4-dioxane (24 ml) and stirred at room temperature for 2 hours. The resulting solid was collected by filtration, washed with diethyl ether, dried in vacuo to give (3-aminophenyl)(1methyl-1H-pyrazole-4 -yl)methanol (104b) (6.01 g, 68%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.47 (s, 1H), 7.46 - 7.20 (m, 5H), 5.69 (s, 1H), 3.76 (s, 3H ); MS (IER+) 204.1 (M+1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide (104c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (4.15 g, 14.76 mmol) in DMF (80 ml) was added (3-aminophenyl) (1-methyl-1H-pyrazol-4-yl)methanol (104b) (2.99 g, 14.76 mmol), N-ethyl-N-isopropan-2-amine (21.00 ml, 121 mmol), Bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBrOP, 7.02 g, 14.76 mmol) and stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (300 ml), washed with water (2x120 ml), brine (120 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 120 g, eluted with hexanes/ethyl acetate (1:0 to 0:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(1- methyl-1Hpyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (104c) (2.9 g, 42%) as a light brown viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.17 (t, J=1.8 Hz, 1H),

- 210 045731

8.01 (dt, J=7.8, 1.3 Hz, 1H), 7.95 (s, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.73 (t, J=0.9 Hz, 1H), 7.63 (t, J=1.9 Hz, 1H), 7.59 - 7.54 (m, 1H), 7, 41 (s, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.21 (d, J=0.8 Hz, 1H), 7.16-7.10 (m, 1H ), 5.67(d, J=4.3 Hz, 1H), 5.61 (d, J=4.4 Hz, 1H), 3.75 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.97; MS (IER+) 467.2 (M+1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4yl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazol-5- carboxamide (104d).

Into a solution of 1 -(3 -cyanophenyl)-N-(3 -(hydroxy( 1 -methyl-1 H-pyrazol-4-yl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazol-5-carboxamide ( 104c) (2.836 g, 6.08 mmol) in dichloromethane (100 ml) at 0°C was added thionyl chloride (1.100 ml, 14.84 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with triethylamine (7.00 ml, 50.2 mmol) and stirred at room temperature for 1 hour, then treated with cyclopropylmethanamine (8.00 g, 109 mmol) and concentrated to remove most of the dichloromethane, after which acetonitrile (75 ml) was added. The reaction mixture was stirred at 70°C for 20 hours and concentrated to dryness. The residue was treated with chloroform (240 ml), washed with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 40 g, eluted with chloroform/methanol (1:0 to 9:1)] to give 1-(3-cyanophenyl)-N-(3((cyclopropylmethylamino)(1 -methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (104d) (1.518 g, 48%) as a brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.8, 1 ,3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 7.69 (m, 2H), 7.63 (s, 1H ), 7.58 - 7.52 (m, 1H), 7.46 (s, 1H), 7.32 - 7.22 (m, 2H), 7.16 (d, J=7.8 Hz, 1H), 4.74 (s, 1H), 3.74 (s, 3H), 2.35-2.15 (m, 2H), 0.96-0.78 (d, J=9.7 Hz , 1H), 0.43-0.27 (m, 2H), 0.09 - -0.020-0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.96; MS (IER+) 520.3 (M+1).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(1-methyl-1H-pyrazol-4yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzylcarbamate (104e).

Into a solution of 1 -(3 -cyanophenyl)-N-(3-((cyclopropylmethylamino)(1 -methyl-1 H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (104d) (1.453 g, 2.8 mmol) in MeOH (40 ml), cooled in ice/water, di-tert-butyl dicarbonate (1.850 g, 8.39 mmol), nickel(II) chloride hexahydrate (0.360) was added g, 1.513 mmol), then sodium borohydride (1.083 g, 28.1 mmol) was added slowly over 5 min and stirred at room temperature for 1 h. The reaction was quenched with N1(2-aminoethyl)ethane-1,2-diamine ( 1.400 ml, 12.83 mmol), stirred the mixture at room temperature for 0.5 h and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (200 ml) and washed with water (100 ml). The aqueous phase was again extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(3((cyclopropylmethylamino)(1-methyl-1 H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (104e) (709 mg, 41%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.69 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.56 - 7.22 (m, 9H ), 7.16 (d, J=7.7 Hz, 1H), 4.73 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.74 (s, 3H ), 2.27 (t, J=6.4 Hz, 2H), 1.37 (s, 9H), 0.96-0.79 (m, 1H), 0.48 - 0.27 (m, 2H), 0.09 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.80; MS (IER+) 624.4 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(1-methyl-1Hpyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (104f).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(1 -methyl-1 H-pyrazol-4-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )benzylcarbamate (104e) (0.614 g, 0.984 mmol) in 1,4dioxane (60 ml), add hydrogen chloride (10.0 ml, 40.0 mmol, 4M in 1,4-dioxane), stir at room temperature for 15, 5 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give 1 -(3 -(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino )(1-methyl-1H-pyrazol-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (104f) (363 mg, 70%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 7.61 (t, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.57 - 7.45 (m, 2H), 7.48 - 7.39 (m, 3H), 7.37 - 7.30 (m, 1H), 7.29 - 7.22 (m, 2H), 7, 19 - 7.12 (m, 1H), 4.72 (s, 1H), 3.79 (s, 2H), 3.74 (s, 3H), 2.36 - 2.18 (m, 3H) , 0.97 - 0.79 (m, 1H), 0.43 - 0.30 (m, 2H), 0.10 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.72; MS (IER+) 525.3 (M+1); (IER-) 522.323 (M-1); ICS (KBr tablet, ^cm'1 ): 3429, 2925, 1616, 1559, 1243; analysis, calculation for C27H ₂₈ F ₃ N ₇ O-0.25CHCl ₃ : C, 59.14; H, 5.15; N, 17.72; experiment: C, 59.07; H, 5.24; N, 17.57.

- 211 045731

Scheme 105

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-M-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105g ).

Step 1. Preparation of (4-methoxyphenyl)(3-nitrophenyl)methanone (105c).

DMF (5 drops) and SOCl ₂ (10.67 g, 89.76 mmol) were added to a stirred solution of 3-nitrobenzoic acid (105a) (5.0 g, 29.92 mmol) in toluene (150 ml) at room temperature. . The reaction mixture was heated at 70°C for 3 hours and concentrated to dryness in vacuo. The resulting residue was dissolved in DCM (100 ml), methoxybenzene (105b) (8.2 ml, 76.1 mmol) was added at room temperature and the reaction mixture was heated to 50°C. AlCl ₃ (15.95 g, 119.672 mmol) was added portionwise to the hot reaction mixture and stirred at 50°C for 30 minutes. Completion of the reaction was monitored by TLC (20% EtOAc in n-hexane) and two spots were observed by TLC. The reaction mixture was cooled to room temperature and poured into crushed ice. Conc. was added to the mixture. HCl (6 ml) and extracted with EtOAc (2x100 ml). Combine the organic layers, wash with brine (100 ml), dry over Na ₂ SO ₄ , filter and concentrate in vacuo. The resulting residue was purified by flash chromatography (silica gel, eluted with mixtures of 0-40% EtOAc in hexanes) to give (4methoxyphenyl)(3-nitrophenyl)methanone (105c) (3.6 g, 46%) as an off-white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 8.40 (t, J=1.9 Hz, 1H), 8.15 - 8.09 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.17 - 7 .09 (m, 2H), 3.88 (s, 3H).

Step 2. Preparation of (3-aminophenyl)(4-methoxyphenyl)methanol (105d).

NiCl ₂ -6H ₂ O (0.646 g, 2.72 mmol) was added to a stirred solution of (4-methoxyphenyl)(3-nitrophenyl)methanone (105c) (3.5 g, 13.61 mmol) in methanol (135 ml) at room temperature. The reaction mixture was cooled to 0°C and at the indicated temperature NaBH ₄ was added in parts. The reaction mixture was warmed to room temperature and continued stirring for 3 hours. Completion of the reaction was monitored by TLC (35% EtOAc in n-hexane). The reaction was quenched with N1-(2-aminoethyl)ethane-1,2diamine (2.5 ml), the mixture was stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was dissolved in a 1:1 mixture of ethyl acetate/water (100 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography (silica gel, eluted with 0 to 30% EtOAc in hexane mixtures) to give (3-aminophenyl)(4methoxyphenyl)methanol (105d) (1.6 g, 51%) as light brown oily thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.30 - 7.22 (m, 2H), 6.94 (t, J=7.7 Hz, 1H), 6.90 -6.83 (m, 2H), 6.59 (t, J=1.9 Hz, 1H), 6.52 (dt, J=7.6, 1.3 Hz, 1H), 6.41 (ddd, J=7.9 , 2.3, 1.0 Hz, 1H), 5.60 (d, J=3.9 Hz, 1H), 5.49 (d, J=3.9 Hz, 1H), 5.00 (s , 2H), 3.74 (s, 3H).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105e).

To a solution of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (9i) (2.24 g, 7.82 mmol) in toluene (50 ml), DMF (5 drops), SOCl ₂ (1.36 ml, 18.77 mmol) at 0°C. The reaction mixture was heated at reflux temperature for 3.5 hours and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (50 ml) and (3-aminophenyl)(4-methoxyphenyl)methanol (105d) (1.5 g, 6.54 mmol) was added, then triethylamine (8.8 ml) was added dropwise at room temperature. temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness in vacuo and the resulting residue was purified by flash

- 212 045731 chromatography (silica gel, eluted with mixtures of ethyl acetate in hexane, 10-50%) to obtain 1-(3cyanophenyl)-N-(3-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H -pyrazole-5carboxamide (105e) (2.6 g, 81%) as a light brown thick liquid; 1H NMR (300 MHz, DMSOd ₆ ) δ 10.62 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.4 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 7.69 (m, 2H), 7.61 (t, J=1 .8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.31-7.18 (m, 3H), 7.11 (d, J=7.7 Hz, 1H ), 6.92 6.80 (m, 2H), 5.84 (d, J=3.9 Hz, 1H), 5.62 (d, J=3.9 Hz, 1H), 3.71 ( s, 3H).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105f ).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (105e) (2.6 g, 5.28 mmol) in dichloromethane (50 ml) at 0°C, thionyl chloride (1.2 g, 10.15 mmol) was added and left to warm to room temperature for 3 hours. The reaction was quenched with cyclopropylmethanamine (8 ml), the mixture was stirred for 1 hour at room temperature and heated at 50°C for 17 hours. Concentrate the reaction mixture to dryness in vacuo, dissolve in chloroform (50 ml), wash with water (25 ml), dry, filter and concentrate in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 050% ethyl acetate/methanol (9:1) in hexane) to give 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino )(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105f) (1.7 g, 59%) as a light brown semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.95 (dt, J=7.8, 1 ,3 Hz, 1H), 7.85 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.60 (t, J=1.8 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.29 - 7.09 (m, 4H), 6.85 - 6.75 (m, 2H), 4 .73 (s, 1H), 3.65 (s, 3H), 2.23 (d, J=6.7 Hz, 2H), 0.94 - 0.79 (m, 1H), 0.38 - 0.25 (m, 2H), 0.05--0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.97; ICS (KBr) 2234 cm ^-1 ; MS (IER+) 546.3 (M+1); (IER-) 545.4 (M-1); analysis, calculation for C ₃₀ H ₂₆ F ₃ N ₅ O ₂ -0.5CH ₂ Cl ₂ : C, 62.30; H, 4.63; N, 11.91; experiment: C, 62.73; H, 4.74; N, 11.60.

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105g).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105f) ( 0.5 g, 0.916 mmol) in anhydrous methanol (20 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.272 g, 1.146 mmol) was added, sodium borohydride (0.173 g, 4 .58 mmol) for 15 min. The reaction mixture was stirred for 15 min at 0°C and quenched with N1-(2-aminoethyl)ethane-1,2diamine (0.297 ml, 2.75 mmol), stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (25 ml) and water (25 ml). The organic layer was separated, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)( 4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (105g) (0.35 g, 0.637 mmol, 69.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 7.72 (t, J=1.7 Hz, 1H), 7.67 (s, 2H), 7.61 ( dt, J=7.3, 1.7 Hz, 1H), 7.58 - 7.47 (m, 3H), 7.37 - 7.29 (m, 2H), 7.26 (d, J= 7.3 Hz, 2H), 6.90 - 6.83 (m, 2H), 4.88 (s, 1H), 4.12 (s, 2H), 3.70 (s, 3H), 2, 34 (d, J=6.8 Hz, 2H), 1.03 - 0.87 (m, 1H), 0.45- 0.35 (m, 2H), 0.07 (dd, J=5, 5, 3.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 550.4 (M+1); (IER-) 548.3 (M-1); analysis, calculation for C ₃₀ H ₃₀ F ₃ N ₅ O ₂ -1.1HCFH ₂ O: C, 59.29; H, 5.49; Cl, 6.42; N, 11.52; experiment: C, 59.08; H, 5.43; Cl, 6.19; N, 11.17.

Scheme 106

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (106a ).

Into a solution of tert-butyl-3-(5-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (49g) ( 0.111 g, 0.153 mmol) in methanol (10 ml), add hydrogen chloride (4N in dioxane, 1.912 ml, 7.65 mmol), stir for 14 hours at room temperature. Excess solvent was pumped out under reduced pressure. The residue was purified by flash column chromatography (first column: silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, second column: silica gel, 25 g, 0-100% methanol in chloroform mixtures) to give 1

- 213 045731 (3-(aminomethyl)phenyl)-N-(3-((2-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (106a) (22 mg, 23% yield) as a white solid; 1H NMR (300 MHz, DMSO-66) δ 10.66 (s, 1H, exchange with D ₂ O), 7.67 - 7.62 (m, 1H), 7.58 - 7.49 (m, 3H ), 7.47 - 7.28 (m, 9H), 7.24 - 7.13 (m, 2H), 7.08 (d, J=7.7 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 5.20 (s, 1H), 5.09 (s, 2H), 3.76 (s, 2H), 2.31 (dd, J=12.0, 6.7 Hz, 1H), 2.21 (dd, J=11.9, 7.0 Hz, 1H), 0.87 (p, J =6.5 Hz, 1H), 0.45-0.23 (m, 2H), -0.01 (s, 2H); ¹ H NMR (300 MHz, DMSO-d6, D2O) δ 7.68 - 7.63 (m, 1H), 7.54 - 7.49 (m, 3H), 7.49 - 7.40 (m, 4H), 7.33 (tt, J=5.1, 2.2 Hz, 5H), 7.26 - 7.14 (m, 2H), 7.10 (d, J=7.7 Hz, 1H ), 7.02 (d, J=8.1 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 5.20 (s, 1H), 5.08 (s, 2H ), 3.74 (s, 2H), 2.37 - 2.15 (m, 2H), 0.85 (h, J=6.6 Hz, 1H), 0.44 - 0.28 (m, 2H), -0.01 - -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.71; MS (IER ⁺ ): MS (IER+) 626.4 (M+1), MS (IER-) 624.3 (M-1).

Scheme 107

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107f ).

Step 1. Preparation of (3-aminophenyl)(3-(benzyloxy)phenyl)methanol (107b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (3.55 g, 12 .00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give (3-aminophenyl)(3-(benzyloxy)phenyl)methanol (107b) (1.258 g, yield 41 %) in the form of a thick yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.47 7.29 (m, 5H), 7.19 (t, J=7.9 Hz, 1H), 7.05-6.97 (m, 1H), 6.96 - 6.86 (m, 2H), 6.83 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 6.58 (t, J=1, 9 Hz, 1H), 6.50 (dt, J=7.6, 1.3 Hz, 1H), 6.38 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.69 (d, J=3.9 Hz, 1H, exchange with D ₂ O), 5.46 (d, J=3.9 Hz, 1H), 5.05 (s, 2H), 4.98 (s, 2H, exchange with D ₂ O); MS (IER ⁺ ): MS (IER+) 328.2 (M+Cl), MS (IER-) 304.2 (M-1).

Step 2. Preparation of N-(3-((3-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (107c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.215 g, 4.32 mmol) in DMF (10 ml) was added (3-aminophenyl)(3 -(benzyloxy)phenyl)methanol (107b) (1.2 g, 3.93 mmol), N-ethyl-N-isopropylpropan-2-amine (3.42 ml, 19.65 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate ( PyBrOP, 2.198 g, 4.72 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0

- 214 045731

100% ethyl acetate in hexanes) to give N-(3-((3-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 107c) (1.637 g, 2.88 mmol, 73.3% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.16 (td, J=1.7, 0.9 Hz, 1H), 8.03 -7.95 (m , 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.64 (t, J=1 ,8 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.46 - 7.30 (m, 5H), 7.23 (dt, J=15.5, 7.9 Hz, 2H), 7.17 - 7.10 (m, 1H), 7.02 (dd, J=2.6, 1.5 Hz, 1H), 6.95 - 6.89 (m, 1H), 6 .85 (ddd, J=8.1, 2.7, 1.0 Hz, 1H), 5.95 (d, J=3.8 Hz, 1H), 5.63 (d, J=3.9 Hz, 1H), 5.05 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.97; MS (IER-) 567.3 (M-1).

Step 3. Preparation of N(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107d).

Into a solution of N-(3-((3-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107c) (1.637 g, 2.88 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (0.63 ml, 8.64 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with cyclopropylmethanamine (0.749 ml, 8.64 mmol) and stirred the mixture at room temperature for another 5 hours. Concentrated the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (4.99 ml, 57.6 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1- (3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107d) (1.16 g, 1.866 mmol, 64.8% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 7.98 (dt, J=7.8, 1 ,3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.75- 7.66 (m, 3H), 7.55 (dt, J=7.9, 1.5 Hz, 1H), 7.457.40 (m, 3H), 7.39 - 7.37 (m, 1H), 7.36 -7.31 (m, 2H), 7 .25 - 7.16 (m, 3H), 7.09 - 7.06 (m, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.83 (ddd, J=8 ,2, 2.6, 1.0 Hz, 1H), 5.04 (s, 2H), 4.79 (s, 1H), 2.35 (s, 1H), 2.27 (s, 2H) , 1.01 - 0.84 (m, 1H), 0.42 -0.32 (m, 2H), 0.05 (dd, J=5.2, 3.8 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.95; MS (IER+) 622.4 (M+1); (IER-) 620.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate ( 107e).

Into a solution of N-(3-((3 -(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1 -(3-cyanophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107d) (1, 0 g, 1.609 mmol) in MeOH (10 mL), cooled in ice/water, di-tert-butyl dicarbonate (1.053 g, 4.83 mmol) and nickel(II) chloride (0.421 g, 1.769 mmol) were added. Sodium borohydride (0.497 g, 12.87 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.527 mL, 4.83 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexanes) to give tert-butyl-3-(5-(3-((3(benzyloxy )phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (107e) (0.304 g, 0.419 mmol, 26.0% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.58 (s, 1H), 7.51 ( q, J=7.1, 6.3 Hz, 2H), 7.46 - 7.30 (m, 9H), 7.27 - 7.14 (m, 3H), 7.11 - 7.05 ( m, 1H), 6.97 (d, J=7.7 Hz, 1H), 6.83 (ddd, J=8.2, 2.6, 1.0 Hz, 1H), 5.05 (s , 2H), 4.78 (s, 1H), 4.18 (d, J=6.2 Hz, 2H), 2.35 (s, 1H), 2.27 (s, 2H), 1.36 (s, 9H), 0.92 (dd, J=13.2, 6.3 Hz, 1H), 0.42 - 0.31 (m, 2H), 0.04 (q, J=5.8 , 5.3 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 60.80; MS (IER+) 726.5 (M+1); (IER-) 724.5 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5- carboxamide(107f).

Into a solution of tert-butyl-3-(5-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (107e) ( 0.125 g, 0.172 mmol) in methanol (volume: 7.5 ml) was added hydrogen chloride (0.359 ml, 4.31 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl )(cyclopropylmethylamino)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (107f) (0.05 g, 0.080 mmol, 46.4% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.84 (s, 1H), 8.50 (d, J=59.1 Hz, 2H), 7.76 (s, 1H), 7.72 ( d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.64 - 7.49 (m, 4H), 7.46 - 7.21 (m, 9H), 7.06 (d, J=7.4 Hz, 1H), 6.90 (dd, J=8.0, 2.5 Hz, 1H), 5.08 (s, 3H), 4.11 (s, 2H) , 2.47 - 2.38 (m, 2H), 1.09 - 0.93 (m, 1H), 0.44 (td, J=5.3, 4.8, 2.8 Hz, 2H) , 0.25-0.07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.78; MS (IER+) 626.4 (M+1); (IER-) 624.4 (M-1); analysis, calculation for C ₃₆ H ₃₄ F ₃ N ₅ O ₂ -1.5HCl-H ₂ O: C, 61.91; H, 5.41; Cl, 7.61; N, 10.03: experiment: C,

- 215 045731

61.51; H, 5.51; Cl, 7.89; N, 9.85.

Scheme 108

Si'

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-III-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (108e).

Step 1. Preparation of 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (108a).

To a stirred solution of 3-formylbenzonitrile (54a) (1.311 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12.00 mmol ) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 3-((3-aminophenyl)(hydroxy)methyl)-benzonitrile (108a) (0.652 g, yield 29 %) as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.76 (t, J=1.7 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.51 (t, J= 7.7 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.60 - 6.48 (m, 2H), 6.40 (ddd, J=7.9, 2 ,3, 1.1 Hz, 1H), 5.97 (d, J=3.9 Hz, 1H, exchange with D ₂ O), 5.58 (d, J=3.9 Hz, 1H), 5 .04 (s, 2H, exchange with D2O); MS (IER ⁺ ): MS (IER+) 225.2 (M+1), 247.1 (M+Na), 223.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108b).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.897 g, 3.19 mmol) in DMF (10 ml) was added 3-((3-aminophenyl )(hydroxy)methyl)-benzonitrile (108a) (0.65 g, 2.90 mmol), N-ethyl-N-isopropylpropan-2-amine (2.52 ml, 14.5 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop) (1.62 g, 3.48 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(hydroxy)methyl)phenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108b) (1.057 g, 2.169 mmol, 74.8% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1 .3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.77 - 7.62 (m, 5H), 7.61 7.56 (m, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.29 (t, J=7.8 Hz , 1H), 7.22 - 7.10 (m, 1H), 6.22 (d, J=3.9 Hz, 1H), 5.77 (d, J=4.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.96; MS (IER+) 510.2 (M+Na); (IER-) 486.2 (M-1); 973.3 (2M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108c).

In a solution of 1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(hydroxy)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (108b) (1.057 g, 2.169 mmol) thionyl was added to dichloromethane (50 ml) at 0°C

- 216 045731 chloride (0.48 ml, 6.51 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with cyclopropylmethanamine (0.564 ml, 6.51 mmol) and the mixture was stirred at room temperature for another 5 hours. Concentrated the reaction mixture to dryness in vacuum. The resulting residue was dissolved in acetonitrile (5 ml) and cyclopropylmethanamine (3.76 ml, 43.4 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108c) (0.459 g, 0.849 mmol, 39.2% yield) as a yellow oily liquid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1 .3 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.77 - 7.64 (m, 5H), 7.60 - 7.46 (m, 2H), 7.32 - 7.19 (m, 2H), 4.92 (s, 1H), 2.63 (s, 1H), 2.27 (s, 2H), 0.96 - 0.87 (m, h), 0 .44 - 0.39 (m, 2H), 0.08 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.96; MS (IER+) 541.304 (M+1); (IER-) 539.269 (M-1).

Step 4. Preparation of 1-(3-(tert-butoxycarbonylaminomethyl)phenyl)-N-(3-((3-(tert-butoxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5carboxamide (108d).

In a solution of 1 -(3-cyanophenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (108c) (0.425 g, 0.786 mmol ) in MeOH (10 mL), cooled in ice/water, di-tert-butyl dicarbonate (0.867 g, 3.93 mmol) and nickel (II) chloride (0.206 g, 0.865 mmol) were added. Sodium borohydride (0.364 g, 9.44 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.429 mL, 3.93 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give 1-(3-(tert-butoxycarbonylaminomethyl)phenyl)-N-(3-( (3-(tert-butoxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108d) (0.143 g, 0.191 mmol, 24.29% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.69 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.55-7.32 (m, 7H ), 7.31 - 7.14 (m, 5H), 7.04 (d, J=7.0 Hz, 1H), 4.78 (s, 1H), 4.19 (d, J=6, 2 Hz, 2H), 4.07 (d, J=6.2 Hz, 2H), 2.38 - 2.19 (m, 3H), 1.37 (d, J=3.2 Hz, 18H) , 0.98 - 0.82 (m, 1H), 0.44 0.31 (m, 2H), 0.11-0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.81; MS (IER+) 749.5 (M+1); (IER-) 747.5 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108e).

Into a solution of 1-(3-(tert-butoxycarbonylaminomethyl)phenyl)-N-(3-((3-(tert-butoxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (108d) (0.148 g, 0.198 mmol) in methanol (10 ml) was added conc. hydrogen chloride (0.824 ml, 9.88 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA-80 in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-((3-(aminomethyl) )phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (108e) (0.05 g, 0.091 mmol, 46.1% yield) as a light yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.67 (s, 1H), 7.66 (s, 1H), 7.60 - 7.11 (m, 12H), 4.79 (s, 1H ), 3.77 (s, 2H), 3.67 (s, 2H), 2.28 (d, J=6.7 Hz, 2H), 1.05-0.83 (m, 1H), 0 .51 - 0.30 (m, 2H), 0.05 (t, J=4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.51; MS (IER+) 549.4 (M+1); (IER-) 547.4 (M-1); analysis, calculation for SzShchzLNAD^ShCHO: C, 64.62; H, 5.78; N, 15.07; experiment: C, 64.34; H, 5.73; N, 14.72.

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Scheme 109

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (109f).

Step 1. Preparation of (3-aminophenyl)(3-methoxyphenyl)methanol (109b).

To a stirred solution of 3-methoxybenzaldehyde (109a) (1.361 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 ml, 12.0 mmol ) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (12.50 ml, 25.00 mmol), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15.00 ml, 30.0 mmol) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-20% ethyl acetate in hexane) to give (3-aminophenyl)(3-methoxyphenyl)methanol (109b) (1.327 g, 58% yield) as yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.18 (t, J=7.8 Hz, 1H), 7.00 - 6.85 (m, 3H), 6.75 (ddd, J=8 ,2, 2.6, 1.0 Hz, 1H), 6.60 - 6.46 (m, 2H), 6.37 (ddd, J=7.9, 2.3, 1.1 Hz, 1H ), 5.68 (d, J=3.9 Hz, 1H, exchange with D2O), 5.46 (d, J=3.9 Hz, 1H), 4.98 (s, 2H, exchange with D2O) , 3.71 (s, 3H); MS (IER ⁺ ): MS (IER+) 230.2 (M+1), 252.1 (M+Na), 228.12 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (109c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.754 g, 6.24 mmol) in DMF (10 ml) was added (3-aminophenyl)(3 -methoxyphenyl)methanol (109b) (1.3 g, 5.67 mmol), Nethyl-N-isopropylpropan-2-amine (4.94 ml, 28.4 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3 .17 g, 6.80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-(hydroxy(3-methoxyphenyl)methyl)phenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (109c) (2.27 g, 4.61 mmol, 81% yield) as a yellow semi-solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.21 - 8.12 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.3, 2.2, 1.2 Hz, 1H), 7.79 - 7.68 (m, 2H), 7.67 - 7.60 ( m, 1H), 7.59 - 7.48 (m, 1H), 7.31 - 7.10 (m, 3H), 6.94 (t, J=2.0 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.77 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 5.95 (d, J=3.8 Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 3.71 (s, 3H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.96; MS (IER-) 491.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (109d).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (109c) (2.27 g, 4.61 mmol) in dichloromethane (25 ml) at 0°C, add thionyl chloride (1 ml, 13.83 mmol) and stir at room temperature for 2 hours. The reaction is quenched with cyclopropylmethanamine (1.199 ml, 13.83 mmol) and stir the mixture at room temperature temperature in

- 218 045731 for another 5 hours. The reaction mixture was concentrated to dryness in vacuum. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (8.00 ml, 92 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (109d) (1.3 g, 2.383 mmol, 51.7% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.19 - 8.14 (m, 1H), 8.00 (dt, J=7.9, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.67 (t, J=1, 9 Hz, 1H), 7.54 (dt, J=8.0, 1.7 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.23 - 7.19 ( m, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.99 (dd, J=2.6, 1.5 Hz, 1H), 6.95 (d, J=7 .9 Hz, 1H), 6.75 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 4.79 (s, 1H), 3.70 (s, 3H), 2 .34 (s, 1H), 2.29 (d, J=7.1 Hz, 2H), 0.99 - 0.85 (m, 1H), 0.43 - 0.33 (m, 2H), 0.09 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.95; ICS (KBr) 2234 cm'¹; MS (IER+) 546.3 (M+1); (IER-) 544.4 (M-1).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (109e).

In a solution of 1 -(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (109d) (1.2 g, 2.200 mmol) in MeOH (20 mL), cooled in ice/water, di-tert-butyl dicarbonate (1.44 g, 6.6 mmol) and nickel(II) chloride (0.575 g, 2.420 mmol) were added. Sodium borohydride (0.679 g, 17.60 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.720 mL, 6.60 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give tert-butyl-3-(5-(3((cyclopropylmethylamino)(3 -methoxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (109e) (0.375 g, 0.577 mmol, 26.2% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.69 (s, 1H), 7.67 - 7.62 (m, 1H), 7.58 (s, 1H), 7.52 (t, J =6.6 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.38 - 7.31 (m, 2H), 7.28 - 7.13 (m, 3H), 7, 02 -6.98 (m, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.75 (ddd, J=8.3, 2.6, 1.0 Hz, 1H) , 4.78 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.71 (s, 3H), 2.42 - 2.31 (m, 1H), 2, 29 (d, J=7.3 Hz, 2H), 1.36 (s, 9H), 1.00 - 0.78 (m, 1H), 0.45- 0.29 (m, 2H), 0 .12 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.79; MS (IER+) 650.4 (M+1); (IER-) 648.3 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (109f) .

In a solution of tert-butyl 3-(5-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)phenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (109e) (0.364 g, 0.560 mmol) in methanol (30 ml) was added conc. hydrogen chloride (1.167 ml, 14.01 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-methoxyphenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (109f) (0.160 g, 0.291 mmol, 52.0% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.76 - 7.68 (m, 3H), 7.65 (dt, J=7.4, 1.6 Hz , 1H), 7.61 - 7.46 (m, 3H), 7.30 - 7.15 (m, 3H), 7.05 - 7.00 (m, 1H), 6.97 (d, J =7.7 Hz, 1H), 6.81 - 6.71 (m, 1H), 4.83 (s, 1H), 4.09 (s, 2H), 3.71 (s, 3H), 2 .31 (dd, J=6.7, 2.5 Hz, 2H), 1.05- 0.79 (m, 1H), 0.51 - 0.26 (m, 2H), 0.16 - - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.59; MS (IER+) 550.4 (M+1); (IER-) 548.3 (M-1); analysis, calculation for C30H30F3N ₅ O2-HCl-1.25H2O: C, 59.21; H, 5.55; Cl, 5.83; N, 11.51; experiment: C, 59.44; H, 5.64; Cl, 5.64; N, 11.15.

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Scheme 110

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(m-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (110f).

Step 1. Preparation of (3-aminophenyl)(m-toluyl)methanol (110b).

To a stirred solution of 3-methylbenzaldehyde (110a) (1.179 ml, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12.00 mmol ) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (12.50 ml, 25 mmol), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give (3-aminophenyl)(m-toluyl)methanol (110b) (1.393 g, 65% yield) in as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.22 - 7.09 (m, 3H), 6.99 (dt, J=6.4, 1.9 Hz, 1H), 6.91 (t , J=7.7 Hz, 1H), 6.56 (t, J=2.0 Hz, 1H), 6.50 (dt, J=7.6, 1.3 Hz, 1H), 6.37 (ddd, J=7.9, 2.4, 1.1 Hz, 1H), 5.64 (d, J=3.8 Hz, 1H, exchange with D ₂ O), 5.45 (d, J =3.8 Hz, 1H), 4.98 (s, 2H, exchange with D2O), 2.26 (s, 3H); MS (IER ⁺ ) 214.2 (M+1), 236.2 (M+Na), MS (IER-) 212.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(m-toluyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (110c).

In a 100 mL one-neck flask, 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.743 g, 6.20 mmol), (3-aminophenyl)(m-toluyl) methanol (110b) (1.322 g, 6.20 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (3.47 g, 7.44 mmol) were treated sequentially with N,Ndimethylformamide (36.0 mL, 465 mmol) and N -ethyl-N-isopropylpropan-2-amine (DIPEA) (5.40 ml, 31.0 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (50 ml) and extracted with chloroform (2x50 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(mtoluyl)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (110c) (2.308 g, 78% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H, exchange with D2O), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7 ,8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 - 7.69 (m, 2H), 7, 62 (t, J=1.8 Hz, 1H), 7.55 (dd, J=8.1, 1.5 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.22 -7.10 (m, 4H), 7.01 (d, J=7.1 Hz, 1H), 5.90 (d, J=3.8 Hz, 1H, exchange with D ₂ O) , 5.62 (d, J=3.8 Hz, 1H), 2.26 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.95; MS (IER ⁺ ): MS (IER+) 499.2 (M+Na), 975.4 (2M+Na), MS (IER-) 475.3 (M-1); IR (KBr, cm ^-1 ): 2235 cm ^-1 (stretching vibrations -CN).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(m-toluyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (110d).

- 220 045731

In a solution of 1 -(3 -cyanophenyl)-N-(3 -(hydroxy(m-toluyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole5-carboxamide (110c) (2.31 g, 4. 85 mmol) in dichloromethane (25 ml) at 0°C, add thionyl chloride (1.06 ml, 14.55 mmol) and stir at room temperature for 2 hours. The reaction is quenched with cyclopropylmethanamine (1.262 ml, 14.55 mmol) and stir the mixture at room temperature for another 5 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (8.41 ml, 97 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(m-toluyl)methyl) phenyl)-3-(trifluoromethyl)III-pyrazole-5-carboxamide (110d) (1.784 g, 3.37 mmol, 69.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.19 - 8.13 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz , 1H), 7.90 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.79 - 7.69 (m, 2H), 7.68 - 7.63 (m , 1H), 7.54 (dt, J=8.0, 1.7 Hz, 1H), 7.30 - 7.12 (m, 5H), 6.99 (dd, J=6.3, 2 .1 Hz, 1H), 4.77 (s, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 1.03 - 0.84 (m, 1H), 0.44 - 0.31 (m, 2H), 0.09 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.94; ICS (KBr) 2234 cm'¹; MS (IER+) 530.3 (M+1); (IER-) 528.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(m-toluyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (110e).

In a solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(m-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (110d) (1.2 g , 2.266 mmol) in MeOH (20 ml), cooled in ice/water, di-tert-butyl dicarbonate (1.5 g, 6.87 mmol) and nickel(II) chloride (0.599 g, 2.52 mmol) were added. . Sodium borohydride (0.708 g, 18.33 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2-aminoethyl)ethane1,2-diamine (0.750 mL, 6.87 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)() m-toluyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (110e) (1.0 g, 1.578 mmol, 68.9% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.46 (m, 2H), 7.45-7.38 (m, 2H), 7.38 - 7.31 (m, 2H), 7.25 (d, J=7.7 Hz, 1H) , 7.22 - 7.13 (m, 4H), 6.99 (dt, J=6.7, 2.0 Hz, 1H), 4.76 (s, 1H), 4.19 (d, J =6.2 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.36 (d, J=1.9 Hz, 9H), 0.99 - 0.82 (m, 1H), 0.42 - 0.33 (m, 2H), 0.10 - -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.80; MC (IER+) 634.4 (M+1); (IER-) 632.4 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(m-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (110f) .

In a solution of tert-butyl 3-(5-(3-((cyclopropylmethylamino)(m-toluyl)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (110e) (0.92 g , 1.452 mmol) in methanol (50 ml) was added conc. hydrogen chloride (3.02 ml, 36.3 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(m-toluyl)methyl) phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (110f) (0.67 g, 1.256 mmol, 86% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.51 (t, J=55.0 Hz, 3H), 7.83 (s, 1H), 7.72 (d , J=1.9 Hz, 1H), 7.71 (s, 1H), 7.64 (dt, J=7.2, 1.8 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.56 - 7.48 (m, 2H), 7.47 - 7.34 (m, 3H), 7.28 (t, J=7.9 Hz, 1H), 7.14 (d , J=7.5 Hz, 1H), 5.36 (s, 1H), 4.12 (s, 2H), 2.70 - 2.57 (m, 2H), 2.29 (s, 3H) , 1.20 - 1.04 (m, 1H), 0.65-0.41 (m, 2H), 0.38 - 0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.60; MS (IER+) 534.4 (M+1); (IER-) 532.3 (M-1); analysis, calculation for C30H ₃ 0F ₃ N ₅ O-2HCl-1.75H2O: C, 56.47; H, 5.61; Cl, 11.11; N, 10.98; experiment: C, 56.59; H, 5.45; Cl, 10.93; N, 10.92.

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Scheme 111

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (111f ).

Step 1. Preparation of (3-aminophenyl)(3-(trifluoromethyl)phenyl)methanol (111b).

To a stirred solution of 3-(trifluoromethyl)benzaldehyde (111a) (1.741 g, 10 mmol) in tetrahydrofuran (5 ml) was added a solution of 3-[bis(trimethylsilyl)amino]phenylmagnesium chloride (49c) (12 ml) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x30 ml). The organic layers were combined, washed with saturated aqueous NH4Cl (30 ml), dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate/hexane mixtures) to give (3-aminophenyl)(3-(trifluoromethyl)phenyl)methanol (111b) (1.121 g, 42% yield) %) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 - 7.48 (m, 4H), 6.94 (t, J=7.7 Hz, 1H), 6.64 - 6.49 (m , 2H), 6.40 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.95 (d, J=3.9 Hz, 1H, exchange with D2O), 5, 62 (d, J=3.9 Hz, 1H), 5.07 (s, 2H, exchange with D2O); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.92; MS (IER ⁺ ): MS (IER+) 268.2 (M+1), 290.1 (M+Na), MC (IER-) 266.15 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (111c).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1.075 g, 3.82 mmol), (3-aminophenyl)(3-(trifluoromethyl) )phenyl)methanol (111b) (1.022 g, 3.82 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 2.139 g, 4.59 mmol), N,N-dimethylformamide (22 ml) and N-ethyl were added sequentially -N-isopropylpropan-2-amine (3.33 ml, 19.12 mmol) under positive nitrogen flow. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (30 ml) and extracted with chloroform (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethyl)phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111c) (1.293 g, 2.438 mmol, 63.8% yield) as a yellow solid; MS (IER+) 553.2 (M+Na); (IER-) 529.2 (M-1), which was used in this form at the next stage.

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111d) .

In a solution of 1 -(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111c) (1.238 g, 2.334 mmol) in dichloromethane (25 ml) at 0°C was added thionyl chloride (0.551 ml, 7 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with cyclopropylmethanamine (1.4 ml, 16.34 mmol) and the mixture was stirred at room tempera

- 222 045731 round for another 5 hours. The reaction mixture was concentrated to dryness in vacuum. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (4.0 ml, 46.7 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-M-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111d) (1.047 g, 77% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H, exchange with D ₂ O), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J =7.7, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.82 -7.66 (m, 5H), 7.60 - 7.51 (m, 3H), 7.35- 7.19 (m, 2H), 4.96 (s, 1H), 2.30 (dd, J=13.8, 7.0 Hz, 2H), 1.00 - 0.84 (m, 1H), 0.45- 0.31 (m, 2H), 0.04 (td, J=5.4, 3.8 Hz, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.85, -60.96; MS (IER+) 584.3 (M+1), MS (IER-) 582.2 (M-1).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (111e ).

In a solution of 1-(3-cyanophenyl)-M-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111d) (0.996 g, 1.707 mmol) in MeOH (20 ml), cooled in ice/water, di-tert-butyl dicarbonate (1.5 g, 6.87 mmol) and nickel (II) chloride (0.599 g, 2.52 mmol) were added ). Sodium borohydride (0.708 g, 18.33 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.750 mL, 6.87 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give tert-butyl-3-(5-(3((cyclopropylmethylamino)(3 -(trifluoromethyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (111e) (0.26 g, 16.50% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 7.79 (s, 1H), 7.71 (dd, J=5.3, 3.7 Hz, 1H), 7.66 (t, J=1.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 3H), 7.51 (d, J=7.3 Hz, 1H), 7. 45- 7.38 (m, 2H), 7.38 - 7.32 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.24 (s, 1H), 5 .03 - 4.81 (m, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.60 (dd, J=13.6, 3.4 Hz, 1H), 2, 37 - 2.18 (m, 2H), 1.35 (s, 9H), 0.99 - 0.83 (m, 1H), 0.45- 0.32 (m, 2H), 0.09 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.85; MS (IER+) 688.4 (M+1); (IER-) 686.4 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (111f).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (111e) ( 0.25 g, 0.364 mmol) in methanol (10 ml) was added conc. hydrogen chloride (0.757 ml, 9.09 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-( trifluoromethyl)phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (111f) (0.132 g, 0.225 mmol, 61.8% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 11.02 (s, 1H), 10.40 (s, 2H), 8.78 - 8.39 (m, 3H), 8.14 (s, 1H ), 8.05 (d, J=7.7 Hz, 1H), 7.92 (s, 1H), 7.77 - 7.60 (m, 7H), 7.59 - 7.49 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 5.75 (s, 1H), 4.12 (s, 2H), 2.69 (d, J=6.7 Hz, 2H), 1.16 (dd, J=13.3, 6.6 Hz, 1H), 0.69 - 0.45 (m, 2H), 0.41 - 0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.60, -60.76; MS (IER+) 588.3 (M+1); (IER-) 586.3 (M-1); analysis, calculation for C ₃₀ H ₂₇ F6N ₅ O-2HCl-1.75H ₂ O: C, 52.07; H, 4.73; Cl, 10.25; N, 10.12; experiment: C, 51.94; H, 4.60; Cl, 10.63; N, 10.05.

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Scheme 112

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (112g).

Step 1. Preparation of 4-(3-nitrobenzoyl)benzenesulfonamide (112c).

Mixture of 4-sulfamoylbenzoic acid (112b) (1 g, 4.97 mmol), 3-nitrophenylboronic acid (112a) (0.996 g, 5.96 mmol), diacetoxypalladium (0.335 g, 0.497 mmol), 1,1'-bis (diphenylphosphino)ferrocene (DPPF) (0.551 g, 0.994 mmol), trimethylacetic anhydride (1.513 ml, 7.46 mmol) was degassed and purged with nitrogen, treated with THF (20 ml) and water (0.224 ml, 12.43 mmol) in positive nitrogen flow. The reaction mixture was heated to 60°C and stirred for 16 hours at the indicated temperature under a positive nitrogen flow. TLC analysis (ethyl acetate/hexanes, v/v, 3/7) indicated good conversion. The reaction mixture was cooled to room temperature. Excess THF was pumped to dryness under reduced pressure, and the resulting residue was diluted with saturated aqueous NH ₄ Cl (50 ml).

The product was extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 50% ethyl acetate/hexanes)] to give 4-(3-nitrobenzoyl)benzenesulfonamide (112c) (311 mg, 20% yield) as a white solid substances; ¹ H NMR (300 MHz, DMSO-06) δ 8.55 (ddd, J=8.3, 2.4, 1.1 Hz, 1H), 8.46 (t, J=2.0 Hz, 1H ), 8.20 (dt, J=7.7, 1.3 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.89 (t, J=8.0 Hz, 1H) , 7.63 (s, 2H, exchange with D2O); MS (IER ⁺ ): MS (IER+) 329.1 (M+1), MS (IER-) 305.1 (M-1), 611.0 (2M-1); analysis, calculation for C ₁₃ H ₁₀ N ₂ O ₅ S: C, 50.98; H, 3.29; N, 9.15; S, 10.47; experiment: C, 50.93; H, 3.36; N, 9.12; S, 10.27.

Step 2. Preparation of 4-((3-aminophenyl)(hydroxy)methyl)benzenesulfonamide (112d).

To a stirred solution of 4-(3-nitrobenzoyl)benzenesulfonamide (112c) (0.256 g, 0.836 mmol) in anhydrous methanol (20 ml), cooled to 0°C, was added nickel (II) chloride hexahydrate (0.248 g, 1.045 mmol), then sodium borohydride (0.253 g, 6.69 mmol) in small portions over 5 minutes. The reaction mixture was stirred for 45 min at 0°C, TLC analysis (ethyl acetate/hexanes, 2/2, v/v) indicated completion of the reaction, after which N1-(2-aminoethyl)ethane-1,2- amine (0.903 ml, 8.36 mmol). The mixture was stirred for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give 4-((3-aminophenyl)(hydroxy)methyl)benzenesulfonamide (112d) (136 mg, yield 58%) as a white solid; 1H NMR (300 MHz, DMSOd ₆ ) δ 7.82 - 7.69 (m, 2H), 7.55 - 7.44 (m, 2H), 7.25 (s, 2H), 6.92 (t , J=7.7 Hz, 1H), 6.58 - 6.47 (m, 2H), 6.39 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5, 89 (d, J=3.9 Hz, 1H, exchange with D2O), 5.58 (d, J=3.8 Hz, 1H), 5.01 (s, 2H, exchange with D2O); MS (IER ⁺ ): MS (IER+) 301.2 (M+Na), 579.2 (2M+Na), MS (IER-) 277.2 (M-1) 555.2 (2M-1) .

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112e).

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In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.130 g, 0.462 mmol), 4-((3-aminophenyl)(hydroxy )methyl)benzenesulfonamide (112d) (0.129 g, 0.462 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.259 g, 0.555 mmol), N,N-dimethylformamide (3 ml) and N-ethyl-N-isopropylpropane were added sequentially -2-amine (DIPEA) (0.403 mL, 2.312 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (30 ml) and extracted with chloroform (2x30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(3(hydroxy(4-sulfamoylphenyl)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112e) (169 mg, 67% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.06 - 7.85 (m, 2H), 7.74 (ddd, J=10.1, 7.2, 2.8 Hz, 4H), 7.64 (d, J=2.2 Hz, 1H), 7.60 - 7.48 (m, 3H), 7.35- 7.24 (m, 3H), 7.15 (d, J=7.7 Hz, 1H), 6.16 (d, J=3.8 Hz, 1H, exchange with D2O ), 5.76 (d, J=3.9 Hz, 1H); ¹ H NMR (300 MHz, DMSO-d6, D ₂ O) δ 10.66 (s, 1H), 8.15 (d, J=2.3 Hz, 1H), 8.04 - 7.87 (m , 2H), 7.79 -7.69 (m, 4H), 7.64 (d, J=2.1 Hz, 1H), 7.60 - 7.50 (m, 3H), 7.33 - 7.28 (m, 2H), 5.76 (s, 1H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -60.95; MS (IER+) 564.18 (M+1), MS (IER-) 540.2 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112f).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (112e) (0.164 g, 0.303 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (0.066 ml, 0.909 mmol) and stir at room temperature for 15 hours. The reaction is quenched with cyclopropylmethanamine (0.182 ml, 2.120 mmol), stir the mixture for 1 hour at room temperature and concentrate dry in a vacuum. The residue was dissolved in cyclopropylmethanamine (0.519 ml, 6.06 mmol), acetonitrile (10 ml) and heated at 80°C for 16 hours. TLC analysis (CHCl ₃ /MeOH, 9/1, v/v) indicated completion of the reaction, the reaction mixture was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4sulfamoylphenyl)methyl)phenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112f) (0.072 g, 40% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H, exchange with D2O), 8.16 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7 ,7, 1.3 Hz, 1H), 7.90 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.79 - 7.69 (m, 4H), 7, 66 (s, 1H), 7.63 - 7.51 (m, 3H), 7.34 - 7.15 (m, 4H), 4.92 (s, 1H), 2.28 (d, J= 4.7 Hz, 3H), 0.92 (s, 1H), 0.46 - 0.33 (m, 2H), 0.05 (q, J=4.8 Hz, 2H); 1H NMR (300 MHz, DMSO-d6, D ₂ O) δ 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H) , 7.94 - 7.87 (m, 1H), 7.79 - 7.70 (m, 4H), 7.66 (d, J=2.1 Hz, 1H), 7.63 - 7.51 (m, 3H), 7.33 - 7.17 (m, 2H), 4.91 (s, 1H), 2.28 (dd, J=6.6, 2.5 Hz, 2H), 0, 92 (d, J=10.4 Hz, 1H), 0.48 - 0.32 (m, 2H), 0.05 (tt, J=5.9, 3.3 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.94; MC (IER+): MC (IER+) 593.24 (M+1), MC (IER-) 595.29 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112g) .

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112f) (0.065 g, 0.109 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel(II) chloride hexahydrate (0.032 g, 0.137 mmol) was added, followed by sodium borohydride (0.033 g, 0.875 mmol) in small portions over 5 min. The reaction mixture was stirred for 15 min at 0°C, after which N1-(2-aminoethyl)ethane-1,2diamine (0.118 ml, 1.093 mmol) was added. The mixture was stirred for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (30 ml) and extracted with chloroform (2x30 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and excess solvents were pumped off under reduced pressure. The residue was purified by column chromatography [(silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0 to 100%)] to give 1-(3-(aminomethyl)phenyl)-M-(3((cyclopropylmethylamino)(4- sulfamoylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (112g) (28 mg, 43% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 7.78 - 7.71 (m, 2H), 7.67 (t, J=1.8 Hz, 1H), 7.63 -7.54 (m, 3H), 7.54 - 7.48 (m, 2H), 7.47 - 7.38 (m, 2H), 7.35 - 7.28 (m, 1H ), 7.27 - 7.16 (m, 2H), 4.91 (s, 1H), 3.77 (s, 2H), 2.37 - 2.19 (m, 2H), 1.24 ( s, 1H), 0.93 (dd, J=8.7, 4.7 Hz, 1H), 0.52 -0.27 (m, 2H), 0.10 - 0.01 (m, 2H) ; 1H NMR (300 MHz, DMSO-d6, D ₂ O) δ 7.72 (d, J=1.8 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.52 - 7 .38 (m, 5H), 7.33 - 7.15 (m, 3H), 4.88 (s, 1H), 3.71 (s, 2H), 2.24 (dd, J=7.0 , 1.7 Hz, 2H), 0.88 (ddt, J=10.8, 7.2, 4.3 Hz, 1H), 0.47 - 0.25 (m, 2H), 0.05- -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.52; MC (IER+): MC (IER+) 599.3 (M+1), (IER-) 597.3 (M-1), 633.3 (M+Na); analysis, calculation for: C ₂ 9H ₂ 9F3N6O3S-H ₂ O-0.15CHCl·,: C, 55.17; H, 4.95; N, 13.24; experiment: C, 55.35; H, 4.66; N, 12.95.

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Scheme 113

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (113P ).

Step 1. Preparation of (3-aminophenyl)(4-(methylsulfonyl)phenyl)methanol (113b).

To a solution of 4-(methylsulfonyl)benzaldehyde (3.68 g, 20 mmol) in tetrahydrofuran (30 ml), cooled to 0°C, was added (3-(bis(trimethylsilyl)amino)phenyl)-magnesium chloride (49c) ( 24.0 ml, 24.0 mmol), stirred at 0°C for 1 hour and at room temperature for 12 hours. The reaction mixture was treated with 1N. HCl (aq, 50 ml), stirred at room temperature for 1 hour, neutralized with NaOH (2N, aq) to pH~8 and extracted with ethyl acetate (2x80 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 80 g, eluted with chloroform/methanol (1:0 to 19:1)] to give (3-aminophenyl)(4-(methylsulfonyl)phenyl)methanol (113b) ( 3.858 g, 70%) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.88 - 7.81 (m, 2H), 7.64 - 7.58 (m, 2H), 6.93 (t, J=7.7 Hz , 1H), 6.60 - 6.50 (m, 2H), 6.40 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 5.98 (d, J=3 .8 Hz, 1H), 5.62 (d, J=3.8 Hz, 1H), 5.04 (s, 2H), 3.17 (s, 3H); MS (IER+) 300.1 (M+23).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-(methylsulfonyl)phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (113c).

To a solution of (3-aminophenyl)(4-(methylsulfonyl)phenyl)methanol (113b) (2.5 g, 9.01 mmol) in DMF (48 ml) was added 1-(3-cyanophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxylic acid (9i) (2.53 g, 9.01 mmol), N-ethyl-N-isopropylpropan-2-amine (13.00 ml, 74.6 mmol), hexafluorophosphate (V ) bromo-tripyrrolidin-1-ylphosphonium (PyBrOP, 4.29 g, 9.01 mmol) and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x80 ml), brine ( 80 ml), dried over MgSO ₄ and concentrated to dryness in vacuo. The crude product was purified by flash column chromatography [silica gel, 80 g, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-( hydroxy(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (113c) (4.15 g, 85%) as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 10.66 (s, 1H), 8.17 - 8.15 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H ), 7.94 - 7.84 (m, 3H), 7.77 - 7.69 (m, 2H), 7.68 - 7.52 (m, 4H), 7.29 (t, J=7 .8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.23 (d, J=3.8 Hz, 1H), 5.81 (d, J=3.9 Hz, 1H), 3.17 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 60.95; MS (IER+) 563.2 (M+23).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (113d) .

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (113c) (1.984 g, 3.67 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (0.780 ml, 10.53 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with triethylamine (4.50 ml, 32.3 mmol ), stirred at room temperature for 1 hour, then treated with cyclopropylmethanamine (5.38 g, 73.4 mmol), conc.

- 226 045731 tririated to remove most of the dichloromethane. Acetonitrile (36 ml) was added to the reaction mixture, heated at 70°C for 14.5 hours and concentrated to dryness in vacuo. The residue was treated with chloroform (150 ml), washed with water (75 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)( 4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (113d) (329 mg, 15%) as a brown viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.18 - 8.13 (m, 1H), 8.01 (dt, J=7.7, 1.3 Hz , 1H), 7.96 - 7.50 (m, 9H), 7.32-7.18 (m, 2H), 4.96 (s, 1H), 3.16 (s, 3H), 2, 35-2.20 (m, 2H), 0.90 (d, J=7.3 Hz, 1H), 0.50-0.25 (m, 2H), 0.11 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.96; MS (IER+) 594.3 (M+1).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate ( 113e).

Into a solution of 1-(3-cyanophenyl)-M-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (113d) (314 mg, 0.529 mmol) in MeOH (9 mL), cooled in ice/water, di-tert-butyl dicarbonate (350 mg, 1.587 mmol), nickel (II) chloride hexahydrate (68.0 mg, 0.286 mmol) was added, then slowly sodium borohydride (204 mg, 5.29 mmol) over 5 min. The reaction mixture was stirred at room temperature for 1 hour, quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.260 mL, 2.380 mmol), stirred at room temperature for 0.5 hour and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (120 ml), washed with water (75 ml). The aqueous phase was again extracted with ethyl acetate (75 ml). The combined organic extracts were washed with brine (75 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(3((cyclopropylmethylamino)(4- (methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (113e) (215 mg, 58%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.69 (s, 1H), 7.87 - 7.82 (m, 2H), 7.72 -7.64 (m, 3H), 7.57 (s, 1H), 7.55- 7.19 (m, 8H), 4.95 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.16 (s, 3H), 2.35-2.22 (m, 2H), 1.36 (s, 9H), 1.00-0.80 (m, 1H), 0.48 - 0.27 (m, 2H) , 0.13 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.78; MS (IER+) 698.4 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5- carboxamide (113f).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(4-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (113e) ( 0.188 g, 0.269 mmol) in 1,4dioxane (20 ml), hydrogen chloride (2.8 ml, 11.21 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 13 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino )(4-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (113f) (107 mg, 66%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.67 (s, 1H), 7.93-7.12 (m, 13H), 4.95 (s, 1H), 3.77 (s, 2H ), 3.16 (s, 3H), 2.36-2.21 (m, 2H), 1.01 -0.82 (m, 1H), 0.47 - 0.31 (m, 2H), 0.13 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.53; MS (IER+): 598.3 (M+1); ICS (KBr tablet, ^cm'1 ): 3365, 3006, 2926, 1683, 1553, 1243, 1148; analysis, calculation for C30H ₃₀ F ₃ N ₅ O ₃ S-1.0H ₂ O: C, 58.53; H, 5.24; N, 11.38; experiment: C, 58.85; H, 5.21; N, 11.29.

- 227 045731

Scheme 114

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmetulamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (114f ).

Step 1. Preparation of (3-aminophenyl)(3-(methylsulfonyl)phenyl)methanol (114b).

To a stirred solution of 3-(methylsulfonyl)benzaldehyde (114a) (1 g, 5.43 mmol) in tetrahydrofuran (10 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (6.51 ml , 6.51 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (13.57 ml, 13.57 mmol), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH4Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give (3-aminophenyl)(3-(methylsulfonyl)phenyl)methanol (114b) (1.004 g, 67% ) in the form of a white viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.93 (t, J=1.7 Hz, 1H), 7.77 (dt, J=7.6, 1.5 Hz, 1H), 7, 66 (dt, J=7.7, 1.5 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.58 (t, J=1.9 Hz, 1H), 6.53 (dt, J=7.5, 1.3 Hz, 1H), 6.40 (ddd, J=8.0, 2, 3, 1.1 Hz, 1H), 5.99 (d, J=3.8 Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 5.05 (s, 2H) , 3.20 (s, 3H); MS (IER+): 278.1 (M+H).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(methylsulfonyl)phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (114c).

In a 100 mL one-neck flask, 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.963 g, 3.43 mmol), (3-aminophenyl)(3-(methylsulfonyl) )phenyl)methanol (114b) (0.95 g, 3.43 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (1.629 g, 3.43 mmol) were sequentially treated with N,N-dimethylformamide (36.0 ml, 465 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (4.80 ml, 27.6 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (120 ml), washed with water (2x60 ml) and brine (60 ml) and dried over anhydrous MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(3 -(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (114c) (1.228 g, 66%) as an off-white solid; 1H NMR (300 MHz, DMSO^) δ 10.68 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.94 (t, J=1.8 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.82 - 7 .77 (m, 1H), 7.76 - 7.64 (m, 4H), 7.63 - 7.55 (m, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.18 (dt, J=7.7, 1.3 Hz, 1H), 6.24 (d, J=3.9 Hz, 1H), 5.82 (d, J=3.9 Hz, 1H ), 3.18 (s, 3H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.98; MS (IER-): 539.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (114d) .

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (114c) (1.18 g, 2.19 mmol) in dichloromethane (25 ml) at 0°C was added

- 228 045731 thionyl chloride (1.06 ml, 14.55 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with triethylamine (2.70 ml, 19.34 mmol), and the mixture was stirred for 1 hour.

The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (22 ml) and cyclopropylmethanamine (3.21 g, 43.8 mmol) was added. The reaction mixture was heated at 70°C for 19 hours, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (120 ml), washed with water (60 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-50% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl )methyl)phenyl)-3-(trifluoromethyl)-1H-nirazol-5-carboxamide (114d) (208 mg, 16%) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.16 (t, J=1.9 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.95-7.87 (m, 1H), 7.80 - 7.51 (m, 7H), 7.33 - 7.18 (m, 2H), 4.97 (s, 1H), 3, 17 (s, 3H), 2.36-2.22 (m, 2H), 1.02 - 0.79 (m, 1H), 0.55-0.29 (m, 2H), 0.17 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.94; MS (IER+): 594.3 (M+1).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate ( 114e).

Into a solution of 1 -(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (114d) (195 mg, 0.328 mmol) in MeOH (6 mL), cooled in ice/water, di-tert-butyl dicarbonate (217 mg, 0.985 mmol) and nickel(II) chloride (42.0 mg, 0.177 mmol) were added. Sodium borohydride (127 mg, 3.28 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.160 mL, 1.462 mmol) , stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in ethyl acetate (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with ethyl acetate (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3 -(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (114e) (135 mg, 59%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 8.00 (br s, 1H), 7.79-7.71 (m, 2H), 7.68 (br .s, 1H), 7.61 - 7.19 (m, 10H), 4.96 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.16 (s, 3H), 2.33-2.22 (m, 2H), 1.36 (s, 9H), 0.99-0.80 (m, 1H), 0.46 - 0.31 (m, 2H) , 0.10-0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.78; MS (IER+): 698.4 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-nirazol-5 - carboxamide (114f).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (114e) ( 120 mg, 0.172 mmol) in 1,4dioxane (15 ml), hydrogen chloride (1.8 ml, 7.2 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 15 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino )(3-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (114f) (49 mg, 48%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.94 (s, 1H), 10.17 (s, 2H), 8.46 - 7.37 (m, 13H), 5.81 (s, 1H ), 4.13 (d, J=5.1 Hz, 2H), 3.22 (s, 3H), 2.83 - 2.67 (m, 2H), 1.13 (lat.s, 1H) , 0.56 (d, J=7.8 Hz, 2H), 0.31 (lat.s, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.77; MS (IER+): 598.3 (M+1); IR (KBr tablet, cm ^-1 ): 3433, 3013, 1675, 1616, 1558, 1246, 1143.

Scheme 115

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(cyclopropanecarboxamido(phenyl)methyl)phen

- 229 045731 nyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (115e).

Step 1. Preparation of tert-butyl-3-(5-((3-(chloro(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (115a).

In a solution of tert-butyl-3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (18c) (133 mg, 0.235 mmol) in dichloromethane (5 ml) at 0°C, add triethylamine (0.131 ml, 0.939 mmol), thionyl chloride (0.026 ml, 0.352 mmol) and stir at room temperature for 2 hours. Concentrate the reaction mixture to dryness in vacuo to obtain tert-butyl-3-( 5-((3-(chloro(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (115a) (137 mg, 100%), which was used as such for next stage.

Step 2. Preparation of tert-butyl-3-(5-((3-(azido(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (115b).

Into a stirred solution of tert-butyl 3-(5-(3-(chloro(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (115a) (137 mg, 0.235 mmol) add sodium azide (61.1 mg, 0.94 mmol) to acetonitrile (10 ml) and heat at reflux temperature for 16 hours. Concentrate the reaction mixture in vacuo, dilute with ethyl acetate (25 ml) and wash with water (2x10 ml) . Extracted the aqueous layer with ethyl acetate (2x25 ml). Combine the organic layers, wash with water (20 mL), brine (10 mL), dry and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 4 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give tert-butyl-3-(5-(3-(azido(phenyl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (115b) (75 mg, 0.127 mmol, 53.9% yield) as a colorless solid; MS (IER+) 614.3 (M+Na), 590.3 (IER-) (M-1).

Step 3. Preparation of tert-butyl-3-(5-((3-(amino(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (115c).

To a suspension of Pd/C (10%, 12.59 mg) in methanol (20 ml) was added tert-butyl-3-(5-(3-(azido(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H -pyrazol-1-yl)benzylcarbamate (115b) (70 mg, 0.118 mmol) and hydrogenated at 60 psi (414 kPa) for 2 hours. The reaction mixture was filtered through celite and concentrated in vacuo.

The crude residue was purified by flash column chromatography (silica gel, 4 g, eluted with mixtures of CMA 80 in chloroform, 0 to 100%) to give tert-butyl-3-(5-(3-(amino(phenyl)methyl)phenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (115c) (24 mg, 35.9% yield) as a colorless foam; MS (IER+) 566.3 (M+1); (IER-) 564.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-((3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (115d).

In a solution of tert-butyl-3-(5-(3-(amino(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol1-yl)benzylcarbamate (115c) (24 mg, 0.042 mmol) in dichloromethane ( 5 ml) cyclopropanecarboxylic acid (5.07 µl, 0.064 mmol), triethylamine (0.024 ml, 0.170 mmol) and EDCI (16.27 mg, 0.085 mmol) were added at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with dichloromethane (2x50 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give tert-butyl-3-(5-(3(cyclopropanecarboxamido-(phenyl)methyl)phenylcarbamoyl)- 3 -(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (115d) (23 mg, 0.036 mmol, 86% yield); MS (ESI+) 656.4 (M+Na); (IER-) 632.3 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (115e).

In a solution of tert-butyl-3-(5-(3-(opropanecarboxamido(phenyl)methyl)phenylcarbamoyl ring)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (115d) (21 mg, 0.033 mmol) in methanol (5 ml) added conc. hydrogen chloride (0.033 ml, 0.133 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 4 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1-(3(aminomethyl)phenyl)-N-(3-(cyclopropanecarboxamido(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (115e) (0.016 g, 0.030 mmol, 90% yield) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.78 (s, 1H), 9.02 (d, J=8.7 Hz, 1H), 8.30 (s, 3H), 7.71 (s, 1H ), 7.64 (s, 1H), 7.62 - 7.54 (m, 3H), 7.52 (q, J=2.1 Hz, 2H), 7.39 -7.30 (m, 3H), 7.27 (d, J=7.1 Hz, 3H), 7.04 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 6.08 (d, J=8.4 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 0.68 (s, 2H), 0.66 (s, 2H); MC (IER+) 534.4 (M+1); (IER-) 532.3 (M-1).

- 230 045731

Scheme 116

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-ethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-N-pyrazole-5-carboxamide (116e).

Step 1. Preparation of (3-aminophenyl)(3-vinylphenyl)methanol (116b).

To a stirred solution of 3-vinylbenzaldehyde (116a) (1.32 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 ml, 12 0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH4Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(3-vinylphenyl)methanol (116b) (1.2 g, yield 53.33 %) in the form of a red-brown oily liquid, which was used in this form in the next stage.

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (116c).

SOCl ₂ (0.928 ml) was added to a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.947 g, 6.924 mmol) in toluene (50 ml) and 15 drops of DMF , 12.78 mmol) at 0°C. The reaction mixture was refluxed for 3.5 hours and concentrated to remove volatile solvent. The resulting residue was dissolved in DCM (50 ml) and (3-aminophenyl)(3vinylphenyl)methanol (116b) (1.2 g, 5.326 mmol), triethylamine (7.2 ml) was added at room temperature. The reaction mixture was stirred overnight at room temperature. Concentrate the reaction mixture and purify by flash column chromatography (silica gel, eluting with 10%-70% ethyl acetate in hexanes) to give the product {3-[hydroxy-(3-vinylphenyl)methyl]phenyl}amide 2(3-cyanophenyl)-5 -trifluoromethyl-2H-pyrazole-3-carboxylic acid (116c) (2.1 g, 80.76%) as a red-brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1 ,3 Hz, 1H), 7.89 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.64 (t, J=1.8 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.46 (d , J=1.8 Hz, 1H), 7.35- 7.22 (m, 4H), 7.15 (d, J=7.6 Hz, 1H), 6.71 (dd, J=17, 7, 10.9 Hz, 1H), 5.97 (d, J=3.9 Hz, 1H), 5.78 (dd, J=17.6, 1.1 Hz, 1H), 5.68 ( d,, J=3.9 Hz, 1H), 5.24 (dd,, J=11.0, 1.0 Hz, 1H).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (116d) .

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (116c) (2.1 g, 4.299 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.65 ml, 8.598 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (50 ml) and cyclopropylmethanamine (5.6 ml, 64.485 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo to give 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(3vinylphenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (116d) (4.9 g) as a red-brown sticky liquid, which was used as such without further purification.

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-ethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (116e) .

In a solution of 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(3-vinylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (116d) (4 .9 g, crude, 8.986 mmol) in MeOH (50 mL), cooled in ice/water, add nickel(II) chloride hexahydrate (2.67 g, 11.233 mmol), then

- Sodium borohydride (2.03 g, 53.916 mmol) was added in 231 045731 parts over 15 minutes. The reaction mixture was stirred at room temperature for 1 hour and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (4.85 mL, 44.92 mmol), then stirred for an additional 0.5 hour. Concentrate the reaction the mixture was dried in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give 1-(3-(aminomethyl)phenyl)-K-(3-((cyclopropylmethylamino)(3-ethylphenyl )methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (116e) (0.041 g, 1% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.70 (d, J=6.3 Hz, 2H), 7.67 (s, 1H), 7.63 - 7.49 (m, 4H), 7.28 7.17 (m, 5H), 7.04 (q, J=3.2, 2.7 Hz, 1H), 4.83 (s, 1H), 4.11 (s, 2H), 2.56 (d, J=7.7 Hz, 2H), 2.29 (dd, J=7.8, 5.1 Hz, 2H), 1.15 (t , J=7.6 Hz, 3H), 1.01 - 0.86 (m, 1H), 0.46 - 0.35 (m, 2H), 0.06 (q, J=4.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.79; MS (IER+) 548.3 (M+1); (IER-) 546.3 (M-1).

Scheme 117

An example of the preparation of 1-(3-(aminomethyl)phenyl)-C-(3-((cyclopropylmethylamino)(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (117e).

Step 1. Preparation of (3-aminophenyl)(2-fluorophenyl)methanol (117b).

To a stirred solution of 2-fluorobenzaldehyde (117a) (1.32 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 ml, 12 0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (12.5 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0100% ethyl acetate in hexanes) to give (3-aminophenyl)(2-fluorophenyl)methanol (117b) (1.8 g, 77.92% yield) in the form of a red-brown oily liquid.

Step 2. Preparation of 1-(3-cyanophenyl)-K-(3-(hydroxy(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (117c).

SOCl ₂ (2.365 g, 19.88 mmol) at 0°C. The reaction mixture was refluxed for 3.5 hours and concentrated to remove volatile solvent. The resulting residue was dissolved in dichloromethane (100 ml) and (3-aminophenyl)(2-fluorophenyl)methanol (117b) (1.8 g, 8.284 mmol) was added, then triethylamine (10.8 ml) was added dropwise at room temperature. The reaction mixture was stirred overnight at room temperature and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography (10-70% ethyl acetate in hexanes) to give the product {3-[(2-fluorophenyl)hydroxymethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid acids (117c) (2.1 g) as a red-brown liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 8.21 (t, J=1.8 Hz, 1H), 8.05 (dt, J=7.8, 1 ,3 Hz, 1H), 7.95 (ddd, J=8.2, 2.1, 1.1 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.69 - 7.53 (m, 3H), 7.38 - 7.29 (m, 2H), 7.25 (td, J=7.5 , 1.3 Hz, 1H), 7.21 - 7.12 (m, 2H), 6.12 (d, J=4.2 Hz, 1H), 5.98 (d, J=4.2 Hz , 1H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)(2-fluorophenyl)methyl]phenyl}amide 2-(3cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (117d).

Into a solution of {3-[(2-fluorophenyl)hydroxymethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H

- 232 045731 pyrazole-3-carboxylic acid (117c) (2.1 g, 4.371 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.65 ml, 8.742 mmol) and stir at room temperature for 4 h. The reaction mixture was concentrated to dryness in vacuum. The resulting residue was dissolved in acetonitrile (50 ml) and cyclopropylmethanamine (5.7 ml, 65.568 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give {3[(cyclopropylmethylamino)(2-fluorophenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5- trifluoromethyl-2-Pyrazole-3-carboxylic acid (117d) (1.05 g, 45.06% yield) as a red-brown sticky liquid.

Step 4. Preparation of 1-(3-(αminomethyl)phenyl)-N-(3-((cyclononylmethylamino)(2-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (117e) .

A solution of {3-[(cyclopropylmethylamino)(2-fluorophenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (117d) (1.05 g, 1.968 mmol) in MeOH (20 mL) cooled in ice/water, nickel(II) chloride hexahydrate (0.584 g, 2.46 mmol) was added, then sodium borohydride (0.45 g, 11.808 mmol) was added portionwise over 15 min. The reaction mixture was stirred at room temperature for 1 hour and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.06 mL, 9.84 mmol), then stirred for an additional 0.5 hour. Concentrate the reaction the mixture was dried in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give {3-[(cyclopropylmethylamino)(2-fluorophenyl)methyl]-phenyl}amide 2-(3-aminomethylphenyl) )-5trifluoromethyl-2P-pyrazole-3-carboxylic acid (117e) (0.29 g, 27.43% yield) as a white solid; 1P NMR (300 MHz, DMSO^) δ 10.78 (s, 1P), 8.37 (s, 3P), 7.72 (s, 1P), 7.70 - 7.56 (m, 5P), 7.56 7.47 (m, 1P), 7.28 (t, J=7.8 Hz, 2P), 7.22 (s, 2P), 7.12 (dd, J=10.7, 8 ,2 Hz, 1P), 5.17 (s, 1P), 4.12 (s, 2P), 2.34 (d, J=6.7 Hz, 2P), 0.94 (d, J=11 ,1 Hz, 1P), 0.48 - 0.35 (m, 2P), 0.12 - 0.02 (m, 2P); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.79, -118.99; MS (IER+) 538.3 (M+1); (IER-) 536.3 (M-1); analysis, calculation for CzoPzoFzN5O2·2.75PCl: C, 54.61; P, 4.70; N, 10.98; experiment: C, 54.63; P, 4.50; N, 11.17.

Scheme 118

118d _118e 118f

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1P-pyrazole-5-carboxamide ( 118f).

Step 1. Preparation of (3-aminophenyl)(10-chloroanthracen-9-yl)methanol (118b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (2.95 g, 9.97 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. PS1 (10.39 ml, 20.77 mmol), stirred for 2 hours. The reaction mixture was treated with 2N. NαOP (12.46 ml, 24.93 mmol) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NP ₄ C1 (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(10-chloroanthracen-9yl)methanol (118b) (2.375 g, 7.11 mmol , yield 86%) as a yellow solid; ¹ P NMR (300

- 233 045731

MHz, DMSO-d ₆ ) δ 8.63 (d, J=9.0 Hz, 2H), 8.49 (dd, J=8.8, 1.2 Hz, 2H), 7.78 - 7, 60 (m, 2H), 7.53 (dd, J=8.9, 6.6 Hz, 2H), 7.16 (d, J=4.3 Hz, 1H), 6.90 (t, J =7.8 Hz, 1H), 6.52 - 6.47 (m, 1H), 6.41 (s, 1H), 6.38 - 6.31 (m, 2H), 4.91 (s, 2H, exchange with D ₂ O); ¹ H NMR (300 MHz, DMSO-d ₆ D2O) δ 8.61 (d, J=9.0 Hz, 2H), 8.51 (dd, J=8.7, 1.2 Hz, 2H), 7.69 (ddd, J=8.9, 6.5, 1.1 Hz, 2H), 7.54 (dd, J=8.9, 6.6 Hz, 2H), 7.16 (s, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.55- 6.43 (m, 2H), 6.37 (dd, J=7.7, 2.2 Hz, 1H ); MS (IER ^- ): MS (IER-) 332.3 (M-1).

Step 2. Preparation of N(3-((10-chloroanthracen-9-yl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide (118c).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (1.264 g, 4.49 mmol), (3-aminophenyl)(10-chloroanthracene- 9-yl)methanol (118b) (1.5 g, 4.49 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop, 2.51 g, 5.39 mmol), N,N-dimethylformamide (26, 1 ml, 337 mmol), N-ethyl-M-isopropylpropan-2amine (3.91 ml, 22.47 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (75 ml), extracted with chloroform (2x75 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give N(3-((10-chloroanthracen-9yl)(hydroxy)methyl)phenyl)-1 -(3 -cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (118c) (1.823 g, 68.0% yield) as a yellow solid. MS (IER-) 595.2 (M-1).

Step 3. Preparation of N(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (118d).

Into a solution of N-(3-((10-chloranthracen-9-yl)(hydroxy)methyl)phenyl)-1 -(3 -cyanophenyl)-3 -(trifluoromethyl)-1H-pyrazol-5-carboxamide (118c) ( 1.685 g, 2.82 mmol) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.618 ml, 8.47 mmol) and stir at room temperature for 18 hours. The reaction is quenched with cyclopropylmethanamine (1.693 ml, 19.76 mmol ), the mixture was stirred for 1 hour at room temperature and concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanamine (4.84 ml, 56.5 mmol) and acetonitrile (20 ml) and the reaction mixture was heated at 80°C for 16 h, TLC analysis (ethyl acetate/hexanes, 3/7, v/v). ) indicated the end of the interaction; the reaction mixture was evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes, 0-100%) to give N-(3-((10-chloroanthracen-9yl)(cyclopropylmethylamino)methyl)phenyl) -1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (118d) (0.903 g, 1.389 mmol, 49.2% yield) as a yellow solid. MS (IER+) 649.19.

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (118f).

Into a stirred solution of N-(3-((10-chloranthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (118d) ( 831 mg, 1.278 mmol) in anhydrous methanol (20 ml), cooled to 0°C, add di-tert-butyl dicarbonate (0.837 g, 3.83 mmol), nickel (II) chloride hexahydrate (0.380 g, 1.598 mmol), then sodium borohydride (0.283 g, 7.668 mmol) in small portions over 5 minutes. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 45 min at 0°C, after which N1-(2-aminoethyl)-ethane1,2-diamine (1.381 ml, 12.78 mmol) was added. The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (50 ml) and extracted with chloroform (2x50 ml). The organic layers were combined, dried over anhydrous MgSO4, filtered, and excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 100%)] to give tert-butyl-3-(5-(3-((10chloroanthracen-9-yl)() cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (118e) (0.463 g, 0.614 mmol, 48.0% yield) as yellow solid and 1-(3(aminomethyl)phenyl )-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (118f) (0.143 g, 0.219 mmol, yield 17 .10%), which was isolated as a free base. The free base of compound 118f was treated with 12N. aqueous HCl (7 equiv., 0.13 ml) in 2 ml IPA and stirred for 10 minutes, then triturated with diethyl ether, refluxed for 1 hour, cooled to room temperature. The resulting solid was collected by filtration, dried under reduced pressure for 16 hours to obtain 1-(3-(aminomethyl)phenyl)-N-(3-((10-chloroanthracen-9-yl)(cyclopropylmethylamino)methyl) hydrochloride salt. phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (118f) (50 mg) as a yellow solid. 1H NMR (300 MHz, DMSO^) δ 10.79 (s, 1H), 10.66 (s, 1H), 9.79 (s, 1H), 8.83 - 8.57 (m, 3H), 8.40 (s, 3H), 8.20 (m, 1H), 7.79 (m, 4H), 7.66 - 7.45 (m, 6H), 7.24 (m, 1H), 7 .15 (s, 1H), 4.09 (q, J=5.8 Hz, 2H), 3.03 (m, 1H), 2.64 (m, 1H), 1.21 - 1.07 ( m, 1H), 0.47 (m, 2H), 0.33 - 0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ 60.86; MS (IER+) 654.3 (M+1); (IER-) 652.3 (M-1); analysis, calculation for €37^1^^0-2.25^1-2^0: C, 57.55; H, 4.86; C1, 14.92; N, 9.07; experiment: C, 57.29; H, 4.96; C1, 14.96; N, 8.87.

- 234 045731

Scheme 119

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide ( 119e).

Step 1. Preparation of (3-aminophenyl)(2-methoxyphenyl)methanol (119b).

To a stirred solution of 2-methoxybenzaldehyde (119a) (1.36 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12 00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH4Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexane) to give (3-aminophenyl)(2-methoxyphenyl)methanol (119b) (0.8 g, 35% yield) in the form of a red-brown oily liquid.

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (119c).

SOCl ₂ (0.618 ml, 12.78 mmol) at 0°C. The reaction mixture was refluxed for 3.5 hours and concentrated to remove volatile solvent. The resulting residue was dissolved in DCM (100 ml) and (3-aminophenyl)(2-methoxyphenyl)methanol (119b) (0.8 g, 3.5 mmol) was added, then triethylamine (4.8 ml) was added dropwise at RT. The reaction mixture was stirred overnight at room temperature and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography (10%-70% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-(hydroxy(2-methoxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1H -pyrazole-5-carboxamide (119c) (1.8 g, 80.76%) as a red-brown oily liquid that solidified on standing; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.20 (t, J=1.9 Hz, 1H), 8.05 (dt, J=7.8, 1 .3 Hz, 1H), 7.95 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.69 (t, J=1.9 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.49 (dd, J=7.8, 1.8 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.19 - 7.11 (m, 1H), 7.03 - 6.94 (m, 2H), 6.03 (d, J=4.1 Hz, 1H), 3.80 (s, 3H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)(2-fluorophenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (119d).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (119c) (1.8 g, 3.655 mmol) Thionyl chloride (0.87 g, 7.310 mmol) was added to dichloromethane (50 ml) at 0°C and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (50 ml) and cyclopropylmethanamine (3.9 g, 54.82 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue (crude, 4.2 g) of (3-[(cyclopropylmethylamino)(2-fluorophenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (119d) in the form of a red-brown oily liquid was used as such in the next step.

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5- carboxamide (119e).

To a solution of {3-[(cyclopropylmethylamino)(2-fluorophenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (119d) (crude, 4.2 g) in MeOH (50 mL), cooled in ice/water, add nickel(II) chloride hexahydrate (2.28 g, 9.628 mmol), then

- 235 045731 sodium borohydride (1.748 g, 46.212 mmol) was added over 15 minutes. The reaction mixture was stirred at room temperature for 1 hour and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (4.85 mL, 44.92 mmol), then stirred for an additional 0.5 hour. Concentrate the reaction the mixture was dried in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)( 2-methoxyphenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (119e) (210 mg, 10%) as a white solid. The solid was re-purified by flash column chromatography (silica gel, 4 g, eluted with 0-25% chloroform/methanol) to give the product, which was dissolved in methanol, 10 eq. conc. HCl and concentrated to dryness in vacuo to give HCl salt 1-(3(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (119e) (10 mg); 1H NMR (300 MHz, DMSO-dg) δ 10.97 (s, 1H), 10.04 (s, 1H), 9.72 (s, 1H), 8.49 (s, 3H), 7.84 (t, J=1.8 Hz, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7 .70 (s, 1H), 7.66 - 7.60 (m, 2H), 7.59 - 7.48 (m, 3H), 7.45 - 7.33 (m, 2H), 7.06 (ddd, J=14.9, 7.9, 1.0 Hz, 2H), 5.74 (s, 1H), 4.12 (s, 2H), 3.82 (s, 3H), 2, 81 - 2.67 (m, 2H), 1.20 - 0.99 (m, 1H), 0.62 - 0.49 (m, 2H), 0.32 - 0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.79; MS (IER+) 550.04 (M+1); (IER-) 548.3 (M-1).

Scheme 120

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamideα ( 120e).

Step 1. Preparation of (3-aminophenyl)(4-isopropylphenyl)methanol (120b).

To a stirred solution of 4-isopropylbenzaldehyde (120a) (1.48 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 ml, 12 0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexane) to give (3-aminophenyl)(4-isopropylphenyl)methanol (120b) (1.85 g, 81% yield) in the form of a red-brown sticky liquid.

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideα(120c).

SOCl ₂ (2.129 g, 17.900 mmol) at 0°C. The reaction mixture was refluxed for 3.5 hours and concentrated to remove volatile solvent.

The resulting residue was dissolved in DCM (100 ml) and (3-aminophenyl)(4isopropylphenyl)methanol (120b) (1.85 g, 7.46 mmol) was added, then triethylamine (7.2 ml) was added dropwise at RT. The reaction mixture was stirred overnight at room temperature and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography (10%-70% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-(hydroxy(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamideα (120c) (3.1 g, 82.44%) as a red-brown sticky liquid; 1H NMR (300 MHz, DMSO-dg) δ 10.63 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1, 3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.64 (t, J =1.8 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.31 - 7.22 (m, 3H),

- 236 045731

7.15 (dd, J=8.5, 6.8 Hz, 3H), 5.86 (d, J=3.7 Hz, 1H), 5.63 (d, J=3.7 Hz, 1H ), 2.83 (p, J=6.9 Hz, 1H), 1.16 (d, J=7.0 Hz, 6H).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (120d) .

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)III-pyrazole-5-carboxamide (120c) (3.8 g, 7. 53 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.89 g, 12.288 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (50 ml) and cyclopropylmethanamine (8.0 ml, 92.17 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (120d) (1.05 g, 30.64% yield) as a red-brown sticky liquid, which was used as such in the next step.

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-M-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (120e).

In a solution of 1-(3-cyanophenyl)-M-(3-(((cyclopropylmethyl)amino)(4-isopropylphenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (120d) (1, 05 g, 1.883 mmol) in MeOH (20 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.559 g, 2.353 mmol) was added, then sodium borohydride (0.427 g, 11.298 mmol) was added portionwise over 15 minutes. The reaction mixture was stirred at room temperature for 1 hour and quenched with Y-(2-aminoethyl)ethane-1,2-diamine (1.2 mL, 11.83 mmol), then stirred for an additional 0.5 hour. Concentrate the reaction the mixture was dried in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give the free base 1-(3-(aminomethyl)phenyl)-M-(3-(((cyclopropylmethyl)amino )(4-isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (120e) (168 mg, 16% yield) as a white solid. The solid was purified again by flash column chromatography (silica gel, 4 g, eluted with 0-25% chloroform/methanol) to give the product (120e) as the free base, which was dissolved in methanol, 10 eq. conc. HCl and concentrated to dryness in vacuo to give HCl salt 1-(3-(aminomethyl)phenyl)-M-(3-(((cyclopropylmethyl)amino)(4isopropylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (120e) (10 mg); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.99 (s, 1H), 10.07 (s, 2H), 8.52 (s, 3H), 7.88 (t, J=1.8 Hz, 1H), 7.72 (d, J=3.6 Hz, 2H), 7.69 - 7.49 (m, 7H), 7.43 (t, J=7.9 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 5.58 - 5.44 (m, 1H), 4.12 (q, J=5.7 Hz, 2H), 2.87 (p , J=6.9 Hz, 1H), 2.70 (q, J=6.1 Hz, 2H), 1.26 - 1.08 (m, 7H), 0.59 - 0.49 (m, 2H), 0.35-0.25 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 562.4 (M+1); (IER-) 560.4 (M-1); analysis, calculation for C ₃₂ H ₃₄ F ₃ N5O-1.95HCl-1.75H ₂ O: C, 57.86; H, 5.99; Cl, 10.41; N, 10.54; experiment: C, 58.01; H, 6.02; Cl, 10.03; N, 10.06.

- 237 045731

Scheme 121

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 121f).

Step 1. Preparation of (3-aminophenyl)(2-(methylsulfonyl)phenyl)methanol (121b).

To a solution of 2-(methylsulfonyl)benzaldehyde (121a) (3.80 g, 20 mmol) in tetrahydrofuran (30 ml), cooled to 0°C, was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c ) (24.00 ml, 24.00 mmol) and stirred at room temperature for 12 hours. The reaction mixture was treated with 1N. HCl (aq, 50 ml), stirred at RT for 1 h, neutralized with NaOH (2N, aq) to pH = ~8 and extracted with ethyl acetate (2x80 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 80 g, eluted with chloroform/methanol (1:0 to 19:1)] to give (3-aminophenyl)(2-(methylsulfonyl)phenyl)methanol (121b) ( 4.912 g, 89%) as white foam; ¹ H NMR (300 MHz, DMSO^) δ 7.92 (dd, J=7.9, 1.4 Hz, 1H), 7.73 - 7.47 (m, 3H), 6.94 (t, J=7.7 Hz, 1H), 6.60-6.55 (m, 2H), 6.48 (dt, J=7.4, 1.2 Hz, 1H), 6.41 (ddd, J =8.0, 2.2, 1.0 Hz, 1H), 6.00 (d, J=5.0 Hz, 1H), 5.04 (s, 2H), 3.13 (s, 3H) ; MS (ESI+): 300.2 (M+Na).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(2-(methylsulfonyl)phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (121c).

To a solution of (3-aminophenyl)(2-(methylsulfonyl)phenyl)methanol (121b) (3.46 g, 12.48 mmol) in DMF (60 ml) was added 1-(3-cyanophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxylic acid (9i) (3.51 g, 12.48 mmol), N-ethyl-N-isopropylpropan-2-amine (18.00 ml, 103 mmol), hexafluorophosphate (V) bromotripyrrolidine -1-ylphosphonium (PyBrOP, 5.93 g, 12.48 mmol) and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (240 ml), washed with water (2x100 ml), brine (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 120 g, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-( hydroxy(2(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121c) (5.302 g, 79%) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.67 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.77 - 7.49 (m, 7H), 7.28 (t, J=7.9 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H), 6.71 (d, J=4.9 Hz, 1H), 6.28 (d, J=4.9 Hz, 1H), 3.23 (s , 3H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.94; MS (ESI+): 563.2 (M+Na).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121d) .

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121c) (3.407 g, 6.30 mmol) in dichloromethane (80 ml) at 0°C was added thionyl chloride (1.2 ml, 16.21 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with triethylamine (7.00 ml, 50, 2 mmol) and stirred at room temperature for 1 hour. The mixture was then treated with cyclopropylmethanamine (8.45 ml, 95 mmol) and concentrated to remove the bulk of the dichloromethane, after which acetonitrile (60 ml) was added, stirred at 70°C for 13 hours and at reverse condensation temperature for 5 hours. Reaction

- 238 045731 the mixture was treated with additional cyclopropylmethanamine (5 ml, 55.92 mmol), refluxed for 14 hours and concentrated to dryness. The residue was treated with chloroform (240 ml), washed with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 80 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)( 2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121d) (976 mg, 26%) as a brown viscous substance. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.18 - 8.15 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz , 1H), 7.95 (dd, J=7.9, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7, 77 - 7.46 (m, 7H), 7.36 - 7.22 (m, 2H), 5.95 (d, J=4.9 Hz, 1H), 3.28 (s, 3H), 2 .75-2.60 (m, 1H), 2.30-2.14 (m, 1H), 0.98-0.80 (m, 1H), 0.47 - 0.26 (m, 2H) , 0.16 - -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-06) δ -60.94; MS (IER+): 594.3 (M+H).

Step 4. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate ( 121e).

In a solution of 1-(3-cyanophenyl)-M-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121d) (700 mg, 1.179 mmol) in MeOH (20 mL), cooled in ice/water, di-tert-butyl dicarbonate (780 mg, 3.54 mmol), nickel chloride hexahydrate (0.3 mmol) was added slowly, then sodium borohydride ( 455 mg, 11.79 mmol) over 5 minutes. The reaction mixture was stirred for 1 hour, treated with N1-(2-aminoethyl)ethane-1,2-diamine (0.570 ml, 5.22 mmol), stirred at room temperature for 0.5 hour and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (150 ml), washed with water (75 ml). The aqueous phase was again extracted with ethyl acetate (75 ml). The combined extracts were washed with brine (75 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 2:1), then chloroform/methanol (1:0 to 9:1)] to give tert-butyl -3-(5-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (121e) (368 mg, 45% ) in the form of white foam; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.64 (s, 1H), 7.93 - 7.87 (m, 1H), 7.66 - 7.16 (m, 13H), 5.89 (s, 1H), 4.14 (d, J=6.3 Hz, 2H), 3.22 (s, 3H), 2.44 - 2.36 (m, 1H), 2.25 - 2, 10 (m, 1H), 1.31 (s, 9H), 0.93 - 0.70 (m, 1H), 0.42-0.22 (m, 2H), 0.09 - -0.07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.62; MS (IER+): 698.4 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5- carboxamide (121f).

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (121e) ( 0.344 g, 0.493 mmol) in 1,4dioxane (40 ml), hydrogen chloride (5.2 ml, 20.8 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 17 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give the free base 1-(3-(aminomethyl)phenyl)-M-(3-( (cyclopropylmethylamino)(2(methylsulfonyl)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121f). The purified product 121f was dissolved in methanol (10 ml) and treated with 4N. HCl (aq, 0.45 ml), then concentrated to dryness to give 1-(3-(aminomethyl)phenyl)-L-(3-((cyclopropylmethylamino)(2-(methylsulfonyl)phenyl)methyl)phenyl) hydrochloride salt -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (121f) (224 mg, 68%) as a white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.96 (s, 1H), 10.27 (s, 1H), 10.13 (s, 1H), 8.33 (s, 3H), 8, 24 (d, J=8.2 Hz, 1H), 8.07 (dd, J=7.9, 1.4 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.84 (s, 1H), 7.76 - 7.66 (m, 3H), 7.66 - 7.53 (m, 3H), 7.53 - 7.44 (m, 2H), 6.62 (d , J=7.0 Hz, 1H), 4.13 (q, J=5.9 Hz, 2H), 3.25 (s, 3H), 3.02 - 2.64 (m, 2H), 1 .09 (t, J=7.0 Hz, 1H), 0.58 (t, J=7.4 Hz, 2H), 0.33 (s, 2H); ¹ H NMR (D2O exchange NMR, 300 MHz, DMSO-d6) δ 8.13 - 7.39 (m, 13H), 6.59 (s, 1H), 4.13 (s, 2H), 3, 22 (s, 3H), 3.00-2.88 (m, 1H), 2.81-2.67 (m, 1H), 1.15-0.95 (m, 1H), 0.67- 0.50 (m, 2H), 0.37-0.22 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77; MS (IER+): 598.3 (M+1); ICS (KBr tablet, ^cm'1 ): 3433, 3015, 1672, 1612, 1553, 1246, 1149; analysis, calculation for C30H ₃₀ F ₃ N ₅ O ₃ S-2HCl-2H ₂ O: C, 50.99; H, 5.14; N, 9.91; experiment: C, 50.86; H, 5.03; N, 9.73.

- 239 045731

Scheme 122

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (122g ).

Step 1. Preparation of (4-aminophenyl)(p-toluyl)methanol (122b).

To a stirred solution of 4-methylbenzaldehyde (122a) (1.2 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12. 00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (12.50 ml), stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexane) to give (4-aminophenyl)(p-toluyl)methanol (122b) (1.5 g, 65% yield) in the form of a gray powder.

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (122c).

SOCl ₂ (2 .0 g, 16.879 mmol) at 0°C. The reaction mixture was refluxed for 3.5 hours and concentrated to remove volatile solvent. The resulting residue was dissolved in DCM (100 ml) and (4aminophenyl)(p-toluyl)methanol (122b) (1.5 g, 7.033 mmol) was added, then triethylamine (7.2 ml) was added dropwise at RT. The reaction mixture was stirred overnight at room temperature and concentrated to dryness in vacuo. The resulting residue was purified by flash chromatography (10%-70% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-(hydroxy(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (122c) (1.8 g, 53.7%) as a brown sticky liquid.

Step 3. Preparation of 1-(3-cyanophenyl)-C-(3-(((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (122d).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (122c) (1.8 g, 3.777 mmol) Thionyl chloride (0.6 ml, 7.555 mmol) was added to dichloromethane (50 ml) at 0°C and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (50 ml) and cyclopropylmethanamine (4.9 ml, 56.669 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3(((cyclopropylmethyl)amino)(p-toluyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (122d) (1.1 g, 55% yield) as a brown sticky liquid.

Step 4. Preparation of tert-butyl-3-(5-((3-(((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)car

- 240 045731 bamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (122e) and tert-butyl-((3-(1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamido)phenyl)(p-toluyl)methyl)(cyclopropylmethyl)carbamate (122f).

In a solution of 1 -(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (122d) (1 .1 g, 2.077 mmol) in MeOH (20 mL), cooled in ice/water, add nickel(II) chloride hexahydrate (0.542 g, 2.284 mmol) and Boc anhydride (2.4 mL, 10.385 mmol), then sodium borohydride (0.94 g, 24.926 mmol) was added portionwise over 15 minutes. The reaction mixture was stirred at room temperature for 20 h and quenched with N1-(2aminoethyl)ethane-1,2-diamine (1.1 mL, 10.385 mmol), then stirred for an additional 0.5 h. Concentrate the reaction mixture to dryness in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give tert-butyl-((3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl )-1 H-pyrazole-5-carboxamido)phenyl)(p-toluyl)methyl)(cyclopropylmethyl)carbamate (122f) (0.214 g) as a white solid and tert-butyl-3-(5-((3- (((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (122e) (0.445 g) as a white solid.

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (122g).

A mixture of tert-butyl-3-(5-((3-(((cyclopropylmethyl)amino)(p-toluyl)methyl)phenyl)-carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate ( 122e) (0.445 g, 0.702 mmol) and tert-butyl-((3-(1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(p-toluyl) methyl)(cyclopropylmethyl)carbamate (122f) (0.214 g, 0.337 mmol) were dissolved separately in methanol (2.5 ml) and conc. HCl (1.0 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. NMR analyzes of the residues in methanol and TLC indicated the production of identical compounds. Combine the products, dry and purify by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-150% methanol in dichloromethane) to give 1-(3-(aminomethyl)phenyl)-K-(3-(((cyclopropylmethyl) amino)(p-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (122g) (0.2 g, 36.1%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 10.19 - 10.00 (m, 2H), 8.55 (d, J=5.7 Hz, 3H), 7.88 - 7.82 (m, 1H), 7.73 (d, J=2.4 Hz, 2H), 7.64 (dq, J=7.8, 2.3 Hz, 3H), 7 ,60 - 7.50 (m, 4H), 7.42 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.7 Hz, 2H), 5.53 (d, J=6.4 Hz, 1H), 4.12 (q, J=5.5 Hz, 2H), 2.76 2.62 (m, 2H), 2.28 (s, 3H), 1.22 - 1.10 (m, 1H), 0.60 - 0.49 (m, 2H), 0.30 (q, J=3.2, 1.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.78; MS (IER+) 534.4 (M+1); 532.3 (M-1); analysis, calculation for CzoН3<^50-2.75НС1-ЗН ₂ 0: C, 52.38; H, 5.68; Cl, 14.17; N, 10.18: experiment: C, 52.64; H, 5.74; Cl, 13.95; N, 9.83.

Scheme 123

- 241 045731

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 123g).

Step 1. Preparation of (3-aminophenyl)(4-(benzyloxy)phenyl)methanol (123b).

To a stirred solution of 4-(benzyloxy)benzaldehyde (123a) (2.122 g, 10 mmol) in tetrahydrofuran (10 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (12.0 ml, 12 .0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding hydrogen chloride (25.00 ml, 25.00 mmol), stirred for 6 hours. The reaction mixture was neutralized with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with brine (50 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate/hexane mixtures) to give (3-aminophenyl)(4-(benzyloxy)phenyl)methanol (123b) (2.691 g, 88% yield) %) in the form of a thick yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.45-7.28 (m, 5H), 7.28 - 7.17 (m, 2H), 6.90 (dd, J=8.2, 7.1 Hz, 3H), 6.55 (t, J=1.9 Hz, 1H), 6.48 (dt, J=7.6, 1.3 Hz, 1H), 6.37 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.58 (d, J=3.8 Hz, 1H), 5.45 (d, J=3.9 Hz, 1H), 5.06 (s, 2H), 4.97 (s, 2H).

Step 2. Preparation of N-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (123c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.73 g, 9.69 mmol) in DMF (10 ml) was added (3-aminophenyl) (4-(benzyloxy)phenyl)methanol (123b) (2.691 g, 8.81 mmol), N-ethyl-N-isopropylpropan-2-amine (7.67 ml, 44.1 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate ( PyBrOP, 4.93 g, 10.57 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0.100% ethyl acetate in hexanes) to give N-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3cyanophenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123c) (2.309 g, 4.06 mmol, 46.1% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.19 - 8.12 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz , 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 -7.69 (m, 2H), 7.61 (d, J=2 .0 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.44 - 7.21 (m, 9H), 7.11 (d, J=7.6 Hz, 1H ), 6.98 - 6.89 (m, 2H), 5.84 (d, J=3.8 Hz, 1H), 5.61 (d, J=3.9 Hz, 1H), 5.06 (s, 2H); MS (ESI+) 591.3 (M+Na); (IER-) 567.3 (M-1).

Step 3. Preparation of N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123d).

Into a solution of N-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123c) (2.309 g, 4.06 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (0.89 ml, 12.18 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with cyclopropylmethanamine (1.057 ml, 12.18 mmol) and stirred at room temperature for another 5 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (7.04 ml, 81 mmol) was added. The reaction mixture was heated at reflux temperature for 48 h, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give

1. N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123d) (0.683 g, 1.099 mmol, 27.1% yield) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.63 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.64 (t, J= 1.7 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.44 7.26 (m, 8H), 7.23 (d, J=7.8 Hz, 1H), 7 .17 (dt, J=7.7, 1.4 Hz, 1H), 6.95- 6.89 (m, 2H), 5.04 (s, 2H), 4.77 (s, 1H), 2.27 (d, J=6.7 Hz, 2H), 0.92 (dt, J=12.8, 4.7 Hz, 1H), 0.44 - 0.31 (m, 2H), 0 .04 (td, J=5.1, 3.4 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.96; MS (IER+) 622.4 (M+1); (IER-) 620.9 (M-1), 656.3 (M+Cl);

2. N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(cyclopropylmethylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123e ) (0.6 g, 0.865 mmol, 21.30% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.77 (t, J=5.6 Hz, 1H), 8.05-7.95 (m, 2H), 7.68 - 7.57 (m, 4H), 7.54 - 7.48 (m, 1H), 7.44 - 7.25 (m, 7H), 7.22 (d, J=7.8 Hz, 1H), 7.16 (dt, J=7.7, 1.4 Hz, 1H), 6.95- 6.89 (m, 2H), 5.04 (s, 2H), 4.76 (s, 1H), 3.15 (dd, J=6.9, 5.5 Hz, 2H), 2.27 (d, J=6.7 Hz, 2H), 1.02 (tdd, J= 8.2, 6.0, 3.2 Hz, 1H), 0.96 - 0.81 (m, 1H), 0.48 - 0.30 (m, 4H), 0.27 - 0.16 ( m, 2H), 0.09 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-06) δ -60.79; MS (IER+) 694.4 (M+1); (IER-) 692.2 (M-1); analysis, calculation for C ₄₀ H ₃₈ F ₃ N ₅ O ₃ -0.5H ₂ O: C, 68.36; H, 5.59; F, 8.11; N, 9.97; experiment: C, 68.37; H, 5.55; F, 7.64; N, 9.87.

Step 4. Preparation of tert-butyl-3-(5-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl- 242 045731 tyl)phenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazole-1 - yl)benzylcarbamate (123f).

Into a solution of N(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-cyanophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123d) (0.68 g, 1.094 mmol) in MeOH (20 mL), cooled in ice/water, di-tert-butyl dicarbonate (0.716 g, 3.28 mmol) and nickel(II) chloride (0.286 g, 1.203 mmol) were added. Sodium borohydride (0.317 g, 8.20 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.358 mL, 3.28 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexanes) to give tert-butyl-3-(5-(3-((4(benzyloxy )phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (123f) (0.304 g, 0.419 mmol, 38.3% yield) as a white solid; Ή NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 7.62 (t, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.52 ( d, J=7.6 Hz, 1H), 7.45 - 7.38 (m, 4H), 7.38 - 7.32 (m, 4H), 7.32 - 7.26 (m, 2H) , 7.22 (d, J=7.8 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.98 - 6.88 (m, 2H), 5.04 (s, 2H ), 4.76 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.27 (d, J=6.5 Hz, 3H), 1.00 - 0.83 (m, 1H), 0.42 - 0.33 (m, 2H), 0.09 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 726.4 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123g).

Into a solution of tert-butyl-3-(5-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (123f) ( 0.32 g, 0.441 mmol) in methanol (10 ml), hydrogen chloride (0.919 ml, 11.02 mmol) was added and stirred at room temperature overnight. Concentrate the reaction mixture to dryness in vacuo and purify by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1(3-(aminomethyl)phenyl)-N-(3-((4-(benzyloxy )phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123g) (0.228 g, 0.364 mmol, 83% yield) as an off-white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.64 (dd, J=4.2, 2.3 Hz, 3H), 7.56 - 7.46 (m , 3H), 7.45- 7.14 (m, 10H), 6.95- 6.89 (m, 2H), 5.05 (s, 2H), 4.76 (s, 1H), 3, 98 (s, 2H), 2.27 (d, J=6.7 Hz, 2H), 0.98 - 0.82 (m, 1H), 0.43 - 0.32 (m, 2H), 0 .04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.76; MS (IER+) 626.4 (M+1); (IER-) 660.3 (M-1); analysis, calculation for C ₃₆ H ₃₄ F ₃ N ₅ O ₂ -2H ₂ O: C, 65.34; H, 5.79; N, 10.58; experiment: C, 65.39; H, 5.55; N, 10.50.

Scheme 124

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124f ).

Step 1. Preparation of (3-aminophenyl)(3-(trifluoromethoxy)phenyl)methanol (124b).

To a stirred solution of 3-(trifluoromethoxy)benzaldehyde (124a) (1.9 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide (49c) (12.0 ml , 12.0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding hydrogen chloride (25.00 ml, 25.00 mmol), stirred for 6 hours. The reaction mixture was neutralized with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with brine (50 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexane mixtures) to give (3-aminophenyl)(3-(trifluoromethoxy)phenyl)methanol (124b) (1.5 g, yield 53%) in the form of a thick yellow oily liquid; ^1H NMR

- 243 045731 (300 MHz, DMSO-d ₆ ) δ 7.47 - 7.29 (m, 3H), 7.18 (ddt, J=7.9, 2.5, 1.2 Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.58 (t,

J=2.0 Hz, 1H), 6.51 (dt, J=7.6, 1.3 Hz, 1H), 6.40 (ddd, J=8.0, 2.3, 1.1 Hz , 1H), 5.91 (d, J=3.9 Hz, 1H), 5.57 (d,

J=3.9 Hz, 1H), 5.05 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -56.58; MS (IER+) 284.2 (M+1), 306.2 (M+Na);

(IER-) 282.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (124c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.495 g, 5.32 mmol) in DMF (20 ml) was added (3-aminophenyl)(3 -(trifluoromethoxy)phenyl)methanol (124b) (1.369 g, 4.83 mmol), N-ethyl-N-isopropylpropan-2-amine (4.21 ml, 24.17 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP, 2.70 g, 5.80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (2x75 ml). Combine the organic layers, wash with brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124c) (2.081 g, 3.81 mmol, 79% yield) as a yellow semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1 ,3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.67 (t, J=1.8 Hz, 1H), 7.58 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.29 (t, J=7.8 Hz, 1H), 7.23 - 7.13 (m, 2H), 6.18 (d, J= 3.9 Hz, 1H), 5.76 (d, J=3.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -56.62, -60.98; MS (IER+) 569.2 (M+Na); (IER-) 545.2 (M-1).

Step 3. Preparation of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (124d ).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124c) (0.44 g, 0.734 mmol) in MeOH (10 ml), cooled in ice/water, di-tert-butyl dicarbonate (0.481 g, 2.202 mmol) and nickel (II) chloride (0.192 g, 0.807 mmol) were added. Sodium borohydride (0.212 g, 5.50 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2-aminoethyl)ethane1,2-diamine (0.240 mL, 2.202 mmol) , stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (60 ml) and water (60 ml). The aqueous phase was separated and extracted again with dichloromethane (60 ml). The organic extracts were combined, washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give tert-butyl-3-(5-(3-((cyclopropylmethylamino)() 3-(trifluoromethoxy)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (124d) (0.304 g, 0.432 mmol, 58.9% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.57 (s, 1H), 7.57 - 7 .38 (m, 6H), 7.37 - 7.35 (m, 1H), 7.33 (s, 1H), 7.29 -7.17 (m, 3H), 4.89 (s, 1H ), 4.19 (d, J=6.2 Hz, 2H), 2.59 - 2.54 (m, 1H), 2.39 - 2.16 (m, 2H), 1.35 (s, 9H), 0.99 - 0.83 (m, 1H), 0.43 - 0.30 (m, 2H), 0.09 - -0.01 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO^) δ 56.60, -60.80; MS (IER+) 704.4 (M+1), 727.5 (M+Na), (IER-) 703.3 (M-1).

Step 4. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124e) .

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124d) (0.769 g, 1.407 mmol) in dichloromethane (25 ml) at 0°C, add thionyl chloride (0.308 ml, 4.22 mmol) and stir at room temperature for 2 hours. The reaction is quenched with cyclopropylmethanamine (0.366 ml, 4.22 mmol) and stir the mixture at room temperature for another 5 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (5 ml) and cyclopropylmethanamine (2.441 ml, 28.1 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-M-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl )methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124e) (0.449 g, 0.749 mmol, 53.2% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1 ,3 Hz, 1H), 7.90 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.79 - 7.66 (m, 3H), 7.60 - 7, 47 (m, 1H), 7.46 - 7.37 (m, 3H), 7.32 - 7.14 (m, 3H), 4.90 (s, 1H), 2.38 - 2.15 ( m, 3H), 1.00 - 0.80 (m, 1H), 0.44 - 0.32 (m, 2H), 0.08 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -56.60, -60.96; MS (IER+) 600.3 (M+1); (IER-) 634.1 (M+Cl).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 - carboxamide (124f).

- 244 045731

Into a solution of tert-butyl-3-(5-(3-((cyclopropylmethylamino)(3-(trifluoromethoxy)phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (124e) ( 0.194 g, 0.276 mmol) in methanol (10 ml), add hydrogen chloride (0.574 ml, 6.89 mmol), stir at room temperature overnight and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-( trifluoromethoxy)phenyl)methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (124f) (0.05 g, 0.083 mmol, 30.0% yield) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.85 (s, 1H), 8.49 (s, 3H), 7.79 - 7.68 (m, 3H), 7.66 7.44 ( m, 6H), 7.29 (dd, J=25.9, 7.6 Hz, 3H), 5.13 (s, 1H), 4.12 (s, 2H), 2.46 - 2.34 (m, 2H), 0.98 (d, J=8.9 Hz, 1H), 0.43 (d, J=7.6 Hz, 2H), 0.26 - 0.05 (m, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -56.61, -60.79; MS (IER+) 604.3 (M+1); (IER-) 602.3 (M-1); analysis, calculation for C ₃₀ H ₂₇ F ₆ N ₅ O ₂ -1.25HCl-0.5H ₂ O: C, 54.75; H, 4.48; Cl, 6.73; N, 10.64; experiment: C, 54.61; H, 4.51; Cl, 6.81; N, 10.50.

Scheme 125

PyBrOP

NC

_NaBH4 (Boc) _2O

Preparation example of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenanthrene-9-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (125g) .

Step 1. Preparation of (3-aminophenyl)phenanthrene-9-ylmethanol (125b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was neutralized with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH4Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)phenanthrene-9-ylmethanol (125b) (2.5 g, 83.5%) in the form of a light brown sticky liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.82 (ddd, J=9.3, 7.3, 2.3 Hz, 2H), 8.16 - 8.07 (m, 1H), 8.06 - 7.97 (m, 2H), 7.74 - 7.58 (m, 3H), 7.52 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.63 (d, J=7.5 Hz, 1H), 6.54 (t, J=1.9 Hz, 1H), 6, 39 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 6.19 (d, J=4.4 Hz, 1H), 5.97 (d, J=4.4 Hz , 1H), 4.95 (s, 2H).

Step 2. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-(hydroxyphenanthrene-9-ylmethyl)phenyl]amide (125c).

(3-Aminophenyl)phenanthrene- 9-ylmethanol (125b) (2.5 g, 8.35 mmol), Nethyl-N-isopropylpropan-2-amine (11.0 ml, 66.8 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3, 89 g, 8.350 mmol) at room temperature. The reaction mixture was stirred at room temperature for 21 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (350 ml), washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%] to give [3-(hydroxyphenanthrene-9-245 045731 ylmethyl)phenyl]amide 2-(3-cyanophenyl)- 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (125c) (2.1 g, 44.77% yield) as a red-brown sticky liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.59 (s,

1H), 8.92 - 8.76 (m, 2H), 8.15-8.00 (m, 4H), 7.98 (dt, J=7.7, 1.3 Hz, 1H), 7 .86 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.73

- 7.59 (m, 6H), 7.56 (s, 1H), 7.51 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.32 - 7.25 (m, 2H), 6.34 (d, J=4.3 Hz, 1H), 6.25 (d, J=4.3 Hz, 1H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (125d).

In a solution of [3-(hydroxyphenanthrene-9-ylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2Hpyrazole-3-carboxylic acid (125c) (2.0 g, 3.56 mmol) in dichloromethane ( 40 ml) at 0°C, add thionyl chloride (0.85 g, 7.11 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (3.79 g, 53.33 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (40 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give {3[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl -2Hpyrazole-3-carboxylic acid (125d) (1.22 g, 55.66%) as a pale solid; 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.81 - 8.74 (m, 1H), 8.74 -8.68 (m, 1H), 8.22 - 8.16 (m, 1H), 8.06 (s, 1H), 8.04 (t, J=1.9 Hz, 1H), 7.90 (ddt, J=7.7, 6.7, 1.6 Hz, 2H), 7.77 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.57 - 7 .54 (m, 3H), 7.51 (dt, J=6.7, 1.4 Hz, 3H), 7.28 (dt, J=7.6, 1.4 Hz, 1H), 7. 24 - 7.16 (m, 1H), 5.54 (s, 1H), 2.38 (d, J=6.8 Hz, 3H), 1.01 - 0.87 (m, 1H), 0 .42 - 0.26 (m, 2H), 0.09 - -0.08 (m, 2H).

Step 4. Preparation of [3-(5-{3-[(cyclopropylmethylamino)-phenanthrene-9ylmethyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]-carbamic acid tert-butyl ester (125e) and [( 3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]amino}phenyl)phenanthrene-9-ylmethyl]-cyclopropylmethylcarbamic acid (125f).

In a solution of {3-[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (125d) (1.2 g, 1.95 mmol) in MeOH (24 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.556 g, 2.338 mmol) and Boc anhydride (1.3 ml, 5.847 mmol) were added, then sodium borohydride (0 .44 g, 11.694 mmol) for 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2aminoethyl)ethane-1,2-diamine (0.5 ml, 4.872 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane mixtures) to give;

1. [3-(5-{3-[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]-phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (125e) (0.3 g, 18.79%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 8.91 (d, J=8.1 Hz, 1H), 8.84 (d, J=8.3 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.75-7.66 (m, 4H), 7. 63 (d, J=8.3 Hz, 2H), 7.49 (d, J=15.4 Hz, 4H), 7.50 - 7.43 (m, 3H), 7.40 - 7.32 (m, 4H), 7.30 (t, J=1.9 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 4.16 (d, J=6.3 Hz , 2H), 3.19 (dt, J=27.1, 7.8 Hz, 2H), 1.36 (s, 18H), 0.86 - 0.70 (m, 1H), 0.01 - -0.06 (m, 2H), -0.15- -0.33 (m, 2H).

2. tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3-carbonyl]amino}phenyl)phenanthrene-9-ylmethyl]cyclopropylmethylcarbamic acid (125f) (0, 62 g, 38.82%) as a white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.55 (s, 1H), 8.80 - 8.74 (m, 1H), 8.74 - 8.65 (m, 1H), 8.25 - 8.15 (m, 1H), 8.06 (s, 1H), 7.91 (dt, J=6.3, 2.6 Hz, 1H), 7.60 - 7.55 (m, 2H ), 7.54 - 7.48 (m, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.34 - 7.15 (m, 7H), 5.53 (s, 1H), 4.08 (d, J=6.3 Hz, 2H), 2.36 (s, 2H), 1.25 (s, 9H), 1.00 - 0.86 (m, 1H), 0.40 - 0.25 (m, 2H), -0.01 (dd, J=9.1, 4.7 Hz, 2H).

Step 5. Preparation of {3-[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (125g).

[3-(5-{3-[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester mixture (125e) (0.250 g, 0.35 mmol ) and tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3-carbonyl]amino}phenyl)phenanthrene-9-ylmethyl]-cyclopropylmethylcarbamic acid (125f) (0 .5 g, 0.695 mmol) were dissolved separately in methanol (10 ml) and conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. NMR analyzes of the residue in methanol and TLC indicated identical compounds. Products were combined, dried and purified by flash column

- 246 045731 chromatography (silica gel, 12 g, eluted with mixtures of 0-15% methanol in dichloromethane) to obtain the free base {3-[(cyclopropylmethylamino)phenanthrene-9-ylmethyl]phenyl}amide 2-(3-aminomethylphenyl)-5- trifluoromethyl-2H-pyrazole-3-carboxylic acid (125g) (0.3 g, 46%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.90 (s, 1H), 10.09 (s, 1H), 8.98 - 8.90 (m, 1H), 8.89 8.83 ( m, 1H), 8.54 (s, 1H), 8.42 (s, 3H), 8.24 - 8.15 (m, 1H), 8.07 - 7.99 (m, 1H), 7 .87 (s, 1H), 7.81 - 7.57 (m, 10H), 7.46 (ddt, J=17.2, 15.4, 7.8 Hz, 3H), 6.43 (s , 1H), 4.10 (s, 2H), 3.12-2.74 (m, 2H), 1.31 - 1.13 (m, 1H), 0.57 (d, J=7.8 Hz, 2H), 0.31 (d, J=26.4 Hz, 2H); 1H NMR (300 MHz, DMSO-d ₆ /D ₂ O) δ 8.96 - 8.90 (m, 1H), 8.87 (d, J=8.0 Hz, 1H), 8.41 (s , 1H), 8.18 (dd, J=8.4, 1.5 Hz, 1H), 8.09 - 8.03 (m, 1H), 7.86 - 7.55 (m, 12H), 7.54 7.42 (m, 3H), 6.41 (s, 1H), 4.10 (s, 2H), 3.13 - 2.76 (m, 2H), 1.26 - 1.16 (m, 1H), 0.59 (d, J=8.0 Hz, 2H), 0.31 (d, J=25.2 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.81; MS (IER+) 620.4 (M+1); (IER-) 654.3 (M+Cl). 1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenanthrene-9-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide free base (125g) (250 mg) obtained above was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-25% methanol in chloroform) and converted to the hydrochloride by dissolving the resulting product in methanol (5 ml) and treating with 10 equivalents of conc. HCl. The resulting solution was concentrated to dryness in vacuo to obtain {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1-yl)methyl]phenyl}amide hydrochloride salt of 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (125g) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.39 (d, J=10.4 Hz, 1H), 10.19 (s, 1H), 8.93 (dd , J=8.4, 1.5 Hz, 1H), 8.90 - 8.81 (m, 1H), 8.66 (s, 1H), 8.53 (s, 3H), 8.21 ( dd, J=8.3, 1.5 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.96 - 7.90 (m, 1H), 7.80 - 7.61 ( m, 9H), 7.56 - 7.37 (m, 3H), 6.46 (t, J=6.2 Hz, 1H), 4.10 (q, J=6.0 Hz, 2H), 3.11 - 2.98 (m, 1H), 2.84 (td, J=9.5, 8.9, 4.2 Hz, 1H), 1.26 (ddd, J=12.6, 6 ,2, 3.6 Hz, 1H), 0.57 (dd, J=8.2, 4.0 Hz, 2H), 0.43 - 0.23 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.80; MS (IER+)

620.4 (M+1); (IER-) 618.4 (M-1); analysis, calculation for C37H32P3K5O-2HCl2H2O: C, 60.99; H, 5.26; Cl, 9.73; N, 9.61; experiment: C, 60.82; H, 5.24; Cl, 9.92; N, 9.66.

Scheme 126

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-(dimethylamino)naphthalene-1 -yl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazol- 5-carboxamide (126g).

Step 1. Preparation of (3-aminophenyl)(4-dimethylaminonaphthalene-1-yl)methanol (126b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 ml, 12.0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and the reaction was quenched by adding 2N. HCl (12.5 ml). The reaction mixture was stirred for 6 hours and made alkaline with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(4dimethylaminonaphthalene-1-yl)methanol (126b) (1.9 g, 65% ) in the form of a light brown oily liquid; 1H NMR (300 MHz, DMSO) δ 8.17 - 8.11 (m, 1H), 8.11 - 8.06 (m, 1H), 7.50 (d, J=7.8 Hz, 1H) , 7.40

- 247 045731 (dqd, J=10.0, 6.7, 1.5 Hz, 2H), 7.09 (d, J=7.7 Hz, 1H), 6.94 - 6.84 (m, 1H), 6.57 - 6.49 (m, 2H), 6.40 - 6.32 (m,

1H), 6.08 (d, J=4.4 Hz, 1H), 5.73 (t, J=2.2 Hz, 1H), 4.93 (s, 2H), 2.78 (s, 6H).

Step 2. Preparation of {3-[(4-dimethylaminonaphthalene-1-yl)hydroxymethyl]phenyl}amide 2-(3cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.9 g, 6.756 mmol) in DMF (22 ml), (3-aminophenyl)(4 -dimethylaminonaphthalene-1-yl)methanol (126b) (1.9 g, 6.756 mmol), N-ethyl-N-isopropylpropan-2-amine (6.98 g, 54.048 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3.065 g, 6.756 mmol) at room temperature. The reaction mixture was stirred at room temperature for 39 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x300 ml), brine (200 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give {3-[(4dimethylaminonaphthalene-1-yl)hydroxymethyl]phenyl}amide 2-(3-cyanophenyl) -5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126c) (0.7 g) as a light brown liquid; 1H NMR (300 MHz, _DMSOd6 ) δ 10.58 (s, 1H), 8.16 - 8.09 (m, 2H), 8.09 - 8.04 (m, 1H), 7.95 (dt , J=7.7, 1.3 Hz, 1H), 7.85 (ddd, J=8.3, 2.2, 1.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.65 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.47 (d, J =7.8 Hz, 1H), 7.39 (dddd, J=17.3, 8.2, 6.8, 1.5 Hz, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.21 (d, J=4.3 Hz, 1H) , 5.97 (d, J=4.2 Hz, 1H), 2.77 (s, 6H).

Step 3: Preparation of {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126d).

Into a solution of {3-[(4-dimethylaminonaphthalene-1-yl)hydroxymethyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (126c) (0.7 g, 1.260 mmol) Thionyl chloride (0.299 g, 2.520 mmol) was added to dichloromethane (50 ml) at 0°C and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (30 ml) and cyclopropylmethanamine (1.34 g, 18.9 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexane) to give {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1-yl)methyl]phenyl}amide 2-( 3-cyanophenyl)5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126d) (0.4 g) as a brown sticky liquid; 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.18 (dd, J=6.7, 3.2 Hz, 1H), 8.14 - 8.08 (m, 1H), 8.07 (t, J=1.9 Hz, 1H), 7.92 (dt, J=7.7, 1.3 Hz, 1H), 7.81 (ddd, J=8.3 , 2.2, 1.2 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 7.59 -7 .52 (m, 2H), 7.52 - 7.45 (m, 1H), 7.44 - 7.35 (m, 2H), 7.24 - 7.14 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 5.47 (s, 1H), 2.72 (s, 6H), 2.32 (d, J=6.6 Hz, 2H), 1.00 - 0.82 (m, 1H), 0.32 (dd, J=7.7, 1.3 Hz, 2H), 0.07 - 0.08 (m, 2H).

Step 4. Preparation of [3-(5-{3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1-yl)methyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (126f) and tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3-carbonyl]amino}phenyl)(4-dimethylaminonaphthalene-1-yl)methyl]cyclopropylmethylcarbamic acid (126e ).

Into a solution of {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalen-1-yl)methyl]-phenyl}amide 2-(3cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126d) (0.4 g , 0.656 mmol) in MeOH (10 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.195 g, 0.821 mmol) and Boc anhydride (0.429 g, 1.968 mmol) were added, then sodium borohydride was added portionwise (0.148 g, 3.936 mmol) for 15 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with K1-(2-aminoethyl)ethane-1,2-diamine (0.270 mL, 2.624 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% chloroform/methanol) to give [3-(5-{3[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1-yl) tert-butyl ether )methyl]-phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid (126f) (0.170 g, 32%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.25 (dt, J=7.8, 2.7 Hz, 1H), 8.05-7.93 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.61 - 7.48 (m, 5H), 7.44 (dd, J=7.0, 2.1 Hz, 2H ), 7.40 - 7.34 (m, 3H), 7.07 (d, J=7.9 Hz, 1H), 6.97 (t, J=8.7 Hz, 2H), 4.21 (d, J=6.2 Hz, 2H), 3.36 - 3.23 (m, 2H), 2.84 (s, 6H), 1.48 - 1.35 (lat.s, 18H), 0.34 (m, 1H), -0.00 (m, 1H), -0.27 (m, 2H), -0.87 (m, 1H); and tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5trifluoromethyl-2H-pyrazole-3-carbonyl]amino}phenyl)(4-dimethylaminonaphthalene-1-yl)methyl]cyclopropylmethylcarbamic acid (126e) ( 0.140 g, 30%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.31 - 8.05 (m, 2H), 7.66 - 7.13 (m, 12H), 7.07 ( d, J=7.9 Hz, 1H), 6.93 (dt,

- 248 045731

J=35.7, 8.2 Hz, 1H), 5.47 (s, 1H), 4.12 (d, J=6.2 Hz, 2H), 2.73 (s, 6H), 2, 33 (d, J=6.8 Hz, 2H), 1.29 (s, 9H), 1.00

- 0.84 (m, 1H), 0.40 - 0.27 (m, 2H), 0.05- -0.07 (m, 3H).

Step 5. Preparation of {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalen-1-yl)methyl]phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126g).

[3-(5-{3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1yl)methyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester mixture (126f) (0.160 g, 0.197 mmol) and tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3carbonyl]amino}phenyl)(4-dimethylaminonaphthalene-1-yl)methyl]cyclopropylmethylcarbamic acid (126e ) (0.13 g, 0.182 mmol) were dissolved separately in methanol (2.5 ml) and conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. NMR analyzes of the residue in methanol and TLC indicated identical compounds. Combine the products, dry and purify by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-150% methanol in dichloromethane) to give {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1yl)methyl]phenyl}amide 2- (3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (126g) (0.135 g, 28%) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.06 (d, J=4.5 Hz, 1H), 10.46 (s, 1H), 10.17 (s, 1H), 8.68 ( s, 3H), 8.26 (q, J=4.9 Hz, 2H), 7.94 (s, 1H), 7.75-7.64 (m, 5H), 7.63 - 7.35 (m, 6H), 6.50 - 6.25 (m, 1H), 4.10 (q, J=5.8 Hz, 2H), 2.93 (s, 8H), 1.25 (d, J=7.5 Hz, 1H), 0.62 - 0.48 (m, 2H), 0.30 (qd, J=9.4, 4.2 Hz, 2H); ¹ H NMR (300 MHz, DMSO-d^) δ 8.37 - 8.30 (m, 1H), 8.28 - 8.21 (m, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.73 - 7.38 (m, 12H), 6.38 (s, 1H), 4.11 (s, 2H ), 3.00 - 2.76 (m, 8H), 1.24 - 1.14 (m, 1H), 0.56 (d, J=8.2 Hz, 2H), 0.42 - 0, 20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.77; MS (IER+) 613.3 (M+1), 635.3 (M+Na); (IER-) 647.3 (M+Cl); analysis, calculation for С^^Рз^О-ЗНСННзО 6.5 NaCl: C, 31.89; H, 4.74; Cl, 25.55; N, 6.38; experiment: C, 32.28; H, 4.39; Cl, 25.46; N, 6.10. {3[(cyclopropylmethylamino)(4-dimethylaminonaphthalen-1-yl)methyl]phenyl}2-(3-aminomethylphenyl)5-trifluoromethyl-2H-pyrazole-3-carboxylic acid amide (126g) (170 mg) prepared above, purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-25% methanol in chloroform) and converted to the hydrochloride salt by dissolving the resulting product in methanol (5 ml) and treating with 10 equivalents of conc. HCl. The resulting solution was concentrated to dryness in a vacuum, dried in a vacuum to obtain the hydrochloride salt of {3-[(cyclopropylmethylamino)(4-dimethylaminonaphthalene-1yl)methyl]phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3 -carboxylic acid (126g) (70 mg, 99%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.98 (d, J=1.6 Hz, 1H), 10.34 (s, 1H), 10.08 (s, 1H), 8.54 ( s, 2H), 8.38 (s, 1H), 8.31-8.17 (m, 2H), 7.94 -7.84 (m, 1H), 7.72 (d, J=1, 9 Hz, 1H), 7.70 - 7.57 (m, 6H), 7.54 (d, J=7.8 Hz, 1H), 7.53 - 7.46 (m, 1H), 7, 41 (td, J=7.9, 1.3 Hz, 1H), 6.39 (t, J=6.3 Hz, 1H), 4.97 (d, J=5.4 Hz, 1H), 4.11 (q, J=5.9 Hz, 2H), 2.97 (s, 6H), 2.43 (d, J=14.0 Hz, 2H), 1.31 - 1.17 (m , 1H), 0.65-0.47 (m, 2H), 0.41-0.19 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.78; MS (ESI-) 647.3 (M+Cl); analysis, calculation for C35H35F3N6O-2.75HCl-H2O: C, 54.81; H, 5.75; Cl, 12.71; N, 10.96: experiment: C, 55.22; H, 5.78; Cl, 12.77; N, 10.28.

Scheme 127

F ₃ C mЪ Η

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-propoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 127f).

Step 1. Preparation of (3-aminophenyl)(4-propoxyphenyl)methanol (127b).

To a stirred solution of 4-propoxybenzaldehyde (127a) (1.2 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12. 00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(4-propoxyphenyl)methanol (127b) (2.0 g, 77.72% ) in the form of a light brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.24 - 7.18 (m, 2H), 6.90 (t, J=7.7 Hz, 1H), 6.85 - 6.80 (m , 2H), 6.55 (t, J=1.9 Hz, 1H), 6.48 (dt, J=7.7, 1.3 Hz, 1H), 6.37 (ddd, J=7, 9, 2.4, 1.0 Hz, 1H), 5.57 (d, J=3.9 Hz, 1H), 5.44 (d, J=3.9 Hz, 1H), 4.97 ( s, 2H), 3.86 (td, J=6.6, 3.3 Hz, 2H), 1.77 - 1.59 (m, 2H), 0.95 (t, J=7.4 Hz , 3H).

Step 2. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid {3-[hydroxy(4-propoxyphenyl)methyl]phenyl}amide (127c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.16 g, 7.69 mmol) in DMF (40 ml) was added (3-aminophenyl) (4-propoxyphenyl)methanol (127b) (1.80 g, 6.99 mmol), N-ethyl-N-isopropylpropan-2-amine (9.8 ml, 55.96 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3.59 g, 7.69 mmol) at room temperature. The reaction mixture was stirred at room temperature for 19 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (2x50 ml), brine (50 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give {3-[hydroxy(4-propoxyphenyl)methyl]phenyl}amide 2-(3-cyanophenyl)- 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (127c) (2.0 g, 55%) as a light brown liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 8.21 (t, J=1.9 Hz, 1H), 8.06 (dt, J=7.8, 1 ,3 Hz, 1H), 7.96 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.84 - 7.73 (m, 2H), 7.67 (t, J=1.8 Hz, 1H), 7.64 - 7.54 (m, 1H), 7.31 (s, 1H), 7.31 - 7.24 (m, 2H), 7.17 (d , J=7.8 Hz, 1H), 6.95- 6.85 (m, 2H), 5.89 (d, J=3.9 Hz, 1H), 5.67 (d, J=3, 9 Hz, 1H), 3.93 (t, J=6.5 Hz, 2H), 1.75 (h, J=7.1 Hz, 2H), 1.01 (t, J=7.4 Hz , 3H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (127d).

A solution of {3-[hydroxy(4-propoxyphenyl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl2H-pyrazole-3-carboxylic acid (127c) (2.0 g, 3.84 mmol) in Thionyl chloride (0.914 g, 7.68 mmol) was added to dichloromethane (40 ml) at 0°C and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (5.0 g, 57.636 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-50% ethyl acetate in hexane) to give {3[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]phenyl}amide 2-(3-cyanophenyl)- 5-trifluoromethyl2H-pyrazole-3-carboxylic acid (127d) (1.14 g, 51.76%) as a pale sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.11 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.8, 1 .3 Hz, 1H), 7.86 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.26 - 7.16 (m, 3H), 7, 16 - 7.09 (m, 1H), 6.82 -6.75 (m, 2H), 4.72 (s, 1H), 3.81 (t, J=6.5 Hz, 2H), 2 .23 (d, J=6.6 Hz, 2H), 1.74 1.53 (m, 2H), 0.90 (t, J=7.4 Hz, 3H), 0.87 - 0.74 (m, 1H), 0.39 - 0.28 (m, 2H), 0.00 (m, 2H).

Step 4. Preparation of [3-(5-{3-[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]-carbamic acid tert-butyl ester (127e).

Into a solution of {3-[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]phenyl}amide 2-(3-cyanophenyl)5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (127d) (1.0 g, 1.74 mmol) in MeOH (24 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.49 g, 2.09 mmol) and Boc anhydride (1.2 ml, 5.23 mmol) were added. then sodium borohydride (0.395 g, 10.46 mmol) was added piecemeal over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.5 mL, 4.36 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-40% ethyl acetate/n-hexane) to give tert-butyl ether [3-(5-{3-[(cyclopropylmethylamino)(4-propoxyphenyl) methyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid (127e) (0.5 g, 42.40%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ

- 250 045731

10.63 (s, 1H), 7.64 - 7.55 (m, 1H), 7.52 (s, 1H), 7.50 - 7.42 (m, 2H), 7.41 - 7, 33 (m, 2H), 7.33 - 7.27 (m, 2H),

7.26 - 7.17 (m, 3H), 7.17 - 7.09 (m, 1H), 6.82 - 6.74 (m, 2H), 4.71 (s, 1H), 4, 15 (d, J=6.2 Hz, 2H), 3.81 (t, J=6.5

Hz, 2H), 2.23 (d, J=6.7 Hz, 2H), 1.64 (q, J=6.9 Hz, 2H), 1.31 (s, 9H), 0.90 ( t, J=7.4 Hz, 3H), 0.85-0.74 (m, 1H),

0.39 - 0.27 (m, 2H), 0.00 (dd, J=5.5, 3.8 Hz, 2H).

Step 5. Preparation of {3-[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]phenyl}amide 2-(3aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (127f).

[3-(5-{3-[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]-phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (127e) (0.500 g, 0.74 mmol) was dissolved in methanol (10 ml) and conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. The product was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-15% methanol in dichloromethane) to give {3-[(cyclopropylmethylamino)(4-propoxyphenyl)methyl]phenyl}amide 2-(3-aminomethylphenyl)- 5-trifluoromethyl-2P-pyrazole-3carboxylic acid (127f) (120 mg, 20.87%) as a pale white powder; 1H NMR (300 MHz, DMSO _d6 ) δ 10.96 (s, 1H), 9.96 (s, 2H), 8.47 (s, 3H), 7.83 (s, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 7.58 (dtt, J=17.6, 6.3, 3.9 Hz, 7H), 7.43 (t, J=7.8 Hz, 1H), 6.96 (d, J=8.2 Hz, 2H), 5.64 - 5.37 (m, 1H), 4.12 (q, J=5.7, 5.3 Hz , 2H), 3.91 (t, J=6.4 Hz, 2H), 2.68 (q, J=9.4, 6.4 Hz, 2H), 1.70 (q, J=6, 9 Hz, 2H), 1.20 - 1.05 (m, 1H), 0.95 (t, J=7.3 Hz, 3H), 0.60 - 0.48 (m, 2H), 0, 30 (t, J=4.7 Hz, 2H); 1H NMR (300 MHz, DMSO- _d6 ) δ 10.95 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7. 64 - 7.41 (m, 8H), 6.98 (d, J=8.3 Hz, 2H), 5.52 (s, 1H), 4.13 (s, 2H), 3.92 (t , J=6.4 Hz, 2H), 2.70 (dd, J=7.1, 3.4 Hz, 2H), 1.70 (q, J=6.9 Hz, 2H), 1.09 (q, J=6.8, 6.1 Hz, 1H), 0.95 (t, J=7.3 Hz, 3H), 0.64 0.50 (m, 2H), 0.29 (d , J=4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.77; MS (IER+) 578.4 (M+1); (IER-) 612.4 (M+Cl); analysis, calculation for C32H34F3N5O2-2.75HCl-5.5H2O: C, 49.47; H, 6.19; Cl, 12.55; N, 9.01; experiment: C, 49.44; H, 5.81; Cl, 12.47; N, 8.83.

Scheme 128

1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalene-2-yl)me Example of preparation of til)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (128g) .

Step 1. Preparation of (3-aminophenyl)naphthalene-2-ylmethanol (128b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)naphthalene-2-ylmethanol (128b) (2.4 g, 96.27%) in the form of a light brown sticky liquid; 1H NMR (300 MHz, DMSO-d;) δ 7.82 (dd, J=8.1, 1.6 Hz, 3H), 7.75 (d, J=8.6 Hz, 1H), 7, 45- 7.36 (m, 3H), 6.87 (t, J=7.7 Hz, 1H), 6.58 - 6.48 (m, 2H), 6.33 (ddd, J=7, 9, 2.3, 1.0 Hz, 1H), 5.79 (d, J=3.8 Hz, 1H), 5.62 (d, J=3.8 Hz, 1H), 4.93 ( s, 2H).

Step 2. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazol-3-carboxylic acid [3-(hydroxynaphthalene-2-ylmethyl)phenyl]amide (128c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxylic acid (9i) (2.4 g, 8.54 mmol) in DMF (48 ml) was added (3-aminophenyl) naphthalene-2-ylmethanol (128b) (2.12 g, 8.535 mmol), Nethyl-N-isopropylpropan-2-amine (11.8 g, 68.24 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3, 97 g, 8.54 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (350 ml), washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%] to give [3-(hydroxynaphthalene-2ylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl- 2H-pyrazole-3-carboxylic acid (128c) (2.6 g, 59.4% yield) as a brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.15 (t, J=1.9 Hz, 1H), 7.99 (dt, J=7.7, 1 ,3 Hz, 1H), 7.95-7.86 (m, 4H), 7.83 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H ), 7.69 (s, 1H), 7.66 (t, J=1.8 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.51 - 7.46 (m, 2H), 7.43 (dd, J=8.7, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.21 (dt, J=7.8 , 1.4 Hz, 1H), 6.11 (d, J=3.8 Hz, 1H), 5.85 (d, J=3.8 Hz, 1H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (128d).

In a solution of [3-(hydroxynaphthalene-2-ylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2Hpyrazole-3-carboxylic acid (128c) (2.6 g, 5.07 mmol) in dichloromethane ( 50 ml) at 0°C, add thionyl chloride (1.2 g, 10.14 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (5.41 g, 76.05 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give {3[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5 -trifluoromethyl-2H-pyrazole-3-carboxylic acid (128d) (0.90 g, 31.39%) as a brown liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.09 (t, J=1.9 Hz, 1H), 7.92 (dt, J=7.7, 1 .3 Hz, 1H), 7.89 - 7.86 (m, 1H), 7.85-7.73 (m, 4H), 7.69 - 7.62 (m, 3H), 7.45 ( dddd, J=19.3, 9.5, 5.3, 2.4 Hz, 4H), 7.24 - 7.16 (m, 2H), 4.94 (s, 1H), 2.36 2 .17 (m, 2H), 0.99 - 0.83 (m, 1H), 0.38 - 0.24 (m, 2H), -0.01 (m, 2H).

Step 4. Preparation of [3-(5-{3-[(cyclopropylmethylamino)-naphthalene-2ylmethyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]-carbamic acid tert-butyl ester (128e) and [( 3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]amino}phenyl)naphthalene-2-ylmethyl]-cyclopropylmethylcarbamic acid (128f).

Into a solution of {3-[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (128d) (0.90 g, 1.59 mmol) in MeOH (20 ml), cooled in ice/water, add nickel (II) chloride hexahydrate (0.47 g, 1.99 mmol) and Boc anhydride (1.04 g, 4.77 mmol), then sodium borohydride (0.36 g, 9.55 mmol) was added in portions over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.7 mL, 6.36 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give:

1. [3-(5-{3-[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (128e) (0.42 g, 34 .31%); 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.75 (dd, J=9.2, 3.2 Hz, 2H), 7.70 (d, J=3, 4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.38 - 7.34 (m, 4H), 7.31 (s, 1H), 7.25- 7, 20 (m, 1H), 7.20 - 7.16 (m, 5H), 6.83 (d, J=7.8 Hz, 1H), 6.30 (s, 1H), 4.02 (d , J=6.2 Hz, 2H), 3.06 - 2.94 (m, 2H), 1.15 (s, 18H), 0.45 (s, 1H), 0.01 (d, J= 8.6 Hz, 2H), -0.32 (s, 2H).

2. tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3-carbonyl]amino}phenyl)naphthalene-2-ylmethyl]cyclopropylmethylcarbamic acid (128f) (0, 26 g, 24.42%); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.81 (d, J=9.8 Hz , 2H), 7.77 - 7.72 (m, 2H), 7.62 (s, 1H), 7.49 - 7.38 (m, 6H), 7.34 (dd, J=8.9 , 2.2 Hz, 2H), 7.30 - 7.25 (m, 2H), 7.19 (d, J=6.5 Hz, 2H), 4.93 (s, 1H), 4.12 (d, J=6.2 Hz, 2H), 2.24 (d, J=18.8 Hz, 2H), 1.29 (d, J=4.5 Hz, 9H), 0.99 - 0 .79 (m, 1H), 0.41 0.26 (m, 2H), -0.01 (q, J=4.9 Hz, 2H).

Step 5: Preparation of 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid {3-[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenyl}amide (128g).

Mixture of [3-(5-{3-[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (128e) (0.42 g, 0. 55 mmol) and tert-butyl ester [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3-carbonyl]amino}phen

- 252 045731 nyl)naphthalene-2-ylmethyl]cyclopropylmethylcarbamic acid (128f) (0.26 g, 0.39 mmol) were dissolved separately in methanol (10 ml) and conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. NMR analyzes of the residue in methanol and TLC indicated identical compounds. Combine the products, dry and purify by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-15% methanol in dichloromethane) to give {3-[(cyclopropylmethylamino)naphthalene-2-ylmethyl]phenyl}amide 2-(3-aminomethylphenyl) -5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (128g) (0.6 g, 95.42%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H), 10.14 (s, 2H), 8.41 (s, 3H), 8.22 (d, J=1.7 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.92 (dt, J=5.8, 3.2 Hz, 3H), 7.76 (dd, J=8 ,6, 1.8 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H), 7.69 - 7.42 (m, 10H), 5.77 (d, J=3, 4 Hz, 1H), 4.12 (d, J=5.6 Hz, 3H), 2.75 (d, J=12.4 Hz, 3H), 1.18 (dd, J=8.1, 3.8 Hz, 1H), 0.66 - 0.50 (m, 2H), 0.38 -0.22 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.80; MS (IER+) 570.3 (M+1); (IER-) 604.3 (M+Cl); analysis, calculation for C ₃₃ H ₃₀ F ₃ N ₅ O-2.05HCl-2H ₂ O: C, 58.25; H, 5.34; Cl, 10.68; N, 10.29; experiment: C, 58.14; H, 5.58; Cl, 11.02; N, 9.90.

Scheme 129

An example of the preparation of 1-(3-(aminomethyl)phenyl)-M-(3-((cyclopropylmethylamino)(naphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (129f) .

Step 1. Preparation of (3-aminophenyl)naphthalene-1-ylmethanol (129b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.0 mL, 12.0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% ethyl acetate in hexane) to give (3-aminophenyl)naphthalene-1-ylmethanol (129b) (2.45 g, 98.27%) in the form of a light brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.16-8.06 (m, 1H), 7.93-7.86 (m, 1H), 7.82 (d, J=8.1 Hz , 1H), 7.71-7.66 (m, 1H), 7.51 (dd, J=8.2, 7.1 Hz, 1H), 7.48 - 7.39 (m, 2H), 6.91 (t, J=7.9 Hz, 1H), 6.63 - 6.49 (m, 2H), 6.38 (ddd, J=7.9, 2.2, 1.1 Hz, 1H), 6.19 (d, J=4.4 Hz, 1H), 5.85 (d, J=4.4 Hz, 1H), 4.96 (s, 2H).

Step 2. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-(hydroxynaphthalene-1-ylmethyl)phenyl]amide (129c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.47 g, 8.8 mmol) in DMF (40 ml) was added (3-aminophenyl) naphthalene-1-ylmethanol (129b) (2.0 g, 8.8 mmol), Nethyl-N-isopropylpropan-2-amine (12.26 ml, 70.42 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 4.1 g, 8.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (350 ml), washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%] to give [3-(hydroxynaphthalene-1-ylmethyl)phenyl]amide 2-(3-cyanophenyl)-5- trifluoromethyl-2H-pyrazole-3-carboxylic acid (129c) (1.0 g, 22.17%) as a brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.17 - 8.08 (m, 2H), 7.99 (dt, J=7.8, 1.3 Hz , 1H), 7.94 - 7.82 (m, 3H), 7.73 (d, J=7.9 Hz, 1H), 7.70 - 7.50 (m, 5H), 7.50 - 7.39 (m, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.21 - 7.12 (m, 1H), 6.34 (d, J=4.3 Hz , 1H), 6.13 (d, J=4.3 Hz, 1H).

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Step 3. Preparation of {3-[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (129d).

In a solution of [3-(hydroxynaphthalene-1-ylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2Hpyrazole-3-carboxylic acid (129c) (1.0 g, 1.95 mmol) in dichloromethane ( 50 ml) at 0°C, add thionyl chloride (0.28 ml, 3.902 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (2.053 g, 29.265 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give {3[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5 -trifluoromethyl-2H-pyrazole-3-carboxylic acid (129d) (0.60 g, 54.40%) as a brown liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.57 (s, 1H), 8.29 - 8.17 (m, 1H), 8.12 - 8.06 (m, 1H), 7.94 (dt, J=7.8, 1.3 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.78 - 7.56 (m, 5H), 7.55- 7.40 (m, 4H), 7.27 - 7.17 (m, 2H), 5.58 (s, 1H), 2.35 (d, J=6.7 Hz, 2H), 1.02 0.87 (m, 1H), 0.44 - 0.24 (m, 2H), 0.11 - -0.07 (m, 2H).

Step 4. Preparation of [(3-{[2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol-3-carbonyl]amino} phenyl)naphthalene-1-ylmethyl]-cyclopropylmethylcarbamic acid tert-butyl ester (129e) .

Into a solution of {3-[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (129d) (0.60 g, 1.04 mmol) in MeOH (12 ml), cooled in ice/water, add nickel (II) chloride hexahydrate (0.29 g, 1.24 mmol) and Boc anhydride (0.713 g, 3.11 mmol), then add in portions sodium borohydride (0.23 g, 6.21 mmol) for 15 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2aminoethyl)ethane-1,2-diamine (0.28 ml, 2.59 mmol), then stirred for an additional 0.5 hours. Concentrated the reaction mixture to dryness in vacuo and dissolve the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give [3-(5-{3-[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenylcarbamoyl tert-butyl ether } -3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid (129e) (0.24 g, 34.46%).

Step 5. Preparation of {3-[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (129f).

Into a solution of [3-(5-{3-[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenylcarbamoyl}-3-trifluoromethylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (129e) (0.240 g, 0.358 mmol) in methanol (10 ml) added conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-15% methanol in dichloromethane) to give {3-[(cyclopropylmethylamino)naphthalene-1-ylmethyl]phenyl}amide 2-(3-aminomethylphenyl) free base -5-trifluoromethyl-2H-pyrazole3-carboxylic acid (129f) (0.08 g, 39.28%) as a light cream solid; 1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.25 (s, 1H), 10.00 (s, 1H), 8.46 (s, 3H), 8.20 (d, J=7.8 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.88 (t, J=1.9 Hz, 1H), 7.73 - 7 .47 (m, 13H), 7.43 - 7.38 (m, 1H), 6.44 (t, J=6.1 Hz, 1H), 4.11 (q, J=5.6 Hz, 2H), 3.03 - 2.74 (m, 2H), 1.20 - 1.14 (m, 1H), 0.55 (dd, J=7.8, 3.4 Hz, 2H), 0 .39 - 0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.79; MS (IER+) 570.3 (M+1); (IER-) 604.3 (M+Cl); 1-(3(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (129f) (0.28 g, 0.492 mmol) obtained above was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% methanol in chloroform) and converted to the hydrochloride salt by dissolving the resulting product in methanol (5 ml) and treating with 10 equivalents conc. HCl. The resulting solution was concentrated to dryness in a vacuum, dried in a vacuum to obtain 1 -(3 -(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(naphthalene-1yl)methyl)phenyl)-3-(trifluoromethyl)- hydrochloride 1H-pyrazole-5-carboxamide (129f) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.38 (s, 1H), 10.10 (d, J=10.5 Hz, 1H), 8.56 (s , 4H), 8.30 - 8.20 (m, 2H), 8.00 (dd, J=7.0, 3.2 Hz, 2H), 7.91 (t, J=1.9 Hz, 1H), 7.75-7.62 (m, 7H), 7.61 - 7.46 (m, 4H), 7.41 (t, J=7.9 Hz, 1H), 6.44 (t , J=6.2 Hz, 1H), 4.11 (q, J=5.6 Hz, 2H), 2.97 - 2.68 (m, 3H), 1.30 - 1.17 (m, 1H), 0.55 (dd, J=7.9, 3.6 Hz, 2H), 0.41 - 0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.78; MS (IER+) 570.3 (M+1); (IER-) 604.3 (M+Cl); analysis, calculation for C33H ₃₀ F ₃ N5O-2HCl-2.25H ₂ O: C, 58.02; H, 5.39; Cl, 10.38; N, 10.25; experiment; C, 57.93; H, 5.30; Cl, 10.28; N, 10.01.

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Scheme 130

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (130g ).

Step 1. Preparation of (3-amino-4-fluorophenyl)(4-nitrophenyl)methanol (130b).

To a stirred solution of 4-nitrobenzaldehyde (130a) (1.813 g, 12 mmol) in tetrahydrofuran (15 ml), cooled to 0°C, was added (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (18.00 ml, 18.00 mmol) and stirred at room temperature for 3 hours. The reaction was quenched with hydrochloric acid (10 ml, 2N) and the mixture was stirred for 30 minutes. The reaction mixture was made basic with sodium bicarbonate solution and extracted with ethyl acetate (2x250 ml). Combine the organic layers, wash with water (2x50 ml), brine (50 ml), dry and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give (3-amino-4-fluorophenyl)(4nitrophenyl)methanol (130b) (1.71 g, 6 .52 mmol, yield 54.3%) as an oily liquid; 1H NMR (300 MHz, DMSO) δ 8.22 - 8.14 (m, 2H), 7.65- 7.58 (m, 2H), 6.90 (dd, J=11.5, 8.2 Hz, 1H), 6.76 (dd, J=9.0, 2.2 Hz, 1H), 6.12 (d, J=3.9 Hz, 1H, exchange with D ₂ O), 5.69 (d, J=3.8 Hz, 1H), 5.13 (s, 2H, exchange with D ₂ O). MC (IER-) 261.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-nitrophenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (130c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.011 g, 7.15 mmol) in DMF (20 ml), fluorophenyl)(4-nitrophenyl)methanol (130b) (1.705 g, 6.50 mmol), N-ethyl-N-isopropylpropan-2-amine (5.66 ml, 32.5 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP , 3.64 g, 7.80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (2x75 ml). Combine the organic layers, wash with brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-nitrophenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (130c) (2.081 g, 3.96 mmol, 60.9% yield) as a brown semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 8.19 (dd, J=8.9, 2.5 Hz, 2H), 8.12 (t, J=1 .8 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.93 - 7.87 (m, 1H), 7.78 - 7.69 (m, 2H), 7.68 - 7.63 (m, 2H), 7.63 - 7.53 (m, 1H), 7.35 - 7.20 (m, 2H), 6.36 (d, J=4.0 Hz, 1H) , 5.88 (d, J=3.9 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.98, -122.64; MS (ESI+) 548.2 (M+Na); (IER-) 524.2 (M-1).

Step 3. Preparation of tert-butyl-3-(5-((5-((4-tert-butoxycarbonylaminophenyl)(hydroxy)methyl)-2fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl )benzylcarbamate (13 0d).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)1H-nirazol-5-carboxamide (130c) (2.119 g, 4.03 mmol) in MeOH (60 ml), cooled in ice/water, di-tert-butyl dicarbonate (3.56 g, 16.13 mmol), nickel(II) chloride hexahydrate (0.516 g, 2.170 mmol) was added , then sodium borohydride (1.557 g, 40.3 mmol) was added slowly in portions over 5 minutes.

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The reaction mixture was stirred at room temperature for 3 hours, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.995 mL, 18.28 mmol) and stirred for 30 minutes. The reaction mixture was concentrated to dryness. The residue was diluted with water (200 ml). The isolated solid was collected by filtration and purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-((5- ((4-tert-butoxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (130d) (0.815 g, 1.165 mmol, yield 28, 9%) in the form of colorless foam; MS (IER+) 722.4 (M+Na), (IER-) 698.3 (M-1), and tert-butyl-3-(5-(5-((4-aminophenyl)(hydroxy)methyl )-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (130e) (0.35 g, 0.584 mmol, 14.47% yield) as a colorless foam; MS (IER+) 622.3 (M+Na), (IER-) 598.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-((5-((4-tert-butoxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1 H- pyrazol-1-yl)benzylcarbamate (130f).

Into a solution of tert-butyl-3-(5-((5-((4-tert-butoxycarbonylaminophenyl)(hydroxy)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzylcarbamate (130d) (0.798 g, 1.141 mmol) in dichloromethane (25 ml), thionyl chloride (0.178 ml, 2.435 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was treated with triethylamine (1.7 ml, 12.19 mmol), stirred at room temperature for 1 hour. The reaction mixture was diluted with cyclopropylmethanamine (2.084 ml, 24.32 mmol) and concentrated to remove the bulk of the dichloromethane, then acetonitrile (25.00 ml) was added and stirred at reflux. condensation for 16 hours. The reaction mixture was concentrated to dryness, treated with chloroform (240 ml), washed with water (100 ml), dried over MgSO ₄ , then filtered and concentrated. The reaction mixture was purified by flash column chromatography (silica gel, eluted with 0 to 20% methanol/chloroform mixtures) to give tert-butyl-3-(5-((5-((4-tert-butoxycarbonylaminophenyl)((cyclopropylmethyl) amino)methyl)-2-fluorophenyl)-carbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (130f) (297 mg, 0.395 mmol, 34.6% yield) as a yellow oily liquid ; MS (IER+) 753.5 (M+1), (IER-) 751.3 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (130g).

Into a solution of tert-butyl-3-(5-((5-((4-tert-butoxycarbonylaminophenyl)-((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1 H-pyrazole -1-yl)benzylcarbamate (130f) (290 mg, 0.385 mmol) in methanol (5 ml), hydrochloric acid (1.170 ml, 38.5 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated to dryness in vacuo. The residue was dried using a vacuum pump and purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-(( 4-Aminophenyl)(cyclopropylmethylamino)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (130g) (60 mg, 0.109 mmol, 28.2% yield) as a white solid. Into a stirred solution of the free base 1-(3(aminomethyl)phenyl)-N-(5-((4-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (130g) (60 mg, 0.109 mmol) in methanol (5 ml) added conc. hydrochloric acid (0.045 ml, 0.543 mmol) and concentrated to remove excess solvents and dried in vacuo to give 1-(3-(aminomethyl)phenyl)-N-(5-((4aminophenyl)(cyclopropylmethylamino)methyl)-2 hydrochloride salt -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (130g) (67.5 mg, 0.108 mmol, 99% yield) as a white solid; 1H NMR (300 MHz, DMSO-06) δ 10.85 (s, 1H, exchange with D2O), 10.28 (s, 2H, exchange with D2O), 8.54 (s, 3H, exchange with D2O), 7.93 (dd, J=7.2, 2.3 Hz, 1H), 7.79 - 7.68 (m, 5H), 7.65 (dt, J=7.3, 1.8 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.44 - 7.34 (m, 1H), 7.22 (d, J=8.1 Hz, 2H), 5.71 - 5 .58 (m, 1H), 4.12 (q, J=5.7 Hz, 2H), 2.70 (d, J=9.0 Hz, 2H), 1.17 (ddt, J=12, 8, 8.1, 4.1 Hz, 1H), 0.59 - 0.50 (m, 2H), 0.31 (td, J=5.8, 4.2 Hz, 2H).

Scheme 131

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (131b ).

Step 1. Preparation of tert-butyl-3-(5-((5-((3-tert-butoxycarbonylaminophenyl)-((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1 H -pyrazol-1-yl)benzylcarbamate (131a).

Into a solution of tert-butyl-3-(5-((5-((3-tert-butoxycarbonylaminophenyl)(hydroxy)methyl)-2-fluoro

- 256 045731 phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (57c) (0.582 g, 0.832 mmol) in dichloromethane (20 ml) at 0°C added thionyl chloride (0.130 ml, 1.776 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with triethylamine (0.771 ml, 5.53 mmol) and stirred at room temperature for 1 hour. The reaction mixture was treated with cyclopropylmethanamine (1.520 ml, 17.73 mmol) and concentrated in vacuo to remove most of the dichloromethane, then add acetonitrile (20.00 ml) and stir at reflux temperature for 16 hours. Concentrate the reaction mixture to dryness in vacuo, dissolve in chloroform (300 ml), wash with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The reaction mixture was purified by flash column chromatography (silica gel, 25 g, eluted with 0 to 20% methanol/chloroform mixtures) to give tert-butyl-3-(5-((5-((3-butoxycarbonylaminophenyl)() (cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (131a) (115 mg, 0.153 mmol, 18.37% yield) as a white foam; MS (IER+) 753.5 (M+1); (IER-) 751.4 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((3-αminophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5- carboxamide (131b).

Into a solution of tert-butyl-3 -(5 -((5-((3-tert-butoxycarbonylaminophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol- 1-yl)benzylcarbamate (131a) (115 mg, 0.153 mmol) in methanol (5 ml), hydrochloric acid (0.464 ml, 15.27 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated to dryness in vacuo. The residue was dried using a vacuum pump and purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-(( 3-aminophenyl)(cyclopropylmethylamino)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (131b). To a stirred solution of the free base of compound 131b (80 mg, 0.145 mmol) in methanol (5 ml) was added conc. hydrochloric acid (0.060 ml, 0.724 mmol), stirred for 30 min and concentrated to dryness in vacuo to give pure 1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethylamino) hydrochloride salt methyl)-2-fluorophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (131b) (19 mg, 20.98% yield) as a white solid; ^1H NMR (300 MHz, DMSO- _d6 ) δ 10.87 (s, 1H, exchange with _D2O ), 10.30 (s, 2H, exchange with D2O), 8.55 (s, 3H, exchange with D2O), 7.91 (dd, J=7.4, 2.3 Hz, 1H), 7.79 7.70 (m, 3H), 7.70 - 7.61 (m, 2H), 7 .60 -7.48 (m, 2H), 7.46 (d, J=8.5 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.18 (d, J=7 .9 Hz, 1H), 5.81 - 5.56 (m, 1H), 4.11 (d, J=5.6 Hz, 2H), 2.77 - 2.66 (m, 2H), 1 .17 (td, J=9.7, 7.6, 4.3 Hz, 1H), 0.60 0.51 (m, 2H), 0.31 (dt, J=6.6, 4.6 Hz, 2H); MS (IER+) 553.3 (M+1), 575.3 (M+23), (IER-) 587.3 (M+35).

Scheme 132

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamideα (132f).

Step 1. Preparation of (3-amino-4-fluorophenyl)(pyridin-4-yl)methanol (132b).

(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (6 .46 g, 18.0 mmol) and stirred at room temperature for 3 hours. The reaction was quenched with hydrochloric acid (10 ml, 2N) and the mixture was stirred for 30 minutes. The reaction mixture was made basic with sodium bicarbonate solution and extracted with ethyl acetate (2x250 ml). United authorities

- 257 045731 the layers were washed with water (2x50 ml), saline (50 ml), dried and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of CMA 80 in chloroform) to give (3-amino-4-fluorophenyl)(pyridin-4-yl)methanol (132b) (2.1 g, yield 80%) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 - 8.53 (m, 1H), 8.42 (dd, J=4.8, 1.7 Hz, 1H), 7.71 - 7 .64 (m, 1H), 7.32 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 6.90 (dd, J=11.5, 8.3 Hz, 1H ), 6.78 (dd, J=9.0, 2.2 Hz, 1H), 6.53 (ddd, J=8.3, 4.4, 2.2 Hz, 1H), 5.97 ( d, J=3.9 Hz, 1H, exchange with D ₂ O), 5.62 (d, J=3.7 Hz, 1H), 5.12 (s, 2H, exchange with D ₂ O); mass spectrum (ESI+) 219.2, 241.1 (M+23), (ESI-) 217.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 132c).

(3-Amino- 4-fluorophenyl)(pyridin-4-yl)methanol (132b) (2.034 g, 9.32 mmol), N-ethyl-N-isopropylpropan-2-amine (8.12 ml, 46.6 mmol) and bromine hexafluorophosphate -trispyrrolidinophosphonium (PyBrOP, 5.21 g, 11.18 mmol) at room temperature. The reaction mixture was stirred at room temperature for 37 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (75 ml) and extracted with ethyl acetate (2x75 ml). Combine the organic layers, wash with brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridine-4- yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (132c) (2.081 g, 4.32 mmol, 46.4% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.57 (s, 1H), 8.51 -8.47 (m, 2H), 8.15-8.10 (m, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.76 - 7.69 (m, 2H), 7.55 (dd, J =7.4, 2.1 Hz, 1H), 7.38 - 7.35 (m, 2H), 7.34 - 7.21 (m, 2H), 6.27 (d, J=4.0 Hz, 1H), 5.73 (d, J=4.1 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSOde) δ -60.99, -122.63; MS (ESI+) 482.2 (M+Na).

Step 3. Preparation of tert-butyl-3-(5-((2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)carbamoyl)3 -(trifluoromethyl)-1 H-pyrazol-1 -yl )benzylcarbamate (132d).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (132c) (3 .44 g, 7.15 mmol) in MeOH (100 ml), cooled in ice/water, di-tert-butyl dicarbonate (6.30 g, 28.6 mmol) and nickel (II) chloride hexahydrate (2.123 g) were added , 8.93 mmol), then sodium borohydride (1.655 g, 42.9 mmol) was added slowly over 5 min and stirred at room temperature for 3 h. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (9.36 ml, 86 mmol), the mixture was stirred at room temperature for 0.5 h and concentrated to dryness in vacuo. The residue was diluted with water (200 ml). The isolated solid was collected by filtration, purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexane, 0-100%) to give tert-butyl-3-(5-((2-fluoro-5-( hydroxy(pyridin-4yl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (132d) (1.172 g, 2.002 mmol, 27%) as an off-white solid; MS (IER+ 586.3 (M+1); (IER-) 584.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (132e ).

Into a solution of tert-butyl-3-(5-((2-fluoro-5-(hydroxy(pyridin-4-yl)methyl)phenyl)-carbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (132d) (1.172 g, 2.002 mmol) in dichloromethane (40 ml) at 0°C was added thionyl chloride (0.312 ml, 4.27 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with triethylamine (1.855 ml, 13, 31 mmol), the mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (3.66 ml, 42.7 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (100 ml), washed with water (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-20% methanol in chloroform) to give tert-butyl-3-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl )-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (132e) (127 mg, 0.199 mmol, 9.94% yield) as a white foam; MS (IER+) 639.4 (M+1), (IER-) 637.4 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (132f).

In a solution of tert-butyl-3-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (132e ) in methanol (5 ml), hydrochloric acid (0.571 ml, 18.79 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)- (pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (132f). Into a stirred solution of the free base 1 -(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (36 mg, 0.067 mmol) in methanol (5 ml) was added conc. hydrochloric acid (0.028 ml, 0.334 mmol), stirred for 30 min and concentrated to dryness in vacuo to give 1-(3-(aminomethyl)phenyl)-N-(5(((cyclopropylmethyl)amino)(pyridine-4 hydrochloride salt -yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (132f) (30 mg, 0.049 mmol, 73.4% yield) as a yellow solid; 1H NMR (300

MHz, DMSO-d ₆ ) δ 10.91 (s, 3H, exchange with _D2O ), 8.95-8.84 (m, 2H), 8.56 (s, 3H, exchange with D2O), 8 ,33 - 8.21 (m, 2H), 8.06 (dd, J=7.1, 2.3 Hz, 1H), 7.85 (ddd, J=8.6, 4.5, 2, 3 Hz, 1H), 7.72 (d, J=1.9 Hz, 2H), 7.65 (dt, J=7.3, 1.8 Hz, 1H), 7.60 - 7.49 ( m, 2H), 7.44 (dd, J=10.3, 8.6 Hz, 1H), 6.01 (s, 1H), 4.12 (q, J=5.8 Hz, 2H), 2.75 (d, J=6.9 Hz, 2H), 1.28 - 1.14 (m, 1H), 0.55 (m, 2H), 0.41 - 0.28 (m, 2H) ; MS (IER+) 539.3 (M+1), (IER-) 537.3 (M-1), 573.3 (M+35); analysis, calculation for C ₂₈ H ₂₆ F ₄ N ₆ O-3HCl-3H ₂ O: C, 47.98; H, 5.03; N, 11.99; Cl, 14.98; experiment: C, 48.20; H, 5.00; N, 11.57; Cl, 14.20.

Scheme 133

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(biphenyl-4-yl(cyclopropylmethylamino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (133g).

Step 1. Preparation of (3-aminophenyl)biphenyl-4-ylmethanol (133b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 mL, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched with 2N. HCl (12.50 ml) and stirred for another 6 hours. The reaction mixture was neutralized with 2N. NaOH (15 ml), extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The resulting crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0100% ethyl acetate in hexanes) to give (3-aminophenyl)biphenyl-4-ylmethanol (133b) (2.0 g, 72.64%) in in the form of a light brown sticky liquid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 - 7.55 (m, 4H), 7.44 (ddt, J=8.4, 6.4, 1.8 Hz, 4H), 7 .37 - 7.28 (m, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.61 (t, J=1.9 Hz, 1H), 6.55 (dt, J=7.7, 1.3 Hz, 1H), 6.39 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.74 (d, J=3.8 Hz , 1H), 5.55 (d, J=3.8 Hz, 1H), 5.00 (s, 2H).

Step 2. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-(biphenyl-4-ylhydroxymethyl)phenyl]amide (133c).

(3-Aminophenyl)biphenyl- 4-ylmethanol (133b) (2.0 g, 7.26 mmol), Nethyl-N-isopropylpropan-2-amine (10 ml, 58.10 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 3.38 g , 7.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours and diluted with ethyl acetate (350 ml). The reaction mixture was washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%) to give [3-(biphenyl-4-ylhydroxymethyl)phenyl]amide 2-(3cyanophenyl)-5-trifluoromethyl- 2H-pyrazole-3-carboxylic acid (133c) (2.0 g, 51.13%) as a red-brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 8.16 (t, J=1.9 Hz, 1H), 8.00

- 259 045731 (dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.71 (d, J=4.8 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.64 - 7.54 ( m, 5H), 7.44 (dd, J=8.4, 6.5 Hz, 4H), 7.37 - 7.30 (m, 1H), 7.27 (d, J=7.9 Hz , 1H),

7.21 - 7.15 (m, 1H), 6.01 (d, J=3.8 Hz, 1H), 5.73 (d, J=3.8 Hz, 1H).

Step 3. Preparation of {3-[biphenyl-4-yl(cyclopropylmethylamino)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (133d).

In a solution of [3-(biphenyl-4-ylhydroxymethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2Hpyrazole-3-carboxylic acid (133c) (2.0 g, 3.71 mmol) in dichloromethane ( 20 ml) at 0°C, add thionyl chloride (0.883 g, 7.43 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (4.2 ml, 55.71 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (40 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give {3-[biphenyl-4yl(cyclopropylmethylamino)methyl]phenyl}amide 2-(3-cyanophenyl)-5 -trifluoromethyl-2H-pyrazole-3-carboxylic acid (133d) (1.0 g, 45.56%) as a pale resinous liquid; 1H NMR (300 MHz, DMSOd6) δ 10.66 (s, 1H), 8.20 - 8.11 (m, 1H), 7.99 (dd, J=7.7, 1.6 Hz, 1H) , 7.93 - 7.87 (m, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (d, J=3.3 Hz, 2H), 7.63 - 7.52 (m, 5H), 7.51 - 7.45 (m, 2H), 7.42 (d, J=7.7 Hz, 1H), 7.37 - 7.32 (m, 1H) , 7.31 - 7.22 (m, 2H), 4.87 (s, 1H), 2.32 (d, J=6.7 Hz, 2H), 1.03 - 0.87 (m, 1H ), 0.50 - 0.29 (m, 2H), 0.18 - -0.04 (m, 2H).

Step 4. Preparation of tert-butyl-([1,1'-biphenyl]-4-yl(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (133e) and tert-butyl-3-(5-((3-([1,1'-biphenyl]-4-yl((cyclopropylmethyl) amino)methyl)phenyl)carbamoyl)-3(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (133f).

Into a solution of {3-[biphenyl-4-yl(cyclopropylmethylamino)methyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (133d) (1.0 g, 1.69 mmol ) in MeOH (24 mL), cooled in ice/water, nickel(II) chloride hexahydrate (0.48 g, 2.03 mmol) and Boc anhydride (1.16 mL, 5.07 mmol) were added, then sodium borohydride (0.44 g, 10.14 mmol) was added portionwise over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.5 mL, 4.23 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-40% ethyl acetate/hexane) to give:

1. tert-butyl-([1,1'-biphenyl]-4-yl(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (133e) (300 mg, 22.3%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.73 (s, 1H), 7.72 - 7.63 (m, 5H), 7.55 (s, 1H), 7.52 - 7.38 (m, 7H), 7.38 - 7.30 (m, 3H), 7.26 (d, J=8.2 Hz, 2H), 7.01 - 6.93 (m, 1H), 6, 33 (s, 1H), 4.18 (d, J=6.2 Hz, 2H), 3.12 (t, J=6.3 Hz, 2H), 1.37 (s, 9H), 1, 32 (s, 9H), 0.92 - 0.77 (m, 1H), 0.20 (d, J=8.1 Hz, 2H), -0.15 (s, 2H);

2. tert-butyl-3-(5-((3-([1,1'-biphenyl]-4-yl((cyclopropylmethyl)amino)methyl)phenyl)-carbamoyl)-3(trifluoromethyl)-1H-pyrazole -1-yl)benzylcarbamate (133f) (280 mg, 23.81%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.71 - 7.67 (m, 1H), 7.63 - 7.55 (m, 5H), 7.53 - 7.46 (m, 3H), 7.45-7.39 (m, 4H), 7.38 - 7.32 (m, 3H), 7.25 (d, J=6.7 Hz, 2H) , 4.87 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.32 (d, J=6.7 Hz, 2H), 1.35 (s, 9H) , 0.99 - 0.89 (m, 1H), 0.47 - 0.32 (m, 2H), 0.12 - -0.02 (m, 2H).

Step 5. Preparation of {3-[biphenyl-4-yl(cyclopropylmethylamino)methyl]phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (133g).

A mixture of tert-butyl-([1,1'-biphenyl]-4-yl(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol- 5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (133e) (300 mg, 0.37 mmol) and tert-butyl-3-(5-((3-([1,1'-biphenyl]-4- yl((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (133f) (280 mg, 0.4 mmol) were dissolved separately in methanol (10 ml) and added conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. NMR analyzes of the residue in methanol and TLC indicated identical compounds. Combine the products, dry and purify by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-15% methanol in dichloromethane) to give {3-[biphenyl-4yl(cyclopropylmethylamino)methyl]phenyl}amide 2-(3-aminomethylphenyl )-5-trifluoromethyl-2H-pyrazole-3carboxylic acid (133g) (0.250 g, 54.56%) as a pale white solid, which was purified again by flash column chromatography (silica gel, 4 g, eluted with mixtures of 0- 25% methanol

- 260 045731 in chloroform) to obtain {3-[biphenyl-4-yl(cyclopropylmethylamino)methyl]phenyl}amide 2-(3aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (133g) (0.14 d) in the form of a white solid; ¹ H NMR (300 MHz, DMSO-06) δ 11.00 (s, 1H), 10.19 (d, J=6.8 Hz, 2H), 8.51 (s, 3H), 7.92 ( s, 1H), 7.81 - 7.59 (m, 12H), 7.56 - 7.43 (m, 4H), 7.39 (d, J=7.2 Hz, 1H), 5.75 - 5.56 (m, 1H), 4.12 (q, J=5.6 Hz, 2H), 2.75 (q, J=5.7, 4.9 Hz, 2H), 1.19 ( td, J=13.0, 10.7, 5.7 Hz, 1H), 0.57 (d, J=7.6 Hz, 2H), 0.42 - 0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (IER+) 596.4 (M+1); (IER-) 630.3 (M+Cl); analysis, calculation for Сз5Нз2РзК5О-2.5НС1-2Н2О: C, 58.16; H, 5.37; Cl, 12.26; N, 9.69; experiment; C, 58.11; H, 5.19; Cl, 11.86; N, 9.47.

Scheme 134

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(6-methoxynaphthalene2-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (134f) .

Step 1. Preparation of (3-aminophenyl)(6-methoxynaphthalene-2-yl)methanol (134b).

To a stirred solution of 6-methoxynaphthalene-2-carbaldehyde (134a) (1.2 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12.00 ml, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours, quenched with 2N. HCl (12.50 ml) and stirred for another 6 hours at room temperature. The reaction mixture was made alkaline with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(6-methoxynaphthalene-2-yl)methanol (134b) (2.4 g, 85.92%) in the form of a light brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.82 - 7.75 (m, 2H), 7.71 (d, J=8.6 Hz, 1H), 7.38 (dd, J=8 .5, 1.7 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.12 (dd, J=9.0, 2.5 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.60 (t, J=1.9 Hz, 1H), 6.56 (dt, J=7.6, 1.3 Hz, 1H), 6 .38 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.77 (d, J=3.7 Hz, 1H), 5.63 (d, J=3.8 Hz, 1H), 4.97 (s, 2H), 3.85 (s, 3H).

Step 2. Preparation of {3-[hydroxy(6-methoxynaphthalen-2-yl)methyl]phenyl}amide 2-(3-cyanophenyl)5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.6 g, 9.45 mmol) in DMF (48 ml) was added (3-aminophenyl) (6-methoxynaphthalen-2-yl)methanol (134b) (2.4 g, 8.59 mmol), N-ethyl-N-isopropylpropan-2-amine (8.88 g, 68.72 mmol) and bromine hexafluorophosphate -trispyrrolidinophosphonium (PyBrOP, 4.40 g, 9.451 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x100 ml), brine (100 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%] to give {3-[hydroxy(6methoxynaphthalene-2-yl)methyl]phenyl}amide 2-(3-cyanophenyl )-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134c) (2.4 g, 51.50% yield) as a red-brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.14 (t, J=1.9 Hz, 1H), 7.99 (dt, J=7.8, 1 ,3 Hz, 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.76 - 7.67 (m, 3H), 7.65 (t, J=1.8 Hz, 1H), 7.56 (dt, J=8.2 , 1.5 Hz, 1H), 7.37 (dd, J=8.5, 1.7 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.27 - 7 .23 (m, 1H), 7.19 (dt, J=7.9, 1.4 Hz, 1H),

- 261 045731

7.14 (dd, J=8.9, 2.5 Hz, 1H), 6.03 (d, J=3.8 Hz, 1H), 5.80 (d, J=3.8 Hz, 1H ), 3.85 (s, 3H).

Step 3. Preparation of {3-[(cyclopropylmethylamino)(6-methoxynaphthalene-2-yl)methyl]-phenyl}amide

2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134d).

In a solution of {3-[hydroxy(6-methoxynaphthalin-2-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134c) (2.4 g, 4.42 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (1.05 g, 8.85 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (4.72 g, 66.3 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (40 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give {3[(cyclopropylmethylamino)(6-methoxynaphthalene-2-yl)methyl]phenyl}amide 2-(3-cyanophenyl )-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134d) (1.3 g, 49.38%) as a light brown sticky liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7.8, 1 .3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.72 - 7.68 (m, 4H), 7.55 (td, J= 4.7, 2.1 Hz, 1H), 7.46 (dd, J=8.5, 1.7 Hz, 1H), 7.25 (t, J=4.0 Hz, 3H), 7, 13 (dd, J=8.9, 2.6 Hz, 1H), 4.95 (s, 1H), 3.84 (s, 3H), 2.33 (d, J=6.7 Hz, 2H ), 1.24 (s, 1H), 0.89 - 0.79 (m, 1H), 0.44 -0.31 (m, 2H), 0.05 (q, J=4.8 Hz, 2H).

Step 4. Preparation of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(6 -methoxynaphthalen-2-yl)methyl)(cyclopropylmethyl)carbamate (134e).

Into a solution of {3-[(cyclopropylmethylamino)(6-methoxynaphthalen-2-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134d) (1.3 g, 2.18 mmol) in MeOH (26 mL), cooled in ice/water, add nickel(II) chloride hexahydrate (0.62 g, 2.619 mmol) and bosanhydride (1.5 mL, 6.547 mmol), then sodium borohydride (0.500 g, 13.095 mmol) was added piecemeal over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with K1-(2-aminoethyl)ethane-1,2-diamine (0.6 mL, 5.456 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(6-methoxynaphthalene-2-yl)methyl)(cyclopropylmethyl)carbamate (134e) (0.90 g, 51.57%) in as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.71 (s, 1H), 7.80 (d, J=5.7 Hz, 1H), 7.77 (d, J=6.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.53 (s, 1H), 7.47 (q, J=6.4 Hz, 2H), 7.39 (t, J=3.7 Hz, 2H), 7.33 (dd, J=7.4, 2.3 Hz, 4H), 7.14 ( dd, J=9.0, 2.5 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.43 (s, 1H), 4.17 (d, J=6 ,1 Hz, 2H), 3.87 (s, 3H), 3.14 (d, J=6.6 Hz, 2H), 1.37 (s, 9H), 1.32 - 1.29 (m , 9H), 0.68 - 0.50 (m, 1H), 0.23 - 0.04 (m, 2H), -0.06 - -0.21 (m, 1H), -0.18 - -0.31 (m, 1H).

Step 5. Preparation of {3-[(cyclopropylmethylamino)(6-methoxynaphthalen-2-yl)methyl]-phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134f).

Into a solution of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamido)phenyl)(6-methoxynaphthalene-2 -yl)methyl)(cyclopropylmethyl)carbamate (134e) (0.90 g, 1.13 mmol) in methanol (10 ml) was added conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to obtain a white solid. The product was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-15% methanol in dichloromethane) to give {3[(cyclopropylmethylamino)(6-methoxynaphthalene-2-yl)methyl]phenyl}amide 2-(3- aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (BCX-7246, 155 mg, 20.5%) as an off-white solid, which was purified again by flash column chromatography (silica gel, 4 g, eluted with mixtures 0-25% methanol in chloroform) to obtain pure {3-[(cyclopropylmethylamino)(6methoxynaphthalen-2-yl)methyl]phenyl}amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (134f) (0.085 g) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.99 (s, 1H), 10.30 - 10.12 (m, 2H), 8.52 (s, 3H), 8.14 (d, J =2.0 Hz, 1H), 7.91 (t, J=1.8 Hz, 1H), 7.84 (dd, J=16.4, 8.9 Hz, 2H), 7.77 - 7 .68 (m, 4H), 7.63 (tt, J=5.8, 1.7 Hz, 2H), 7.57 - 7.42 (m, 3H), 7.34 (d, J=2 .6 Hz, 1H), 7.22 (dd, J=8.9, 2.5 Hz, 1H), 5.82 - 5.57 (m, 1H), 4.11 (d, J=5, 6 Hz, 2H), 3.87 (s, 3H), 2.81 - 2.66 (m, 2H), 1.20 (td, J=8.0, 3.9 Hz, 1H), 0, 62 - 0.45 (m, 2H), 0.40 - 0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (ESI+) (ESI) 634.3 (M+Cl); analysis, calculation for C ₃₄ H ₃₂ F ₃ N ₅ O ₂ -2HCl-2H ₂ O: C, 57.63; H, 5.41; Cl, 10.01; N, 9.88; experiment: C, 57.50; H, 5.11; Cl, 9.86; N, 9.68.

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Scheme 135

1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-hydroxyphe Example of preparation of nil)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (135c ).

Step 1. Preparation of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(4 -hydroxyphenyl)methyl)(cyclopropylmethyl)carbamαtα (135a) and tert-butyl-3-(5-((3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)carbamoyl)-3(trifluoromethyl)- 1 H-pyrazol-1-yl)benzylcarbamate (13 5b).

In a solution of 1-(3-cyanophenyl)-N-(3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1I-pyrazole-5-carboxamide (123d) (1, 2 g, 2.26 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.57 g, 2.4 mmol) and Boc anhydride (1.26 ml, 5.79 mmol), then sodium borohydride (0.44 g, 11.58 mmol) was added portionwise over 15 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2-aminoethyl)ethane1,2-diamine (1.1 mL, 7.72 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-60% ethyl acetate/hexane) to give:

1. tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamido)phenyl)(4-hydroxyphenyl )methyl)(cyclopropylmethyl)carbamate (135a) (0.167 g, 7.55%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.70 (s, 1H), 9.47 (s, 1H), 7.68 7.58 (m, 1H), 7.55 (s, 1H) , 7.53 - 7.45 (m, 1H), 7.46 - 7.37 (m, 2H), 7.37 - 7.25 (m, 3H), 6.97 (dd, J=8, 4, 6.5 Hz, 2H), 6.92 - 6.85 (m, 1H), 6.77 - 6.70 (m, 2H), 6.22 (s, 1H), 4.25 - 4 ,13 (m, 2H), 3.12 (dd, J=14.5, 6.7 Hz, 1H), 2.95 (dd, J=14.5, 6.6 Hz, 1H), 1, 37 (s, 9H), 1.31 (s, 9H), 0.58 (d, J=25.7 Hz, 1H), 0.17 (ddt, J=13.6, 9.2, 4, 4 Hz, 2H), -0.11 (dd, J=9.0, 4.6 Hz, 1H), -0.30 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.78; MS (IER+) 736.5 (M+1); (IER-) 734.1 (M-1);

2. tert-butyl-3-(5-((3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)-carbamoyl)-3(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate ( 135b) (0.209 g, 10.93%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 9.23 (s, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.57 ( s, 1H), 7.557.46 (m, 1H), 7.42 (dd, J=9.9, 3.1 Hz, 2H), 7.37 - 7.31 (m, 2H), 7.22 (t, J=7.8 Hz, 1H), 7.18 - 7.13 (m, 3H), 6.68 -6.62 (m, 2H), 4.69 (s, 1H), 4, 19 (d, J=6.2 Hz, 2H), 2.26 (d, J=6.7 Hz, 2H), 1.36 (s, 9H), 1.00 - 0.81 (m, 1H ), 0.41 - 0.32 (m, 2H), 0.07 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 636.4 (M+1); (IER-) 634.4 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (135c).

Into a solution of tert-butyl-3-(5-((3-((cyclopropylmethyl)amino)(4-hydroxyphenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (135b) ( 0.199 g, 0.313 mmol) in methanol (3 ml) was added 12N. aq. HCl (0.652 ml, 7.83 mmol), the solution was stirred at 50°C for 6 h and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0-50% methanol/chloroform mixtures) to give (135c) (39 mg, 23% yield) as a white solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 10.92 (s, 1H, exchange with _D2O ), 9.74 (s, 1H, exchange with D2O), 8.43 (s, 3H, exchange with D2O), 7.80 (s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.48 (m, 5H), 7.47 -7.33 (m, 3H), 6.78 (d, J=8.4 Hz, 2H), 5.40 (s, 1H), 4.12 (s, 2H), 2.65 (s, 2H), 1.11 (d, J=11.2 Hz, 1H), 0.54 (d, J=8.0 Hz, 2H), 0.27 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.78; MS (IER+): MS (IER+) 536.3 (M+1), MS (IER-) 570.2 (M+Cl); analysis, calculation for: CaHF^Or^HO^SSHCl: C, 52.28; H, 5.35; Cl, 12.50; N, 10.51; experiment- 263 045731

Pd/C, H ₂ ment: C, 52.16; H, 5.25; Cl, 12.39; N, 10.30 Scheme 136

An example of the preparation of 1-(3-(aminomethyl)phenyl)-M-(3-(4-hydroxybenzyl)phenyl)-3-(trifluoromethyl)-1Ppyrazole-5-carboxamide (136a).

Into a solution of 1-(3-(aminomethyl)phenyl)-N-(3-((4-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123f ) (0.2 g, 0.320 mmol) in methanol (30 ml) was added hydrogen chloride (4N in dioxane, 0.799 ml, 3.20 mmol) and palladium (10% Pd on a carbon support) (0.102 g, 0.096 mmol). The reaction mixture was hydrogenated at 60 psi (414 kPa) for 14 hours. The reaction mixture was filtered through a small pad of Celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-25% methanol in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-(4hydroxybenzyl)phenyl)- hydrochloride salt 3-(trifluoromethyl)-1P-pyrazole-5-carboxamide (136a) (0.211 g) as an off-white solid; 1P NMR (300 MHz, DMSO-d ₆ ) δ 10.73 (s, 1P), 9.26 (s, 1P), 8.39 (s, 3P), 7.71 (t, J=1.7 Hz, 1P), 7.65 (d, J=0.7 Hz, 1P), 7.62 (dt, J=7.4, 1.6 Hz, 1P), 7.56 (d, J=7 ,8 Hz, 1P), 7.51 (ddd, J=5.7, 3.5, 1.5 Hz, 2P), 7.44 (t, J=1.9 Hz, 1P), 7.24 (t, J=7.8 Hz, 1P), 7.02 - 6.94 (m, 3P), 6.74 - 6.63 (m, 2P), 4.12 (s, 2P), 3, 79 (s, 2P); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 467.3 (M+1); (IER-) 501.2 (M-1); analysis, calculation for SzzSHL^Oz'PSPPO: C, 57.64; P, 4.64; Cl, 6.81; N, 10.76; experiment; C, 57.91; P, 4.75; Cl, 6.96; N, 10.64.

Scheme 137 f ₃ c

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1 P-pyrazole-5-carboxamide (137a) and 1-(3-(aminomethyl)phenyl)-N(3 -(3 -hydroxybenzyl)phenyl)-3 -(trifluoromethyl)-1 P-pyrazole-5-carboxamide (137b).

Into a solution of 1 -(3-(aminomethyl)phenyl)-N-(3-((3-(benzyloxy)phenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1P-pyrazole-5-carboxamide (107f ) (0.31 g, 0.495 mmol) in methanol (30 ml) was added hydrogen chloride (4N in dioxane, 1.239 ml, 4.95 mmol) and palladium (10% Pd on a carbon support) (0.158 g, 0.149 mmol). The reaction mixture was hydrogenated at 60 psi (414 kPa) for 14 hours. The reaction mixture was filtered through a small pad of Celite and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-25% methanol in chloroform) to give:

1. 1-(3-(aminomethyl)phenyl)-N-(3-(3-hydroxybenzyl)phenyl)-3-(trifluoromethyl)-1P-pyrazole-5-carboxamide (137b) (0.211 g, 0.452 mmol, yield 91%) as a white solid; 1P NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1P), 9.34 (s, 1P), 8.49 -8.32 (m, 3P), 7.72 (t, J= 1.7 Hz, 1P), 7.66 (s, 1P), 7.64 - 7.57 (m, 1P), 7.56 - 7.45 (m, 4P), 7.26 (t, J =7.8 Hz, 1P), 7.11 - 6.97 (m, 2P), 6.66 - 6.51 (m, 3P), 4.12 (q, J=5.8 Hz, 2P) , 3.81 (s, 2P); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 467.3 (M+1); 489.2 (M+Na), (IER-) 465.3 (M-1); 501.2 (M+Cl); analysis, calculation for C25П21FзN4O2·HCl·П2O: C, 57.64; P, 4.64; Cl, 6.81; N, 10.76; experiment: C, 57.65; P, 4.64; Cl, 7.21; N, 10.68;

2. 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1P-pyrazole-5-carboxamide (137a) (0, 02 g, 0.037 mmol, yield 7.54%) as a hygroscopic solid; 1P NMR (300 MHz, DMSO-d ₆ ) δ 11.05 (s, 1P), 10.09 (s, 2P), 9.80 (s, 1P), 8.62 (s, 4P), 7, 88 - 7.83 (m, 1P), 7.76 (s, 1P), 7.74 (d, J=2.1 Hz, 1P), 7.69 - 7.60 (m, 3P), 7 .58 - 7.48 (m, 2P), 7.42 (t, J=7.9 Hz, 1P), 7.25 - 7.10 (m, 2P), 7.03 - 6.97 (m , 1P), 6.78 (ddd, J=7.9, 2.4, 1.1 Hz, 1P), 5.44 (d, J=6.2 Hz, 1P), 4.11 (s, 3P), 2.78-2.59 (m,2P), 1.17 (tt, J=7.8, 4.5 Hz, 1P), 0.63 - 0.44 (m, 2P), 0 .32 (dt, J=6.5, 4.4 Hz, 2P); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (IER+) 536.3 (M+1); (IER-) 570.3 (M-1); analysis, calculation for C29H28FзN5O2 2.5C4H ₉ 2.5ПCl 2.25ПCl 3.25П2O: C, 49.56; P, 6.59; Cl, 17.82; N, 11,12; experiment: C,

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49.81; H, 6.58; Cl, 17.65; N, 10.70 (according to NMR analysis and integration results, the sample contained an impurity of 2.5 equivalents of cyclopropylmethylamine hydrochloride).

Scheme 138

An example of the preparation of N-(3 -((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1 -(3 -(aminomethyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (138f).

Step 1. Preparation of N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (138b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (7, 40 ml, 7.40 mmol) at 0°C. The reaction mixture was stirred for 12 hours, quenched with 2N. HCl (15 ml) and stirred for another 6 hours at room temperature. The reaction mixture was made alkaline with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography [silica gel, 40 g, eluted with chloroform/methanol (1:0 to 9:1)] to give N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl) acetamide (138b) (1.455 g, 93%) as a yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 9.86 (s, 1H), 7.50 - 7.41 (m, 2H), 7.29 - 7.18 (m, 2H), 6.90 (t, J=7.7 Hz, 1H), 6.54 (t, J=2.0 Hz, 1H), 6.51 - 6.46 (m, 1H), 6.37 (ddd, J= 7.9, 2.3, 1.1 Hz, 1H), 5.61 (d, J=3.8 Hz, 1H), 5.44 (d, J=3.8 Hz, 1H), 4, 97 (s, 2H), 2.00 (s, 3H); MS (ESI+): 279.2 (M+Na).

Step 2. Preparation of N(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (138c).

N-(4-((( 3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (138b) (1.38 g, 5.38 mmol), N-ethyl-N-isopropanylpropan-2-amine (7.70 ml, 44.2 mmol) and Bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP, 2.56 g, 5.38 mmol) at room temperature. The reaction mixture was stirred at room temperature for 22 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x80 ml), brine (80 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give N(3-((4-acetamidophenyl)(hydroxy)methyl )phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (138c) (2.28 g) as a yellow solid, which was used as such in the next step. MS (ESI+): 542.2 (M+Na).

Step 3. Preparation of tert-butyl-3-(5-(3-((4-acetamidophenyl)(hydroxy)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (138d).

In a solution of N-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-nirazole-5-carboxamide (138c) (2.13 g, 4.10 mmol) in MeOH (70 mL), cooled in ice/water, nickel(II) chloride hexahydrate (0.524 g, 2.206 mmol) and di-tert-butyl dicarbonate (3.62 g, 16.40 mmol) were added. , then sodium borohydride (1.583 g, 41.0 mmol) was added piecemeal over 15 minutes. The reaction mixture was stirred at room temperature for 2 h and quenched with N ¹ -(2-aminoethyl)ethane1,2-diamine (2.0 mL, 18.33 mmol), then stirred for an additional 0.5 h. Concentrate the reaction with 265 045731 the mixture was dried to dryness in a vacuum and the resulting residue was dissolved in ethyl acetate (200 ml) and water (200 ml). The aqueous layer was separated and extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (100 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with chloroform/methanol (1:0 to 9:1)] to give tert-butyl-3-(5-(3-((4-acetamidophenyl) (hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (138d) (1.284 g, 41% in 2 steps). 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 9.88 (s, 1H), 7.60 - 7.20 (m, 13H), 7.11 (d, J =7.7 Hz, 1H), 5.86 (d, J=3.8 Hz, 1H), 5.60 (d, J=3.8 Hz, 1H), 4.19 (d, J=6 .2 Hz, 2H), 2.01 (s, 3H), 1.37 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.79; MS (ESI+): 646.3 (M+Na).

Step 4. Preparation of tert-butyl-3-(5-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (138e).

In a solution of tert-butyl-3-(5-(3-((4-acetamidophenyl)(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (138d) (0.218 g, 1.953 mmol) in dichloromethane (36 ml) at 0°C, add thionyl chloride (0.3 ml, 4.05 mmol) and stir at room temperature for 2 hours. The reaction is quenched with triethylamine (1.800 ml, 12.92 mmol), stir for 1 hour and concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (27 ml) and cyclopropylmethanamine (3.70 ml, 41.4 mmol) was added. The reaction mixture was heated at 70°C for 14 h, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (240 ml), washed with water (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(3-((4-acetamidophenyl) (cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (138e) (240 mg) as a white solid; MS (IER+): 677.4 (M+H).

Step 5. Preparation of N-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (138f) .

In a solution of tert-butyl 3-(5-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (138e) (227 mg, 0.335 mmol) in 1,4-dioxane (22 ml), hydrogen chloride (3.70 ml, 14.79 mmol, 4M in 1,4-dioxane) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by CombiFlash silica gel column chromatography using chloroform/CMA 80 mixtures (1:0 to 2:1) to give the free base N-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)- 1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (138f) (43 mg) as a white solid. The purified product (138f) (41 mg) was dissolved in methanol (10 ml) and treated with 4N. HCl (aq, 0.08 ml), then concentrated to dryness to give N-(3-((4-acetamidophenyl)(cyclopropylmethylamino)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3- hydrochloride salt (trifluoromethyl)-1H-pyrazole-5-carboxamide (43 mg, 3.8% in 2 steps) as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.14 (s, 1H), 9.85 (s, 2H), 8.37 (s, 3H), 7.83 (s, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.67 (s, 1H), 7.64 - 7.48 (m, 9H), 7.44 (t, J=7.9 Hz, 1H), 5.51 (t, J=5.5 Hz, 1H), 4.13 (d, J=5.3 Hz, 2H), 2.78 - 2.63 ( m, 3H), 2.04 (s, 3H), 1.12 (td, J=13.2, 12.5, 7.0 Hz, 1H), 0.64 - 0.47 (m, 2H) , 0.37 - 0.22 (m, 2H); 1H NMR (300 MHz, DMSO-d6, exchange with D2O) δ 7.79 (t, 1H), 7.70 (t, 1H), 7.64 - 7.40 (m, 11H), 5.51 ( s, 1H), 4.13 (s, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.05 (s, 3H), 1.16 - 0.98 (m, 1H ), 0.64-0.54 (m, 2H), 0.32-0.24 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.79; MS (IER+): 577.3 (M+H); analysis, calculation for Cз1Нз _l· FзN6O2·2HCl·3H2O: C, 52.92; N, 5.59; N, 11.94; experiment: 52.66; N, 5.51; N, 11.56; C, 52.66; N, 5.51; N, 11.56.

Scheme 139

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((4-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (139b).

Step 1. Preparation of tert-butyl-3-(5-((5-((4-(tert-butyloxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzylcarbamate (139a).

Into a solution of tert-butyl-3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52g) ( 155 mg, 0.234 mmol) in MeOH (5 mL), cooled in ice/water, add nickel(II) chloride hexahydrate (30.0 mg, 0.126 mmol) and di

- 266 045731 tert-butyl dicarbonate (206 mg, 0.936 mmol), then sodium borohydride (90 mg, 2.339 mmol) was added portionwise over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.110 ml, 1.006 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and dissolved the resulting residue in ethyl acetate (100 ml) and water (60 ml). The aqueous layer was separated and extracted with ethyl acetate (60 ml). The combined extracts were washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-((5-((4(tert -butyloxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)-2fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (139a) (70 mg, 39%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-de) δ 10.54 (s, 1H), 7.68 - 7.10 (m, 14H), 4.81 (s, 1H), 4.19 (d, J= 6.4 Hz, 2H), 4.05 (d, J=6.7 Hz, 2H), 2.29 - 2.23 (m, 2H), 1.38 (s, 18H), 1.00- 0.80 (m, 1H), 0.43 0.28 (m, 2H), 0.07 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.81, -123.76; MS (IER+): 767.5 (M+H).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((4-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (139b).

Into a solution of tert-butyl-3-(5-((5-((4-(tert-butyloxycarbonylaminomethyl)phenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3 -(trifluoromethyl)-1 H -pyrazol-1-yl)benzylcarbamate (139a) (60 mg) in 1,4-dioxane (7 ml) was added hydrogen chloride (0.970 ml, 3.88 mmol, 4M in 1,4-dioxane) and stirred at room temperature in for 21 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-( (4-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (139b) (23 mg, 46%) as a colorless viscous substance. The purified free base (139b) was dissolved in methanol (10 ml) and 4N was added. HCl (aq, 0.04 ml), stirred for 30 min, then concentrated to dryness to give 1-(3-(aminomethyl)phenyl)-N-(5-((4(aminomethyl)phenyl)(cyclopropylmethylamino) hydrochloride salt )methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 carboxamide (139b) (31 mg) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 10.29 (d, J=38.5 Hz, 0H), 8.40 (s, 6H), 7.95 ( s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.71 (d, J=4.4 Hz, 3H), 7.657.60 (m, 1H), 7.57 ( d, J=7.8 Hz, 1H), 7.55- 7.50 (m, 3H), 7.40 (t, J=9.3 Hz, 1H), 5.68 (s, 1H), 4.13 (s, 2H), 4.00 (s, 2H), 2.75-2.63 (m, 2H), 1.23 - 1.09 (m, 1H), 0.56 (m, 2H), 0.30 (m, 2H); 1H NMR (D ₂ O exchange NMR, 300 MHz, DMSO-d ₆ ) δ 7.89 (d, J=6.9 Hz, 1H), 7.74 - 7.48 (m, 10H), 7, 42 (t, J=9.5 Hz, 1H), 5.66 (s, 1H), 4.12 (s, 2H), 4.02 (s, 2H), 2.78 - 2.67 (m , 2H), 1.14-1.00 (m, 1H), 0.59 (d, J=7.8 Hz, 2H), 0.28 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, -120.56; MS (IER+): 567.3 (M+1); analysis, calculation for CsoHzoE^O-ZHa^O: C, 48.17; H, 5.52; N, 11.23; experiment: C, 47.79; H, 5.78; N, 10.84.

Scheme 140

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(m-toluyl)methyl)-2-267 045731 fluorophenyl)-3 -(trifluoromethyl)-1 H-pyrazole -5-carboxamide (140e).

Step 1. Preparation of (3-amino-4-fluorophenyl)(m-toluyl)methanol (140a).

(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)-magnesium bromide (52c) (18.00 mL, 18.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (10 ml, 20 mmol), stirred for 0.5 h. The reaction mixture was made basic with aqueous NaHCO3 and extracted with ethyl acetate (2x250 ml). The organic layers were combined, washed with water (2x50 ml), brine (50 ml), dried over anhydrous MgSO4, filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0-100% ethyl acetate/hexane mixtures) to give (3-amino-4-fluorophenyl)(mtoluyl)methanol (140a) (1.771 g, 7.66 mmol, yield 51.1%) in the form of a light yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.23 -7.06 (m, 3H), 7.00 (dt, J=7.1, 1.7 Hz, 1H), 6.86 (dd , J=11.5, 8.3 Hz, 1H), 6.75 (dd, J=9.0, 2.1 Hz, 1H), 6.49 (ddd, J=8.3, 4.5 , 2.2 Hz, 1H), 5.70 (d, J=3.8 Hz, 1H, exchange with D2O), 5.48 (d, J=3.7 Hz, 1H), 5.05 (s , 2H, exchange with D2O), 2.26 (s, 3H); mass spectrum (ESI+) 254.1 (M+24); (IER-) 230.1 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(m-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (140b) .

In a 100 mL round bottom flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (2.341 g, 8.32 mmol), (3-amino-4-fluorophenyl)( m-toluyl)methanol (140a) (1.75 g, 7.57 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (4.23 g, 9.08 mmol), N,N-dimethylformamide (20) was added sequentially ml) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (6.59 ml, 37.8 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 20 h under a positive nitrogen flow. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x200 ml). Combine the organic layers, wash with water (2x100 ml), brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(2-fluoro-5(hydroxy(m-toluyl)methyl )phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (140b) (2.29 g, 4.63 mmol, 61.2% yield) as a yellow semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H, exchange with D2O), 8.16 - 8.10 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.77 - 7.68 (m, 2H), 7.50 (d, J=7.2 Hz, 1H), 7.30 - 7.10 (m, 5H), 7.05-6.98 (m, 1H), 5.96 (d, J=3.9 Hz, 1H, exchange with D2O), 5.64 ( d, J=3.9 Hz, 1H), 2.26 (s, 3H); MS (IER+) 517.2 (M+Na), (IER-) 493.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(m-toluyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 140c).

In a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(m-toluyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (140b) (2.12 g , 4.29 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.668 ml, 9.15 mmol), stir at room temperature for 2 hours and quench the reaction with triethylamine (3.97 ml, 28.5 mmol ). The reaction mixture was stirred for 1 hour and cyclopropylmethanamine (7.83 mL, 91 mmol) was added and concentrated in vacuo to remove dichloromethane. The resulting residue was dissolved in acetonitrile (20 ml) and cyclopropylmethanamine (7.83 ml, 91 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (300 ml), washed with water (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0 to 20%) to give 1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)( mtoluyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (140c) (1.3 g, 2.374 mmol, 55.4% yield) as an oily liquid; MS (IER+) 548.3 (M+1), (IER-) 546.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-((5-(((cyclopropylmethyl)amino)(m-toluyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1 -yl)benzylcarbamate (140d).

In a solution of 1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(m-toluyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (140c) (1.25 g, 2.283 mmol) in MeOH (25 ml), cooled in ice/water, di-tert-butyl dicarbonate (1.993 g, 9.13 mmol) and nickel(II) chloride (0.136 g, 0.571 mmol) were added ). Sodium borohydride (0.818 g, 22.83 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (1.110 mL, 10 .27 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was diluted with water (200 ml). The isolated solid was collected by filtration and purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-3-(5-((5- (((cyclopropylmethyl)amino)(m-toluyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (140d) (0.864 g, 1.326 mmol, yield 58, 1%) as a white solid.

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-M-(5-(((cyclopropylmethyl)amino)(m-toluyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol- 5-carboxamide (140e).

- 268 045731

Into a solution of tert-butyl-3-(5-((5-(((cyclopropylmethyl)amino)(m-toluyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )benzylcarbamate (140d) (0.8 g, 1.228 mmol) in methanol (10 ml) was added conc. hydrogen chloride (3.73 ml, 123 mmol), stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-100% CMA-80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino )(m-toluyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (140e). To a solution of the free base of compound 140e in methanol (10 ml) was added conc. hydrochloric acid (0.121 ml, 1.450 mmol), stirred for 30 min and concentrated to dryness in vacuo to give 1-(3-(aminomethyl)phenyl)-^(5-(((cyclopropylmethyl)amino)(m-toluyl) hydrochloride salt )methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (140e) (110 mg, 60.7% yield) as a white solid. Ή NMR (300 MHz, DMSO) δ 10.82 (s, 1H, exchange with D2O), 10.12 (s, 2H, exchange with D2O), 8.45 (s, 3H, exchange with D2O), 7, 92 (dd, J=7.3, 2.3 Hz, 1H), 7.76 - 7.66 (m, 3H), 7.63 (dt, J=7.3, 1.8 Hz, 1H) , 7.57 (d, J=7.8 Hz, 1H), 7.55-7.48 (m, 3H), 7.40 (dd, J=10.3, 8.6 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 5.59 (s, 1H), 4.13 (s, 2H), 2.69 (s, 2H), 2.30 (s, 3H), 1.14 (dd, J=10.1, 5.5 Hz, 1H), 0.60 - 0.51 (m, 2H) , 0.29 (dd, J=5.8, 4.1 Hz, 2H). MS (IER+) 552.3 (M+1), (IER-) 550.2 (M-1), 586.3 (M+35); analysis, calculation for C3oH29F4N50-2HC1-2H ₂ 0: C, 56.14; H, 5.18; N, 10.91; Cl, 10.90; experiment: C, 56.01; H, 5.27; N, 10.72; Cl, 11.14.

Scheme 141

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-(((cyclopronylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (141e).

Step 1. Preparation of (3-amino-4-fluorophenyl)(3-methoxyphenyl)methanol (141a).

(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)-magnesium bromide (52c) (18.0 mL, 18.0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (10 ml, 20 mmol), stirred for 0.5 h. The reaction mixture was made basic with saturated aqueous NaHCO ₃ and extracted with ethyl acetate (2x250 ml). The organic layers were combined, washed with water (2x50 ml), brine (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-amino-4-fluorophenyl)(3-methoxyphenyl)methanol (141a) (1.8 g, 7.28 mmol , yield 48.5%) in the form of a light brown oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.19 (t, J=7.9 Hz, 1H), 6.93 - 6.87 (m, 2H), 6.85 (d, J=8 ,2 Hz, 1H), 6.75 (ddd, J=8.5, 2.7, 1.2 Hz, 2H), 6.50 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.75 (d, J=3.9 Hz, 1H, exchange with D ₂ O), 5.48 (d, J=3.9 Hz, 1H), 5.05 (s, 2H , exchange with D ₂ O), 3.71 (s, 3H); mass spectrum (ESI+) 270.2 (M+23); (IER-) 246.2 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (141b).

In a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.227 g, 7.92

- 269 045731 mmol) in DMF (20 ml) was added (3-amino-4-fluorophenyl)(3-methoxyphenyl)methanol (141a) (1.78 g, 7.20 mmol), N-ethyl-N-isopropylpropane- 2-amine (6.27 mL, 36.0 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP, 4.03 g, 8.64 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with water (2x100 ml), brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3methoxyphenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141b) (2.105 g, 4.12 mmol, 57.3% yield) as a yellow semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H, exchange with D2O), 8.12 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7 ,8, 1.3 Hz, 1H), 7.90 (dt, J=8.4, 1.3 Hz, 1H), 7.79 - 7.63 (m, 2H), 7.52 (d, J=7.2 Hz, 1H), 7.35-7.09 (m, 3H), 6.95-6.88 (m, 2H), 6.83 - 6.68 (m, 1H), 6 .00 (d, J=4.0 Hz, 1H, exchange with D2O), 5.66 (d, J=3.9 Hz, 1H), 3.70 (s, 3H); MS (IER+) 533.2 (M+Na) (IER-) 509.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141c).

Into a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141b) (2, 05 g, 4.02 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (0.626 ml, 8.57 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with triethylamine (3.72 ml, 26, 7 mmol), stir the mixture for 1 hour and add cyclopropylmethanamine (1.52 ml, 17.73 mmol) and concentrate in vacuo to remove dichloromethane.

The reaction mixture was diluted with acetonitrile (10 ml) and cyclopropylmethanamine (8.00 ml, 92 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (300 ml), washed with water (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of CMA 80 in chloroform, 0 to 20%) to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(3methoxyphenyl)methyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141c) (0.838 g, 37.0% yield) as an off-white semi-solid; MS (IER+) 564.3 (M+1) (IER-) 562.3 (M-1).

Step 4. Preparation of tert-butyl-3-(5-((5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1 H-pyrazole-1 - yl)benzylcarbamate (141d).

Into a solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141c) (0 .8 g, 1.42 mmol) in MeOH (25 ml), cooled in ice/water, di-tert-butyl dicarbonate (1.239 g, 5.68 mmol) and nickel (II) chloride (0.084 g, 0.355 mmol) were added ). Sodium borohydride (0.508 g, 14.20 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.690 mL, 6.39 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was diluted with water (200 ml). The isolated solid was collected by filtration, dried in vacuo and purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give tert-butyl-3-(5-( (5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (141d) (0.35 g, yield 14.47%) as a white solid.

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (141e).

Into a solution of tert-butyl-3-(5-((5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )benzylcarbamate (141d) (0.69 g, 1.033 mmol) in methanol (10 ml), hydrogen chloride (3.14 ml, 103 mmol) was added, stirred at room temperature overnight and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl) amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141e) as a white solid. Into a solution of the free base 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (141e) in methanol (10 ml), add hydrochloric acid (10 eq.) and stir at room temperature for 30 min and concentrate to dryness in vacuo to give 1-(3(aminomethyl)phenyl)-N- hydrochloride salt (5-(((cyclopropylmethyl)amino)(3-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (141e) (200 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H, exchange with _D2O ), 10.09 (s, 2H, exchange with D2O), 8.36 (d, J=16.1 Hz, 3H, exchange with D2O), 7.94 (s, 1H), 7.75-7.48 (m, 6H), 7.36 (dt, J=16.4, 9.2 Hz, 3H) , 7.21 (s, 1H), 6.92 (d, J=8.3 Hz, 1H), 5.58 (s, 1H), 4.13 (s, 2H), 3.75 (s, 3H), 2.68 (s, 2H), 1.17-1.07 (m, 1H), 0.54 (d, J=7.5 Hz, 2H), 0.28 (s, 2H); MS (IER+) 568.3(M+1), 590.3 (M+23); (IER-) 566.3 (M-1), 602.3 (M+35); analysis, calculation for

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C ₃₀ H ₂₉ F ₄ N ₅ O ₂ -3HCl-1.25H ₂ O: C, 51.60; H, 4.98; N, 10.03; Cl, 15.03; experiment: C, 51.02; H, 4.85; N, 9.63;

Cl, 15.63.

Scheme 142

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (142f).

Step 1. Preparation of (3-amino-4-fluorophenyl)(4-methoxyphenyl)methanol (142b).

(3-(bis(trimethylsilyl)amino)-4-fluorophenyl)-magnesium bromide (52c) (20.25 mL, 20.25 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 2N. HCl (10 ml, 20 mmol), stirred for 0.5 h. The reaction mixture was made basic with saturated aqueous NaHCO ₃ and extracted with ethyl acetate (2x250 ml). The organic layers were combined, washed with water (2x50 ml), brine (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 80 g, eluted with 0-100% ethyl acetate in hexanes) to give (3-amino-4fluorophenyl)(4-methoxyphenyl)methanol (142b) (2.125 g, 8.59 mmol , yield 57.3%). 1H NMR (300 MHz, DMSOL) δ 7.28 - 7.13 (m, 2H), 6.86 (dd, J=11.2, 8.4 Hz, 3H), 6.74 (dd, J= 9.1, 2.2 Hz, 1H), 6.47 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.65 (d, J=3.9 Hz, 1H , exchange with D2O), 5.47 (d, J=3.9 Hz, 1H), 5.04 (s, 2H, exchange with _D2O ), 3.71 (s, 3H). MS (IER+) 270.2 (M+23); (IER-) 246.2 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (142c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.63 g, 9.34 mmol) in DMF (20 ml), 4-fluorophenyl)(4-methoxyphenyl)methanol (142b) (2.1 g, 8.49 mmol), N-ethyl-N-isopropylpropan-2-amine (7.40 ml, 42.5 mmol) and bromine hexafluorophosphate -trispyrrolidinophosphonium (PyBrOP, 4.75 g, 10.19 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with water (2x100 ml), brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxy(4methoxyphenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (142c) (3.23 g, 6.33 mmol, 74.5% yield) as a yellow semi-solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H, exchange with D ₂ O), 8.12 (t, J=1.8 Hz, 1H), 8.00 (dt, J =7.8, 1.3 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.76 - 7.69 (m, 2H), 7.52 - 7.45 (m, 1H ), 7.26 - 7.22 (m, 3H), 6.88 - 6.82 (m, 3H), 5.90 (d, J=4.0 Hz, 1H, exchange with D ₂ O), 5.64 (dd, J=4.0, 2.3 Hz, 1H), 3.71 (s, 3H); MS (IER+) 533.2 (M+Na), (IER-) 509.2 (M-1).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 142d).

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In a solution of 1-(3-cyanophenyl)-M-(2-fluoro-5-(hydroxy(4-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (142c) (2, 75 g, 5.39 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.840 ml, 11.50 mmol) and stir at room temperature for 2 hours. The reaction is quenched with triethylamine (0.771 ml, 5.53 mmol ), stir the mixture for 1 hour, add cyclopropylmethanamine (1.52 ml, 17.73 mmol) and concentrate in vacuo to remove dichloromethane. The reaction mixture was diluted with acetonitrile (10 ml) and cyclopropylmethanamine (1.520 ml, 17.73 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in chloroform (300 ml), washed with water (100 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of CMA 80 in chloroform, 0 to 20%) to give 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(4methoxyphenyl)methyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (142d) (1.448 g, 47.7% yield) as a white semi-solid; MS (IER+) 564.3 (M+1), (IER-) 562.3 (M-1).

Step 4. Preparation of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl) (4-methoxyphenyl)methyl)(cyclopropylmethyl)carbamate (142e).

In a solution of 1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (142d) (1 .4 g, 2.484 mmol) in MeOH (25 mL), cooled in ice/water, di-tert-butyl dicarbonate (2.169 g, 9.94 mmol) and nickel(II) chloride (0.148 g, 0.621 mmol) were added. Sodium borohydride (0.890 g, 24.84 mmol) was added slowly over 15 min and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with N1-(2aminoethyl)ethane-1,2-diamine (1.208 mL, 11.18 mmol), stirred the mixture for 0.5 h and concentrated to dryness in vacuo. The resulting residue was diluted with water (200 ml). The isolated solid was collected by filtration, dried in vacuo and purified by flash column chromatography (silica gel, 40 g, eluted with 0-100% (9:1) ethyl acetate/methanol in hexane) to give tert-butyl-((3-(1 -(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-4-fluorophenyl)(4-methoxyphenyl)methyl)(cyclopropylmethyl)carbamate (142e ) (0.906 g, 47.5% yield) as a white solid.

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (142f).

Into a solution of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamido)-4-fluorophenyl)(4- methoxyphenyl)methyl)(cyclopropylmethyl)carbamate (142e) (0.88 g, 1.146 mmol) in methanol (5 ml), add hydrogen chloride (3.48 ml, 115 mmol), stir at room temperature overnight and concentrate to dryness in vacuo . The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl) amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (142f) (0.487 g, 74%) as a white solid. Into a solution of the free base 1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (142f) (0.46 g, 0.81 mmol) in methanol (10 ml), add hydrochloric acid (10 eq) and stir at room temperature for 30 min and concentrate to dryness in vacuo to give hydrochloride salt 1 -(3-(aminomethyl)phenyl)-N-(5(((cyclopropylmethyl)amino)(4-methoxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (142f) (80 mg) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.78 (s, 1H, exchange with D2O), 9.99 (s, 1H, exchange with D2O), 8.45 (s, 2H, exchange with D2O) , 7.85 (s, 1H), 7.71 (d, J=7.1 Hz, 2H), 7.57 (dq, J=17.6, 9.1, 8.4 Hz, 6H), 7.37 (t, J=9.6 Hz, 1H), 6.96 (d, J=8.2 Hz, 2H), 5.48 (s, 1H), 4.12 (s, 2H), 3.74 (s, 3H), 2.62 (s, 2H), 1.10 (s, 1H), 0.53 (d, J=7.8 Hz, 2H), 0.26 (s, 2H ); mass spectrum (ESI-) 566.3 (M-1), 602.2 (M+35); analysis, calculation for G^cFNsO^HCl^H^: C, 53.31; H, 5.22; N, 10.36; Cl, 10.35; experiment: C, 53.53; H, 5.12; N, 10,11; Cl, 10.59.

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Scheme 143

MeOH/ΤΓΦ

143d minor isomer

NaBH ₄ (Boc) ₂ O

NaBHz

NiCI ₂ 6H ₂ O

RuVgor □ REA

SnCI ₂ 2H ₂ O

NaNOo.HC

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (1431).

Step 1. Preparation of 4-methoxyimino-2-oxopentaneperoxocarboxylic acid ethyl ester (143 c) and 2-methoxyimino-4-oxopentane peroxocarboxylic acid ethyl ester (143d).

To a suspension of 2,4-dioxopentanoic acid ethyl ester (143b) (25 g, 158.07 mmol) in ethanol (325 ml) was added methoxylamine hydrochloride (13.86 g, 165.97 mmol) and molecular sieves (125 g). The reaction mixture was stirred at room temperature overnight and filtered through a Hyflow pad. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in diethyl ether (600 ml). The organic layer was washed with brine (300 ml), dried, filtered and concentrated in vacuo to give the crude product. The crude residue was purified by flash column chromatography (silica gel, 400 g, eluted with mixtures of 0-20% ethyl acetate in hexanes) to give:

1. 2-methoxyimino-4-oxopentaneperoxoacid ethyl ester (143d) (8 g, 27%); ^1H NMR (300 MHz, DMSO-d6) δ 4.28 - 4.16 (m, 2H), 3.96 (s, 3H), 3.65 (s, 2H), 1.76 (d, J =1.4 Hz, 3H), 1.30 - 1.16 (m, 3H).

2. 4-methoxyimino-2-oxopentaneperoxoacid ethyl ester (143c) (12 g, 41%); 1H NMR (300 MHz, DMSO-d6) δ 4.20 (q, J=7.1 Hz, 2H), 3.95 (s, 3H), 3.71 (s, 2H), 2.15 (s , 3H), 1.23 (t, J=7.1 Hz, 3H).

Step 2. Preparation of 3-hydrazinylbenzonitrile hydrochloride (143a).

HCl (136 mL) was slowly added dropwise to 3-aminobenzonitrile (10a) (34 g, 287.79 mmol) at 0°C. A previously prepared solution of sodium nitrite (25.81 g, 374.13 mmol) in 50 ml H2O was added dropwise to the resulting mixture at a rate to maintain the internal temperature between 0 and 5°C. The reaction mixture was stirred for 1 hour at 0°C, then a freshly prepared solution of tin(II) chloride dihydrate (142.8 g, 633.147 mmol) in conc. HCl (95.2 ml), maintaining internal temperature between 0 and 10°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The crude 3-hydrazinylbenzonitrile hydrochloride (143a), which was obtained as a creamy liquid, was used directly as such in the next step.

Step 3. Preparation of 2-(3-cyanophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (143e).

To a suspension of 4-methoxyimino-2-oxopentaneperoxoacid ethyl ester (143c) (12 g, 64.11 mmol) in ethanol (120 ml) was added 3-hydrazinobenzonitrile hydrochloride salt obtained in step 2 (288 ml) with stirring. The reaction mixture was heated at reflux temperature overnight. The reaction was checked by TLC (EtOAc/n-hexane = 2:8). After

- 273 045731 When the reaction was completed, the reaction mixture was concentrated in vacuo to remove ethanol. The resulting residue was extracted with ethyl acetate (200x3). Combine the organic layers, wash with brine (300 mL), dry, filter and concentrate in vacuo to give the crude product. The crude residue was purified by flash column chromatography (silica gel, 250 g, eluted with mixtures of 0-16% ethyl acetate in hexanes) to give 2-(3cyanophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (143e) ( 9 g, 55%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.06 - 8.03 (m, 1H), 7.92 (dt, J=7.7, 1.4 Hz, 1H), 7.83 (ddd , J=8.2, 2.2, 1.2 Hz, 1H), 7.73 - 7.64 (m, 1H), 6.96 (d, J=0.6 Hz, 1H), 4, 19 (q, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.17 (t, J=7.1 Hz, 3H).

Step 4. Preparation of 2-(3-cyanophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (143f).

To a suspension of 2-(3-cyanophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (143e) (8.5 g, 33.3 mmol) in MeOH/THF (1/3, 21+63 ml) added 3N. NaOH (4 g, 100 mmol) with stirring. The reaction mixture was stirred for 2 hours (the progress of the reaction was checked by TLC (MeOH/CHCl ₃ = 1/9)). The reaction mixture was concentrated in vacuo to remove THF and methanol. The aqueous layer was acidified with conc. HCl at 5-15°C and extracted with ethyl acetate (3x100). Combine the organic layers, wash with brine (300 mL), dry, filter and concentrate in vacuo to give crude 2-(3-cyanophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (143f) (6.7 g , 89%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.01 (t, J=1.9 Hz, 1H), 7.89 (dt, J=7.7, 1.4 Hz, 1H), 7, 81 (ddd, J=8.2, 2.2, 1.2 Hz, 1H), 7.66 (t, J=7.9 Hz, 1H), 6.88 (s, 1H), 2.27 (s, 3H).

Step 5. Preparation of (3-aminophenyl)phenylmethanol (143h).

Nickel (II) chloride hexahydrate (0.29 g, 1.22 mmol), then sodium borohydride (1.11 g, 29.4 mmol) was added portionwise over 45 min. The reaction mixture was stirred for 15 min at room temperature and quenched with N1-(2-aminoethyl)ethane-1,2diamine (1.057 mL, 9.79 mmol). The reaction mixture was stirred for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (25 ml), extracted with ethyl acetate (2x25 ml). Combine the organic layers, wash with brine (25 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 100%)] to give (3-aminophenyl)phenylmethanol (143h) (772 mg, 3.87 mmol, yield 79 %) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.36 - 7.24 (m, 4H), 7.21 - 7.14 (m, 1H), 6.91 (t, J=7.7 Hz , 1H), 6.57 (t, J=2.0 Hz, 1H), 6.51 (dt, J=7.5, 1.3 Hz, 1H), 6.37 (ddd, J=8, 0, 2.4, 1.1 Hz, 1H), 5.69 (d, J=3.8 Hz, 1H), 5.50 (d, J=3.8 Hz, 1H), 4.99 ( s, 2H); MS (IER+) 222.1 (M+1), (IER-) 198.0 (M-1).

Step 6. Preparation of 2-(3-cyanophenyl)-5-methyl-2H-pyrazole3-carboxylic acid [3-(hydroxyphenylmethyl)phenyl]amide (143i).

To a stirred solution of 2-(3-cyanophenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (143f) (2.5 g, 11.002 mmol) in DMF (50 ml) was added (3-aminophenyl)phenylmethanol (143h ) (2.19 g, 11.00 mmol), DIPEA (11.38 g, 88.02 mmol) and PyBrop (5.13 g, 11.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was checked by TLC (EtOAc/n-hexane = 4:6). After completion of the reaction, the mixture was diluted with water (200 ml) and extracted with ethyl acetate (3x200 ml). Combine the organic layers, wash with water (2x200 ml), brine (200 ml), dry, filter and concentrate in vacuo to give the crude product. The crude residue was purified by flash column chromatography (silica gel, 100 g, eluted with mixtures of 15-35% ethyl acetate in hexanes) to give [3-(hydroxyphenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-methyl-2H-pyrazole -3-carboxylic acid (143i) (0.55 g), which was used as such in the next step.

Step 7. Preparation of {3-[(cyclopropylmethylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5methyl-2H-pyrazole-3-carboxylic acid (143j).

In an ice-cold solution of 2-(3-cyanophenyl)-5-methyl-2H-pyrazole-3carboxylic acid [3-(hydroxyphenylmethyl)phenyl]amide (143i) (0.5 g, 1.22 mmol) in acetonitrile (10 ml) Thionyl chloride (0.29 g, 2.45 mmol) was added dropwise while maintaining the internal temperature at 5-10°C. The reaction mixture was allowed to warm to room temperature for 3.5 hours. The reaction mixture was concentrated to dryness in vacuo and acetonitrile (5 ml), cyclopropylmethylamine (1.31 g, 18.36 mmol) were added to the residue. The reaction mixture was heated at reflux temperature overnight. The reaction was checked by TLC (EtOAc/n-hexane = 4:6). After completion of the reaction, the reaction mixture was concentrated to dryness in vacuo. Water (50 ml) was added to the residue and extracted with ethyl acetate (3x50 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and concentrate in vacuo to give the crude product. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 20-45% ethyl acetate in hexane) to give {3-[(cyclopropylmethylamino)phenylmethyl]-phenyl}amide 2-(3-cyanophenyl)-5-methyl2H -pyrazole-3-carboxylic acid (143j) (0.4 g, 71%); 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 7.95 (t, J=1.9 Hz, 1H), 7.87 (dq, J=2.4, 1 .5, 1.1 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.78 - 7.73 (m, 1H), 7.72 - 7.66 (m, 2H),

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7.66 - 7.60 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.41 (d, J=1.7 Hz, 1H), 7.38 (s , 1H), 7.29 (d, J=7.2 Hz, 2H), 7.21 7.17 (m, 2H), 6.98 (s, 1H), 6.67 (s, 1H), 3.45 (dd, J=12.8, 6.3 Hz, 2H), 1.87 - 1.82 (m, 3H), 0.91 - 0.77 (m, 1H),

0.46 - 0.25 (m, 2H), 0.11 - -0.05 (m, 2H).

Step 8. Preparation of [3-(5-{3-[(cyclopropylmethylamino)phenylmethyl]phenylcarbamoyl}-3-methylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (143k).

A solution of {3-[(cyclopropylmethylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-methyl-2-ipyrazole-3-carboxylic acid (143j) (0.36 g, 0.78 mmol) in MeOH (10 ml) cooled in ice/water, nickel(II) chloride hexahydrate (0.22 g, 0.94 mmol) and Boc anhydride (0.51 g, 2.34 mmol) were added, then sodium borohydride was added portionwise (0.17 g, 4.67 mmol) for 15 min. The reaction mixture was stirred at room temperature for 0.5 h and quenched with N ¹ -(2-aminoethyl)ethalane-1,2diamine (0.17 ml, 1.56 mmol), then stirred for an additional 0.5 h. Concentrated the reaction mixture was dried to dryness in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 30-45% ethyl acetate/hexane) to give [3-(5-{3-[(cyclopropylmethylamino)phenylmethyl]phenylcarbamoyl}-3-methylpyrazol-tert-butyl ether 1-yl)benzyl]carbamic acid (143k) (0.19 g, 43%); ^1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.67 (s, 1H), 7.55-7.10 (m, 12H), 6.83 (s, 1H ), 4.80 (s, 1H), 4.15 (d, J=6.2 Hz, 2H), 3.23 (d, J=6.5 Hz, 2H), 2.26 (s, 3H ), 1.39 (d, J=1.7 Hz, 9H), 0.99 - 0.87 (m, 1H), 0.38 (dt, J=8.1, 2.9 Hz, 2H) , 0.04 (q, J=4.8 Hz, 2H).

Step 9. Preparation of {3-[(cyclopropylmethylamino)phenylmethyl]phenyl}amide 2-(3-aminomethylphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid (143l).

In a solution of [3-(5-{3-[(cyclopropylmethylamino)phenylmethyl]phenylcarbamoyl}-3-methylpyrazol-1-yl)benzyl]carbamic acid tert-butyl ester (143k) (0.18 g, 0.32 mmol) in methanol (10 ml) added conc. HCl (1 ml). The reaction mixture was stirred at room temperature overnight and concentrated to dryness in vacuo. The residue was azeotroped with toluene (2x10 ml) and ethanol (10 ml), dried using a vacuum pump to give a residue which was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-6% methanol in dichloromethane) yielding product (0.08 g, 54%) as a yellow solid. The product was repurified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA80 in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(phenyl)methyl )phenyl)-3-methyl-1H-pyrazole-5-carboxamide (143l) (10.74 µmol, 6.67% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 7.69 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.457.42 ( m, 1H), 7.42 - 7.37 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.24 (m, 1H), 7.23 - 7, 14 (m, 4H), 6.83 (s, 1H), 4.80 (s, 1H), 3.76 (s, 2H), 2.29 (s, 3H), 2.27 (d, J =2.9 Hz, 2H), 1.00 - 0.88 (m, 1H), 0.44 - 0.30 (m, 2H), 0.08 0.01 (m, 2H); MS (IER+) 466.4 (M+1); (IER-) 464.4 (M-1); 500.3 (M+Cl).

Scheme 144

Example of preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((isopropylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (144d)

Step 1. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2Hpyrazole-3-carboxylic acid [3-(hydroxyphenylmethyl)phenyl]amide (144a).

In a 100 ml one-neck flask to 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.682 g, 2.427 mmol), (3-aminophenyl)(phenyl)methanol (143h ) (0.403 g, 2.023 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop, 1.131 g, 2.427 mmol) was added sequentially

- 275 045731

N,N-dimethylformamide (DMF, 12 ml) and N-ethyl-N-isopropylpropan-2-amine (DIPEA, 1.762 ml, 10.11 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (30 ml) and extracted with ethyl acetate (2x30 ml). Combine the organic layers, wash with water (30 ml), brine (30 ml), dry over anhydrous MgSO ₄ , filter and concentrate to dryness in vacuo. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with methanol/chloroform mixtures, 080%] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (144a) (0.853 g, 1.845 mmol, 91% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H, exchange with D ₂ O), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J= 7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 - 7.69 (m, 2H), 7 .64 (t, J=1.8 Hz, 1H), 7.55 (dt, J=8.1, 1.5 Hz, 1H), 7.38 - 7.31 (m, 3H), 7. 30 (t, J=1.3 Hz, 1H), 7.27 (d, J=1.7 Hz, 1H), 7.25- 7.17 (m, 1H), 7.16 - 7.12 (m, 1H), 5.95 (d, J=3.8 Hz, 1H, exchange with D2O), 5.67 (d, J=3.8 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.96; MS (ESI+) 485.2 (M+Na), MS (ESI-) 590.3923 (M+Cl), 959.2 (2M-1).

Step 2. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-(isopropylaminophenylmethyl)phenyl]amide (144b).

In a solution of [3-(hydroxyphenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3carboxylic acid (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0° C, thionyl chloride (0.514 g, 4.325 mmol) was added and stirred at room temperature for 3 hours. Isopropylamine (0.638 g, 10.81 mmol) was added and stirred for 30 minutes. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and isopropylamine (0.638 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give [3-(isopropylaminophenylmethyl)phenyl]amide 2-(3cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3 -carboxylic acid (144b) (0.65 g, 60%) as a colorless liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.15 (t, J=1.9 Hz, 1H), 7.99 (dt, J=7.8, 1 .3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.54 (dt, J=7.9, 1.8 Hz, 1H), 7.43 - 7.37 (m, 2H), 7, 28 (dd, J=8.2, 6.6 Hz, 2H), 7.24 - 7.14 (m, 3H), 4.91 (s, 1H), 2.59 - 2.52 (m, 1H), 1.01 (d, J=6.2 Hz, 6H); MS (IER-) 502.3 (M-1).

Step 3. Preparation of (3-{5-[3-(isopropylaminophenylmethyl)phenylcarbamoyl]-3-trifluoromethylpyrazol-1 -yl}benzyl)carbamic acid tert-butyl ester (144c).

In a solution of [3-(isopropylaminophenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2Hpyrazole-3-carboxylic acid (144b) (0.6 g, 1.19 mmol) in MeOH (15 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.35 g, 1.49 mmol) and Boc anhydride (0.779 g, 3.57 mmol) were added, then sodium borohydride (0.27 g) was added portionwise , 7.15 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2 diamine (0.49 g, 4.764 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give tert-butyl ether (3-{5-[3-(isopropylaminophenylmethyl)phenylcarbamoyl]-3-trifluoromethylpyrazole-1 -yl}benzyl)carbamic acid (144c) (0.420 g) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 7.69 - 7.16 (m, 14H), 4.19 (d, J=6.2 Hz, 1H), 1.36 (s, 9H), 1.21 - 1.09 (m, 6H); MS (IER-) 606.3 (M-1).

Step 4. Preparation of 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-(isopropylaminophenylmethyl)phenyl]amide (144d).

A solution of (3-{5-[3-(isopropylaminophenylmethyl)phenylcarbamoyl]-3trifluoromethylpyrazol-1-yl}benzyl)carbamic acid tert-butyl ester (144c) (0.4 g, 1.65 mmol) in MeOH (10 ml ) added conc. HCl (0.5 ml). The reaction mixture was stirred at room temperature for 19 hours. The reaction mass was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-15% MeOH/DCM) to give [3(isopropylaminophenylmethyl)phenyl]amide 2-(3-aminomethylphenyl)-5-trifluoromethyl-2H-pyrazol- 3-carboxylic acid (0.250 g, 30%) as a yellowish solid, which was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA-80 in chloroform) to give 1-(3- (aminomethyl)phenyl)-N-(3-((isopropylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (144d) (0.092 g, 36.8% yield) in as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.80 (s, 2H), 8.50 (s, 3H), 7.98 - 7.92 (m, 1H) , 7.81 - 7.75 (m, 2H), 7.74 - 7.70 (m, 3H), 7.66 - 7.36 (m, 7H), 5.65 (s, 1H), 4 .12 (s, 2H), 3.03 (s, 1H), 1.43 -1.21 (m, 7H); ¹⁹ F NMR

- 276 045731 (282 MHz, DMSO) δ -60.78; MS (IER+) 508.3 (M+1); 530.3 (M+Na); (IER-) 506.3 (M-1); 542.3 (M+Cl);

analysis, calculation for C ₂₈ H ₂₈ F ₃ N ₅ O-1.95HCi-2.25H ₂ O: C, 54.31; H, 5.61; Cl, 11.17; N, 11.31; experiment: C,

54.55; H, 5.37; Ci, 10.98; N, 11.00.

Scheme 145

145b ^145c

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((2-hydroxyethylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (145c).

Step 1. Preparation of {3-[(2-hydroxyethylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (145a).

In a solution of [3-(hydroxyphenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3carboxylic acid (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0° C, thionyl chloride (0.514 g, 4.325 mmol) was added and stirred at room temperature for 3 hours. 2-aminoethanol (0.660 g, 10.81 mmol) was added and stirred for 30 minutes. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-aminoethanol (0.660 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give {3-[(2-hydroxyethylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5- trifluoromethyl-2H-pyrazole-3-carboxylic acid (145a) (0.75 g, 69%) as a colorless liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.18 - 8.11 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz , 1H), 7.89 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 7.54 (dd, J=8.0, 1.9 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7, 33 - 7.23 (m, 3H), 7.22 - 7.18 (m, 2H), 4.79 (d, J=4.6 Hz, 1H), 4.56 (t, J=5, 4 Hz, 1H), 3.85-3.68 (m, 1H), 3.54 - 3.49 (m, 2H); MC (IER-) 504.3 (M-1).

Step 2. Preparation of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamido)phenyl)( phenyl)methyl)(2-hydroxyethyl)carbamate (145b).

To a solution of {3-[(2-hydroxyethylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl2H-pyrazole-3-carboxylic acid (145a) (0.7 g, 1.38 mmol) in MeOH (15 mL), cooled in ice/water, add nickel (II) chloride hexahydrate (0.41 g, 1.73 mmol) and Boc anhydride (0.91 g, 4.15 mmol), then add portions sodium borohydride (0.31 g, 8.30 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2 diamine (0.57 g, 5.54 mmol), then stirred for an additional 0.5 hours. The reaction mixture was concentrated to dryness in vacuo and dissolve the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl )phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamido)phenyl)(phenyl)methyl)(2-hydroxyethyl)carbamate (145b) (0.35 g, 36%) as a brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 7.72 7.66 (m, 1H), 7.57 (s, 1H), 7.50 (t, J= 6.3 Hz, 1H), 7.44 - 7.39 (m, 3H), 7.38 - 7.34 (m, 3H), 7.32 (d, J=7.5 Hz, 3H), 7.18-7.11 (m, 2H), 6.93 - 6.87 (m, 1H), 6.29 (s, 1H), 4.46 (t, J=5.3 Hz, 1H) , 4.19 (d, J=6.2 Hz, 2H), 3.31 3.10 (m, 2H), 3.09 - 2.83 (m, 2H), 1.32 (s, 18H) ; MS (IER-) 708.3 (M-1).

Step 3. Preparation of 2-(3-aminomethylphenyl)5-trifluoromethyl-2H-pyrazole-3-carboxylic acid {3-[(2-hydroxyethylamino)phenylmethyl]phenyl}amide (145c).

Into a solution of tert-butyl-((3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H- 277 045731 pyrazole-5-carboxamido)phenyl)(phenyl )methyl)(2-hydroxyethyl)-carbamate (145b) (0.32 g, 0.45 mmol) in MeOH (10 ml) was added conc. HCl (0.4 ml). The reaction mixture was stirred at room temperature for 19 hours. The reaction mass was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-15% MeOH/DCM) to give {3-[(2-hydroxyethylamino)phenylmethyl]phenyl}amide 2-(3-aminomethylphenyl)-5- trifluoromethyl2H-pyrazole-3-carboxylic acid (145c) (0.06 g, 26%) as a yellowish solid. The product was purified again by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0100% CMA-80 in chloroform) to give pure (145c) (0.02 g) as an off-white solid; ^1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.97 (s, 2H), 8.41 (s, 3H), 7.85 (s, 1H), 7. 73 (d, J=2.1 Hz, 1H), 7.70 - 7.48 (m, 7H), 7.47 - 7.33 (m, 4H), 5.62 (s, 1H), 5 .24 (s, 1H), 4.13 (s, 2H), 3.71 (d, J=5.5 Hz, 2H), 2.89 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 510.3 (M+1); (IER-) 508.3 (M-1); 544.2 (M+Cl).

Scheme 146

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-H-(3-((cyclopropylmethylamino)(2,5-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (146g).

Step 1. Preparation of (3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (146b).

To a stirred solution of 2,5-bis(benzyloxy)benzaldehyde (146a) (3.2 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12 .00 ml, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (146b) (2.4 g, 58.32%) as a light brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.46 - 7.29 (m, 10H), 7.14 (d, J=3.1 Hz, 1H), 6.94 - 6.84 (m , 2H), 6.80 (dd, J=8.9, 3.1 Hz, 1H), 6.57 (t, J=1.9 Hz, 1H), 6.50 6.44 (m, 1H ), 6.38 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 5.86 (d, J=4.4 Hz, 1H), 5.52 (d, J= 4.4 Hz, 1H), 5.01 (d, J=1.2 Hz, 4H), 4.93 (s, 2H).

Step 2. Preparation of N-(3-((2,5-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 146c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.57 g, 5.589 mmol) in DMF (40 ml) was added (3-aminophenyl)(2 ,3-bis(benzyloxy)phenyl)methanol (146b) (2.3 g, 5.589 mmol), N-ethyl-N-isopropylpropan-2-amine (5.8 g, 44.93 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop, 2.6 g, 5.589 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (350 ml), washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness in vacuo. The resulting residue was purified by flash column

- 278 045731 chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%) to give N(3-((2,5-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-( 3-cyanophenyl)-3-(trifluoromethyl)-III-pyrazole5-carboxamide (146c) (2.55 g, 67.62%) as an off-white solid; 1H NMR (300 MHz, DMSOd6) δ 10.61 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.8, 1.3 Hz , 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.757.66 (m, 2H), 7.64 (d, J=1.9 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.45 - 7.27 (m, 10H), 7.21 (t, J=7.8 Hz, 1H), 7.13 (d , J=3.1 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 6.82 (dd, J =8.9, 3.1 Hz, 1H), 5.96 (d, J=4.3 Hz, 1H), 5.79 (d, J=4.3 Hz, 1H), 5.00 (d , J=1.9 Hz, 4H).

Step 3. Preparation of N-(3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazol- 5-carboxamide (146d).

Into a solution of N-(3-((2,5-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (146c ) (2.5 g, 3.705 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (0.53 g, 7.41 mmol) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (4.826 g, 55.57 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give N-(3((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl) -1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (146d) (0.9 g, 33.37%) as a brown sticky liquid; 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.14 (t, J=1.8 Hz, 1H), 7.95 (dt, J=7.7, 1, 3 Hz, 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.69 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.46 - 7.24 (m, 11H), 7.21 (t, J=7.8 Hz, 1H), 7.13 (d, J=3.1 Hz, 1H), 7.08 (dt, J=7.8, 1.3 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 6 .80 (dd, J=8.9, 3.1 Hz, 1H), 5.17 (s, 1H), 5.00 (d, J=3.3 Hz, 4H), 2.24 (qd, J=12.0, 6.7 Hz, 2H), 1.86 (dt, J=4.9, 2.4 Hz, 1H), 0.93 - 0.74 (m, 1H), 0.38 - 0.27 (m, 2H), 0.09 - -0.20 (m, 2H).

Step 4. tert-Butyl-3-(5-((3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3 -(trifluoromethyl)-1 H- pyrazol-1-yl)benzylcarbamate (146f).

Into a solution of N-(3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (146d) (0.9 g, 1.236 mmol) in MeOH (12 ml), cooled in ice/water, add nickel(II) chloride hexahydrate (0.367 g, 1.548 mmol) and bocanhydride (0.809 g, 3.708 mmol) , then sodium borohydride (0.280 g, 7.416 mmol) was added piecemeal over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.510 ml, 4.944 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give:

1. tert-butyl-((2,5-bis(benzyloxy)phenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol- 5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (146e) (0.08 g, 6.94%); 1H NMR (300 MHz, DMSO- _d6 ) δ 10.71 (s, 1H), 7.65 (s, 2H), 7.56 (s, 1H), 7.51 - 7.24 (m, 17H ), 7.10 6.83 (m, 2H), 6.63 -6.47 (m, 2H), 5.02 (t, J=11.7 Hz, 4H), 4.18 (d, J =5.1 Hz, 2H), 3.23 - 2.82 (m, 1H), 1.37 (s, 18H), 0.93 - 0.82 (m, 1H), 0.23 - 0, 04 (m, 2H), -0.13 - -0.42 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.65; MS (IER+) 954.5 (M+Na); (IER-) 930.5 (M-1).

2. tert-butyl-3-(5-((3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (146f) (0.12 g, 11.67%); 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.49 (t , J=8.1 Hz, 1H), 7.34 (dtq, J=11.8, 9.6, 4.8 Hz, 13H), 7.20 (t, J=7.8 Hz, 1H) , 7.15- 6.75 (m, 2H), 5.01 (d, J=4.7 Hz, 2H), 4.17 (d, J=6.0 Hz, 2H), 1.36 ( d, J=4.1 Hz, 9H), 1.23 - 1.13 (m, 1H), 0.85 (s, 2H), 0.36 (dd, J=21.4, 8.4 Hz , 2H); ¹⁹ F NMR (282 MHz, DMSO) δ 60.784; MS (IER+) 832.5 (M+1); (IER-) 830.4 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,5-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (146g) .

Into a solution of tert-butyl-3-(5-((3-((2,5-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (146f) (0.12 g, 0.144 mmol) in dichloromethane (10 ml), cooled to 0°C, trimbromoborane (1M solution in dichloromethane) (0.577 ml, 0.577 mmol) was added dropwise under nitrogen. . The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with methanol (5 ml) and the mixture was concentrated to dryness in vacuo. The resulting residue was triturated with methanol and dried in vacuo, this step being repeated four times to obtain the crude product. The resulting residue was purified twice by flash column chromatography [silica gel, 12 g and 4 g, eluted with mixtures of CMA-80 in chloroform, 0-100%] to give 1-(3-(aminomethyl)phenyl)-N-(3-( (cyclopropyl

- 279 045731 methylamino)(2,5-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (146g) (0.045 g, 56.6%) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.74 (s, 1H), 8.63 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.59 - 7.50 (m, 3H), 7.46 - 7.40 (m, 2H), 7.32 (dd, J=6.4, 2.7 Hz, 1H), 7.27 (d, J= 7.8 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.50 (d, J=8.3 Hz, 1H), 6.47 - 6.40 (m, 2H), 4.91 (s, 1H), 3.78 (s, 2H), 2.43 - 2.18 (m, 2H), 0.94 (m, 1H), 0.40 (m, 2H), 0 .08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.70; MS (IER+) 552.3 (M+1); (IER-) 550.3 (M+1); analysis, calculation for C ₂₉ H ₃₁ N ₅ O ₃ -0.75HBr: C, 62.39; H, 5.73; N, 12.54; experiment: C, 62.23; H, 5.44; N, 12,16.

Scheme 147

An example of the preparation of N-(3-((4-acetamodophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147e).

Step 1. Preparation of N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (147b).

To a stirred solution of N-(4-formylphenyl)acetamide (147a) (3.26 g, 20 mmol) in tetrahydrofuran (30 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (24 ml , 24.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at the indicated temperature and quenched by adding 12N. HCl (4.17 ml, 50.0 mmol), stirred for 1 hour. The reaction mixture was treated with 2N. NaOH (30.0 ml, 60.0 mmol) and extracted with ethyl acetate (2x50 ml). They combined the organic layers and washed us. NH ₄ Cl (50 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide (147b) (2.098 d, 41% yield) as a yellow solid, which was used as such in the next step; MS (IER-): 255.2 (M-1).

Step 2. Preparation of N-(3-((4-acetamudophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (147c).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-nirazole-5carboxylic acid (9i) (2.61 g, 9.28 mmol), N-(4-((3 -aminophenyl)(hydroxy)methyl)phenyl)acetamide (147b) (1.983 g, 7.74 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 4.33 g, 9.28 mmol), N,N- was added successively dimethylformamide (44.9 ml, 580 mmol) and N-ethyl-Nisopropylpropan-2-amine (6.74 ml, 38.7 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (250 ml) and extracted with chloroform (2x250 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures] to give N(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147c) (1.159 g, 29% yield) as a yellow solid; MS (IER-) 518.2 (M-1).

Step 3. Preparation of N-(3-((4-acetamodophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147d).

In a solution of N-(3-((4-acetamidophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (147c) (1.139 g, 2.193 mmol ) in dichloromethane (20 ml) at 0°C, add thionyl chloride (0.480 ml, 6.58 mmol), the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with triethylamine (1.528 ml, 10.96 mmol) and Stir the solution for 30 min at room temperature and concentrate to dryness in vacuo. Remainder

- 280 045731 was dissolved in acetonitrile (20 ml), cyclopropylmethanol (18.64 ml, 254 mmol) and triethylamine (1.528 ml, 10.96 mmol) were added to the resulting mixture and stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature, evaporated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of methanol in chloroform, 0-100%) to give N-(3 -((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1 -(3 - cyanophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147d) (0.494 g, 39% yield) as a brown solid; 1H NMR (300 MHz, DMSO-th ₆ ) δ 10.67 (s, 1H), 9.92 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 8.00 ( dt, J=7.8, 1.3 Hz, 1H), 7.90 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.78 -7.70 (m, 2H), 7.59 (t, J=3.3 Hz, 2H), 7.54 - 7.47 (m, 2H), 7.35 - 7.20 (m, 3H), 7.11 (d , J=7.7 Hz, 1H), 5.38 (s, 1H), 3.21 (d, J=6.8 Hz, 2H), 2.01 (s, 3H), 1.04 (d , J=5.2 Hz, 1H), 0.49 - 0.42 (m, 2H), 0.17 - 0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.93; MC (IER+): MC (IER+) 574.4 (M+1), 596.4 (M+Na), MC (IER-) 572.2 (M-1).

Step 4. Preparation of N(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147e).

Into a stirred solution of N(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147d) (0.481 g, 0.839 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.100 g, 0.419 mmol) was added, then sodium borohydride (0.254 g, 6.71 mmol) was added in small portions over 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 15 min at 0°C, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.906 ml, 8.39 mmol) was added. The mixture was left to stir for another 30 minutes, after which the solvent was evaporated. The residue was treated with water (30 ml) and extracted with chloroform (2x30 ml), then ethyl acetate (2x30 ml), the combined organic layers were dried over anhydrous MgSO ₄ and filtered, excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with CMA 80/chloroform, 0 to 100%)] to give N(3-((4-acetamidophenyl)(cyclopropylmethoxy)methyl)phenyl)-1- (3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (147e) (203 mg, 42% yield) as a colorless solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.71 (s, 1H), 9.93 (s, 1H, exchange with _D2O ), 7.62 - 7.48 (m, 6H), 7 .47 - 7.41 (m, 2H), 7.36 - 7.20 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 5.37 (s, 1H), 3.79 (s, 2H), 3.21 (dd, J=6.8, 1.3 Hz, 2H), 2.01 (s, 3H), 1.04 (ddd, J=12.7, 8.5, 5.3 Hz, 1H), 0.55-0.38 (m, 2H), 0.14 (tq, J=4.5, 2.3, 1.9 Hz, 2H); 1H NMR (300 MHz, DMSO-d6, D2O) δ 7.62 - 7.41 (m, 8H), 7.37 - 7.21 (m, 4H), 7.11 (d, J=7.7 Hz, 1H), 5.37 (s, 1H), 3.78 (s, 2H), 3.21 (d, J=6.8 Hz, 2H), 2.01 (s, 3H), 1, 13 - 0.96 (m, 1H), 0.46 (dd, J=7.6, 2.3 Hz, 2H), 0.13 (dd, J=4.5, 2.3 Hz, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.71; MS (IER ⁺ ): MS (IER+) 578.3 (M+1), MS (IER-) 612.3 (M+Cl); analysis, calculation for C31H30F3N5O3: C, 64.46; H, 5.24; N, 12.12; experiment: C, 64.03; H, 5.24; N, 11.77.

Scheme 148

An example of the preparation of 1 -(3-(αminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalene-1yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (148b ).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (148a ).

In a solution of {3-[hydroxy(2-methoxynaphthalin-1-yl)methyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (51c) (3.5 g, 6.45 mmol) in dichloromethane (50 ml) at 0°C was added thionyl chloride (1.413 ml, 19.35 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with triethylamine (5.40 ml, 38.7 mmol ) and stirred at room temperature for 8 hours. The reaction mixture was treated with cyclopropanemethanol (10.22 ml, 129 mmol), concentrated to remove the bulk of the dichloromethane, then acetonitrile (50.0 ml) was added and heated at reflux temperature for 16 h. The reaction mixture was concentrated to dryness, diluted with water (200 ml) and extracted with ethyl acetate (3x300 ml). Combine the organic layers, wash with water (100 ml), brine (100 ml), dry over MgSO4, then filter and concentrate. The residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of 0 to 30% ethyl acetate in hexanes) to give pure 1-(3-cyanophenyl)-N(3-((cyclopropylmethoxy)(2-methoxynaphthalene-1 -yl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (148a) (2.5 g, 65.0% yield) as a white solid.

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(2-methoxynaphthalene-1

- 281 045731 yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (148b).

Into a stirred solution of 1-(3-cyanophenyl)-I-(3-((cyclopropylmethoxy)(2-methoxynaphthalene-1yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (148a) (1.862 g, 3.12 mmol) in methanol (70 ml) at 0°C was added nickel (II) chloride hexahydrate (0.162 g, 0.680 mmol). Sodium tetrahydroborate (1.181 g, 31.2 mmol) was added to the resulting mixture in small portions over 10 minutes. The reaction mixture was stirred for 1 hour, quenched by adding N1-(2-aminoethyl)ethane-1,2diamine (0.805 g, 7.80 mmol) and stirred for 1 hour. Concentrate the reaction mixture to remove methanol, dilute with water (150 ml) and stirred for 30 min. The isolated solid was collected by filtration, dried in vacuo and purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, from 0 to 100%) to give 1-(3-(aminomethyl)phenyl)-I-(3 -((cyclopropylmethoxy)(2-methoxynaphthalene-1-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (148b) (0.91 g, 48.5% yield) as a colorless solid substances; ^1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H,), 9.93 (s, 1H, exchange with D2O), 7.62 -7.48 (m, 6H), 7, 47 - 7.41 (m, 2H), 7.36 - 7.20 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 5.37 (s, 1H), 3 .79 (s, 2H), 3.21 (dd, J=6.8, 1.3 Hz, 2H), 2.01 (s, 3H), 1.04 (ddd, J=12.7, 8 ,5, 5.3 Hz, 1H), 0.55-0.38 (m, 2H), 0.14 (tq, J=4.5, 2.3, 1.9 Hz, 2H); 1H NMR (300 MHz, DMSO-d6, D2O) δ 7.62 -7.41 (m, 8H), 7.37-7.21 (m, 4H), 7.11 (d, J=7.7 Hz, 1H), 5.37 (s, 1H), 3.78 (s, 2H), 3.21 (d, J=6.8 Hz, 2H), 2.01 (s, 3H), 1, 13 - 0.96 (m, 1H), 0.46 (dd, J=7.6, 2.3 Hz, 2H), 0.13 (dd, J=4.5, 2.3 Hz, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.71; MS (IER+) 578.3 (M+1), MS (IER-) 612.3 (M+Cl); analysis, calculation for C31H30F3N5O3: C, 64.46; H, 5.24; N, 12.12; experiment: C, 64.03; H, 5.24; N, 11.77.

Scheme 149

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (149b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (149a).

Into a solution of N-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (123c) (1 .0 g, 1.759 mmol) in dichloromethane (30 ml), cooled to 78°C, tribromoborane (1 M solution in dichloromethane) (5.28 ml, 5.28 mmol) was added dropwise under a positive stream of nitrogen over 10 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The reaction was quenched with cyclopropylmethanol (6.44 ml, 88 mmol), evaporated, the cycle repeated twice, then concentrated to dryness. Cyclopropylmethanol (6.44 ml, 88 mmol) and hydrogen chloride (8.79 ml, 35.2 mmol) were added to the resulting residue and refluxed for 16 hours. Excess solvent was evaporated, 5 g of silica gel and chloroform were added to the flask ( 30 ml) and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl )phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (149a) (0.485 g, 52% yield) as a white solid, which was used as such in the next step; MS (ESI-) 531.1 (M-1), 567.1 (M+Cl).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (149b ).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (149a) (0.430 g, 0.807 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.096 g, 0.404 mmol) was added, then sodium borohydride (0.244 g, 6.46 mmol) was added in small portions over 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 15 min at 0°C, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.872 ml, 8.07 mmol) was added. The mixture was left stirring for 30 minutes and concentrated to dryness in vacuo. The residue was treated with water (50 ml) and extracted with chloroform (2x50 ml), then ethyl acetate (2x50 ml), the combined organic layers were dried over anhydrous MgSO ₄ and filtered, excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 100% CMA 80/chloroform)] to give 1-(3-(aminomethyl)phenyl)-I-(3-((cyclopropylmethoxy) (4-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (149b) (51 mg, 12% yield) as a colorless solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.70 (s, 1H, exchange with

- 282 045731

D2O), 9.37 (s, 1H, exchange with D2O), 7.59 - 7.51 (m, 4H), 7.45- 7.41 (m, 2H), 7.35- 7.23 ( m, 2H), 7.15- 7.05 (m,

3H), 6.71 (s, 1H), 6.68 (s, 1H), 5.31 (s, 1H), 3.79 (s, 2H), 3.19 (d, J=6.7 Hz, 2H), 2.39 (s, 2H, exchange with D ₂ O),

1.11 - 0.96 (m, 1H), 0.44 (ddd, J=7.9, 3.7, 2.5 Hz, 2H), 0.13 (ddd, J=6.7, 3 ,3, 2.0 Hz, 2H); Ή NMR (300 MHz,

DMSO-d ₆ D2O) δ 7.62 - 7.49 (m, 4H), 7.45 (dd, J=4.8, 2.3 Hz, 2H), 7.36 - 7.25 (m, 2H), 7.15-7.08 (m, 3H), 6.75-6.68 (m, 2H), 5.32 (s, 1H), 3.77 (s, 2H), 3.19 (d, J=6.8 Hz, 2H), 1.11 - 0.96 (m, 1H), 0.45 (ddd, J=7.8, 3.7, 2.4 Hz, 2H), 0.13 (ddd, J=6.7, 3.3, 2.0 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.71; MS (IER ⁺ ): MS (IER+) 537.3 (M+1), MS (IER-) 535.3 (M-1), 571.3 (M+Cl); analysis, calculation for: C ₂₉ H ₂₇ F ₃ N ₄ O ₃ -0.5H ₂ O: C, 63.85; H, 5.17; N, 10.27; experiment: C, 63.91; H, 5.30; N, 10.24.

Scheme 150

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,3-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (150f).

Step 1. Preparation of (3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (150b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12 .00 ml, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (150b) (2.5 g, 60.75%) as a light brown solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.53 - 7.46 (m, 2H), 7.41 - 7.30 (m, 8H), 7.05 (s, 3H), 6.89 (t, J=7.7 Hz, 1H), 6.54 (t, J=1.9 Hz, 1H), 6.45 (dt, J=7.7, 1.3 Hz, 1H), 6 .37 (ddd, J=8.0, 2.3, 1.1 Hz, 1H), 5.90 (d, J=4.4 Hz, 1H), 5.55 (d, J=4.5 Hz, 1H), 5.15 (s, 2H), 4.96 (s, 2H), 4.91 (d, J=10.5 Hz, 1H), 4.75 (d, J=10.5 Hz, 1H).

Step 2. N-(3-((2,3-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (150c).

In a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.2 g, 4.26 mmol) in toluene (30 ml) and DMF (15 drops) SOCl ₂ (1.16 g, 9.79 mmol) was added at 0°C and heated at reflux temperature for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (100 ml) and (3-aminophenyl)(2,3-bis(benzyloxy)phenyl)methanol (150b) (2.5 g, 3.58 mmol) and triethylamine (5 ml) were added. The reaction mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (350 ml), washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%] to give N(3 -((2,3-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1 -(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (150c) (2.4 g, 83.50%) as a brown solid; 1H NMR (300 MHz, DMSOd6) δ 10.62 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.98 (dt, J=7.8, 1.3 Hz , 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.76 7.67 (m, 2H), 7.61 (t, J=1, 8 Hz, 1H), 7.58 - 7.44 (m, 3H), 7.39 (s, 2H), 7.37 - 7.24 (m, 6H), 7.22 (t, J=7 .9 Hz, 1H), 7.11 - 6.97 (m, 4H), 6.01 (d, J=4.2 Hz, 1H), 5.81 (d, J=4.3 Hz, 1H ), 5.15 (s, 2H), 4.99 - 4.77 (m, 2H).

Step 3. N-(3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazol- 5-carboxamide (150d).

In a solution of N-(3-((2,3-bis(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (3 .0 g, 4.44 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (1.0 g, 8.40 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and

- 283 045731 cyclopropylmethanamine (1.26 g, 17.76 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give N-(3-((2,3bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl )-1-(3-cyanophenyl)-3-(trifluoromethyl)III-pyrazole-5-carboxamide (150d) (2.0 g, 61.8%) as a brown sticky liquid; 1H NMR (300 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.97 (dt, J=7.8, 1, 3 Hz, 1H), 7.89 (ddd, J=8.3, 2.3, 1.2 Hz, 1H), 7.75- 7.67 (m, 2H), 7.64 (t, J =1.9 Hz, 1H), 7.55-7.47 (m, 3H), 7.42 - 7.27 (m, 8H), 7.22 (t, J=7.9 Hz, 1H) , 7.07 (d, J=14.4 Hz, 4H), 5.14 (d, J=2.3 Hz, 3H), 4.90 (d, J=2.7 Hz, 2H), 2 .24 (dt, J=11.4, 5.6 Hz, 1H), 2.18 2.07 (m, 2H), 0.84 (dq, J=9.7, 6.1 Hz, 1H) , 0.37 - 0.25 (m, 2H), 0.09 - -0.11 (m, 2H).

Step 4. Preparation of tert-butyl-3-(5-((3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzylcarbamate (150e).

Into a solution of N-(3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1 -(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (150d) (2.0 g, 2.748 mmol) in MeOH (12 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.78 g, 3.297 mmol) and bocanhydride (1.8 g) were added , 8.244 mmol), then sodium borohydride (0.623 g, 16.488 mmol) was added portionwise over 15 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ (2-aminoethyl)ethane-1,2-diamine (0.75 ml, 6.870 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolved the resulting residue in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give tert-butyl-3-(5-((3-((2,3-bis(benzyloxy)phenyl )((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (150e) (0.530 g, 23.18%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.50 (dt, J=7.8 , 2.3 Hz, 4H), 7.43 - 7.39 (m, 3H), 7.37 - 7.28 (m, 8H), 7.20 (t, J=7.8 Hz, 1H) , 7.08 (s, 1H), 7.05 (s, 3H), 5.18 - 5.08 (m, 2H), 4.89 (d, J=2.7 Hz, 2H), 4, 18 (d, J=6.2 Hz, 2H), 2.29 - 2.18 (m, 1H), 2.11 (s, 2H), 1.36 (s, 9H), 1.30 - 1 .20 (m, 2H), 0.90 - 0.78 (m, 2H), 0.36 -0.28 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 832.5 (M+1); (IER-) 830.4 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2,3-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (150f) .

Into a solution of tert-butyl-3-(5-((3-((2,3-bis(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (150e) (0.375 g, 0.451 mmol) in dichloromethane (10 ml), cooled to 0°C, boron trichloride (1M solution in dichloromethane, 1.8 ml, 1.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with methanol (5 ml) and the mixture was concentrated to dryness in vacuo. The resulting residue was triturated with methanol and dried in vacuo, this step being repeated four times to obtain the crude product. The resulting residue was purified twice by flash column chromatography [silica gel, 12 g and 4 g, eluted with mixtures of CMA-80 in chloroform, 0-100%] to give 1-(3-(aminomethyl)phenyl)-N-(3-( (cyclopropylmethylamino)(2,3-dihydroxyphenyl)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxamide (150f) (0.02 g, 0.036 mmol, 8.04% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 7.65 (t, J=1.8 Hz, 1H), 7.59 - 7.50 (m, 3H), 7.46 - 7.38 (m, 2H), 7.36 - 7.24 (m, 2H), 7.24 - 7.16 (m, 1H), 6.59 (dd, J=7.6 , 1.9 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.43 (dd, J=7.7, 1.9 Hz, 1H), 4.96 (s , 1H), 3.78 (s, 2H), 2.42 (m, 1H), 2.27 (m, 1H), 1.02 - 0.88 (m, 1H), 0.53 - 0, 29 (m, 2H), 0.22 - 0.02 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.70; ¹³ C NMR (75 MHz, DMSO) δ 191.41, 173.39, 156.44, 145.17, 145.04, 144.57, 143.73, 139.01, 137.92, 128.75, 127.74, 127.15, 123.40, 123.38, 123.27, 122.64, 118.82, 118.72, 118.43, 114.03, 64.03, 51.75, 44, 67, 10.46, 3.49, 3.28; MS (IER+) 552.3 (M+1); (IER-) 550.3 (M-1); analysis, calculation for C ₂₉ H ₂₈ F ₃ N ₅ O ₃ 0.75H ₂ O: C, 61.64; H, 5.26; N, 12.39; experiment: C, 62.01; H, 5.23; N, 11.92.

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Scheme 151

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxy-3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (151g).

Step 1. Preparation of (3-aminophenyl)(2-(benzyloxy)-3-methoxyphenyl)methanol (151b).

To a stirred solution of 2-(benzyloxy)-3-methoxybenzaldehyde (151a) (3.2 g, 10 mmol) in tetrahydrofuran (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12 .00 ml, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(2-(benzyloxy)-3methoxyphenyl)methanol (151b) (3.2 g, 86.97%) in the form of a light brown sticky liquid; ^1H NMR (300

MHz, DMSO-di) δ 7.49 - 7.30 (m, 5H), 7.10 - 6.99 (m, 2H), 6.94 (dd, J=7.5, 2.2 Hz, 1H), 6.88 (t, J=7.7 Hz, 1H), 6.53 (t, J=1.9 Hz, 1H), 6.44 (dt, J=7.7, 1.3 Hz, 1H), 6.37 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 5.52 (d , J=4.4 Hz, 1H), 4.95 (s, 2H), 4.89 (d, J=10.8 Hz, 1H), 4.77 (d, J=10.8 Hz, 1H ), 3.82 (s, 3H); MS (IER-) 334.3 (M-1).

Step 2. Preparation of N-(3-((2-(benzyloxy)-3-methoxyphenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (151c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (3.018 g, 10.73 mmol) in DMF (72 ml) was added (3-aminophenyl)(2 -benzyloxy-3-methoxyphenyl)methanol (151b) (3.2 g, 9.54 mmol), N-ethyl-N-isopropylpropan-2-amine (11.097 g, 85.864 mmol) and bromotris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 5.003 g, 10.73 mmol) at room temperature. The reaction mixture was stirred at room temperature for 42 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (350 ml), washed with water (2x150 ml), brine (120 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-30%] to give N(3-((2-(benzyloxy)-3-methoxyphenyl)(hydroxy)methyl)phenyl)-1 -(3-cyanophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (151c) (2.4 g, 37.36%) as a yellow sticky liquid; 1H NMR (300 MHz, DMSO-di) δ 10.63 (s, 1H), 8.14 (t, J=1.8 Hz, 1H), 7.98 (dt, J=7.7, 1, 4 Hz, 1H), 7.94 (s, 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.43 (dd, J=5.2, 1.6 Hz, 3H), 7.38 - 7.34 (m, 2H), 7.22 (t, J=7.9 Hz, 1H), 7 .06 - 6.99 (m, 3H), 6.00 (d, J=4.4 Hz, 1H), 5.81 (d, J=4.3 Hz, 1H), 4.93 (s, 2H), 4.85 (d, J=8.6 Hz, 1H), 4.76 (d, J=10.8 Hz, 1H), 3.82 (s, 3H).

Step 3. Preparation of N-(3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1 -(3-cyanophenyl)-3 -(trifluoromethyl)-1 H-pyrazole -5-carboxamide (151d).

Into a solution of N-(3-((2-(benzyloxy)-3-methoxyphenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (151c ) (2.0 g, 3.34 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.795 g, 6.68 mmol) and stir at room temperature for 4 hours.

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The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (40 ml) and cyclopropylmethanamine (3.56 g, 50.1 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (50 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexane) to give N-(3((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl) -1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (151d) (1.01 g, 46.40%) as a brown liquid.

Step 4. Preparation of tert-butyl-((2-(benzyloxy)-3-methoxyphenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (151e) and tert-butyl-3-(5-((3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino) methyl)phenyl)carbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (151f).

Into a solution of N-(3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 151d) (1.0 g, 1.53 mmol) in MeOH (12 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.40 g, 1.683 mmol) and bocanhydride (1.00 g) were added , 4.59 mmol), then sodium borohydride (0.34 g, 9.18 mmol) was added portionwise over 15 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2aminoethyl)ethane-1,2-diamine (0.4 mL, 3.825 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and the resulting residue was dissolved in chloroform (25 ml) and water (25 ml). The aqueous layer was separated and extracted with chloroform (25 ml). The combined extracts were washed with brine (25 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 24 g, eluted with 0-25% ethyl acetate/hexane) to give:

1. tert-butyl-((2-(benzyloxy)-3-methoxyphenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (151e) (0.130 g, 9.9%) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.55 (s, 1H), 7.49 ( t, J=6.2 Hz, 1H), 7.44 - 7.27 (m, 9H), 7.26 (d, J=8.0 Hz, 1H), 7.13 6.99 (m, 2H), 6.77 (d, J=7.7 Hz, 1H), 6.52 (dd, J=6.5, 2.7 Hz, 1H), 4.96 (d, J=10.8 Hz, 1H), 4.83 (d, J=10.8 Hz, 1H), 4.17 (d, J=6.2 Hz, 2H), 3.86 (s, 3H), 3.82 - 3.76 (m, 1H), 3.25- 3.17 (m, 1H), 2.94 (dd, J=14.5, 6.9 Hz, 1H), 1.36 (d, J= 1.6 Hz, 18H), 0.62 - 0.46 (m, 1H), 0.27 - 0.06 (m, 2H), -0.09 - -0.23 (m, 1H), - 0.32 - -0.55 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (ESI+) 878.5 (M+Na); (IER-) 854.5 (M-1);

2. tert-butyl-3-(5-((3-((2-(benzyloxy)-3-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (151f) (0.020 g, 1.72%) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.66 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.50 (d, J=7.3 Hz, 1H), 7.44 - 7.39 (m, 5H), 7.39 - 7.28 (m, 5H), 7.19 (t, J=7.8 Hz, 1H), 7.05 (d , J=4.5 Hz, 1H), 7.02 (s, 1H), 6.93 (dd, J=7.0, 2.6 Hz, 1H), 5.11 (s, 1H), 4 .88 (s, 2H), 4.18 (d, J=6.2 Hz, 3H), 3.82 (s, 3H), 2.16 - 2.04 (m, 3H), 1.36 ( s, 9H), 0.91 - 0.71 (m, 1H), 0.34 - 0.28 (m, 2H), -0.03 (dd, J=9.1, 2.7 Hz, 2H ); ¹⁹ F NMR (282 MHz, DMSO) δ -60.78; MS (IER+) 756.5 (M+1); (IER-) 754.5 (M-1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-hydroxy-3methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (151g).

Into a solution of tert-butyl-((2-(benzyloxy)-3-methoxyphenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (151e) (0.012 g, 0.014 mmol) in methanol (10 ml) was added carbon-supported palladium (10%, 0.037 mg) and conc. HCl (0.023 ml, 0.280 mmol). The mixture was hydrogenated for 2 hours at 50 psi (345 kPa) and filtered through a pad of celite. The filtrate was concentrated to dryness in vacuo. The resulting residue was purified twice by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA-80 in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(3((cyclopropylmethylamino)(2 -hydroxy-3-methoxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (151g) (0.013 g, 0.023 mmol, 16.4% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.66 - 7.61 (m, 1H), 7.60 - 7.49 (m, 3H), 7.48 - 7.38 (m, 2H), 7.35- 7.23 (m, 2H), 7.19 (dt, J=7.9, 1.4 Hz, 1H), 6.77 (dd, J= 6.5, 3.1 Hz, 1H), 6.64 (d, J=6.6 Hz, 2H), 5.01 (s, 1H), 3.77 (s, 2H), 3.72 ( s, 3H), 2.44 - 2.20 (m, 2H), 1.03 - 0.87 (m, 1H), 0.49 - 0.30 (m, 2H), 0.17 - 0, 02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.70; MS (IER+) 566.3 (M+1); (IER-) 564.3 (M-1); analysis, calculation for C ₃₀ H ₃₀ F ₃ N ₅ O ₃ -2H ₂ O: C, 59.89; H, 5.70; N, 11.64; experiment: C, 59.69; H, 5.27; N, 11.36.

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Scheme 152

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (152d).

Step 1. Preparation of 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (152a).

To a stirred solution of 3-formylbenzonitrile (54a) (3.93 g, 30 mmol) in tetrahydrofuran (50 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (36.0 ml, 36 0 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature and quenched by adding 2N. HCl (37.5 mL, 75 mmol) was stirred for an additional 1 hour at room temperature. The reaction mixture was treated with 2N. NaOH (45 ml, 90 mmol) and extracted with ethyl acetate (2x100 ml). They combined the organic layers and washed us. NH ₄ Cl (100 ml), dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (152a) (3.56 g, 15 .87 mmol, 52.9% yield) as a yellow solid; ¹ H NMR (300 MHz, DMSO-d6) δ 7.76 (t, J=1.6 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.51 (t, J=7 ,7 Hz, 1H), 6.94 (t, J=7.7 Hz, 1H), 6.61 - 6.48 (m, 2H), 6.41 (ddd, J=8.0, 2, 4, 1.1 Hz, 1H), 5.96 (d, J=3.9 Hz, 1H, exchange with D2O), 5.59 (d, J=3.9 Hz, 1H), 5.04 ( s, 2H, exchange with D2O); MC (IER+) 225.2 (M+1), 247.1 (M+Na); MC (IER-) 223.1 (M-1), 447.2 (2M-1).

Step 2. Preparation of tert-butyl-3-(5-(3-((3-cyanophenyl)(hydroxy)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (152b).

1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (7.27 g, 18.86 mmol) was placed in a 100 mL one-neck flask. , 3-((3-aminophenyl)(hydroxy)methyl)benzonitrile (152a) (3.524 g, 15.71 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 8.79 g, 18.86 mmol), was treated sequentially N,N-dimethylformamide (91 ml) and Nethyl-N-isopropylpropan-2-αamine (13.69 ml, 79 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The residue was treated with water (75 ml) and extracted with ethyl acetate (2x75 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 80 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give tert-butyl-3-(5-(3-((3-cyanophenyl)(hydroxy)methyl) phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (152b) (3.799 g, 6.42 mmol, 40.9% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H, exchange with D2O), 7.80 (t, J=1.7 Hz, 1H), 7.69 (ddt, J=8 ,6, 5.7, 1.5 Hz, 2H), 7.62 (t, J=1.7 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.54 - 7, 39 (m, 3H), 7.38 - 7.25 (m, 3H), 7.16 (dt, J=7.7, 1.3 Hz, 1H), 6.20 (d, J=3, 9 Hz, 1H, exchange with D2O), 5.76 (d, J=3.9 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s, 9H) ; ¹⁹ F NMR (282 MHz, DMSOL) δ -60.78; IR (KBr, cm' ¹ ): 2232 cm- ¹ (stretching vibrations -CN); MS (IER+): MS (IER+) 614.3 (M+Na), MS (IER-) 590.3 (M-1), 626.3 (M+Cl).

Step 3. Preparation of tert-butyl-3-(5-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (152c).

Into a solution of tert-butyl-3-(5-(3-((3-cyanophenyl)(hydroxy)methyl)phenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (152b) (3.71 g , 6.27 mmol) in dichloromethane (40 ml) at 0°C was added thionyl chloride (1.372 ml, 18.81 mmol), the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with cyclopropylmethanamine (3.81 ml , 43.9 mmol) and stirred the solution for 30 min at room temperature and concentrated to dryness in vacuo

- 287 045731 m. The residue was dissolved in acetonitrile (40 ml), then cyclopropylmethanamine (3.81 ml, 43.9 mmol) was added, stirred at 80°C for 16 hours, TLC analysis (ethyl acetate/hexanes, 1:1, v/v). ) indicated complete conversion, the reaction mixture was cooled to room temperature. The reaction mixture was treated with silica gel (6 g) and evaporated under reduced pressure until a dry suspension was obtained. The residue was purified by flash column chromatography (silica gel, 40 g, run on two separate columns, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give tert-butyl-3-(5-(3-((3cyanophenyl)(cyclopropylmethylamino) )methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (152c) (0.704 g, 17% yield) as a white solid, which was used as such in the next step; MS (IER+) 645.1 (M+1); MS (IER-) 643.2 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (152d) .

In a solution of tert-butyl 3-(5-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (152c) (0.285 g, 0.442 mmol) in dioxane (9 ml), hydrogen chloride (4N) (3.17 ml, 19.01 mmol) was added, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of methanol in chloroform, 0-100%) to give 1-(3-(aminomethyl)phenyl)-N-(3-((3-cyanophenyl)(cyclopropylmethylamino)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (152d) (39 mg, 16% yield) as a white solid; ¹ H NMR (300 MHz, DMSO^) δ 10.76 (s, 1H, exchange with D2O), 7.87 (t, J=1.7 Hz, 1H), 7.74 (dt, J=7, 8, 1.5 Hz, 1H), 7.67 (ddd, J=7.9, 3.6, 2.2 Hz, 4H), 7.61 - 7.43 (m, 5H), 7.32 - 7.18 (m, 2H), 4.91 (s, 1H), 4.04 (s, 2H), 2.26 (dt, J=9.4, 4.8 Hz, 2H), 1, 02 - 0.83 (m, 1H), 0.44 - 0.33 (m, 2H), 0.05 (tt, J=5.8, 3.2 Hz, 2H); 1H NMR (300 MHz, DMSO-d6, D2O) δ 7.86 (t, J=1.7 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.70 - 7.62 ( m, 3H), 7.60 7.49 (m, 5H), 7.46 (dt, J=6.3, 2.5 Hz, 1H), 7.34 - 7.19 (m, 2H), 4.92 (s, 1H), 4.02 (s, 2H), 2.34 - 2.21 (m, 2H), 0.98 - 0.84 (m, 1H), 0.44 - 0, 35 (m, 2H), 0.07 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.76; IR (KBr, cm- ¹ ): 2230 cm' ¹ (stretching vibrations -CN); MS (IER ⁺ ): MS (IER+) 545.3 (M+1), MS (IER-) 543.3 (M-1); analysis, calculation for: C30H27F3N6O-2H2O-2HC1: C, 55.14; H, 5.09; N, 12.86; experiment: C, 55.41; H, 5.30; N, 12.20.

Scheme 153

END NH4OH

H ₂ O ₂ •conh ₂

NHBoc conh ₂

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (153b ).

Step 1. Preparation of tert-butyl-3-(5-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (153a) .

Into a solution of tert-butyl-3-(5-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (52g) ( 161 mg, 0.243 mmol) in ethanol (6 ml) added conc. aqueous ammonia (2.4 ml), then hydrogen peroxide (30% aqueous solution, 0.09 ml) was added dropwise. The reaction mixture was stirred at room temperature for 21 hours and concentrated to dryness in vacuo. The residue was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(5-((4carbamoylphenyl)(cyclopropylmethylamino) methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (153a) (17 g, 10%) as a colorless viscous substance; 1H NMR (300 MHz,

DMSO-dg) δ 10.55 (s, 1H), 7.88 (s, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.66 - 7.26 (m, 9H ), 7.20 (t, J=9.6 Hz, 1H), 4.90 (s, 1H), 4.19 (d, J=6.1 Hz, 2H), 2.30-2.22 (m, 2H), 1.37 (s, 9H), 0.99-0.80 (m, 1H), 0.46 - 0.31 (m, 2H), 0.10 - 0.03 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.81, -123.53; MS (IER+): 681.4 (M+H).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (153b).

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In a solution of tert-butyl-3-(5-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (153 a) (15 mg, 0.022 mmol) in 1,4dioxane (4 ml), hydrogen chloride (0.240 ml, 0.961 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 16 hours. The reaction mixture was treated with hexanes, decanted, washed hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 1 -(3-(aminomethyl)phenyl)-N-(5-((4 -carbamoylphenyl)(cyclopropylmethylamino)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (153b). The purified product was dissolved in methanol (10 ml) and treated with 4N. HCl (aq, 0.03 mL), then concentrated to dryness to give 1-(3-(aminomethyl)phenyl)-N-(5-((4-carbamoylphenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl) hydrochloride salt. -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (153b) (19 mg) as an off-white solid; 1H NMR (300 MHz, DMSO) δ 10.81 (s, 1H), 10.26 (s, 2H), 8.43 (s, 3H), 8.04 (s, 1H), 7.95 (s , 1H), 7.94 - 7.87 (m, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.74 - 7.68 (m, 3H), 7.64 - 7.51 (m, 2H), 7.47 (s, 1H), 7.41 (dd, J=10.3, 8.6 Hz, 1H), 5.73 (t, J=6.3 Hz , 1H), 4.12 (q, J=5.9 Hz, 2H), 2.72 (d, J=8.9 Hz, 2H), 1.23 - 1.08 (m, 2H), 0 .64 - 0.46 (m, 2H), 0.41 - 0.20 (m, 1H); ¹ H NMR (D2O exchange NMR, 300 MHz, DMSO-d6) δ 7.95-7.82 (m, 3H), 7.73 - 7.48 (m, 8H), 7.43 (dd, J =10.2, 8.6 Hz, 1H), 5.70 (s, 1H), 4.12 (s, 2H), 2.78 - 2.72 (m, 2H), 1.21 0.97 (m, 1H), 0.66 - 0.54 (m, 2H), 0.33-0.24 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.81, -120.35; MS (IER+): 581.3 (M+1); analysis, calculation for C ₃₀ H ₂₈ F ₄ N ₆ O ₂ -2HCl-3H ₂ O: C, 50.93; H, 5.13; N, 11.88; experiment: C, 50.56; H, 5.23; N, 11.55.

Scheme 154

Example of preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154e) .

Step 1. Preparation of (3-aminophenyl)(4-methoxynaphthalene-1-yl)methanol (154b).

(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (13.20 mL, 13.20 mmol) at 0°C. The reaction mixture was stirred for 15 hours at temperature and quenched by slowly adding 12N. aq. HCl (2.292 ml, 27.5 mmol) and stirred for 1 hour. The reaction mixture was treated with 1N. NaOH (16.50 ml, 33.0 mmol) and extracted with ethyl acetate (2x50 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give (3-aminophenyl)(4-methoxynaphthalene-1-yl)methanol (154b) (2.818 g, 92% yield ) as a whitish solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.25-8.00 (m, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.43 (dt, J=6 ,5, 3.4 Hz, 2H), 7.01 -6.85 (m, 2H), 6.54 (dp, J=3.4, 1.4 Hz, 2H), 6.37 (ddd, J=7.9, 2.2, 1.0 Hz, 1H), 6.08 (d, J=4.4 Hz, 1H), 5.74 (d, J=4.4 Hz, 1H, exchange with D2O), 4.95 (s, 2H, exchange with _D2O ), 3.96 (s, 3H); MS (IER ⁺ ): MS (IER+) 302.2 (M+Na), MS (IER-) 278.3 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxynaphthalen-1-yl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (154c).

In a 250 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-nirazole-5carboxylic acid (9i) (3.30 g, 11.7 mmol), (3-aminophenyl)(4- methoxynaphthalin-1-yl)methanol (154b) (2.73 g, 9.77 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 5.47 g, 11.73 mmol), N,N-dimethylformamide ( 56.8 mL, 733 mmol) and N-ethyl-N-isonronylpropan-2amine (DIPEA, 8.51 mL, 48.9 mmol) under positive nitrogen flow at room temperature. Received

- 289 045731 the reaction mixture was stirred for 16 hours at room temperature under a positive nitrogen flow. The reaction mixture was treated with water (150 ml) and extracted with chloroform (2x100 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(4-methoxynaphthalene-1yl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154c) (4.274 g, 81% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H, exchange with D ₂ O), 8.21 - 8.13 (m, 2H), 8.06 (dt, J=7, 7, 2.7 Hz, 1H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.88 (ddd, J=8.2, 2.2, 1.1 Hz , 1H), 7.77 - 7.66 (m, 2H), 7.58 (dd, J=6.7, 1.4 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.26 (t, J=8.2 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.97 (d , J=8.0 Hz, 1H), 6.23 (d, J=4.3 Hz, 1H), 6.02 (d, J=4.3 Hz, 1H, exchange with D2O), 3.97 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.96; MS (IER ⁺ ): MS (IER+) 565.3 (M+Na), MS (IER-) 541.2 (M-1); IR (KBr, cm ^-1 ): 2235 cm ^-1 (stretching vibrations -CN).

Step 3. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalene-1yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154d).

In a solution of 1 -(3-cyanophenyl)-N-(3-(hydroxy(4-methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154c) (2.693 g , 4.96 mmol) in dichloromethane (40 ml) at 0°C was added thionyl chloride (1.086 ml, 14.89 mmol) and left to warm to room temperature and stirred for 3 hours. The reaction was quenched with cyclopropylmethanamine (2.98 ml, 34 .7 mmol) and stirred for 1 hour at room temperature and then concentrated to dryness in vacuo. The residue was dissolved in cyclopropylmethanamine (8.51 ml, 99 mmol) and acetonitrile (40 ml) and the reaction mixture was heated at 80°C for 16 hours. TLC analysis (CHCl ₃ /MeOH, 9/1, v/v) indicated the completion of the reaction, the reaction mixture was evaporated to dryness. The residue was purified by flash column chromatography (first column: silica gel, 40 g, second column: 80 g, eluted with mixtures of methanol in chloroform, 050%) to give 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino) (4-methoxynaphthalene-1yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154d) (1.64 g, 55% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H, exchange with D2O), 8.24 - 8.12 (m, 3H), 7.99 (dt, J=7.7, 1.3 Hz, 1H), 7.93 - 7.84 (m, 1H), 7.78 - 7.41 (m, 8H), 7.26 (q, J=3.7, 2.5 Hz , 2H), 6.98 (d, J=8.2 Hz, 1H), 5.52 (s, 1H), 3.95 (s, 3H), 2.39 (d, J=6.6 Hz , 2H), 1.08 -0.89 (m, 1H), 0.38 (dd, J=7.6, 6.0 Hz, 2H), 0.06 (td, J=4.5, 3 ,8, 2.5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.94; MS (IER ⁺ ): MS (IER+) 596.3 (M+1), MS (IER-) 594.3 (M-1); IR (KBr, cm ^-1 ): 2234 cm ^-1 (stretching vibrations -CN).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalene-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (154e).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154d) (1.51 g, 2.54 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.301 g, 1.268 mmol) was added, then sodium borohydride (0.767 g, 20 .28 mmol) for 5 min. The interaction occurred with the release of heat and gas. The reaction mixture was stirred for 15 min at 0°C, after which N1-(2-αminoethyl)ethαn-1,2-diαamine (2.74 ml, 25.4 mmol) was added. The mixture was left to stir for another 30 minutes, after which the solvent was evaporated. The residue was treated with water (30 ml) and extracted with chloroform (2x30 ml), then ethyl acetate (2x30 ml), the combined organic layers were dried over anhydrous MgSO4 and filtered, excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with CMA 80/chloroform, 0 to 100%)] to give 430 mg of 1-(3(aminomethyl)phenyl)-N-(3-( (cyclopropylmethylamino)(4-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154e) in the form of a yellow oily liquid, which was placed and dissolved in methanol, into the resulting solution according to 2N was added to the drops. HCl (1.901 ml, 3.80 mmol), stirred for 30 min, evaporated to dryness to give 1-(3(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(4-methoxynaphthalen-1-yl) hydrochloride methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (154e) (483 mg, 32% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.23 (s, 1H, exchange with D2O), 10.02 (s, 1H, exchange with D2O), 8.53 ( s, 3H, exchange with D2O), 8.29 - 8.10 (m, 3H,), 7.86 (t, J=1.8 Hz, 1H), 7.77 - 7.35 (m, 11H ), 7.13 (d, J=8.2 Hz, 1H), 6.45- 6.19 (m, 1H), 4.11 (q, J=6.2 Hz, 2H), 4.01 (s, 3H), 3.01 -2.72 (m, 2H), 1.19 (ddt, J=10.6, 7.4, 3.5 Hz, 1H), 0.55 (dd, J =8.0, 3.7 Hz, 2H), 0.41 - 0.16 (m, 2H); 1H NMR (300 MHz, DMSO-d6, D2O) δ 10.93 (s, 1H), 8.30 8.22 (m, 1H), 8.19 - 8.11 (m, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.61 7.56 (m , 4H), 7.54 (s, 1H), 7.51 - 7.42 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 6.31 (s, 1H) , 4.12 (s, 2H), 4.02 (s, 3H), 3.07 - 2.73 (m, 2H), 1.14 (tt, J=8.6, 4.7 Hz, 1H ), 0.71 - 0.47 (m, 2H), 0.42 - 0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.77; MC (IER ⁺ ): MS (IER+) 600.3 (M+1), MC (IER-) 598.3 (M-1); analysis, calculation for: C34H ₃₂ F ₃ N ₅ O ₂ -2.5HCl-1.75H ₂ O-0.17CHCl ₃ : C, 55.26; H, 5.18; Cl, 14.37; N, 9.43; experiment: C, 55.33; H, 5.04; Cl, 14.59; N, 9.28.

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Scheme 155

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 -carboxamide (155c).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (155a).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (3.42 g, 12.16 mmol), 3-((3-amino- 4-fluorophenyl)-(hydroxy)methyl)benzonitrile (54b) (1.964 g, 8.11 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrtOP, 4.54 g, 9.73 mmol), N,N- added sequentially dimethylformamide (47 ml) and N-ethyl-N-isopropylpropan-2-amine (7.06 ml, 40.5 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The rest was processed for us. NH ₄ Cl (30 ml) and extracted with ethyl acetate (2x50 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with 0-100% methanol/chloroform mixtures] to give 1-(3-cyanophenyl)-N-(5((3-cyanophenyl)(hydroxy)methyl) -2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (155a) (1.479 g, 2.93 mmol, 36.1% yield) as a white solid; MS (IER ⁺ ): MS (IER+) 265.2 (M+Na), MS (IER-) 504.2 (M-1).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (155b).

In a solution of 1-(3-cyanophenyl)-N-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (155a) (1.003 g, 1.984 mmol) in dichloromethane (20 ml) at 0°C was added thionyl chloride (0.434 ml, 5.95 mmol), the reaction mixture was left to warm to room temperature and stirred for 3 hours. The reaction was quenched with cyclopropylmethanamine (1.205 ml, 13, 89 mmol) and stirred the solution for 30 min at room temperature and concentrated to dryness in vacuo. The residue was dissolved in acetonitrile (20 ml), cyclopropylmethanamine (1.205 ml, 13.89 mmol) was added, stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and the resulting residue was purified by flash column chromatography (silica gel , 40 g, eluted with mixtures of methanol in chloroform, 0-100%) to give 1(3-cyanophenyl)-H-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl )1H-pyrazole-5-carboxamide (155b) (376 mg, 34% yield) as a yellow solid; ¹ H NMR (300 MHz, DMSOL) δ 10.54 (s, 1H, exchange with D ₂ O), 8.16 - 8.09 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.79 - 7.64 (m, 4H), 7.62 - 7.55 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.36 (ddd, J=7.4, 4.8, 2.2 Hz, 1H), 7.23 (dd, J=10.3, 8 .5 Hz, 1H), 4.94 (d, J=3.2 Hz, 1H), 2.72 (d, J=4.8 Hz, 1H, exchange with D ₂ O), 2.25 (t , J=6.0 Hz, 2H), 1.01 0.82 (m, 1H), 0.44 - 0.31 (m, 2H), 0.05 (td, J=5.1, 1, 6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.97, 122.76; MS (IER ⁺ ): MS (IER+) 559.3 (M+1), MS (IER-) 557.2 (M-1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-((3-(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole -5-carboxamide (155c).

Into a stirred solution of 1-(3-cyanophenyl)-C-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (155b) ( 351 mg, 0.628 mmol) in anhydrous methanol (10 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.149 g, 0.628 mmol) was added, then sodium borohydride (0.380 g, 10.05 mmol) was added in small portions for 5 minutes The reaction mixture was stirred for 15 min at 0°C, quenched with H1-(2-aminoethyl)ethane-1,2-diamine (1.358

- 291 045731 ml, 12.57 mmol), stirred for another 30 minutes and concentrated in vacuo. The residue was treated with water (30 ml) and extracted with chloroform (2x30 ml), then ethyl acetate (2x30 ml), the combined organic layers were dried over anhydrous MgSO ₄ and filtered, excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 100% CMA 80/chloroform)] to give the free base 1-(3(aminomethyl)phenyl)-N-(5-((3 -(aminomethyl)phenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (155c) (83 mg) as a waxy solid, which was dissolved in methanol and added 2N. HCl (0.566 mL, 1.131 mmol, 7.5 eq.), stirred for 30 min, evaporated to dryness to give 1-(3-(aminomethyl)phenyl)-N-(5((3-(aminomethyl)phenyl) hydrochloride salt )(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (155c) (78 mg, 22% yield) as a white solid; 1H NMR (300 MHz, DMSOd6) δ 10.90 (s, 1H, exchange with D2O), 10.21 (s, 2H, exchange with D2O), 8.46 (s, 7H, exchange with D2O), 8, 02 - 7.91 (m, 1H), 7.87 - 7.68 (m, 5H), 7.67 - 7.46 (m, 5H), 7.40 (dd, J=10.3, 8 .6 Hz, 1H), 5.73 - 5.51 (m, 1H), 4.12 (d, J=5.8 Hz, 2H), 4.00 (d, J=5.7 Hz, 2H ), 2.71 (d, J=7.6 Hz, 2H), 1.16 (s, 1H), 0.67 - 0.44 (m, 2H), 0.40 - 0.22 (m, 2H); ¹ H NMR (300 MHz, DMSO-d6, D2O) δ 7.90 (d, J=6.8 Hz, 1H), 7.76 - 7.48 (m, 10H), 7.47 - 7.37 (m, 1H), 5.63 (s, 1H), 4.12 (s, 2H), 4.03 (s, 2H), 2.74 (d, J=7.5 Hz, 2H), 1 .10 (s, 1H), 0.58 (d, J=7.6 Hz, 2H), 0.41 - 0.23 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.59, -119.65. MS (IER ⁺ ): MS (IER+) 567.3 (M+1), MS (IER-) 565.3 (M-1), 601.3 (M+Cl); analysis, calculation for C30H30F4N6O4.25H2O-3.05HCl: C, 47.76; H, 5.55; Cl, 14.33; N, 11.14; experiment: C, 47.58; H, 5.16; Cl, 14.65; N, 10.96.

Scheme 156

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3 -yl)propyl)phenyl)-3 -(trifluoromethyl)-1 H- pyrazole-5-carboxamide (156c).

Step 1. Preparation of 3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)aniline (156a).

Thionyl chloride ( 1.039 ml, 14.23 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature and quenched with methanol (2.88 mL, 71.2 mmol) and triethylamine (4.96 mL, 35.6 mmol). The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The crude residue was purified twice by flash column chromatography [silica gel, 40 g, eluted with mixtures of methanol in chloroform (0 to 10% to 100%)] to give 3-(3-cyclopropyl-1-methoxy-1-(pyridin-3yl )propyl)aniline (156a) (491 mg, yield 48.9%). MS (ESI+): 283.3 (M+H), and (E)-3-(3-cyclopropyl-1(pyridin-3-yl)prop-1-enyl)aniline (250 mg, 0.999 mmol, yield 28.1%). MS (IER+): 251.2 (M+H).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1 N-pyrazole -5-carboxamide (15 6b).

3-(3- cyclopropyl-1-methoxy-1-(pyridin-3yl)propyl)aniline (156a) (0.48 g, 1.700 mmol), N-ethyl-N-isopropylpropan-2-αmin (1.480 ml, 8.50 mmol) and Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.792 g, 1.700 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x200 ml). Combine the organic layers, wash with water (2x100 ml), brine (50 ml), dry, filter and evaporate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of CMA 80 in chloroform) to give 1-(3cyanophenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3-yl) propyl)phenyl)-3-(trifluoromethyl)-1 Hpyrazole-5-carboxamide (156b) (332 mg, 36%); MS (IER+) 546.3 (M+1).

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Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (156c).

Into a stirred solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (156b) (0.295 g, 0.541 mmol) Nickel (II) chloride (0.088 g, 0.676 mmol) was added in methanol (20 ml) at 0°C. Sodium tetrahydroborate (0.205 g, 5.41 mmol) was added to the resulting mixture in small portions over 15 minutes. The reaction mixture was stirred for 30 minutes and quenched by adding N1-(2-aminoethyl)ethane-1,2-diamine (0.449 ml, 4.33 mmol) and stirred for another 30 minutes at room temperature. The reaction mixture was concentrated to remove methanol. The reaction mixture was diluted with water (50 ml) and stirred for 12 hours. The isolated solid was collected by filtration. The solid was suspended in ethanol (100 ml) and concentrated to remove water. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform) to give the free base 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1 -(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (156c) (89 mg, 0.162 mmol, 29.9% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H, exchange with D2O), 8.52 (d, J=2.2 Hz, 1H), 8.41 (dd, J=4 ,7, 1.6 Hz, 1H), 7.72 - 7.56 (m, 4H), 7.51 (s, 1H), 7.42 (d, J=6.6 Hz, 2H), 7 .37 - 7.24 (m, 3H), 7.09 (d, J=8.0 Hz, 1H), 3.77 (s, 2H), 3.01 (s, 3H), 2.46 - 2.40 (m, 2H), 1.99 (s, 2H, exchange with D2O), 0.92 (h, J=8.1 Hz, 2H), 0.66 (t, J=7.0 Hz , 1H), 0.35 (dt, J=8.2, 3.0 Hz, 2H), -0.02 - -0.21 (m, 2H); mass spectrum (ESI+) 550.4; (IER-) 548.3(M-1), 584.3 (M+35); analysis, calculation for C ₃₀ H ₃₀ F ₃ N ₅ O-2(H ₂ O) ₀₅ : C, 64.48; H, 5;51,N, 12.54; experiment: C, 64.79; H, 5.51; N, 12.27.

Free base 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-methoxy-1-(pyridin-3yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (156c) (50 mg), suspended in hydrogen chloride (3M solution in isopropanol, 2 ml, 6.00 mmol), stirred for 30 min and concentrated to dryness in vacuo to give 1-(3-(aminomethyl) hydrochloride salt phenyl)-N-(3-(3cyclopropyl-1-methoxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (156c) as a white solid . 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 8.71 (s, 1H), 8.67 (d, J=5.4 Hz, 1H), 8.39 ( s, 3H, exchange with D2O), 8.11 (d, J=7.9 Hz, 1H), 7.79 - 7.47 (m, 9H), 7.32 (t, J=7.9 Hz , 1H), 7.13 (d, J=7.8 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 3.04 (s, 3H), 2.44 (dt , J=3.9, 2.3 Hz, 2H), 1.00 - 0.75 (m, 2H), 0.67 (s, 1H), 0.46 - 0.29 (m, 2H), -0.07 (q, J=3.7, 3.1 Hz, 2H); analysis, calculation for C ₃₀ H ₃₀ F ₃ N ₅ O ₂ -2.25HCl-2H2O-0.5C ₃ H ₈ O: C, 54.29; H, 5.82; N, 10.05; Cl, 11.30; experiment: C, 54.73; H, 5.65; N, 10.00; Cl, 11.48.

Scheme 157

An example of the preparation of 1-(4-chlorophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (157a).

In a 50 mL one-neck flask containing 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (12c) (0.291 g, 1.001 mmol), 1-(3-amino-4-fluorophenyl)- 3-cyclopropyl-1-(pyridin-2yl)propan-1-ol (59a) (0.344 g, 1.202 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (0.560 g, 1.202 mmol), N,N- dimethylformamide (10 ml) and N-ethyl-Nisopropylpropan-2-amine (0.872 ml, 5.01 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml). The aqueous layer was extracted with ethyl acetate (2x50 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1(4-chlorophenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridine- 2-yl)propyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (157a) (436 mg, 78% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H, exchange with D2O), 8.49 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7, 78 7.68 (m, 2H), 7.67 - 7.53 (m, 6H), 7.41 (ddd, J=8.7, 4.8, 2.3 Hz, 1H), 7.24 - 7.11 (m, 2H), 5.83 (s, 1H, exchange with D2O), 2.46 - 2.27 (m, 2H), 1.03 (ddt, J=18.2, 12, 4, 7.1 Hz, 2H), 0.57 (d, J=12.5 Hz, 1H), 0.42 - 0.20 (m, 2H), 0.04 - -0.18 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.88, -124.19; MS (IER ⁺ ): MS (IER+) 559.2 (M+1), MS (IER-) 557.3 (M-1).

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Scheme 158

An example of the preparation of 1-(6-chloronaphthalene-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (158a).

In a 50 mL one-neck flask containing 1-(6-chloronaphthalene-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (14d) (0.200 g, 0.587 mmol), 1-(3-amino-4 -fluorophenyl)-3-cyclopropyl-1-(pyridin2-yl)propan-1-ol (59a) (0.202 g, 0.704 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (0.328 g, 0.704 mmol), were added sequentially N,N-dimethylformamide (6 ml) and N-ethyl-Nisopropylpropan-2-amine (0.511 ml, 2.94 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The aqueous layer was again extracted with ethyl acetate (2x30 ml). Combine the organic layers, wash with water (30 ml), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The residue was purified by flash column chromatography [silica gel, 25 g, eluted with mixtures of ethyl acetate in hexanes, 0100%] to give 1 -(6-chloronaphthalene-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy- 1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (158a) (0.235 g, 0.386 mmol, 65.7% yield) as a yellow solid substances; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H, exchange with D2O), 8.48 (d, J=4.7 Hz, 1H), 8.18 (s, 2H), 8.06 (t, J=10.0 Hz, 2H), 7.67 (dq, J=17.8, 8.7 Hz, 6H), 7.39 (s, 1H), 7.26 7, 08 (m, 2H), 5.81 (s, 1H, exchange with D2O), 2.44 - 2.27 (m, 2H), 1.00 (s, 2H), 0.57 (s, 1H) , 0.30 (d, J=7.7 Hz, 2H), -0.13 (d, J=4.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.67, -123.96; Ή NMR (300 MHz, DMSO-d ₆ ) D2O δ 8.48 (dt, J=4.7, 1.4 Hz, 1H), 8.18 (t, J=2.0 Hz, 2H), 8 .07 (t, J=8.9 Hz, 2H), 7.80 - 7.56 (m, 6H), 7.40 (ddd, J=8.8, 4.8, 2.4 Hz, 1H ), 7.27 - 7.10 (m, 2H), 2.45 - 2.28 (m, 2H), 0.98 (ddt, J=19.9, 14.0, 7.2 Hz, 2H ), 0.57 (q, J=6.8, 6.2 Hz, 1H), 0.38 - 0.24 (m, 2H), -0.13 (h, J=3.6 Hz, 2H ); MS (IER ⁺ ): MS (IER+) 609.3 (M+), 632.2 (M+Na), MS (IER-) 608.1 (M-1).

Scheme 159

An example of the preparation of 1-(5-chloropyridin-2-yl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (159a).

In a 50 mL one-neck flask containing 1-(5-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (13d) (7 mg, 0.024 mmol), 1-(3-amino-4 -fluorophenyl)-3-cyclopropyl-1-(pyridin-2yl)propan-1-ol (59a) (10.31 mg, 0.036 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP) (0.013 g, 0.029 mmol), N,N-dimethylformamide (0.232 mL) and N-ethylN-isopropylpropan-2-amine (0.021 mL, 0.120 mmol) were added sequentially under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with water (25 ml). The aqueous layer was extracted with ethyl acetate (2x25 ml). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 4 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 1-(5-chloropyridin-2-yl)-N-(5-(3-cyclopropyl-1- hydroxy-1(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (159a) (5 mg, 37% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H, exchange with D2O), 8.70 (d, J=2.5 Hz, 1H), 8.51 (dt, J=4 ,9, 1.4 Hz, 1H), 8.34 (dd, J=8.8, 2.6 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.81 7.72 (m, 2H), 7.70 - 7.64 (m, 2H), 7.44 (ddd, J=8.7, 4.7, 2.3 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.86 (s, 1H, exchange with D2O), 2.45-2.34 (m, 2H), 1.11 - 1.01 (m, 2H), 0. 61 (td, J=7.5, 3.9 Hz, 1H), 0.37 - 0.31 (m, 2H), -0.08 (dt, J=4.7, 2.0 Hz, 2H ); ¹⁹ F NMR (282 MHz, DMSO^) δ -56.83, -124.52; MS (IER ⁺ ): MS (IER+) 560.2 (M+1); MS (IER-) 558.2 (M-1).

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Scheme 160

An example of the preparation of N-(5-(3-cyclopropyl-1 -hydroxy-1 -(pyridin-2-yl)propyl)-2-fluorophenyl)-1 -(4methoxyphenyl)-3-(trifluoromethyl)-III-pyrazole-5 -carboxamide (160a).

In a 50 mL one-neck flask containing 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (11c) (100 mg, 0.349 mmol), 1-(3-amino-4-fluorophenyl)- 3-cyclopropyl-1-(pyridin-2yl)propan-1-ol (59a) (0.120 g, 0.419 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP) (0.195 g, 0.419 mmol), treated sequentially with N,N- dimethylformamide (3.38 ml, 43.7 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.304 ml, 1.747 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water (30 ml). The aqueous layer was again extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [first column: silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%, second column: silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0-20%] to give N- (5-(3-cyclopropyl-1-hydroxy-1(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 160a) (31 mg, 16% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.43 (s, 1H, exchange with D2O), 8.49 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 7 .73 (td, J=7.7, 1.9 Hz, 2H), 7.63 (dt, J=8.0, 1.1 Hz, 1H), 7.55 (s, 1H), 7. 48 - 7.35 (m, 3H), 7.25 - 7.11 (m, 2H), 7.07 - 6.99 (m, 2H), 5.82 (s, 1H, exchange with D2O), 3.81 (s, 3H), 2.45-2.25 (m, 2H), 1.01 (dddd, J=25.1, 13.6, 9.9, 6.3 Hz, 2H), 0.71 - 0.50 (m, 1H), 0.39 - 0.25 (m, 2H), 0.10 (h, J=3.4 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.71, -124.38; MS (IER ⁺ ): MS (IER+) 555.3 (M+1), 577.3 (M+Na), 553.3 (M-1).

Scheme 161

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide ( 161e).

Step 1. Preparation of tert-butyl-6-amino-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161b).

Into a solution of tert-butyl-7-fluoro-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161a) (0.5 g, 1.688 mmol) (prepared as described in the literature: (a) Harling, JD ; Watson, NS; Young, RJ WO 2006/108709 A1, 19 October 2006; (b) Watson, NS; Adams, C.; Belton, D.; Brown, D.; Burns-Kurtis, CL; Chaudry, L .; Chan, C.; Convery, Maire A.; Davies, DE; Exall, AM et al., Bioorganic & Medicinal Chemistry Letters (2011), 21(6), 1588-1592) palladium was added to methanol (20 ml) on a carbon support (10%) (0.359 g, 3.38 mmol) and hydrogenated for 3 hours at 60 psi (414 kPa). The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give tert-butyl-6-amino-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161b) (0.256 g, 57% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.81 (d, J=12.0 Hz, 1H), 6.51

- 295 045731 (d, J=9.1 Hz, 1H), 4.98 (s, 2H, exchange with D ₂ O), 4.31 (s, 2H), 3.47 (t, J=5, 9 Hz, 2H), 2.59 (t, J=5.9 Hz, 2H), 1.41 (s,

9H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -137.71; MS (IER ⁺ ): MS (IER+) 289.2 (M+Na), 555.4 (2M+Na), MS (IER-) 265.1 (M-1); analysis, calculation for C ₁₄ H ₁₉ FN ₂ O ₂ : C, 63.14; H, 7.19; N, 10.52; experiment: C, 63.41; H,

7.27; N, 10.43.

Step 2. Preparation of tert-butyl-6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)- carboxylate (161c).

To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (0.250 g, 0.889 mmol) in N,N-dimethylformamide (6 ml) was added tert-butyl-6 -amino-7-fluoro-3,4dihydroisoquinoline-2(1H)-carboxylate (161b) (0.237 g, 0.889 mmol), N-ethyl-N-isopropylpropan-2-amine (1.239 ml, 7.11 mmol) and hexafluorophosphate bromo-tris-pyrrolidinophosphonium (PyBroP) (0.456 g, 0.978 mmol) at room temperature. The resulting reaction mixture was stirred at 20°C for 16 hours. The reaction was quenched with water (25 ml) and the mixture was extracted with ethyl acetate (50 ml, 20 ml, 20 ml). The organic layers were combined, washed with water (25 ml), brine (25 ml), dried over MgSO ₄ , filtered, concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of hexanes in ethyl acetate, 0-100%) to give tert-butyl-6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161c) (235 mg, 50% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H, exchange with D ₂ O), 8.12 (t, J=1.9 Hz, 1H), 8.00 (dt, J= 7.7, 1.3 Hz, 1H), 7.957.85 (m, 1H), 7.80 - 7.68 (m, 2H), 7.35 (d, J=7.7 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 4.48 (s, 2H), 3.53 (t, J=5.9 Hz, 2H), 2.72 (t, J=5 .8 Hz, 2H), 1.42 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d^ δ -59.40 --62.27 (m), -125.03; MS (ESI-): 527.7 (M-1).

Step 3. Preparation of tert-butyl-6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-7-fluoro-3,4 -dihydroisoquinoline-2(1H)-carboxylate (161d).

Into a stirred solution of tert-butyl 6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161c) (0.223 g, 0.421 mmol) in anhydrous methanol (10 ml), cooled to 0°C, added di-tert-butyl dicarbonate [Boc anhydride] (0.184 g, 0.842 mmol), nickel (II) chloride hexahydrate (0.020 g, 0.084 mmol), then sodium borohydride (0.159 g, 4.21 mmol) was added in small portions over 5 min. The reaction mixture was stirred for 15 min at room temperature, quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.091 mL, 0.842 mmol), stirred for 30 min and concentrated to dryness in vacuo. The residue was treated with ethyl acetate (25 ml), washed with water (25 ml), brine (25 ml), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-20% ethyl acetate in hexanes) to give tert-butyl-6-(1-(3-((tertbutoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (161d) (98 mg, 37% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H, exchange with D ₂ O), 7.58 (s, 1H), 7.49 (dd, J=14.5, 7.5 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.35 (t, J=6.2 Hz, 2H), 7.17 (d, J=11.1 Hz, 1H), 4.47 (s, 2H), 4.19 (d, J=6.4 Hz, 2H), 3.52 (t, J=5.8 Hz, 2H), 2.72 (t, J=5.6 Hz, 2H), 1.41 (s, 9H), 1.38 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, 125.28; MS (IER ⁺ ): MS (IER+) 656.3 (M+Na), MS (IER-) 632.4 (M-1). Analysis, calculation for: C31H ₃₅ F ₄ N ₅ O ₅ : C, 58.76; H, 5.57; N, 11.05; experiment: C, 58.65; H, 5.86; N, 10.69.

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (161e).

Into a solution of tert-butyl-6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamido)-7-fluoro-3,4-dihydroisoquinoline-2( 1H)-carboxylate (161d) (0.086 g, 0.136 mmol) in dioxane (4 ml), hydrogen chloride (4M in dioxane, 1.9 ml, 7.60 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture was diluted hexanes, filtered, dried in vacuum to obtain 1-(3-(aminomethyl)phenyl)-N-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (161e) (28 mg, 48% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO-di) δ 10.75 (s, 1H, exchange with _D2O ), 9.64 (s, 2H, exchange with _D2O ), 8.47 (s, 3H, exchange with D2O), 7.72 (s, 2H), 7.67 - 7.61 (m, 2H), 7.56 (s, 1H), 7.52 (m, 1H), 7.50 - 7, 43 (m, 1H), 7.23 (d, J=11.0 Hz, 1H), 4.22 (s, 2H), 4.12 (s, 2H), 3.35 (m, 2H), 2.97 (m, 2H); 1H NMR (300 MHz, DMSO-d6 D2O) δ 7.71 (s, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.58 - 7.45 (m, 3H ), 7.23 (d, J=11.0 Hz, 1H), 4.25 (s, 2H), 4.12 (s, 2H), 3.39 - 3.31 (m, 2H), 2 .98 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.82, -124.02; MS (IER ⁺ ): MS (IER+) 434 (M+1), (IER-) 431.8 (M-1); analysis, calculation for C ₂ 1H19F ₄ N ₅ O-2.25HCl-3H ₂ O: C, 44.29; H, 4.82; N, 12.30; experiment: C, 44.29; H, 4.82; N, 12.30.

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Scheme 162

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 162c).

Step 1. Preparation of tert-butyl-6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4- Dihydroisoquinoline-2(1H)-carboxylate (162b).

To a solution of 1 -(3 -((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 carboxylic acid (10d) (58.0 mg, 0.151 mmol) in DMF (1.4 ml) tert-butyl-6-amino-5-fluoro3,4-dihydroisoquinoline-2(1H)-carboxylate (162a) (40 mg, 0.150 mmol) was added (prepared according to the method described in the literature: (a) Watson, Nigel S. et al; Bioorganic & Medicinal Chemistry Letters, 21(6), 15881592; 2011 (b) Preparation of 3-sulfonylaminopyrrolidin-2-ones as factor Xa inhibitors. Harling, John David et al; WO 2006/108709, October 19 2006), N-ethyl-N-isopropylpropan-2-amine (0.210 ml, 1.206 mmol) and bromo-tripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (72.0 mg, 0.151 mmol) and stirred at room temperature for 14 h. The reaction mixture was diluted with ethyl acetate (75 ml), washed with water (2x30 ml), brine (30 ml) and dried over MgSO ₄ , then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 4 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-6-(1-(3-((tert-butoxycarbonylamino)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (162b) (49 mg, 52%) as a colorless film; 1H NMR (300 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.53 - 7.33 (m, 5H), 7, 16 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 4.53 (s, 2H), 4.37 (d, J=6.1 Hz, 2H), 3, 63 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 1.48 (s, 9H), 1.43 (s, 9H); MS (IER+): 655.9 (M+23).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3(trifluoromethyl)-1H-pyrazol-5-carboxamide ( 162c).

Into a solution of tert-butyl-6-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2( 1H)-carboxylate (162b) (48 mg, 0.076 mmol) in 1,4-dioxane (5 ml) was added hydrogen chloride (1.100 ml, 4.40 mmol, 4 M in 1,4-dioxane) and stirred at room temperature for 17 hours. The reaction mixture was treated with hexanes, filtered, and washed with hexanes. The insoluble crude product was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give 1-(3-(aminomethyl)phenyl)-N-(5-fluoro- 1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (27.5 mg, 84%) as a white solid; 1H NMR (300 MHz, methanol-d ₄ ) δ 7.58 7.28 (m, 6H), 6.88 (d, J=8.3 Hz, 1H), 3.93 - 3.89 (m, 2H), 3.85 (s, 2H), 3.06 (t, J=6.1 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H); ¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ -63.69, -130.74; MS (IER+): 434.08 (M+H).

Scheme 163

- 297 045731

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (163g ).

Step 1. Preparation of 6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (163b).

In a cooled solution of potassium salt of peroxonitric acid (4.50 g, 44.5 mmol) in conc. 6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (163a) (prepared according to the literature method: Kurouchi, H.; Kawamoto, K.; Sugimoto, H.; Nakamura) was added dropwise to sulfuric acid (22 ml) , S. Otani, Y.; Ohwada, T. Journal of Organic Chemistry (2012), 77(20), 9313-9328) (5.45 g, 33.0 mmol) for ten minutes. The reaction mixture was stirred for 17 hours at room temperature, then the solution was poured into a mixture of 104 g of ice and 120 ml of water. The precipitate was collected by filtration, washed with cold water (300 ml) and dried under reduced pressure over P2O5 to give 6-fluoro-7-nitro-3,4-dihydroisoquinolin1(2H)-one (163b) (6.42 g, yield 93 %) as a colorless solid; 1H NMR (300 MHz, DMSOd6) δ 8.47 (d, J=7.9 Hz, 1H), 8.33 (s, 1H), 7.64 (d, J=11.8 Hz, 1H), 3.43 (td, J=6.6, 2.9 Hz, 2H), 3.04 (t, J=6.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -114.89; MS (IER ⁺ ): MS (IER+) 211.1 (M+1), 233.1 (M+Na), 443.3 (2M+Na), MS (IER-) 209.1 (M-1 ). Analysis, calculation for C ₉ H ₇ FN ₂ O ₃ : C, 51.43; H, 3.36; N, 13.33; experiment: C, 51.27; H, 3.27; N, 13,14.

Step 2. Preparation of 7-amino-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (163c).

Carbon-supported palladium (10% ) (0.471 g, 4.43 mmol) and hydrogenated at 60 psi (414 kPa) for 3 hours. Remove the catalyst by filtration through Celite and concentrate the filtrate in vacuo. The residue was purified by flash column chromatography [silica gel, 40 g, eluted with ethyl acetate/methanol (9:1) in hexanes, 0-100%] to give 7-amino-6-fluoro-3,4dihydroisoquinoline-1(2H)- she (163c) (1.011 g, 63% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 7.84 - 7.65 (m, 1H), 7.30 (d, J=9.4 Hz, 1H), 6.94 (d, J=11, 6 Hz, 1H), 5.17 (s, 2H, exchange with D2O), 3.33 - 3.26 (m, 2H), 2.71 (t, J=6.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d;) δ -130.21; MS (IER ⁺ ): MS (IER+) 181.2 (M+1), 360.08 (2M+1), 383.01 (2M+1).

Step 3. Preparation of 6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-amine (163d).

A suspension of 7-amino-6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (163c) (0.8 g, 4.44 mmol) in THF (30 ml) was treated with lithium aluminum hydride (22.20 ml, 22.20 mmol) (1M in THF) at room temperature, then reflux for 15 hours. TLC analysis indicated incomplete reaction, then the mixture was cooled to room temperature and additional lithium aluminum hydride was added (22.20 ml, 22 .20 mmol) at room temperature, then refluxed for 16 hours, cooled to room temperature and very carefully treated with 20% aq. Na ₂ SO ₄ (30 ml) for 10 min at 10-15°C, then diluted with CMA50 (150 ml), filtered through Celite, washed with CMA50 (50 ml), methanol (50 ml), evaporated the filtrate to dryness. The residue was purified by flash column chromatography (40 g silica gel, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-amine (163d) (0.557 g, 3.35 mmol, 75% yield) as a white solid, which was used as such in the next step; MS (IER ⁺ ): MS (IER+) 167.3 (M+1).

Step 4. tert-Butyl-7-amino-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163e).

A solution of 6-fluoro-1,2,3,4-tetrahydroisoquinoline-7-amine (163d) (532 mg, 3.20 mmol) in dichloromethane (20 ml) and MeOH (10 ml) was treated by dropwise addition of di-tert -butyl dicarbonate (0.710 g, 3.22 mmol) and triethylamine (TEA; 0.892 ml, 6.40 mmol), then stirred at room temperature for 12 hours. Excess solvent was siphoned off, extracted with chloroform (2x75 ml), washed with water (50 ml), dried over MgSO4, then filtered and concentrated. The crude residue was purified by flash column chromatography (25 g silica gel, using ethyl acetate in hexanes, 0100%) to give tert-butyl-7-amino-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163e) (0.289 g, 1.085 mmol, 33.9% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 6.77 (d, J=12.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 4.96 (s, 2H, exchange with D2O), 4.31 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.59 (t, J=5.9 Hz, 2H), 1, 41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.46; analysis, calculation for C ₁₄ H ₁₉ FN ₂ O ₂ : C, 63.14; H, 7.19; N, 10.52; experiment: C, 63.13; H, 7.23; N, 10.47.

Step 5. Preparation of tert-butyl-7-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-6-fluoro-3,4 -dihydroisoquinoline-2(1H)-carboxylate (163f).

A solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (150 mg, 0.389 mmol) in N,N-dimethylformamide (2.5 ml) added tert-butyl-7-amino-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163e) (104 mg, 0.389 mmol), N-ethylN-isopropylpropan-2-amine (0.542 ml, 3 .11 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP) (0.218 g, 0.467 mmol) at room temperature. The resulting reaction mixture was stirred at 25°C for 16 hours. Excess DMF was completely removed under reduced pressure, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (50 ml, 25 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with hexanes in ethyl acetate/hexanes, 0-100%) to give tert-butyl-7-(1-(3-((tert-butoxycarbonylamino) methyl)phenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (163f) (116 mg, 47% yield) as a white solid substances; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 7.58 (s, 1H), 7.42 (m, 6H), 7.12 (d, J=11.0 Hz, 1H), 4.45 (s, 2H), 4.19 (s, 2H), 3.52 (t, J=5.9 Hz, 2H), 2.75 (t, J=6.0 Hz, 2H), 1.42 (s, 9H), 1.37 (s, 9H); MS (IER ⁺ ): MS (IER+) 656.0 (M+Na), (IER-) 631.7 (M-1); analysis, calculation for C ₃₁ H ₃₅ F ₄ N ₅ O ₅ : C, 58.76; H, 5.57; N, 11.05; experiment: C, 58.65; H, 5.65; N, 10.75.

Step 6. Preparation of 1-(3-(aminomethyl)phenyl)-N-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 163g).

Into a solution of tert-butyl-7-(1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-6-fluoro-3,4-dihydroisoquinoline- 2(1H)-carboxylate (163f) (95 mg, 0.150 mmol) in dioxane (4 ml), hydrogen chloride (4 M in dioxane) (2.099 ml, 8.40 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture diluted with hexanes, filtered, dried in vacuum to obtain 1-(3-(aminomethyl)phenyl)-N-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3(trifluoromethyl)-1H- pyrazole-5-carboxamide (163g) (46 mg, 71% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.75 (s, 1H, exchange with D2O), 9.61 (s, 2H, exchange with D2O), 8.48 (s, 2H, exchange with _D2 O), 7.72 (s, 2H), 7.67 - 7.43 (m, 4H), 7.21 (d, J=11.0 Hz, 1H), 4.20 (s, 2H), 4.16 - 4.07 (m, 2H), 3.33 (d, J=6.0 Hz, 2H), 3.00 (d, J=6.3 Hz, 2H); 1H NMR (300 MHz, DMSO-d6-O ₂ O) δ 7.71 (s, 1H), 7.67 (s, 1H), 7.64 - 7.44 (m, 4H), 7.23 ( d, J=11.0 Hz, 1H), 4.22 (s, 2H), 4.12 (s, 2H), 3.36 (t, J=6.1 Hz, 2H), 3.00 ( t, J=6.3 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81, -123.09; MS (IER ⁺ ): MS (IER+) 434.0 (M+1), (IER-) 431.7 (M-1); analysis, calculation for SDNts^O^NSM^HgO: C, 47.69; H, 4.48; Cl, 13.41; N, 13.24; experiment: C, 47.39; H, 4.23; Cl, 13.78; N, 13.84.

Scheme 164

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6yl)-3 -(trifluoromethyl)-1H-pyrazol-5- carboxamide (164e).

Step 1. Preparation of tert-butyl-6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)- carboxylate (164a).

A solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (180 mg, 0.640 mmol) in DMF (6 ml) was treated with tert-butyl-6-amino-5- fluoro-3,4-dihydroisoquinoline-2(1H)carboxylate (162a) (170 mg, 0.638 mmol), N-ethyl-N-isopropyln-pronan-2-amine (0.890 ml, 5.11 mmol) and bromine hexafluorophosphate (V) -tripyrrolidin-1-ylphosphonium (PyBrOP, 306 mg, 0.643 mmol), then stirred at RT for 15 hours. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2x75 ml) and brine (75 ml) and dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 4 g, eluted with hexanes/ethyl acetate (1:0 to 2:1)] to give tert-butyl-6-(1-(3-cyanophenyl)-3(trifluoromethyl )-1H-pyrazole-5-carboxamido)-5-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (164a) (166 mg, 49%) as a yellow solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.55 (s, 1H), 8.16 - 8.10 (m, 1H), 8.02 - 7.98 (m, 1H), 7.90 (ddd, J=8.1, 2.1, 1.1 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 4.51 (s, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.73 (t, J=5 .8 Hz, 2H), 1.42 (s, 9H); MS (IER+): 552.2 (M+23).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (164b) .

Solution of tert-butyl 6-(1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamido)-5-fluoro3,4-dihydroisoquinoline-2(1H)-carboxylate (164a) (100 mg, 0.189 mmol) in 1,4-dioxane (10 ml) was treated with hydrogen chloride (2.0 ml, 8.00 mmol, 4M in 1,4-dioxane) and stirred at RT for 17 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica

- 299 045731 gel, eluted with mixtures of chloroform/CMA 80 (from 1:0 to 2:1)] to obtain 1-(3-cyanophenyl)-K-(5fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl )-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (164b) (74 mg, 91%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.48 (s, 1H), 8.14-8.10 (m, 1H), 8.00 (dt, J=7.7, 1.3 Hz , 1H), 7.93 -7.87 (m, 1H), 7.80 - 7.67 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 6.88 ( d, J=8.2 Hz, 1H), 3.82 (s, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.97, 127.51; MS (IER+): 430.2 (M+1).

Step 3. Preparation of 1-(3-cyanophenyl)-K-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3(trifluoromethyl)-1H-pyrazol-5- carboxamide (164c).

Solution of 1-(3-cyanophenyl)-C-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (164b) (35 mg, 0.082 mmol) in formic acid (0.3 ml) was treated with formaldehyde (7.00 μl, 0.094 mmol), then stirred at 70°C for 6 hours. The reaction mixture was concentrated to dryness. The residue was treated with ethanol and then concentrated again (this process was repeated two more times). The crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 4:1)] to give 1-(3cyanophenyl)-K-(5-fluoro-2-methyl-1,2,3 ,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-III-pyrazole-5carboxamide (164c) (34 mg, 94%) as a light yellow viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 8.16 - 7.68 (m, 5H), 7.29 (t, J=7.9 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 3.49 (s, 2H), 2.75 (t, 2H), 2.62 (t, 2H), 2.35 (s, 3H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.98, -126.90; MS (IER+): 444.2 (M+1).

Step 4. Preparation of tert-butyl-3-(5-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazole-1 - yl)benzylcarbamate (164d).

Into a solution of 1-(3-cyanophenyl)-K-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 164c) (30 mg, 0.068 mmol) in MeOH (2 ml), cooled in ice/water, di-tert-butyl dicarbonate (45.0 mg, 0.204 mmol), nickel (II) chloride hexahydrate (4.0 mg) was added , 0.017 mmol), then sodium borohydride (16.00 mg, 0.414 mmol) was added portionwise and stirred at RT for 1 hour. The reaction mixture was treated with K1-(2-aminoethyl)ethane-1,2-diamine (0.015 ml, 0.140 mmol), then stirred at RT for 0.5 h and concentrated to dryness. The residue was treated with chloroform (120 ml) and washed with water (60 ml). The aqueous phase was again extracted with chloroform (60 ml). The combined extracts were dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(5-fluoro-2-methyl-1,2 ,3,4-tetrahydroisoquinolin-6-ylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (164d) (13 mg, 35%) as a colorless foam; 1H NMR (300 MHz, methanol- _d4 ) δ 7.55-7.28 (m, 6H), 6.95-6.86 (m, 1H), 4.29 (s, 2H), 3.59 (s, 2H), 2.89 (dt, J=7.1, 3.6 Hz, 2H), 2.74 (t, J=5.8 Hz, 2H), 2.45 (s, 3H) , 1.42 (s, 9H); ¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ -63.71, -130.50; MS (IER+): 548.3 (M+1).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-K-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6yl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (164e).

A solution of tert-butyl-3-(5-(5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate ( 164d) (13 mg, 0.024 mmol) in 1,4-dioxane (2 ml) was treated with hydrogen chloride (0.250 ml, 1.002 mmol, 4M in 1,4-dioxane), then stirred at RT for 14 hours. The reaction mixture was treated with hexanes , decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, 4 g, eluted with chloroform/CMA 80 (1:0 to 1:2)] to give the product (3.9 mg, 37%) as a light yellow viscous substances; 1H NMR (300 MHz, methanol- _d4 ) δ 7.55-7.28 (m, 6H), 6.956.86 (m, 1H), 4.29 (s, 2H), 3.59 (s, 2H ), 2.89 (dt, J=7.1, 3.6 Hz, 2H), 2.74 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 1.42 (s, 9H); ¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ -63.71, -130.50; MS (IER+): 448.09 (M+1).

- 300 045731

Scheme 165

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (165e) .

Step 1. Preparation of (-)-(3-nitrophenyl)(phenyl)methanol (165a).

To a cooled [-40°C (acetone/dry ice)] stirred solution of (3-nitrophenyl)(phenyl)methanone (18a) (4 g, 17.60 mmol) in THF (150 ml) was added dropwise (R)- 1-Methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (4.40 ml, 4.40 mmol) and stirred at room temperature for 1 h under a positive stream of nitrogen, then borane methyl sulfide complex (17.60 mL, 35.2 mmol) was added slowly under a positive stream of nitrogen over 1 hour. The reaction mixture was stirred at -40°C for 2 hours. TLC analysis indicated completion of the reaction. The reaction was carefully quenched with 60 ml of methanol at -40°C and the mixture was stirred for 12 hours at room temperature, and then treated with silica gel to obtain a suspension under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 120 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give (-)-(3-nitrophenyl)(phenyl)methanol (165a) (3.808 g, yield 94%) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (t, J=2.0 Hz, 1H), 8.09 (ddd, J=8.2, 2.5, 1.1 Hz, 1H ), 7.86 -7.78 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.45-7.39 (m, 2H), 7.37 - 7, 29 (m, 2H), 7.28 - 7.20 (m, 1H), 6.25 (d, J=4.1 Hz, 1H), 5.88 (d, J=4.1 Hz, 1H ); MS (IER-) 457.3 (2M-1); optical rotation: [u]d=(-) 40.65 [CHCl ₃ , 1.23].

Ref. literature: For absolute stereochemistry, see Truppo, M.; Morley, K.; Pollard, D.; Devine, P.; edited by Whittall, J.; Sutton, P.; Practical Methods for Biocatalysis and Biotransformations (2010), 288-290.

Step 2. Preparation of (-)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (165b).

KHMDS (0.5M in toluene) was added to a stirred solution of (-)-(3-nitrophenyl)(phenyl)methanol (165 a) (3.8 g, 16.58 mmol) in THF (60 ml) at 0°C. (39.8 ml, 19.89 mmol), (bromomethyl)cyclopropane (6.43 ml, 66.3 mmol) and stirred at 0°C for 3 h under a positive stream of nitrogen. TLC analysis (ethyl acetate/hexanes, 2/8, v/v) indicated complete conversion. The reaction was carefully extinguished by us. NH4C1 (100 ml) and the mixture was extracted with ethyl acetate (2x100 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with 0 to 50% ethyl acetate/hexanes)] to give (-)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (165b) ( 0.224 g, yield 5%) in the form of a clear oily liquid; ^1H NMR (300 MHz, DMSO-dg) δ 8.17 (t, J=2.0 Hz, 1H), 8.05 (ddd, J=8.2, 2.4, 1.1 Hz, 1H ), 7.76 (dt, J=7.7, 1.3 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.40 - 7.17 (m, 5H) , 5.63 (s, 1H), 3.21 (d, J=6.8 Hz, 2H), 1.02 (dddd, J=10.0, 6.7, 4.0, 1.6 Hz , 1H), 0.41 (ddd, J=8.0, 3.9, 2.0 Hz, 2H), 0.10 (ddd, J=6.0, 4.7, 3.2 Hz, 2H ); optical rotation: [a] _D =(-) 28.57 [CHCl ₃ , 1.905].

Step 3. Preparation of (-)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline (165c).

Nickel chloride hexahydrate was added to a stirred solution of (-)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (165b) (0.211 g, 0.745 mmol) in anhydrous methanol (30 ml), cooled to 0°C (II) (0.089 g, 0.372 mmol), then sodium borohydride (0.169 g, 4.47 mmol) in small portions

- 301 045731 within 5 minutes. The reaction mixture was stirred for 15 min at 0°C. TLC analysis (ethyl acetate/hexanes, 2/8, v/v) indicated the reaction was complete, after which N1-(2aminoethyl)ethane-1,2-diamine (0.805 mL, 7.45 mmol) was added. The mixture was left stirring for 30 minutes, after which the solvent was evaporated. The rest was processed for us. NH ₄ Cl (25 ml) and extracted with ethyl acetate (2x25 ml). The organic layer was dried over anhydrous MgSO ₄ , filtered and excess solvents were pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give (-)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline (165c) (0.141 g, 75% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 7.23 - 7.12 (m, 4H), 7.09 - 7.00 (m, 1H), 6.78 (t, J=7.7 Hz, 1H), 6.42 (t, J=1.9 Hz, 1H), 6.34 (dt, J=7.5, 1.3 Hz, 1H), 6.25 (ddd, J=8.0 , 2.3, 1.1 Hz, 1H), 5.10 (s, 1H), 4.90 (s, 2H, exchange with D2O), 3.14 - 2.98 (m, 2H), 1, 01 - 0.80 (m, 1H), 0.40 - 0.25 (m, 2H), 0.06 --0.07 (m, 2H); MS (IER+) 254.2 (M+1), 276.2 (M+Na); optical rotation: [a] _D =(-) 5.68 [CHCl ₃ , 1.055].

Step 4. Preparation of (-)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (165d).

1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (0.210 g, 0.746 mmol), (-)-3-((cyclopropylmethoxy)(phenyl) was placed in a 100 ml one-neck flask. methyl)aniline (165c) (0.126 g, 0.497 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.278 g, 0.597 mmol), N,N-dimethylformamide (6 mL) and N-ethyl-N-isopropylpropane ^Λ were added sequentially -amine (0.433 mL, 2.487 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 12 hours under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The rest was processed for us. NH4C1 solution (30 ml) and extracted with ethyl acetate (2x50 ml), the combined organic layers were dried over anhydrous MgSO4, filtered, evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give (-)1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (165d) (0.234 g, 91% yield) as a colorless waxy solid; 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H, exchange with D2O), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7, 7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.79 - 7.69 (m, 2H), 7.67 - 7.56 (m, 2H), 7.40 - 7.19 (m, 6H), 7.14 (dt, J=7.6, 1.3 Hz, 1H), 5.45 (s, 1H ), 3.24 (d, J=6.7 Hz, 2H), 1.06 (m, 1H), 0.55-0.38 (m, 2H), 0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.97; MS (IER+): MS (IER+) 517.3 (M+1), 539.2 (M+Cl), MS (IER-) 515.2 (M-1); optical rotation: [a] _D =(-) 1.24 [CHCl ₃ , 1.285].

Step 5. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (165e).

Into a stirred solution of (-)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (165d) (0.183 g, 0.354 mmol) in anhydrous methanol (30 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.105 g, 0.443 mmol) was added, then sodium borohydride (0.107 g, 2.83 mmol) was added in small portions over 5 minutes. The reaction mixture was stirred for 10 min, TLC analysis (methanol/chloroform, 1/9, v/v) indicated complete reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.383 ml) was added , 3.54 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was processed for us. NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml), the combined organic layers were dried over MgSO4, filtered, evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with methanol/chloroform, 0 to 50%)] to give (-)-1-(3-(aminomethyl)phenyl)-N-(3-( (cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (165e) (122 mg, 66% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H, exchange with D2O), 7.63 (t, J=1.9 Hz, 1H), 7.60 - 7.50 (m , 3H), 7.47 - 7.39 (m, 2H), 7.37 - 7.20 (m, 7H), 7.13 (dt, J=7.6, 1.3 Hz, 1H), 5.44 (s, 1H), 3.79 (s, 2H), 3.23 (dd, J=6.7, 1.4 Hz, 2H), 2.73 (s, 2H, exchange with D2O) , 1.15- 0.97 (m, 1H), 0.46 (ddd, J=8.5, 3.2, 2.1 Hz, 2H), 0.15 (dt, J=4.2, 3.1 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSOd ₆ ) δ -60.72; MS (IER+): MS (IER+) 521.3 (M+1), MS (IER-) 519.3 (M-1); chiral HPLC: 59.69% ee, determined by HPLC on a Chiralpak AD-H column (eluted with isopropanol/hexanes=80:20 with 0.1% triethylamine, 0.8 ml/min, UV, 250 nm) : Rt=6.58 min (minor), Rt=5.90 min (main); optical rotation: [a] _D =(-) 2.64 [CHCl ₃ , 1.06]; analysis, calculation for C ₂₉ H ₂₇ F ₃ N ₄ O ₂ -0.5H ₂ O: C, 65.77; H, 5.33; N, 10.58; experiment: C, 65.81; H, 5.30; N, 10.70.

- 302 045731

Scheme 166

An example of the preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)3-(trifluoromethyl)-III-pyrazole-5-carboxamide (166e).

Step 1. Preparation of (+)-(3-nitrophenyl)(phenyl)methanol (166a).

Into a stirred solution of (3-nitrophenyl)(phenyl)methanone (18a) (3.95 g, 17.38 mmol) in THF (60 mL), cooled to -40°C (acetonitrile/dry ice), under positive nitrogen flow add (S)-1-methyl3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (4.35 ml, 4.35 mmol) and stir for 1 h, then slowly add borane complex -methyl sulfide (17.38 ml, 34.8 mmol) under positive nitrogen flow. The reaction mixture was stirred at -40°C for 3 hours. TLC analysis indicated completion of the reaction. The reaction was carefully quenched with 60 ml of methanol at 0°C and the mixture was stirred for 12 hours at room temperature, and then treated with silica gel to obtain a suspension under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 120 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give (+)-(3-nitrophenyl)(phenyl)methanol (166a) (3.73 g , yield 94%) in the form of a yellow oily liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.25 (t, J=2.0 Hz, 1H), 8.08 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.82 (ddt, J=7.7, 1.6, 0.8 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.37 - 7.29 (m, 2H), 7.28 - 7.20 (m, 1H), 6.25 (d, J=4.1 Hz, 1H, exchange with D ₂ O), 5.88 (d, J=4.1 Hz, 1H); optical rotation: [a] _D =(+) 45.97 [CHCl ₃ , 1.34].

Step 2. Preparation of (+)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (166b).

KHMDS (0.5 M in toluene) (19, 74 ml, 9.87 mmol), (bromomethyl)cyclopropane (3.19 ml, 32.9 mmol) and stirred at 0°C for 3 hours under a positive stream of nitrogen. TLC analysis (ethyl acetate/hexanes, 2/8, v/v) indicated complete conversion. The reaction was carefully extinguished by us. NH ₄ Cl (60 ml) and the mixture was extracted with ethyl acetate (2x60 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 40 g, eluted with ethyl acetate/hexanes, 0 to 50%)] to give (+)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (166b) ( 137 mg, yield 6%) in the form of a clear oily liquid; 1H NMR (300 MHz, chloroform-d) δ 8.27 (t, J=1.9 Hz, 1H), 8.10 (ddd, J=8.2, 2.4, 1.1 Hz, 1H) , 7.68 (ddt, J=7.8, 1.6, 0.8 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.36 (d, J=4 ,3 Hz, 4H), 7.33 - 7.28 (m, 1H), 5.48 (s, 1H), 3.33 (d, J=6.8 Hz, 2H), 1.13 (dddd , J=13.3, 6.8, 5.0, 2.6 Hz, 1H), 0.67 - 0.46 (m, 2H), 0.29 - 0.12 (m, 2H); MS (IER+) 306.2 (M+Na); optical rotation: [a] _D =(+) 36.07 [CHCl ₃ , 0.755].

Step 3. Preparation of (+)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline (166c).

Nickel chloride hexahydrate was added to a stirred solution of (+)-1-((cyclopropylmethoxy)(phenyl)methyl)-3-nitrobenzene (166b) (133 mg, 0.469 mmol) in anhydrous methanol (30 ml), cooled to 0°C (II) (0.056 g, 0.235 mmol), then sodium borohydride (0.107 g, 2.82 mmol) in small portions over 5 minutes. The reaction mixture was stirred for 23 min at 0°C. TLC analysis (ethyl acetate/hexanes, 5/95, v/v) indicated the reaction was complete, after which N1-(2aminoethyl)ethane-1,2-diamine (0.507 mL, 4.69 mmol) was added. The mixture was left to stir for 30 minutes, after

- 303 045731 whereupon the solvent was evaporated. The rest was processed for us. NH ₄ Cl (25 ml) and extracted with ethyl acetate (2x25 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and excess solvent was pumped off under reduced pressure. The residue was purified by flash column chromatography [(silica gel, 12 g, eluted with 0 to 50% ethyl acetate/hexanes)] to give (+)-3-((cyclopropylmethoxy)(phenyl)methyl)aniline (166c) (101 mg, yield 85%) as a yellow solid; ¹ H NMR (300 MHz, chloroform-d) δ 7.38 - 7.30 (m, 3H), 7.29 - 7.21 (m, 2H), 7.09 (t, J=7.7 Hz , 1H), 6.79 - 6.69 (m, 2H), 6.56 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 5.31 (s, 1H), 3.31 (dd, J=6.8, 3.1 Hz, 2H), 1.12 (ttt, J=8.0, 6.7, 4.8 Hz, 1H), 0.62 - 0, 45 (m, 2H), 0.18 (dt, J=6.0, 4.4 Hz, 2H); MS (IER+): MS (IER+) 254.2 (M+1), 276.2 (M+Na), MS (IER-) 515.2 (M-1); optical rotation: [a] _D =(+) 6.868 [CHCl ₃ , 1.19].

Step 4. Preparation of (+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (166d).

In a 100 mL one-neck flask containing 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (155 mg, 0.551 mmol), (+)-3-((cyclopropylmethoxy)(phenyl )methyl)aniline (166c) (0.093 g, 0.367 mmol), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 0.205 g, 0.441 mmol), N,N-dimethylformamide (4.26 ml) and N-ethyl-N were added sequentially -isopropylpropan-2amine (0.320 ml, 1.835 mmol) under positive nitrogen flow at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under a positive nitrogen flow. Excess DMF was pumped out under reduced pressure. The residue was treated with water (30 ml) and extracted with chloroform (2x50 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was then purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-50%] to give (+)-1-(3-cyanophenyl)-N-(3((cyclopropylmethoxy)(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (165d) (172 mg, 91% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H, exchange with D2O), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7 ,7, 1.3 Hz, 1H), 7.91 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 7.81 -7.69 (m, 2H), 7, 68 - 7.55 (m, 2H), 7.46 - 7.21 (m, 6H), 7.18 - 7.09 (m, 1H), 5.45 (s, 1H), 3.23 ( d, J=6.8 Hz, 2H), 1.12 - 0.99 (m, 1H), 0.57 - 0.40 (m, 2H), 0.15 (tdd, J=4.2, 2.6, 1.6 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.96; MS (IER+): MS (IER+) 539.3 (M+1), MS (IER-) 515.2 (M-1); optical rotation: [a]D=(+) 0.84 [СНС1з, 0.955].

Step 5. Preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (166e).

In a solution of (+)-1-(3-cyanophenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (166d) (0.151 g , 0.292 mmol) in anhydrous methanol (30 ml), cooled to 0°C, nickel(II) chloride hexahydrate (0.087 g, 0.365 mmol) was added, followed by sodium borohydride (0.088 g, 2.339 mmol) in small portions over 5 min. The reaction mixture was stirred for 10 min, TLC analysis (methanol/chloroform, 1/9, v/v) indicated complete reaction, after which N1-(2-aminoethyl)ethane-1,2-diamine (0.316 ml) was added , 2.92 mmol). Excess methanol was pumped out under reduced pressure. The reaction mixture was processed for us. NH ₄ Cl (30 ml) and the product was extracted with chloroform (2x30 ml), the combined organic layers were dried over MgSO ₄ , filtered, evaporated to dryness. The residue was purified by flash column chromatography [(silica gel, 25 g, eluted with methanol/chloroform, 0 to 50%)] to give (+)-1-(3-(αmunomethyl)phenyl)-N-(3(( cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (166e) (107 mg, 70% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H, exchange with D2O), 7.63 (t, J=1.8 Hz, 1H), 7.60 - 7.50 (m , 3H), 7.42 (d, J=6.6 Hz, 2H), 7.37 - 7.20 (m, 7H), 7.16 -7.10 (m, 1H), 5.44 ( s, 1H), 3.77 (s, 2H), 3.23 (dd, J=6.8, 1.3 Hz, 2H), 1.05 (m, 1H), 0.46 (dq, J =8.5, 3.5, 2.6 Hz, 2H), 0.19 - 0.09 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO^) δ -60.72; MS (IER+): MS (IER+) 521.3 (M+1), MS (IER-) 519.3 (M-1); chiral HPLC: 72.95% ee, determined by HPLC on a Chiralpak AD-H column (eluted with isopropanol/hexanes = 20:80 with 0.1% triethylamine, 0.8 ml/min, UV 250 nm): Rt=5.97 min (minor), Rt=6.52 min (main). Optical rotation: [a] _D =(+) 3.018 [CHCl ₃ , 1.06]; analysis, calculation for C ₂₉ H ₂₇ F ₃ N ₄ O ₂ -0.25H ₂ O: C, 66.34; H, 5.28; N, 10.67; experiment: C, 66.23; H, 5.30; N, 10.38.

- 304 045731

Scheme 167

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4yl)phenyl)-3 -( trifluoromethyl)-1H-pyrazole-5-carboxamide (167f).

Step 1. Preparation of (3-aminophenyl)(2-nitrophenyl)methanol (167b).

To a solution of 2-nitrobenzaldehyde (167a) (4.63 g, 30 mmol) in tetrahydrofuran (30 ml), cooled to 0°C, was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (36 .0 ml, 36.0 mmol) and stirred at room temperature for 12 hours. The reaction mixture was treated with 1N. HCl (aq, 75 ml), stirred at room temperature for 3 hours, neutralized with NaOH (2N, aq) to pH = ~8 and extracted with ethyl acetate (2x100 ml). The combined extracts were washed with brine (80 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 120 g, eluted with chloroform/methanol (1:0 to 19:1)] to give (3-aminophenyl)(2-nitrophenyl)methanol (167b) (3.76 g, 51%). ¹ H NMR (300 MHz, DMSO-66) δ 7.87 - 7.82 (m, 1H), 7.77 - 7.67 (m, 2H), 7.50 (ddd, J=8.0, 6.6, 2.2 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 6.46 (t, J=1.9 Hz, 1H), 6.41 (ddd, J=7.9, 2.3, 1.0 Hz, 1H), 6.36 (dt, J=7.6, 1.3 Hz, 1H), 6.05 (s, 2H), 5.04 (s, 2H); MC (IER+): 267.2 (M+Na).

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(hydroxy(2-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxαmideα (167c).

A solution of (3-aminophenyl)(2-nitrophenyl)methanol (167b) (3.6 g, 14.74 mmol) in DMF (75 ml) was treated with 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxylic acid (9i) (4.14 g, 14.74 mmol), N-ethyl-N-isopropan-2-αamine (21.00 ml, 121 mmol) and bromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (PyBrOP, 7.01 g, 14.74 mmol), then stirred at RT for 16 hours. The reaction mixture was diluted with ethyl acetate (400 ml), washed with water (2x120 ml) and brine (120 ml) and dried over MgSO4, then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 120 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-(hydroxy(2- nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (167c) (3.45 g, 46%) as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 10.66 (s, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.93-7.87 (m, 2H), 7.78 - 7.69 (m, 4H), 7.65-7.49 (m, 3H), 7.28 (t, J=7.9 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.30 (d, J=4.7 Hz, 1H), 6.18 (d, J= 4.6 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.96; MS (ESI+): 530.2 (M+Na).

Step 3. Preparation of tert-butyl-3-(5-((3-((2-tert-butyloxycarbonylaminophenyl)-(hydroxy)methyl)phenyl)carbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl )benzylcarbamate (167d).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(2-nitrophenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (167c) (3.309 g, 6.52 mmol ) in MeOH (110 ml), cooled in ice/water, di-tert-butyl dicarbonate (5.75 g, 26.1 mmol), nickel (II) chloride hexahydrate (0.834 g, 3.51 mmol) was added, then sodium borohydride (2.52 g, 65.2 mmol) was added slowly over 5 min and stirred at RT for 1 h. The reaction mixture was treated with N1-(2-aminoethyl)ethane-1,2-diamine (3.30 ml , 30.3 mmol), then stirred at RT for 0.5 h and concentrated to dryness. The residue was treated with ethyl acetate (300 ml), washed with water (120 ml). The aqueous phase was again extracted with ethyl acetate (150 ml). The combined extracts were washed with brine (150 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography [silica gel, 80 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-((3-((2-tert-butyloxycarbonylaminophenyl )(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (167d) (975 mg, 22%) as a light yellow solid; 1H NMR (300 MHz, DMSO-06) δ 10.70 (s, 1H), 8.58 (s, 1H), 7.61 (s, 1H), 7.59 - 7.18 (m, 11H) , 7.087.00 (m, 2H), 6.49 (d, J=4.0 Hz, 1H), 5.88 (d, J=3.9 Hz, 1H), 4.19 (d, J= 6.2 Hz, 2H), 1.37 (s, 9H), 1.36 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.82; MS (ESI+): 704.4 (M+Na).

Step 4. Preparation of tert-butyl-3-(5-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenylcarbamoyl)-3-( trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (167e).

Solution of tert-butyl 3-(5-((3-((2-tert-butyloxycarbonylaminophenyl)(hydroxy)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (167d) (970 mg, 1.402 mmol) in dichloromethane (28 ml) at 0°C was treated with thionyl chloride (0.220 ml, 2.97 mmol) and left to warm to room temperature for 2 hours. The reaction mixture was treated with triethylamine (1.30 ml, 9. 33 mmol), then stirred at RT for 1 hour, then treated with cyclopropylmethanamine (2.70 ml, 30.2 mmol) and concentrated to remove most of the dichloromethane, then added acetonitrile (21 ml), stirred at 70°C in for 14 h and concentrated to dryness. The residue was treated with chloroform (200 ml), washed with water (100 ml), dried over MgSO ₄ then filtered and concentrated. The crude product was purified by flash column chromatography on 25 g silica gel using hexanes/ethyl acetate (1:0 to 1:1) to give tert-butyl-3-(5-(3-(2-oxo-2,4dihydro -1H-benzo[d][1,3]oxazin-4-yl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (167e) (255 mg, 30%) as an off-white solid substances; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.83 (s, 1H), 10.35 (s, 1H), 8.12 - 7.25 (m, 10H), 7.09 (d, J =7.6 Hz, 1H), 7.04 - 6.87 (m, 3H), 6.53 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.36 (s, 9H); MS (ESI+): 630.3 (M+Na).

Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4yl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (167f).

A solution of tert-butyl-3-(5-(3-(2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenylcarbamoyl)-3(trifluoromethyl)-1H -pyrazol-1-yl)benzylcarbamate (167e) (120 mg, 0.198 mmol) in 1,4-dioxane (12 ml) was slowly treated with hydrogen chloride (2.2 ml, 8.8 mmol, 4M in 1,4-dioxane) , then stirred at RT for 14.5 hours. The reaction mixture was treated with hexanes, decanted, washed with hexanes and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 1:1)] to give the free base 1 -(3 -(aminomethyl)phenyl)-N-(3 -(2- oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (167f) (33 mg) in in the form of a colorless viscous substance. The purified product (167f) (31 mg, 33%) was dissolved in methanol (10 ml) and treated with 4N. HCl (aq, 0.06 ml), then concentrated to dryness to give 1-(3-(aminomethyl)phenyl)-N(3-(2-oxo-2,4-dihydro-1H-benzo [d ][1,3]oxazin-4-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (33 mg) as an off-white solid; 1H NMR (D2O exchange NMR, 300 MHz, DMSO-66) δ 7.73 7.49 (m, 7H), 7.42 (t, J=7.9 Hz, 1H), 7.35-7, 27 (m, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.03 (td, J=7.5, 1.2 Hz, 1H), 6.97 (d, J =8.0 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.53 (s, 1H), 4.13 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 60.80; MS (IER+): 508.2 (M+H); ICS (KBr tablet, ^cm'1 ): 3441, 3256, 1700, 1601, 1558, 1491, 1246; analysis, calculation for €26^3^03^01-2^20: C, 53.02; H, 4.45; N, 11.89; experiment: C, 53.22; H, 4.37; N, 11.33.

Scheme 168

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (168b).

- 306 045731

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)3 -(trifluoromethyl)-1H-pyrazol-5- carboxamide (168a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (144a) (1.0 g, 2.16 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.5 g, 4.33 mmol) and stir at room temperature for 3 hours. Add 2-amino-1-butanol (0.96 g, 10.81 mmol) and stirred the mixture at room temperature for 30 min. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-amino-1-butanol (0.964 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N(3-(((1-hydroxybutan-2-yl)amino )(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideα (168a) (0.42 g, 36%) as an off-white semi-solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (d, J=2.2 Hz, 1H), 8.15 (dd, J=2.1, 1.2 Hz, 1H), 7 .99 (dt, J=7.8, 1.3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.65 (d, J=14.3 Hz, 1H), 7.58 - 7.51 (m, 1H) , 7.40 (td, J=8.2, 1.4 Hz, 2H), 7.32 - 7.27 (m, 2H), 7.26 (d, J=1.5 Hz, 1H), 7.24 - 7.19 (m, 2H), 4.96 (s, 1H), 4.48 (dt, J=6.5, 5.3 Hz, 1H), 3.56 3.40 (m , 1H), 3.34 - 3.27 (m, 1H), 2.34 - 2.26 (m, 1H), 1.43 - 1.36 (m, 2H), 0.80 (dd, J =7.6, 1.7 Hz, 3H); MS (IER-) 532.8 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H- pyrazole-5-carboxamide (16 8b).

Into a solution of 1-(3-cyanophenyl)-N-(3-(((1-hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideα ( 168a) (0.42 g, 0.74 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.21 g, 0.89 mmol) was added, then added portionwise sodium borohydride (0.16 g, 4.44 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 h and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diαamine (0.19 g, 1.85 mmol), then stirred for an additional 0.5 h. Concentrated the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 65 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-(( (1-Hydroxybutan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1P-pyrazol-5-carboxamide (168b) (0.2 g, 50%) as a yellow powder. The resulting material was purified again by flash column chromatography (silica gel, 12 g, eluted with methanol/chloroform mixtures) to give 1-(3-(αminomethyl)phenyl)-N-(3-(((1hydroxybutan-2-yl)amino) (phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (168b) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.80 - 10.57 (m, 1H), 7.66 (dd, J=9.9, 2.2 Hz, 1H), 7.59 - 7 .48 (m, 3H), 7.41 (dd, J=8.4, 6.7 Hz, 4H), 7.35-7.13 (m, 6H), 4.96 (s, 1H), 3.77 (s, 2H), 3.49 3.30 (m, 2H), 2.28 (q, J=5.5 Hz, 1H), 1.40 (p, J=7.1 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.71; MS (IER+) 538-04 (M+1); (IER-) 536.4 (M-1); analysis, calculation for C29H3(^3^O2-0.5H2O: C, 63.72; H, 5.72; N, 12.81; experiment: C, 64.02; H, 5.69; N, 12 ,63.

Scheme 169

169b OH

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1 -yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (169b).

Step 1. 1-(3-Cyanophenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 169a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (144a) (1.0 g, 2.16 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Add pyrrolidine-2-307 045731 ylmethanol (1.093 g, 10.81 mmol) and stir for 30 min. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and pyrrolidin-2-ylmethanol (1.093 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((2-(hydroxymethyl)pyrrolidine-1- yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (169a) (1.0 g, 83%) as a brownish oily liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (d, J=2.1 Hz, 1H), 8.20 - 8.12 (m, 1H), 8.00 (dq, J= 7.7, 1.2 Hz, 1H), 7.90 (ddt, J=8.2, 2.3, 1.3 Hz, 1H), 7.77 - 7.62 (m, 3H), 7 .61 - 7.50 (m, 1H), 7.41 (dd, J=8.0, 6.3 Hz, 2H), 7.31 - 7.17 (m, 5H), 4.73 (d , J=6.3 Hz, 1H), 4.30 (dt, J=7.8, 5.3 Hz, 1H), 3.23 - 2.98 (m, 2H), 2.76 (ddd, J=22.8, 10.8, 5.9 Hz, 2H), 2.37 - 2.20 (m, 1H), 1.81 - 1.59 (m, 4H); MS (IER-) 544.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (169b).

Into a solution of 1-(3-cyanophenyl)-N-(3-((2-(hydroxymethyl)pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (169a ) (1.0 g, 1.834 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.547 g, 2.303 mmol) was added, then sodium borohydride (0.416 g, 11 .0 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.473 g, 4.585 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((2-(hydroxymethyl )pyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (169b) (0.25 g, 25%) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.67 (d, J=16.9 Hz, 1H), 7.62 - 7.46 (m, 4H), 7 .41 (td, J=7.4, 3.6 Hz, 3H), 7.24 (dddd, J=17.1, 10.8, 7.4, 3.2 Hz, 6H), 4.72 (d, J=5.7 Hz, 1H), 3.90 (s, 2H), 3.03 (dd, J=22.4, 9.8 Hz, 1H), 2.89 - 2.66 ( m, 2H), 2.33 -2.21 (m, 2H), 1.69 (d, J=22.5 Hz, 4H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.73, -60.74; MS (IER+) 550.4 (M+1); (IER-) 548.4 (M-1) 584.4, (M+Cl); analysis, calculation for C30H ₃₀ F ₃ N ₅ O ₂ -HCl-1.5H ₂ O: C, 58.77; H, 5.59; N, 11.42; experiment: C, 59.10; H, 5.54; N, 11.25.

Scheme 170

An example of the preparation of 1-(3-(αminomethyl)phenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1I-pyrazole-5-carboxamide ( 170b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (170a ).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (144a) (1.0 g, 2.16 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Add pyrrolidin-3-ol (0.94 g, 10.81 mmol) and stir for 30 min. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and pyrrolidin-3-ol (0.94 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 025% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (170a) (0.6 g, 52%) as a brownish

- 308 045731 oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H), 8.20 - 8.13 (m, 1H), 8.03 - 7.97 (m,

1H), 7.93 - 7.87 (m, 1H), 7.78 - 7.66 (m, 3H), 7.56 (dt, J=7.1, 2.2 Hz, 1H), 7 .46 - 7.42 (m, 1H), 7.41 (s, 1H), 7.31

- 7.23 (m, 4H), 7.17 (t, J=7.2 Hz, 1H), 4.72 (dd, J=4.1, 2.4 Hz, 1H), 4.25- 4.14 (m, 2H), 2.59 (dt, J=11.0, 6.0 Hz,

1H), 2.45- 2.15 (m, 2H), 2.03 (d, J=8.0 Hz, 1H), 1.56 (d, J=8.7 Hz, 1H), 1, 22 (d, J=1.9 Hz, 1H); MC (IER-)

530.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (170b).

Into a solution of 1-(3-cyanophenyl)-N-(3 -((3 - hydroxypyrrolidin-1 -yl)(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (170a) ( 0.6 g, 1.28 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.32 g, 1.35 mmol) was added, then sodium borohydride ( 0.25 g, 6.77 mmol) over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.29 g, 2.822 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((3- hydroxypyrrolidin-1-yl)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (170b) (0.15 g, 22%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.75-10.66 (m, 1H), 7.68 (s, 1H), 7.66 - 7.60 (m, 2H), 7.52 ( t, J=6.5 Hz, 3H), 7.49 - 7.38 (m, 3H), 7.30 - 7.21 (m, 4H), 7.19 (d, J=7.3 Hz , 1H), 6.61 (s, 2H), 4.71 (s, 1H), 4.20 (s, 2H), 4.00 (s, 2H), 2.66 -2.58 (m, 1H), 2.44 (dd, J=3.8, 1.9 Hz, 1H), 2.38 -2.17 (m, 1H), 1.98 (dd, J=13.4, 6, 8 Hz, 1H), 1.56 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.76; MC (IER+) 536.4 (M+1); (IER-) 535.1 (M-1); 570.4 (M+Cl); analysis, calculation for C29H28F ₃ N5O2-HCl-1.5H2O: C, 58.14; H, 5.38; N, 11.69; experiment: C, 58.37; H, 5.27; N, 11.82.

Scheme 171

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (171b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (171a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (144a) (1.0 g, 2.16 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Add cycloheptylamine (1.2 g, 10.81 mmol) and stir for 30 minutes. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and cycloheptylamine (1.2 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with 025% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (171a) (1.01 g, 84%) as yellow powder; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.15 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7.8, 1 ,3 Hz, 1H), 7.89 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.61 (t, J=1.7 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.40 7.34 (m, 2H), 7.32 - 7.21 (m, 3H), 7.21 - 7.13 (m, 2H), 4.89 (s, 1H), 2.48 - 2.38 (m, 1H), 1.88 - 1 .73 (m, 2H), 1.64 - 1.48 (m, 2H), 1.50 - 1.34 (m, 4H), 1.28 - 1.19 (m, 4H); MC (IER-) 556.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (171b).

In a solution of 1-(3-cyanophenyl)-N-(3-((cycloheptylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (171a) (1.0 g, 1.783 mmol) in MeOH (25 ml), cooled in ice/water, add nickel (II) chloride hexahydrate (0.532 g, 2.241 mmol), then add sodium borohydride (0.406 g, 10.758 mmol) in portions over 5 min . The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.739 g, 7.172 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((cycloheptylamino)(phenyl )methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (171b) (0.41 g, 41%) as an off-white solid. ^1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.63 - 7.54 (m, 4H), 7.55 - 7.48 (m, 1H), 7.50 - 7.39 (m, 2H), 7.42 - 7.31 (m, 3H), 7.31 - 7.23 (m, 2H), 7.25 - 7.09 (m, 2H), 4 .88 (s, 1H), 3.87 (s, 2H), 2.43 (dd, J=3.7, 1.7 Hz, 1H), 1.79 (s, 2H), 1.66 - 1.49 (m, 4H), 1.44 - 1.27 (m, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.74; MS (IER+) 562.5 (M+1); (IER-) 596.3 (M+Cl); analysis, calculation for C ₃₂ H ₃₄ F ₃ N ₅ OH ₂ O: C, 66.31; H, 6.26; N, 12.08; experiment: C, 66.47; H, 6.26; N, 11.76.

Scheme 172

FoC

_H2N

172b

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((pentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (172b).

Step 1. Preparation of 2-(3-cyanophenyl)-5-trifluoromethyl2H-pyrazole-3-carboxylic acid [3-(pentylaminophenylmethyl)phenyl]amide (172a).

In a solution of [3-(hydroxyphenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3carboxylic acid (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0° C, thionyl chloride (0.514 g, 4.325 mmol) was added and stirred at room temperature for 3 hours. Amylamine (0.941 g, 10.81 mmol) was added and stirred for 30 minutes. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and amylamine (0.941 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give [3-(pentylaminophenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3 -carboxylic acid (172a) (1.050 g) as a yellow powder; MS (IER) 530.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((pentulamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (172b).

In a solution of [3-(pentylaminophenylmethyl)phenyl]amide 2-(3-cyanophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (172a) (1.0 g, 1.882 mmol) in MeOH (20 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.53 g, 2.258 mmol) was added, then sodium borohydride (0.42 g, 11.292 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.48 g, 4.705 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue twice by flash column chromatography (silica gel, 66 g, eluted with 012% MeOH/DCM) to give 1-(3-(aminomethyl)phenyl)-N-(3-((pentylamino)(phenyl )methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (172b) (0.020 g) as a yellow solid; 1H NMR (300 MHz, DMSO-06) δ 10.68 (s, 1H), 7.63 (s, 1H), 7.59 (s, 4H), 7.55-7.42 (m, 2H) , 7.45- 7.32 (m, 3H), 7.32 7.23 (m, 2H), 7.25- 7.13 (m, 2H), 4.73 (s, 1H), 3, 92 (s, 1H), 2.39 (t, J=7.2 Hz, 2H), 1.43 (d, J=7.7 Hz, 2H), 1.22 (q, J=3.5 Hz, 4H), 0.90 - 0.77 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.75; MS (IER+) 536.4 (M+1); (IER-) 534.4 (M-1), 570.4 (M+Cl); analysis, calculation for C30H ₃ 2F ₃ N5O-1.25H2O: C, 64.04; H, 6.27; N, 12.45; experiment: C, 64.08; H, 6.13; N, 11.73.

- 310 045731

Scheme 173

An example of the preparation of 1-(3 -(aminomethyl)phenyl)-N-(3 -(((1 -hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (173b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 -carboxamide (173a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 2-methylethanolamine (0.812 g, 10.81 mmol) and stir for 30 min. . The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-methylethanolamine (0.812 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexanes) to give 1-(3-cyanophenyl)-N-(3(((1-hydroxypropan-2-yl)amino )(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (173a) (0.88 g) as a whitish sticky liquid; MS (IER-) 518.3.

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxypropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (173b).

A solution of {3-[(2-hydroxy-1-methylethylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5trifluoromethyl-2H-pyrazole-3-carboxylic acid (0.8 g, 1.539 mmol) in MeOH ( 20 mL) cooled in ice/water, nickel(II) chloride hexahydrate (0.491 g, 2.068 mmol) was added, then sodium borohydride (0.349 g, 9.234 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.635 g, 6.156 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue twice by flash column chromatography (silica gel, 70 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-(((1- hydroxypropan2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (173b) (0.180 g) as a light yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.67 (s, 1H), 7.61 (d, J=2.1 Hz, 2H), 7.56 - 7 .44 (m, 3H), 7.40 (ddd, J=7.9, 3.6, 1.7 Hz, 3H), 7.34 - 7.14 (m, 5H), 5.64 (s , 2H), 4.36 (s, 1H), 3.94 (s, 2H), 3.51 (t, J=6.7 Hz, 2H), 2.37 (dd, J=7.9, 5.7 Hz, 2H), 2.11 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.76; MS (IER+) 524.4 (M+1); (IER-) 558.3 (M+Cl); analysis, calculation for C28H2sF3N5O2-2H2O: C, 60.10; H, 5.76; N, 12.52; experiment: C, 60.07; H, 5.70; N, 12.03.

Scheme 174

- 311 045731

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-III -pyrazole-5-carboxamide (174b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(((1-hydroxy-2-methylpropαn-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (174a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 2-amino-2-methyl-1-propanol (0.964 g, 10.81 mmol) and stirred for 30 min. The reaction mixture was concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-amino-2-methyl-1-propanol (0.964 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3cyanophenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl) amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (174a) (0.9 g) as a yellow sticky semi-solid; MS (IER-) 532.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((1-hydroxy-2-methylpropαn-2-yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (174b).

In solution 1-(3-cyanophenyl)-N-(3-(((1-hydroxy-2-methylpropan-2-yl)amino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazol-5 -carboxamideα (174a) (0.9 g, 1.68 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.479 g, 2.016 mmol) was added, then borohydride was added portionwise sodium (0.38 g, 10.08 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 h and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.46 g, 4.5 mmol), then stirred for an additional 0.5 h. Concentrated the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 65 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-(( (1-hydroxy-2-methylpropan-2yl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1P-pyrazole-5-carboxamide (174b) (0.100 g) as a white crystal; 1H NMR (300 MHz, DMSO<) δ 10.66 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.52 - 7.47 (m, 1H), 7.46 - 7.42 (m, 2H), 7.42 - 7.27 (m, 4H), 7.27 - 7.19 (m, 3H), 7, 19 - 7.11 (m, 1H), 4.97 (s, 1H), 4.64 (s, 1H), 3.20 (s, 2H), 0.86 (s, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.73; MS (IER+) 538.4 (M+1); (IER-) 536.4 (M-1), 572.3 (M+Cl); analysis, calculation for C29H30F3N5O2-0.75H2O: C, 63.20; H, 5.76; N, 12.71; experiment: C, 63.11; H, 5.79; N, 12.02.

Scheme 175

h ₂ n

175b

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazol-5 -carboxamide (175b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxαmideα (175a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add C-(tetrahydrofuran-2-yl)methylamine (1.093 g, 10.81 mmol ) and stirred for 30 minutes. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and C-(tetrahydrofuran-2-yl)methylamine (1.093 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by

- 312 045731 flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl )amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (175 a) (1.1 g) as a yellow-brown oily liquid.

MS (IER-) 544.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (175b).

Into a solution of 1 -(3-cyanophenyl)-N-(3-(phenyl(((tetrahydrofuran-2-yl)methyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (175a) (1.0 g, 1.833 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.544 g, 2.291 mmol) was added, then sodium borohydride (0.416 g, 10.998 mmol) was added portionwise ) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.756 g, 7.332 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 70 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(((tetrahydrofuran -2yl)methyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (175b) (0.280 g) as an off-white solid; 1H NMR (300 MHz, DMSOL) δ 10.69 (s, 1H), 7.73 - 7.07 (m, 14H), 4.79 (s, 1H), 3.91 (d, J=6, 9 Hz, 3H), 3.74-3.64 (m, 1H), 3.65-3.51 (m, 1H), 2.51-2.40 (m, 2H), 1.82 (ddt , J=33.3, 13.6, 6.8 Hz, 3H), 1.51 (dq, J=10.9, 7.1 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.75; MS (IER+) 550.4 (M+1); (IER-) 548.4 (M-1), 584.4 (M+Cl); analysis, calculation for C3oH3oF ₃ N502-1.25H20: C, 62.98; H, 5.73; N, 12.24; experiment: C, 62.85; H, 5.57; N, 12.03.

Scheme 176

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17 6b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (176a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add isoamylamine (0.94 g, 10.81 mmol) and stir for 30 min. . The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and isoamylamine (0.94 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (176a) (1.0 g) as a yellow oily liquid; MS (IER-) 530.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (17 6b).

In a solution of 1-(3-cyanophenyl)-N-(3-((isopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (176a) (1.0 g, 1.882 mmol) in MeOH (20 ml), cooled in ice/water, add nickel (II) chloride hexahydrate (0.53 g, 2.258 mmol), then add sodium borohydride (0.42 g, 11.292 mmol) portionwise over 5 min . The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.48 g, 4.705 mmol), then stirred for an additional 0.5 hours. Concentrated the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 70 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((isopentylamino) (phenyl)methyl)phenyl)-3

- 313 045731 (trifluoromethyl)-1H-pyrazole-5-carboxamide (176b) (0.350 g) as a white solid; 1H NMR (300 MHz, DMSO-de) δ 10.68 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.58 (d, J=2.6 Hz, 2H ), 7.52 (dt, J=7.8, 1.7 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.44 (d, J=7.5 Hz , 1H), 7.37 (ddt, J=5.0, 3.9, 1.9 Hz, 3H), 7.31-7.12 (m, 5H), 4.73 (s, 1H), 3.89 (s, 2H), 2.45-2.35 (m, 2H), 1.60 (dq, J=13.2, 6.6 Hz, 1H), 1.40 - 1.28 ( m, 2H), 0.80 (d, J=6.6 Hz, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.73; MC (IER+) 536.4 (M+1); (IER-) 570.4 (M+Cl); analysis, calculation for C30H32F3N5O· 1.25^0: C, 64.56; H, 6.23; N, 12.55; experiment: C, 64.42; H, 6.00; N, 12.53.

Scheme 177

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-nirazole-5-carboxamide (177b).

Step 1. Preparation of 1-(3-cyanophenyl)-K-(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (177a ).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 2-methylbutylamine (0.942 g, 10.81 mmol) and stir for 30 min. . The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-methylbutylamine (0.942 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N(3-(((2-methylbutyl)amino)(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (177a) (0.8 g) as a yellow oily liquid; MS (IER-) 530.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide ( 17 7b).

Into a solution of 1-(3-cyanophenyl)-^(3-(((2-methylbutyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (177a) (0.8 g, 1.505 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.43 g, 1.806 mmol) was added, then sodium borohydride (0.34 g, 9. 03 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with X1-(2-aminoethyl)ethane-1,2-diamine (0.388 g, 3.762 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give pure 1-(3-(aminomethyl)phenyl)-N(3-(((2-methylbutyl) amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (177b) (0.400 g) as a colorless oily liquid; 1H NMR (300 MHz, DMSO-dg) δ 10.65 (s, 1H), 7.67 - 7.11 (m, 14H), 4.71 (s, 1H), 3.88 (s, 2H) , 2.39 - 2.14 (m, 2H), 1.57 - 1.32 (m, 2H), 1.07 (dt, J=13.8, 7.3 Hz, 1H), 0.92 - 0.71 (m, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.35; MS (IER+) 536.4 (M+1); (IER-) 570.3 (M+Cl); analysis, calculation for C30H32F3N5OO75H2O: C, 65.62; H, 6.15; N, 12.75; experiment: C, 65.62; H, 6.25; N, 12.03.

- 314 045731

Scheme 178

preparing 1-(3-(aminomethyl)phenyl)-M-(3-((bis(2-hydroxyethyl)amino)(phenyl)mePrimer til)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 178b).

Step 1. Preparation of N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (178a ).

To a solution of (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 2- (2-hydroxyethylamino)ethanol (1.13 g, 10.81 mmol) and stirred for 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-(2-hydroxyethylamino)ethanol (1.13 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-1 -(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamide (178a) (0.500 g) as a yellow oily liquid. MS (IER-) 548.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 -carboxamide (17 8b).

Into a solution of N-(3-((bis(2-hydroxyethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (178a) ( 0.5 g, 0.910 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.25 g, 1.092 mmol) was added, then sodium borohydride (0.20 g) was added portionwise , 5.46 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.23 g, 2.275 mmol), then stirred for an additional 0.5 hours. The reaction mixture was concentrated to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 012% MeOH/DCM) to give 1-(3-(aminomethyl)phenyl)-N-(3-((bis(2- hydroxyethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (178b) (0.080 g) as a white crystal; 1H NMR (300 MHz, DMSO-I6) δ 10.69 (s, 1H), 7.74 - 7.33 (m, 10H), 7.36 - 7.22 (m, 2H), 7.27 - 7.14 (m, 2H), 4.84 (s, 1H), 3.97 (s, 2H), 3.44 (t, J=6.9 Hz, 4H), 2.55 (t, J =6.9 Hz, 4H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.57; MS (IER+) 554.4 (M+1); (IER-) 552.3 (M-1), 588.3 (M+Cl); analysis, calculation for C25H30F3N5O _r HCl 3H2O: C, 54.08; H, 5.79; N, 10.87; experiment: C, 54.03; H, 5.78; N, 11.01.

Scheme 179

- 315 045731

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-X-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide ( 17 9b).

Step 1. Preparation of 1-(3-cyanophenyl)-X-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (179a) .

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add C-pyridin-3-ylmethylamine (1.168 g, 10.81 mmol) and stir within 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and C-pyridin-3-ylmethylamine (1.168 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3cyanophenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl )-3-(trifluoromethyl)-1H-nirazole-5carboxamide (179a) (0.580 g) as a white solid; MS (IER-) 551.2 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-X-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 - carboxamide (17 9b).

Into a solution of 1 -(3-cyanophenyl)-X-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (179a) (0 .5 g, 0.9048 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.25 g, 1.085 mmol) was added, then sodium borohydride (0.26 g, 5.428 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.23 g, 2.262 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 012% MeOH/DCM) to give 1-(3-(aminomethyl)phenyl)-X-(3-(phenyl((pyridine-3 -ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (179b) (0.055 g) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.68 (s, 1H), 8.48 (s, 1H), 8.44 (d, J=4.9 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.68 (s, 1H), 7.62 - 7.57 (m, 2H), 7.58 - 7.51 (m, 1H), 7.48 (d, J=6 .5 Hz, 2H), 7.41 (d, J=6.1 Hz, 3H), 7.36 - 7.26 (m, 3H), 7.28 - 7.16 (m, 3H), 4 .74 (s, 1H), 3.93 (s, 2H), 3.62 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.43; MS (IER+) 557.4 (M+1); (IER-) 555.4 (M-1), 591.3 (M+Cl); analysis, calculation for C^Fj^O-HCbS^HzO: C, 57.14; H, 5.34; N, 12.90; experiment: C, 57.37; H, 5.14; N, 12.33.

Scheme 180

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((butylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (180b).

Step 1. Preparation of X-(3-((butylamino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (180a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add butylamine (0.79 g, 10.81 mmol) and stir for 30 min. . The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and butylamine (0.79 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give N-(3-((butylamino)(phenyl)methyl)phenyl)-1(3 -cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (180a) (0.960 g) as a brown oily liquid; MS (IER-) 516.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((butylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (180b).

In a solution of N-(3-((butylamino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (180a) (0.960 g, 1.856 mmol) in MeOH (20 mL) cooled in ice/water, nickel(II) chloride hexahydrate (0.551 g, 2.32 mmol) was added, then sodium borohydride (0.421 g, 11.136 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.478 g, 4.527 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((butylamino)(phenyl )methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (180b) (0.040 g) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.66 (d, J=2.7 Hz, 2H ), 7.63 - 7.45 (m, 4H), 7.39 (d, J=7.1 Hz, 2H), 7.34 - 7.12 (m, 5H), 4.76 (s, 1H), 4.09 (s, 2H), 2.41 (t, J=7.0 Hz, 2H), 1.43 (q, J=7.3 Hz, 2H), 1.28 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.2 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (IER+) 522.4 (M+1); (IER-) 520.3 (M-1), 556.4 (M+Cl); analysis, calculation for C29H30F3N5O-HCl-1.25H2O: C, 60.00; H, 5.82; N, 12.06; experiment: C, 60.34; H, 5.95; N, 11.52.

Scheme 181

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (181b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (181a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 4-aminocyclohexanol (1.25 g, 10.81 mmol) and stir for 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and trans-4-aminocyclohexanol (1.25 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3cyanophenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl )methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (181a) (0.600 g) as a brownish solid; MS (IER-) 558.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (181b).

Into a solution of 1-(3-cyanophenyl)-N-(3-((((trans)-4-hydroxycyclohexyl)amino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (181a ) (0.600 g, 1.072 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.3 g, 2.32 mmol) was added, then sodium borohydride (0. 2 g, 6.432 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.276 g, 2.68 mmol), then stirred for an additional 0.5 hours. The reaction mixture was concentrated to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM) to give pure 1-(3-(aminomethyl)phenyl)-N-(3-((( (trans)-4-hydroxycyclic

- 317 045731 logexyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (181b) (0.140 g) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.68 (s, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 7.58 - 7.47 (m, 3H ), 7.39 - 7.29 (m, 3H), 7.48 - 7.30 (m, 4H), 7.31 - 7.22 (m, 2H), 7.24 - 7.06 (m , 3H), 4.93 (s, 1H), 4.43 (s, 1H), 3.82 (s, 2H), 2.31-2.11 (m, 1H), 1.94 - 1, 83 (m, 1H), 1.79 - 1.66 (m, 2H), 1.18 - 0.86 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.73; MS (IER+) 564.4 (M+1); (IER-) 562.5 (M-1), 598.4 (M+Cl); analysis, calculation for C31H32F3N5O2-2.25H2O: C, 61.63; H, 6.09; N, 11.59; experiment: C, 61.69; H, 5.89; N, 11.38.

Scheme 182

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxynponyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (182b ).

Step 1. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxynponyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (182a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5 carboxamide (1.0 g, 2.162 mmol) in dichloromethane ( 50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 1-aminopropan-2-ol (0.811 g, 10.81 mmol) and stir in for 30 minutes. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 1-aminopropan-2-ol (0.811 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino) (phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (182a) (0.600 g) as a brownish oily liquid; MS (IER-) 518.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (182b).

Into a solution of 1-(3-(aminomethyl)phenyl)-N-(3-(((2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (182a ) (0.600 g, 1.154 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.32 g, 1.38 mmol) was added, then sodium borohydride (0. 26 g, 6.924 mmol) over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.29 g, 2.885 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM) to give pure 1-(3-(aminomethyl)phenyl)-N-(3-((( 2-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (182b) (0.020 g) as a white solid; 1H NMR (300 MHz, DMSO-d^ δ 10.70 (d, J=1.8 Hz, 1H), 7.64 (s, 1H), 7.61 - 7.34 (m, 8H), 7 .33 - 7.15 (m, 5H), 4.75 (s, 1H), 4.68 - 4.40 (m, 1H), 3.89 (s, 2H), 3.73 (q, J =6.7, 6.3 Hz, 1H), 2.35 (d, J=6.0 Hz, 2H), 1.02 (d, J=6.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.74; MS (IER+) 524.4 (M+1); (IER-) 522.3 (M-1), 558.3 (M+Cl); analysis, calculation for C ₂₈ H ₂₈ F ₃ N ₅ O ₂ -2.75H ₂ O: C, 58.68; H, 5.89; N, 12.22; experiment: C, 59.01; H, 5.60; N , 11.89.

- 318 045731

Scheme 183

An example of the preparation of N-(3-(((3 -(1 H-imidazol-1 -yl)propyl)amino)(phenyl)methyl)phenyl)-1 -(3 -(aminomethyl)phenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (183b).

Step 1. Preparation of N-(3-(((3-(1H-imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (183a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (1.0 g, 2.162 mmol) in dichloromethane (50 ml ) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 3-imidazol-1-ylpropylamine (1.35 g, 10.81 mmol) and stir in for 30 minutes. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 3-imidazol-1-ylpropylamine (1.35 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give N-(3(((3 -(1H-imidazol-1-yl)propyl)amino)(phenyl) methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (183a) (0.350 g) as a brownish oily liquid; MS (IER-) 568.3 (M-1).

Step 2. Preparation of N-(3-(((3-(1H-imidazol-1-yl)propyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl )-1 H-pyrazole-5-carboxamide (183b).

Into a solution N-(3-(((3 -(1 H-imidazol-1 -yl)propyl)amino)(phenyl)methyl)phenyl)-1 -(3 -(aminomethyl)phenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (183a) (0.350 g, 0.6144 mmol) in MeOH (20 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.17 g, 0.737 mmol) was added , then sodium borohydride (0.139 g, 3.686 mmol) was added piecemeal over 5 minutes. The reaction mixture was stirred at room temperature for 2 h and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.15 g, 1.536 mmol), then stirred for an additional 0.5 h. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give N-(3-(((3-(1H-imidazol-1-yl)propyl )amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (183b) (0.050 g) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.55-7.35 (m, 8H) , 7.33 - 7.24 (m, 3H), 7.19 (q, J=7.0, 6.5 Hz, 2H), 7.10 (t, J=1.1 Hz, 1H), 6.83 (t, J=1.1 Hz, 1H), 5.90 (s, 2H), 4.71 (s, 1H), 4.02 (t, J=7.0 Hz, 2H), 3.96 (s, 2H), 2.37 -2.34 (m, 2H), 1.88 (q, J=6.5 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.76; MS (IER+) 574.4 (M+1); (IER-) 572.4 (M-1), 608.3 (M+Cl); analysis, calculation for C31H ₃₀ F ₃ N ₇ O-HCl-0.75H ₂ O: C, 59.71; H, 5.25; N, 15.72; experiment: C, 60.09; H, 5.43; N, 15.48.

Scheme 184

- 319 045731

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (184b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (184a).

In a solution of 1-(3-cyanophenyl)-N-(3 -(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add N,N,N'-trimethylethane-1,2-diamine (1.104 g, 10.81 mmol) and stirred for 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and N,N,N'-trimethylethane-1,2-diamine (1.104 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (184a) (0.200 g) as a brownish oily liquid; MS (IER-) 488.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (184b).

In a solution of 1-(3-cyanophenyl)-N-(3-((dimethylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (184a) (0.190 g, 0.347 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.103 g, 0.433 mmol) was added, then sodium borohydride (0.078 g, 2.082 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.089 g, 0.867 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((dimethylamino)(phenyl )methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (184b) (0.025 g) as an off-white solid; 1H NMR (300 MHz, DMSOL) δ 10.69 (s, 1H), 7.72 (s, 1H), 7.66 - 7.09 (m, 13H), 4.06 (s, 1H), 3 .86 (s, 2H), 2.10 (s, 6H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.75; MS (IER+) 494.3 (M+1); (IER-) 492.3 (M-1), 528.3 (M+Cl); analysis, calculation for C ₂₇ H ₂₆ F ₃ N ₅ O-1.5H ₂ O: C, 62.30; H, 5.62; N, 13.45; experiment: C, 62.27; H, 6.18; N, 11.54.

Scheme 185

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((ohexylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (185b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (185a).

In a solution of 1-(3 - cyanophenyl)-N-(3 -(hydroxy(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add cyclohexylamine (1.07 g, 10.81 mmol) and stir for 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and cyclohexylamine (1.07 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3-320 045731 ((cyclohexylamino)(phenyl)methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (185a) (0.9 g) as a yellow-brown sticky liquid; MS (IER-) 542.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (185b).

In a solution of 1-(3-cyanophenyl)-N-(3-((cyclohexylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (185a) (0.9 g, 1.655 mmol) in MeOH (20 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.491 g, 2.069 mmol) was added, then sodium borohydride (0.375 g, 9.93 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.682 g, 6.62 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 70 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-X-(3-((cyclohexylamino) (phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (185b) (0.160 g) as an off-white solid; ^1H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.65-7.57 (m, 3H), 7.57 - 7.42 (m, 3H), 7.42 - 7.12 (m, 8H), 4.97 (s, 1H), 3.91 (s, 2H), 2.20 (d, J=11.9 Hz, 1H), 1.89 (d, J=8.1 Hz, 2H), 1.63 (s, 2H), 1.49 (s, 1H), 1.16 - 0.97 (m, 5H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.76; MS (IER+) 548.4 (M+1); (IER-) 546.4 (M-1), 582.3 (M+Cl); analysis, calculation for C31H ₃₂ F ₃ N ₅ O-1.5H ₂ O: C, 64.79; H, 6.14; N, 12.19; experiment: C, 64.97; H, 5.85; N, 11.81.

Scheme 186

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (186b ).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (186a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add pyridin-4-ylmethylamine (1.168 g, 10.81 mmol) and stir for 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and C-pyridin-4-ylmethylamine (1.168 g, 10.805 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3cyanophenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl )-3-(trifluoromethyl)-1H-nirazol-5carboxamide (186a) (0.3 g) as a red oily liquid; MS (IER-) 551.2 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (186b).

Into a solution of 1 -(3 -cyanophenyl)-N-(3 -(phenyl((pyridin-4-ylmethyl)amino)methyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (186a) (0 .3 g, 0.543 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.170 g, 0.716 mmol) was added, then sodium borohydride (0.123 g, 3.258 mmol) was added portionwise to for 5 minutes The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.140 g, 1.357 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 70 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl((pyridine- 4-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (186b) (0.065 g) as a whitish solid; 1H NMR (300 MHz, DMSOL) δ 10.70 (s, 1H), 8.56 - 8.43 (m, 1H), 7.73 - 7.15 (m, 17H), 4.73 (s, 1H), 3.93 (s, 2H), 3.62 (d, J=5.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.51; MS (IER+) 557.4 (M+1);

(IER-) 555.4 (M-1), 591.3 (M+Cl); analysis, calculation for C ₃₁ H ₂₇ F ₃ N ₆ O-2.25H ₂ O: C, 62.36; H, 5.32; N, 14.07;

experiment: C, 62.58; H, 5.30; N, 13.36.

Scheme 187 f ₃ c

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (187b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (187a).

In solution of 1 -(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 1,1-dimethylpropylamine (0.942 g, 10.81 mmol) and stir within 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 1,1-dimethylpropylamine (0.942 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N(3-((neopentylamino)(phenyl)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (187a) (0.480 g) as a yellow sticky oily liquid; MS (IER-) 530.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (187b).

In a solution of 1-(3-cyanophenyl)-N-(3-((neopentylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (187a) (0.480 g, 0.910 mmol) in MeOH (20 mL) cooled in ice/water, nickel(II) chloride hexahydrate (0.268 g, 1.128 mmol) was added, then sodium borohydride (0.204 g, 5.41 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.372 g, 3.612 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM mixtures) to give pure 1-(3-(aminomethyl)phenyl)-N-(3-((neopentylamino)( phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (187b) (0.080 g) as a white crystal; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.70 (s, 1H), 7.70 - 7.07 (m, 14H), 4.94 (s, 1H), 4.04 (s, 2H ), 0.90 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 536.3 (M+1); (IER-) 534.3 (M-1), 570.1 (M+Cl).

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Scheme 188

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((butylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (188b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (188a).

In a solution of 1-(3-cyanophenyl)-N-(3 -(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add cyclobutylamine (0.768 g, 10.81 mmol) and stir for 30 min. . The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and cyclobutylamine (0.768 g, 10.805 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N-(3((cyclobutylamino)(phenyl)methyl)phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (188a) (0.7 g) as a red oily liquid; MS (IER-) 514.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-X-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (188b).

In a solution of 1-(3-cyanophenyl)-N-(3-((cyclobutylamino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (188a) (0.7 g, 1.032 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.29 g, 1.23 mmol) was added, then sodium borohydride (0.23 g, 6.192 mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.266 g, 2.58 mmol), then stirred for an additional 0.5 hours. Concentrated the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 70 g, eluted with 0-12% MeOH/DCM mixtures) to give 1-(3-(aminomethyl)phenyl)-N-(3-((cyclobutylamino) (phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (188b) (0.120 g) as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.56 - 7 .50 (m, 2H), 7.51 7.12 (m, 10H), 4.72 (s, 1H), 3.82 (s, 2H), 3.07 - 2.89 (m, 1H) , 1.99 (dt, J=13.1, 7.4 Hz, 2H), 1.74 (dp, J=18.1, 9.3, 8.8 Hz, 2H), 1.60 - 1 .35 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.75; MS (IER+) 520.3 (M+1); (IER-) 518.3 (M-1), 554.2 (M+Cl): analysis, calculation for C ₂₈ H ₂₈ F ₃ N ₅ OH ₂ O: C, 64.79; H, 5.62; N, 13.03; experiment: C, 64.99; H, 5.58; N, 12.95.

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Scheme 189

An example of the preparation of N-(3-(((4-aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)-3(trifluoromethyl)-III-pyrazole-5-carboxamide (189b) .

Step 1. Preparation of N-(3-(((4-aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (189a ).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 4-aminomethylphenylamine (1.31 g, 10.81 mmol) and stir for 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 4-aminomethylphenylamine (1.31 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give N-(3-(((4aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3 -cyanophenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (189a) (0.5 g) as a yellow oily liquid; MS (IER-) 565.3 (M-1).

Step 2. Preparation of N-(3-(((4-aminobenzyl)amino)(phenyl)methyl)phenyl)-1-(3-(aminomethyl)phenyl)3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (189b).

To a solution of {3-[(4-aminobenzylamino)phenylmethyl]phenyl}amide 2-(3-cyanophenyl)-5-trifluoromethyl2H-pyrazole-3-carboxylic acid (0.5 g, 0.884 mmol) in MeOH (20 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.26 g, 1.105 mmol) was added, then sodium borohydride (0.200 g, 5.304 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.364 g, 3.536 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM) to give pure {3-[(4-aminobenzylamino)phenylmethyl]phenyl}amide 2-(3-aminomethylphenyl) -5-trifluoromethyl-2P-pyrazole-3-carboxylic acid (0.020 g) as a white solid and a mixture (0.060 g) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.34 (s, 3H), 7.77 - 7.68 (m, 2H), 7.66 (s, 1H) , 7.62 - 7.17 (m, 11H), 6.96 (d, J=8.1 Hz, 2H), 6.57 - 6.43 (m, 2H), 5.05 (s, 3H ), 4.12 (s, 2H), 3.67 - 3.43 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 571.3 (M+1); (IER-) 569.3 (M-1), 605.3 (M+Cl); analysis, calculation for Cз2H29FзN6O·HCl·1.5H2O: C, 60.61; H, 5.25; N, 13.25; experiment: C, 60.56; H, 5.20; N, 13.31.

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Scheme 190

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)3-(trifluoromethyl)-1 H-pyrazole-5 - carboxamide (190b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1 H-pyrazole-5-carboxamide (190a).

In a solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 2-methylsulfanylethylamine (0.985 g, 10.81 mmol) and stir for 30 min. . The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 2-methylsulfanylethylamine (0.985 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3cyanophenyl)-N-(3-(((2-(methylthio)ethyl)αmino)(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (190a) (0.81 g) as a light brown oily liquid; MS (IER-) 534.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole -5-carboxamide (190b).

In a solution of 1-(3-cyanophenyl)-N-(3-(((2-(methylthio)ethyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (190a ) (0.8 g, 1.493 mmol) in MeOH (20 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.443 g, 1.866 mmol) was added, then sodium borohydride (0.338 g, 8.958 mmol) for 5 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.616 g, 5.972 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM) to give 1-(3-(αminomethyl)phenyl)-N-(3-(((2-( methylthio)ethyl)αmino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (190b) as a light yellowish solid; ^1H NMR (300 MHz, DMSO^) δ 10.72 (s, 1H), 7.75-7.13 (m, 14H), 6.04 (s, 2H), 4.81 (s, 1H) , 3.97 (s, 2H), 2.60 (s, 4H), 1.98 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (IER+) 540.3 (M+1); (IER) 538.2 (M-1), 601.3 (M+Cl); analysis, calculation for C ₂₈ H ₂₈ F ₃ N ₅ OS-0.5H ₂ O: C, 61.30; H, 5.33; N, 12.77; experiment: C, 61.20; H, 5.27; N, 12.01.

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Scheme 191

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide ( 191b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (191a).

A solution of 1-(3-cyanophenyl)-N-(3-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5carboxamide (144a) (1.0 g, 2.162 mmol) in dichloromethane (50 ml) at 0°C, add thionyl chloride (0.514 g, 4.325 mmol) and stir at room temperature for 3 hours. Check by TLC and add 3-aminopropan-1-ol (0.811 g, 10.81 mmol) and stir within 30 min. The reaction mixture was then concentrated to dryness in vacuo. The resulting residue was dissolved in acetonitrile (20 ml) and 3-aminopropan-1-ol (0.811 g, 10.81 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with water (2x25 ml), dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-25% ethyl acetate in hexane) to give 1-(3-cyanophenyl)-N(3-(((3-hydroxypropyl)amino)(phenyl) methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (191a) (0.65 g) as a brown thick liquid; MS (IER-) 518.3 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (191b).

Into a solution of 1 -(3-cyanophenyl)-N-(3-(((3-hydroxypropyl)amino)(phenyl)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (191a) (0, 6 g, 1.154 mmol) in MeOH (20 ml), cooled in ice/water, nickel(II) chloride hexahydrate (0.343 g, 1.443 mmol) was added, then sodium borohydride (0.261 g, 6.924 mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N ¹ -(2-aminoethyl)ethane-1,2-diamine (0.476 g, 4.616 mmol), then stirred for an additional 0.5 hours. Concentrate the reaction mixture to dryness in vacuum and purify the resulting residue by flash column chromatography (silica gel, 60 g, eluted with 0-12% MeOH/DCM) to give 1-(3-(aminomethyl)phenyl)-N-(3-(((3-hydroxypropyl )amino)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (191b) (0.060 g) as a light yellowish solid; 1H NMR (300 MHz, DMSO^6) δ 10.73 (s, 1H), 7.69 (s, 1H), 7.64 (d, J=2.8 Hz, 2H), 7.60 - 7 .45 (m, 4H), 7.40 (d, J=1.7 Hz, 1H), 7.37 (s, 1H), 7.33 - 7.24 (m, 3H), 7.20 ( dt, J=8.9, 5.6 Hz, 2H), 4.74 (s, 1H), 4.09 (s, 2H), 3.43 (m, 2H), 2.46 (m, 2H ), 1.60 (p, J=6.8 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, MS (ESI+) 524.3 (M+1); (IER-) 558.2 (M+Cl); analysis, calculation for C28H28F3N5O2-HCl-1.5H2O: C, 57.29; H, 5.49; N, 11.93; experiment: C, 57.37; H, 5.35; N, 12.31.

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Scheme 192

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(benzo[d][1,3]dioxol-4-yl(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (192f).

Compound (192f) was prepared using benzo[d][1,3]dioxole-4-carbaldehyde (192a) (10 mmol) as the starting material in five steps as shown in Scheme 192 using the method described in Scheme 109 , obtained 1-(3-(aminomethyl)phenyl)-N-(3-(benzo[d][1,3]dioxol-4-yl(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (192f) (30 mg) as an off-white solid; 1H NMR (300 MHz, methanol-d ₄ ) δ 7.66 (t, J=1.9 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.53 - 7.41 (m , 4H), 7.35 (s, 1H), 7.30 - 7.17 (m, 2H), 6.84 (dd, J=8.0, 1.4 Hz, 1H), 6.75 ( t, J=7.8 Hz, 1H), 6.67 (dd, J=7.6, 1.4 Hz, 1H), 5.87 (s, 2H), 4.99 (s, 1H), 4.04 (s, 2H), 2.44 - 2.28 (m, 2H), 1.01 - 0.83 (m, 1H), 0.50 0.38 (m, 2H), 0.10 - -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, MeOD) δ -63.76; MS (IER+) 564.3 (M+1); (IER-) 598.3 (M+Cl); analysis, calculation for C ₃₀ H ₂₈ F ₃ N ₅ O ₃ -HCH,75H ₂ O: C, 57.05; H, 5.19; N, 11.09; experiment: C, 57.31; H, 5.25; N, 10.74.

Scheme 193

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(o-toluyl)methyl)phenyl)-3 -(trifluoromethyl)-1 H-nirazol-5-carboxamide ( 193f).

Compound (193f) was prepared using 2-methylbenzaldehyde (193a) (10 mmol) as the starting material in five steps as shown in Scheme 193, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl)phenyl )-N-(3-(((cyclopropylmethyl)amino)(o-toluyl)methyl)phenyl)-3(trifluoromethyl)-1H-nirazole-5-carboxamide (193f) (30 mg) as a light green solid ; 1H NMR (300 MHz, DMSO-dg) δ 10.94 (s, 1H), 9.84 (s, 2H), 8.41 (s, 3H), 7.92 - 7.17 (m, 13H) , 5.61 (s, 1H), 4.22 4.03 (m, 2H), 2.83 - 2.67 (m, 2H), 2.31 (s, 3H), 1.19 - 1, 01 (m, 1H), 0.54 (d, J=8.2 Hz, 2H), 0.36 - 0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 534.3 (M+1); (IER-) 532.3 (M-1), 568.2 (M+Cl); analysis, calculation for C ₃₀ H ₃₀ F ₃ N ₅ O-2HCl-2.75H ₂ O: C, 54.92; H, 5.76; N, 10.68; experiment: C, 55.08; H, 5.54; N, 10.50.

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Scheme 194

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((2-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (194f ).

Compound (194f was prepared using 2-chlorobenzaldehyde (194a) (10 mmol) as the starting material in five steps as shown in Scheme 194, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl)phenyl) -N-(3-((2-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (194f) (20 mg) as a white solid; ¹ H NMR (300 MHz, DMSO-dg) δ 10.70 (s, 1H), 7.77 - 7.65 (m, 1H), 7.64 - 7.49 (m, 4H), 7.49 - 7.10 (m, 8H), 5.24 (s, 1H), 3.78 (s, 2H), 2.28 (dd, J=6.8, 2.6 Hz, 2H), 0.99 - 0.83 (m, 1H), 0.49 - 0.30 (m, 2H), 0.11 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60, 72; MS (IER+) 554.3 (M+1); (IER-) 552.3 (M-1); analysis, calculation for C ₂₉ H ₂₇ ClF ₃ N ₅ O-0.5H ₂ O: C , 61.87; H, 5.01; N, 12.44; experiment: C, 61.68; H, 5.01; N, 12.43.

Scheme 195

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(3-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (195f ).

Compound (195f) was prepared using 3-fluorobenzaldehyde (195a) (10 mmol) as the starting material in five steps as shown in Scheme 195, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl)phenyl )-N-(3-(((cyclopropylmethyl)amino)(3-fluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (195f) (40 mg) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.95 (s, 1H), 10.11 (s, 2H), 8.39 (s, 3H), 7.88 (s, 1H), 7. 73 (s, 1H), 7.68 (s, 1H), 7.67 - 7.39 (m, 9H), 7.23 (dt, J=8.0, 4.8 Hz, 1H), 5 .65 (d, J=7.0 Hz, 1H), 4.13 (d, J=5.7 Hz, 2H), 2.79 -2.65 (m, 2H), 1.26 - 1, 05 (m, 1H), 0.65-0.48 (m, 2H), 0.44 - 0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, 111.69; MS (IER+) 538.4 (M+1); (IER-) 572.3 (M+Cl); analysis, calculation for C ₂₉ H ₂₇ F ₄ N ₅ O-2HCl-3.5H ₂ O: C, 51.71; H, 5.39; N, 10.40; experiment: C, 51.94; H, 5.24; N, 10.33.

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Scheme 196

An example of the preparation of 1-(3-(aminomethyl)phenyl)-I-(3-(((cyclopropylmethyl)amino)(2,4-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (196f).

Compound (196f) was prepared using 2,4-difluorobenzaldehyde (196a) (10 mmol) as the starting material in five steps as shown in Scheme 196, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl )phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,4-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-nirazol-5-carboxamide (196f) (40 mg) as pale orange solid. 1H NMR (300 MHz, DMSO-dg) δ 10.95 (s, 1H), 10.19 (s, 1H), 8.42 (s, 3H), 8.07 (d, J=13.3 Hz , 1H), 7.85-7.22 (m, 11H), 5.72 (s, 1H), 4.13 (s, 2H), 2.87 - 2.65 (m, 2H), 1, 21-1.00 (m, 1H), 0.67 -0.40 (m, 2H), 0.38-0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, -108.86, -111.97; MS (IER+) 556.3 (M+1); (IER-) 554.4 (M-1), 590.4 (M+Cl); analysis, calculation for C ₂₉ H ₂₆ F ₅ N ₅ O-2HCl-1.5H ₂ O: C, 53.14; H, 4.77; N, 10.68; experiment: C, 53.05; H, 4.68; N, 11.21.

Scheme 197

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5 - carboxamide (197f).

Compound (197f) was prepared using 2,5-difluorobenzaldehyde (197a) (10 mmol) as the starting material in five steps as shown in Scheme 197, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl )phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (197f) (40 mg) as yellow solid; 1H NMR (300 MHz, DMSO-dg) δ 10.79 (s, 1H), 8.35 (s, 3H), 7.72 (d, J=1.9 Hz, 1H), 7.71 - 7 .41 (m, 6H), 7.42 - 7.07 (m, 5H), 5.15 (s, 1H), 4.13 (s, 2H), 2.42 - 2.27 (m, 2H ), 1.00 - 0.89 (m, 1H), 0.41 (m, 2H), 0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, -118.15, -124.26, MS (ESI+) 556.3 (M+1); (IER-) 590.3 (M+Cl); analysis, calculation for C ₂₉ H ₂₆ F ₅ N ₅ O-HCl-2H ₂ O: C, 55.46; H, 4.98; N, 11.15; experiment: C, 55.18; H, 4.82; N, 11.39.

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Scheme 198

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,6-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (198f).

Compound (198f) was prepared using 2,6-difluorobenzaldehyde (198a) (10 mmol) as the starting material in five steps as shown in Scheme 198, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl )phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,6-difluorophenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (198f) (10 mg) as white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.72 (s, 1H), 7.65-7.49 (m, 4H), 7.47 - 7.40 (m, 3H), 7.42 - 7.23 (m, 3H), 7.09 (dd, J=19.0, 8.0 Hz, 2H), 5.24 (s, 1H), 3.77 (d, J=2.1 Hz , 2H), 2.48 - 2.22 (m, 2H), 0.90 (dp, J=13.0, 6.1 Hz, 1H), 0.44 - 0.33 (m, 2H), 0.21 - 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.71, -114.27; MS (IER+) 556.4 (M+1); (IER-) 554.4 (M-1), 590.3 (M+Cl).

Scheme 199

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((6-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (199f ).

Compound (199f) was prepared using 4-chlorobenzaldehyde (199a) (10 mmol) as the starting material in five steps as shown in Scheme 199, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl)phenyl )-N-(3-((6-chlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (199f) (15 mg) as a white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.68 (s, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.59 - 7.49 (m, 3H), 7 .44 - 7.14 (m, 9H), 4.82 (s, 1H), 3.77 (s, 2H), 2.27 (d, J=6.6 Hz, 2H), 1.00 - 0.81 (m, 1H), 0.49 - 0.28 (m, 2H), 0.12 - -0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.72; MS (IER+) 556.3 (M+1); analysis, calculation for C ₂₉ H ₂₇ ClF ₃ N ₅ O: C, 62.87; H, 4.91; N, 12.64; experiment: C, 62.63; H, 5.01; N, 12.55.

- 330 045731

Scheme 200

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((2,4-dichlorophenyl)-((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazol-5- carboxamide (200f).

Compound (200f) was prepared using 2,4-dichlorobenzaldehyde (200a) (10 mmol) as the starting material in five steps as shown in Scheme 200, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl) phenyl)-I-(3-((2,4-dichlorophenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (200f) (30 mg) as beige solid; Ή NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.66 - 7.41 (m, 9H), 7.27 (t, J=7.7 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.67 (s, 2H), 5.20 (s, 1H), 4.01 (s, 2H), 2.27 (dd, J=6.3, 3.4 Hz, 2H), 0.99 - 0.77 (m, 1H), 0.47 - 0 .31 (m, 2H), 0.10 - -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.78; MS (ESI+) 588.3, 590.3 ( M+1); analysis, calculation for C ₂₉ H ₂₆ Cl ₂ F ₃ N ₅ O-1.5H ₂ O: C, 56.59; H, 4.75; N, 11.38; experiment: C, 56 .67; H, 4.87; N, 10.99.

Scheme 201

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-(((cyclopronylmethyl)amino)(2,4-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (201f).

Compound (201f) was prepared using 2,4-dimethylbenzaldehyde (201a) (10 mmol) as the starting material in five steps as shown in Scheme 201, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl )phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,4-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (201f) (110 mg) as yellow solid; Ή NMR (300 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 9.71 (s, 1H), 8.34 (s, 3H), 7.78 - 7.37 (m, 10H ), 7.14 (d, J=7.8 Hz, 1H), 7.05 (s, 1H), 5.59 (s, 1H), 4.13 (s, 2H), 2.85- 2 .67 (m, 2H), 2.32 - 2.21 (m, 6H), 1.17 - 0.96 (m, 1H), 0.64 - 0.48 (m, 2H), 0.23 (d, J=19.7 Hz, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 548.4 (M+1); (IER-) 582.3 (M+Cl); analysis, calculation for C ₃₁ H ₃₂ F ₃ N ₅ O-2HCl-3.25H ₂ O: C, 54.83; H, 6.01; N, 10.31; experiment: C, 54.90; H, 6.02; N, 9.64.

- 331 045731

Scheme 202

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (202f).

Compound (202f) was prepared using 2,5-dimethylbenzaldehyde (202a) (10 mmol) as the starting material in five steps as shown in Scheme 202, using the method described in Scheme 109 to obtain 1-(3-(aminomethyl )phenyl)-N-(3-(((cyclopropylmethyl)amino)(2,5-dimethylphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (202f) (60 mg) as light green solid; 1H NMR (300 MHz, DMSO^) δ 10.95 (s, 1H), 9.73 (s, 2H), 8.35 (d, J=14.1 Hz, 3H), 7.80 (s, 1H), 7.73 (s, 1H), 7.69 - 7.42 (m, 8H), 7.15 - 7.05 (m, 2H), 5.59 (s, 1H), 4.12 (d, J=5.1 Hz, 2H), 2.96 -2.63 (m, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.21 - 1, 01 (m, 1H), 0.56 (d, J=8.0 Hz, 2H), 0.28 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 548.4 (M+1); analysis, calculation for C31H32F3N5O-4HCl-2H2O: C, 49.81; H, 5.66; N, 9.37;

experiment: C, 49.85; H, 5.53; N, 8.86.

Scheme 203

Preparation example of 1 -(3-(aminomethyl)phenyl)-N-(3-((4-(tert-butyl)phenyl)-((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (203f).

Compound (203f) was prepared using 4-(tert-butyl)benzaldehyde (203a) (10 mmol) as the starting material in five steps as shown in Scheme 203, using the method described in Scheme 109 to obtain 1-( 3-(aminomethyl)phenyl)-N-(3-((4-(tert-butyl)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (203f ) (20 mg) as a light yellow solid. 1H NMR (300 MHz, DMSO-d^) δ 10.70 (s, 1H), 7.66 (s, 1H), 7.61 (s, 2H), 7.57 - 7.34 (m, 4H ), 7.30 (s, 4H), 7.24 - 7.18 (m, 2H), 4.77 (s, 1H), 3.95 (s, 2H), 2.27 (d, J= 6.5 Hz, 2H), 1.23 (s, 9H), 1.02 - 0.70 (m, 1H), 0.46 - 0.29 (m, 2H), 0.08 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77; MS (IER+) 576.4 (M+1); analysis, calculation for C ₃₃ H ₃₆ F ₃ N ₅ O-2H ₂ O: C, 64.80; H, 6.59; N, 11.45; experiment: C, 65.10; H, 6.38; N, 10.61.

- 332 045731

Scheme 204

An example of the preparation of (-)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-( trifluoromethyl)-1H-pyrazol-5-carboxamide (204d) and (+)-U-(5-(1-amino-3cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-( 3-(aminomethyl)phenyl)-3-(trifluoromethyl)-Spirazole-5-carboxamide (204e).

Compounds 204d and 204e can be prepared from compound 58b as shown in Scheme 205.

Free base analysis data (-)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (204d) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (brs, 1H) 8.58 (d, J=2.4 Hz, 1H), 8.36 (dd, J=4.7, 1.6 Hz, 1H), 7.75 (dt, J=8.1, 2.0 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.50 (s, 1H), 7.47 - 7.36 (m, 2H), 7.30 (m, 3H), 7.18 (t, J=9.4 Hz, 1H), 3.77 (s, 2H), 2.37 - 2.03 (m, 2H), 1.03 (m, 2H), 0.63 (m, 1H), 0.41 - 0.24 (m, 2H), 0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.74, -124.19; MS (IER+) 553.4 (M+1), (IER-) 551.4 (M-1); optical rotation: [a] _D =(-) 1.87 [CH3OH, 0.535].

Free base analysis data (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (204e) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.57 (brs, 1H), 8.61 (m, 1H), 8.35 (m, 1H), 7.87 - 7.08 (m, 10H) , 3.73 (s, 2H), 2.38 - 2.05 (m, 2H), 1.07 (m, 2H), 0.65 (m, 1H), 0.36 (m, 2H), 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.43, -124.00; MS (IER+) 553.4 (M+1); [a] _D =(+) 0.685 [CH3OH, 1.75].

Scheme 205

An example of the preparation of (-)-I-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-( trifluoromethyl)-1H-pyrazol-5-carboxamide (205d) and (+)-N-(5-(1-amino-3cyclopropyl-1 -(pyridin-2-yl)propyl)-2-fluorophenyl)-1 -( 3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1 Hpyrazole-5-carboxamide (205e).

Compounds 205d and 205e can be prepared as shown in Scheme 205. Chiral purity was verified by chiral HPLC: AD-H column, 90/10/0.2 hexane/ethanol/TEA, 0.8 mL/min, UV 260 nm, cycle 45 min (temperature 40°C). Rt=20.976 (1 peak corresponding to 205d); Rt=26.044 (2nd peak, corresponding to 205e).

- 333 045731

Data from the analysis of the hydrochloride salt of (-)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-III-pyrazole-5-carboxamide (205d) as a white solid; _{Melting point} : 252.6°C; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.85 (s, 1H), 9.08 (s, 3H), 8.69 8.62 (m, 1H), 8.53 (s, 3H) , 7.89 (td, J=7.8, 1.9 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.64 (m, 2H), 7.55 (d, J =7.9 Hz, 1H), 7.51 (dd, J=3.6, 1.7 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.41 (m, 1H) , 7.38 (m, 1H), 7.36 - 7.27 (m, 1H), 4.11 (q, J=5.5 Hz, 2H), 2.67 - 2.50 (m, 2H ), 1.27 - 1.15 (m, 1H), 1.03 - 0.89 (m, 1H), 0.75 - 0.58 (m, 1H), 0.37 (m, 2H), 0.04 --0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.82, -120.56; MS (IER+) 553.4 (M+1), (IER-) 551.6 (M-1); chiral purity >99.9% ee; HPLC purity 98.4034%; optical rotation: [a]D=(-) 19.234 [CH ₃ OH, 1.175].

Data from the analysis of the hydrochloride salt of (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (205e) as a white solid; _{Melting point} : 227.9°C; ^1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.02 (s, 3H), 8.66 (m, 1H), 8.42 (s, 3H), 7. 89 (td, J=7.8, 1.8 Hz, 1H), 7.73 (m, 1H), 7.70 (m, 1H), 7.67 - 7.59 (m, 2H), 7 .56 (d, J=7.9 Hz, 1H), 7.51 (dd, J=3.9, 2.0 Hz, 1H), 7.44 (m, 1H), 7.39 (m, 1H), 7.36 (m, 1H), 7.34 - 7.28 (m, 1H), 4.12 (d, J=5.9 Hz, 2H), 2.57-2.40 (m , 2H), 1.21 (m, 1H), 0.96 (m, 1H), 0.66 (m, 1H), 0.42 - 0.32 (m, 2H), -0.03 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.82, -120.56; MS (IER+) 553.4 (M+1), (IER-) 587.2 (M+Cl); chiral purity >99.9% ee; HPLC purity >99.9%; optical rotation: [a]D=(+) 19.43 [CH3OH, 0.525].

Scheme 206

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (206d).

Step 1. Preparation of N-(3-((bis(cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (206a).

Compound 206a can be prepared from compound 144a as described in Step 1 of Scheme 168 using bis-cyclopropylmethylamine (preparation described in Baruah, Anima et al., Preparation of novel benzylamine derivatives as CETP inhibitors; WO 2006/073973).

Step 2. Preparation of (-)-N-(3-((bis(cyclopropylmethyl)amino)(phenyl)methyl)phenyl)-1-(3-cyanophenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 - carboxamide (206b).

Compound 206b can be obtained by resolving compound 206a obtained in step 1 by preparative chiral HPLC; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.11 (s, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.60 (d, J=7.5 Hz, 1H), 7.41 - 7 .14 (m, 7H), 4.92 (s, 1H), 2.44 (d, J=3.9 Hz, 4H), 0.90 (t, J=7.5 Hz, 2H), 0 .47 - 0.30 (m, 4H), -0.04 - -0.14 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.95, -123.40; IR 2237 cm ^-1 (-CN); MS (IER+) 588.3 (M+1); optical rotation: No=(-) 18.97 [CH3OH, 2.52]; analysis, calculation for C33H29F4N5O: C, 67.45; H, 4.97; N, 11.92; experiment: C, 67.32; H, 5.08; N, 11.75.

Step 3. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (206d).

Into a stirred solution of (-)-N-(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (206b) (6.0 g, 10.21 mmol) in anhydrous methanol (100 ml), cooled to 0°C, nickel (II) chloride hexahydrate (0.607 g, 2.55 mmol) was added to the reaction mixture in small sodium borohydride (2.90 g, 77 mmol) was added in portions over 45 minutes. The reaction mixture was stirred for 30 min at 0°C and quenched with N1-(2-aminoethyl)ethane-1,2diamine (2.206 ml, 20.42 mmol), stirred for 30 min and concentrated to dryness in vacuo. The resulting residue was stirred in water overnight. The solid was dissolved by adding

- 334 045731 niya conc. HCl (25.00 ml, 300 mmol). Insoluble solid was removed by filtration. The filtrate was neutralized with solid NaOH (12 g, 300 mmol) and further basified to pH=12 using 3N. NaOH. The pink solution was extracted with chloroform (2x100 ml). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0-25% methanol in chloroform) to give the free base (-)-1-(3-(aminomethyl)phenyl)-N-(5-(( bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (206d) (2.18 g, 3.68 mmol, 36.1% yield) in the form of white foam; ^1H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.70 - 7.62 (m, 1H), 7.57 (s, 1H), 7.52 (s, 1H ), 7.47 - 7.25 (m, 8H), 7.24 - 7.15 (m, 2H), 4.91 (s, 1H), 3.79 (s, 2H), 2.45 ( dd, J=6.2, 2.3 Hz, 4H), 0.90 (tq, J=11.4, 6.5, 5.7 Hz, 2H), 0.50 - 0.26 (m, 4H), -0.03 - -0.18 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.74, -123.73; MS (IER+) 592.4 (M+1); (IER-) 590.4 (M-1); HPLC (Rt=5.047, 98.4644); optical rotation: [a]D= (-) 1.51 [CH3OH, 1.565]; analysis, calculation for C33H ₃₃ F ₄ N ₅ O-0.5H ₂ O: C, 65.99; H, 5.71; N, 11.66; experiment: C, 66.29; H, 5.75; N, 11.57. The solid obtained above (1.68 g, 2.8 mmol) was dissolved in ethanol (5 ml) and conc. HCl (1.17 ml, 14 mmol), water (5 ml), stirred for 30 min and concentrated to dryness in vacuo to give 1.7 g HCl (-)-1-(3(aminomethyl)phenyl)-M salt -(5-((bis(cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (206d) as a white solid; Melting _point : 199°C; 1H NMR (300 MHz, DMSO-de) δ 11.61 (s, 1H), 10.86 (s, 1H), 8.52 (d, J=7.1 Hz, 3H), 8.20 (dd , J=7.0, 2.3 Hz, 1H), 8.08 - 7.92 (m, 3H), 7.76 - 7.69 (m, 2H), 7.67 - 7.51 (m , 3H), 7.46 - 7.31 (m, 4H), 5.81 (d, J=9.8 Hz, 1H), 4.12 (q, J=5.8 Hz, 2H), 3 .08 (dtt, J=17.1, 8.4, 4.5 Hz, 4H), 1.20 (ddt, J=12.6, 8.5, 5.0 Hz, 2H), 0.58 (ddq, J=7.4, 3.3, 1.9 Hz, 4H), 0.36 - 0.04 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.81, -120.39; MS (IER+) 592.4 (M+1); (IER-) 626.4 (M+Cl); optical rotation: [a]D=(-) 11.11 [CH3OH, 1.17]; analysis, calculation for

C33H33F4N5O-2HCl-1.75H2O: C, 56.94; H, 5.57; Cl, 10.19; N, 10.06; experiment: C, 56.98; H, 5.47; Cl, 10.44; N, 9.99.

Scheme 207

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(3-((3-bromo-4-hydroxyphenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 207j).

Step 1. (3-Aminophenyl)(4-(benzyloxy)-3-bromophenyl)methanol (207b) and (3-aminophenyl)(4(benzyloxy)phenyl)methanol (207c).

To a stirred solution of 4-(benzyloxy)-3-bromobenzaldehyde (207a) (3.2 g, 10 mmol) in THF (5 ml) was added (3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride (49c) (12 .00 ml, 12.00 mmol) at 0°C. The reaction mixture was stirred for 14 hours at room temperature, quenched by adding 2N. HCl (12.50 ml) and stirred for 6 hours. The reaction mixture was treated with 2N. NaOH (15 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with saturated aqueous NH ₄ Cl (50 ml), dry over anhydrous MgSO ₄ , filter, evaporate to dryness. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with 0100% ethyl acetate in hexanes) to give a mixture of (3-aminophenyl)(4-(benzyloxy)-3-bromophenyl)methanol

- 335 045731 (207b) and (3-aminophenyl)(4-(benzyloxy)phenyl)methanol (207c) (3.0 g).

Step 2. Preparation of No. (3-((4-(benzyloxy)-3-bromophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 207e) and N(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (207d).

A mixture of (3-aminophenyl)(4-( benzyloxy)-3-bromophenyl)methanol (207b) and (3aminophenyl)(4-(benzyloxy)phenyl)methanol (207c) (1 mmol), N-ethyl-N-isopropylpropan-2-amine (6 eq.) and hexafluorophosphate bromo-tris-pyrrolidinophosphonium (PyBrOP, 1.1 eq.) at room temperature. The reaction mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, eluted with mixtures of ethyl acetate in hexanes] to give the mixture N(3-((4-(benzyloxy)-3bromophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (207e) and N-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-( trifluoromethyl)-1Hpyrazole-5-carboxamide (207d).

Step 3. Preparation of N-(3-((3-(benzyloxy)-4-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1 -(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazole -5-carboxamide (207f) and N-(3-((4-(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole5 -carboxamide (207g).

Into a solution of a mixture of N-(3-((4-(benzyloxy)-3-bromophenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (207e ) and N-(3-((4-(benzyloxy)phenyl)(hydroxy)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (207d) (1 .0 mmol) in dichloromethane (10 ml) at 0°C, add thionyl chloride (3 mmol) and stir at room temperature for 4 hours. Concentrate the reaction mixture to dryness in vacuo. The resulting residue was dissolved in acetonitrile (10 ml) and cyclopropylmethanamine (10 mmol) was added. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in dichloromethane, washed with water, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate/hexane mixtures) to give a mixture (0.77 g) of N(3-((3-(benzyloxy)-4-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl) -1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (207f) and N-(3-((4-(benzyloxy)phenyl)-((cyclopropylmethyl)amino)methyl)phenyl )-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (207g).

Step 4. Preparation of tert-butyl-((4-(benzyloxy)phenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamido)phenyl)methyl)(cyclopropylmethyl)carbamate (207h) and tert-butyl-3-(5-((3-((4-(benzyloxy)-3-bromophenyl)((cyclopropylmethyl)amino)methyl)phenyl )carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (207i).

Into a solution of a mixture of N-(3-((3-(benzyloxy)-4-methoxyphenyl)((cyclopropylmethyl)amino)methyl)phenyl)1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (207f) and N-(3-((4-(benzyloxy)phenyl)((cyclopropylmethyl)amino)methyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (207g) (0.77 g) in MeOH (10 ml), cooled in ice/water, nickel (II) chloride hexahydrate (0.25 eq.) and Boc anhydride (4 eq.) were added, then sodium borohydride (6 equiv.) was added in portions over 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and quenched with N(2-aminoethyl)ethane-1,2-diamine (2 eq.), then stirred for another 0.5 hours. Concentrate the reaction mixture to dryness in vacuo and dissolve the resulting residue in chloroform and water. The aqueous layer was separated and extracted again with chloroform. The combined extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with ethyl acetate/hexane mixtures) to give:

1. tert-butyl-((4-(benzyloxy)phenyl)(3-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamido )phenyl)methyl)(cyclopropylmethyl)carbamate (207h) (0.24 g, 22%) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 7.49 - 7.38 (m, 9H), 7.34 (d, J=7.2 Hz, 4H), 7.17 (q, J=8.6 Hz, 2H), 6.93 (d, J=7 .9 Hz, 1H), 6.16 (s, 1H), 5.21 (s, 2H), 4.18 (d, J=6.2 Hz, 2H), 3.22 - 2.91 (m , 2H), 1.37 (s, 9H), 1.30 - 1.23 (m, 9H), 0.750.56 (m, 1H), 0.23 (d, J=8.2 Hz, 2H) , -0.04 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.71; MS (ESI+) 848.8.5 (M+Na); (IER-) 824.5 (M-1);

2. tert-butyl-3-(5-((3-((4-(benzyloxy)-3-bromophenyl)((cyclopropylmethyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (207i) (0.35 g, 39.6%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.69 (s, 1H), 7.61 (d, J=2.0 Hz, 2H), 7.57 (s, 1H), 7.53 ( s, 1H), 7.45-7.39 (m, 6H), 7.37 - 7.32 (m, 4H), 7.25 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 5.15 (s, 2H), 4.77 (s, 1H), 4.19 (d, J=6.3 Hz, 2H), 2.26 (d, J=6.4 Hz, 2H), 1.35 (s, 9H), 0.94 - 0.84 (m, 1H) , 0.46 0.28 (m, 2H), 0.05 (t, J=4.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79; MS (IER+) 804.4, 806.3 (M+1).

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Step 5. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((3-bromo-4-hydroxyphenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide (207j).

Into a solution of tert-butyl-3 -(5-((3-((4-(benzyloxy)-3-bromophenyl)(cyclopropylmethylamino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )benzylcarbamate (207i) (0.120 g, 0.149 mmol) in dichloromethane (10 ml), cooled to 0°C, tribromoborane (1 M solution in dichloromethane, 0.596 ml, 0.596 mmol) was added dropwise under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with methanol (5 ml) and the mixture was concentrated to dryness in vacuo. The resulting residue was triturated with methanol and dried in vacuo, this step being repeated four times to obtain the crude product. The resulting residue was purified twice by flash column chromatography [silica gel, 12 g and 4 g, eluted with mixtures of CMA-80 in chloroform, 0-100%] to give 1-(3-(aminomethyl)phenyl)-N-(3-( (3-bromo-4hydroxyphenyl)(cyclopropylmethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (207j) (0.045 g, 0.073 mmol, 49.1% yield) as a brownish-orange solid substances; 1H NMR (300 MHz, DMSO) δ 10.89 (s, 1H), 10.62 (s, 1H), 9.58 (s, 2H), 8.26 (s, 3H), 7.81 (s , 1H), 7.76 - 7.71 (m, 2H), 7.67 (s, 1H), 7.62 - 7.46 (m, 6H), 7.38 (dd, J=8.5 , 2.2 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 5.56 (d, J=6.4 Hz, 1H), 4.24 - 4.06 (m , 2H), 2.72 (d, J=6.3 Hz, 2H), 1.08 (ddt, J=12.7, 8.3, 4.1 Hz, 1H), 0.56 (dt, J=9.4, 3.0 Hz, 2H), 0.30 (t, J=4.9 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80; MS (IER+) 616.3 (M+2); (IER-) 612.4 (M-2); HPLC purity (95.8256%); analysis, calculation for C ₂₉ H ₂₇ BrF ₃ N ₅ O ₂ -2.1HBr-2H2O: C, 42.46; H, 4.07; Br, 30.19; N, 8.54; experiment: C, 42.22; H, 3.99; Br, 30.56; N, 8.35.

Scheme 208 (8)-2-methylpropane-2-sulfinamide

An example of the preparation of (+)-K-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-( trifluoromethyl)-III-pyrazole-5-carboxamide (208d)

Step 1. Preparation of (+)-X-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide (208a).

To a stirred solution of 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c) (3.98 g, 22.69 mmol) in tetrahydrofuran (30 ml) was added (S)-2-methylpropan- 2-sulfinamide (2.5 g, 20.63 mmol), tetraisopropoxytitanium (12.34 ml, 41.3 mmol) and heated at reflux temperature for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with saline ( 20 ml) and tetrahydrofuran (100 ml). The isolated solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was suspended in dichloromethane (300 ml), washed with brine (50 ml), dried, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes) to give (+)-K-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2sulfinamide (208a) (1.32 g, 4.74 mmol, 22.99% yield) as a yellow thick liquid; 1(H NMR 300 MHz, DMSO-d ₆ ) δ 9.25 (d, J=2.3 Hz, 1H), 8.93 (dd, J=4.8, 1.7 Hz, 1H), 8 .46 (d, J=8.1 Hz, 1H), 7.75 (dd, J=8.0, 4.8 Hz, 1H), 3.69 - 3.41 (m, 2H), 1, 68 (q, J=7.4 Hz, 2H), 1.45 (s, 9H), 0.96 (m, 1H), 0.67 -0.48 (m, 2H), 0.30 0, 22 (m, 2H); optical rotation [a] _D =(+) 25.77 [0.52, MeOH].

Step 2. Preparation of (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)2-methylpropan-2-sulfinamide ( 208b).

Into a stirred solution of (+)-C-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2sulfinamide (208a) (4.12 g, 14.80 mmol) in toluene (30 ml ) at -20°C, a freshly prepared solution of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (29.6 mL, 29.6 mmol) was added dropwise over 10 min. The reaction mixture was stirred at -20°C for 1 hour and the reaction was quenched with 1N. aqueous KHSO4 (25 ml). The reaction mixture was stirred for 1 hour at room temperature and extracted with ethyl acetate (2x200 ml). Combine organic layers, wash with water (2x50 ml),

- 337 045731 saline solution (50 ml), dried and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography (silica gel, 50 g, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give (S)-N-((+)-1-(3-amino-4-fluorophenyl) -3-cyclopropyl-1-(pyridin-3yl)propyl)-2-methylpropane-2-sulfinamide (208b) (1.15 g, 2.95 mmol, 19.95% yield) as a white solid; 1H NMR (300 MHz, DMSO^) δ 8.51 (dd, J=2.5, 0.8 Hz, 1H), 8.40 (dd, J=4.7, 1.5 Hz, 1H), 7.70 (dt, J=8.1, 2.0 Hz, 1H), 7.32 (ddd, J=8.1, 4.7, 0.8 Hz, 1H), 6.90 (dd, J=11.3, 8.5 Hz, 1H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.50 (ddd, J=8.5, 4.3, 2.4 Hz, 1H), 5.27 (s, 1H), 5.11 (s, 2H), 2.67 - 2.54 (m, 2H), 1.12 (s, 10H), 0, 90 (m, 1H), 0.65 (m, 1H), 0.41 - 0.29 (m, 2H), -0.01 - -0.17 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 137.66; MS (IER+) 390.4 (M+1), 412.4 (M+Na), 779.6 (2M+1), 801.6 (2M+Na), (IER-) 388.3 (M -1); optical rotation [a] _D =(+)110.34 [0.145, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)1 -(pyridin-3-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (208c).

To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (10d) (1.251 g, 3.25 mmol) in DMF (17 ml) was added ( S)-N-((+)-1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide (208b) (1.15 g, 2.95 mmol), N-ethyl-N-isopropylpropan-2-amine (2.57 mL, 14.76 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop, 1.514 g, 3.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 6 hours, diluted with water (40 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-( (S)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (208c) (1,2 g, 0.696 mmol, 53% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.558.45 (m, 1H), 8.41 (dd, J=4.7, 1.5 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.51 (t, J=6.3 Hz, 1H), 7, 42 (d, J=4.9 Hz, 2H), 7.38 - 7.30 (m, 3H), 7.25 (d, J=10.0 Hz, 2H), 5.58 (s, 1H ), 4.19 (d, J=6.2 Hz, 2H), 2.73 2.54 (m, 2H), 1.38 (s, 9H), 1.12 (s, 10H), 0, 92 (m, 1H), 0.64 (m, 1H), 0.41-0.24 (m, 2H), -0.02--0.19 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.81, -123.10; MS (IER+) 757.4 (M+1), 779.4 (M+Na), (IER-) 755.4 (M1). Optical rotation [a] _D =(+) 67.17 (0.265, methanol).

Step 4. Preparation of (+)-M-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (208d).

Into a stirred solution of tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1 -(pyridin-3-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (208c) (1 g, 1.321 mmol) in ethanol (20 ml) was added conc. HCl (1.101 ml, 13.21 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 24 g, eluted with mixtures of CMA 80 in chloroform, from 0 to 100%) to give the product, which was purified again by flash column chromatography (silica gel, 24 g, eluted with mixtures of methanol in chloroform, 0 to 50%) to give the free base (+)-N-(5-(1 -amino-3-cyclopropyl-1-(pyridin3 -yl)propyl)-2-fluorophenyl)-1 -(3 -(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (208d) (560 mg, 1.013 mmol, 77% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (d, J=2.4 Hz, 1H), 8.36 (dd, J=4.7, 1.6 Hz, 1H), 7, 75 (dt, J=8.1, 2.0 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.50 (s, 1H), 7.47 - 7.36 (m, 2H), 7.30 (td, J=8.0, 7.4, 3.6 Hz, 3H), 7.18 (t, J=9.4 Hz, 1H), 3.77 (s, 2H ), 2.37 - 2.03 (m, 2H), 1.03 (t, J=6.4 Hz, 2H), 0.63 (td, J=9.0, 8.0, 4.3 Hz, 1H), 0.41 - 0.24 (m, 2H), -0.08 (td, J=5.3, 3.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73, -124.20; MS (IER+) 553.4 (M+1), (IER-) 551.4 (M-1).

Into a stirred solution of the free base (+)-M-(5-(1-amino-3-cyclopropyl-1-(pyridin-3yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (208d) (495 mg, 0.896 mmol) in ethanol (5 ml) was added conc. HCl (0.373 ml, 4.48 mmol), water (3 ml), stirred for 10 min and concentrated to dryness to give (+)-N-(5(1-amino-3-cyclopropyl-1-(pyridine) hydrochloride salt -3-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (208d) (0.491 g, 0.785 mmol, 88% yield , >99.99 e.i.) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.84 (s, 1H), 9.60 (s, 3H), 8.72 - 8.63 (m, 2H), 8.45 (s, 3H), 8.02 (d, J=8.4 Hz, 1H), 7.75- 7.32 (m, 9H), 4.11 (q, J=5.8 Hz, 2H), 2.64 - 2 .54 (m, 2H), 1.10 (dd, J=17.8, 7.7 Hz, 2H), 0.68 (d, J=8.0 Hz, 1H), 0.43 - 0, 33 (m, 2H), 0.07-0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d;) δ 60.80, -120.42 (d, J=10.5 Hz); MS (IER+) 553.5 (M+1), (IER-) 551.5 (M-1); optical rotation [a] _D =(+) 2.55 [1.02, MeOH]; chiral purity was checked by chiral HPLC on a chiral AD-H column, 1 ml/min, solvent: 85% hexane, 20% EtOH, 0.1% TEA, UV = 260 nm, 20°C (>99.99 ee .).

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Scheme 209

An example of the preparation of (-)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (209d).

Step 1. Preparation of (-)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2-sulfinamide (209a).

Compound (209a) was prepared from 3-cyclopropyl-1-(pyridin-3-yl)propan-1-one (47c) (3.98 g, 22.69 mmol) and (R)-2-methylpropan-2-sulfinamide (2.5 g, 20.63 mmol) according to the method of preparation of compound 208a described in step 1 of scheme 208, (-)-N-(3-cyclopropyl-1-(pyridin-3yl)propylidene)-2-methylpropane- 2-sulfinamide (209a) (2.5 g, 8.98 mmol, 43.5% yield) as a yellow thick liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 8.24 (d, J=8 ,1 Hz, 1H), 7.53 (dd, J=8.1, 4.8 Hz, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 1.47 (q , J=7.4 Hz, 2H), 1.24 (s, 9H), 0.82 0.66 (m, 1H), 0.44 - 0.29 (m, 2H), 0.12 - 0 .01 (m, 2H); optical rotation [a]D=(-) 17.29 [0.59, MeOH].

Step 2. Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)2-methylpropan-2-sulfinamide ( 209b).

Into a stirred solution of (-)-N-(3-cyclopropyl-1-(pyridin-3-yl)propylidene)-2-methylpropane-2sulfinamide (209a) (82 g, 295 mmol) in toluene (1700 ml) at -20 °C, a freshly prepared solution of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (920 mL, 736 mmol) was added dropwise over 120 min. The reaction mixture was stirred at -20°C for 1 hour and the reaction was quenched with 1N. aqueous KHSO4 (1600 ml). The reaction mixture was stirred for 1 hour at room temperature, made alkaline with 2N. NaOH to pH~8 and extracted with ethyl acetate (1500, 700 ml). Combine the organic layers, wash with water (2x700 ml), brine (700 ml), dry and concentrate in vacuo. The crude residue was purified by flash column chromatography (silica gel, eluted with 9:1 ethyl acetate/methanol in hexanes, 0 to 50%) to give (R)-N-((-)-1-(3-amino- 4fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide (209b) (54.155 g, 139 mmol, 47.2% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 - 8.48 (m, 1H), 8.39 (dd, J=4.7, 1.5 Hz, 1H), 7.70 (dt , J=8.1, 2.0 Hz, 1H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 6.90 (dd, J=11.2, 8.5 Hz, 1H), 6.73 (dd, J=8.8, 2.4 Hz, 1H), 6.56 - 6.45 (m, 1H), 5.26 (s, 1H), 5.10 (s, 2H), 2.67-2.54 (m, 2H), 1.281.11 (m, 1H), 1.12 (s, 9H), 0.91 (m, 1H), 0.64 ( m, 1H), 0.40 -0.30 (m, 2H), -0.02 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.67; MS (IER+) 390.4 (M+1); (IER-) 388.4 (M-1); optical rotation No=(-) 105.71 [0.28, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)1 -(pyridin-3-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (208c).

Compound (209c) was prepared using 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (21.76 g, 56.5 mmol) and (R)-N-((-)-1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-methylpropane-2-sulfinamide (209b) (20 g, 51.3 mmol) using the method for compound 208c described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1 -((R)- 1,1-Dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (209c) (16 g, 21.4 mmol, yield 41.2%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.41 (dd, J=4.7, 1 .5 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.63-7.15 (m, 10H), 5.57 (s, 1H), 4.18 (d , J=6.3 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s, 9H), 1.22-1.01 (m, 1H), 1.12 ( s, 9H), 1.00-0.80 (m, 1H), 0.72-0.54 (m, 1H), 0.40-0.28 (m, 2H), -0.02- - 0.16 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.61, -122.92; MS (IER+) 757.6 (M+1); (IER-) 755.6 (M-1); optical rotation [(a]D (-) 66.4 [0.25, MeOH].

Step 4. Preparation of (-)-K-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (209d).

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Into a stirred solution of tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1 -(pyridin-3-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (209c) (15.76 g, 20.82 mmol) in ethanol (720 ml) was added conc. hydrochloric acid (17.40 ml, 209 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and dissolve the resulting residue in ethanol (50 ml), triturate with methyl tert-butyl ether (300 ml , 200 ml) and decanted. The solid was dried in vacuo, dissolved in water (100 ml) and concentrated in vacuo. The off-white solid was redissolved in water (30 ml) and concentrated to dryness in vacuo to give HCl salt (-)-N-(5-(1-amino-3cyclopropyl-1-(pyridin-3-yl)propyl)-2- fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (209d) (11.966 g) as an off-white solid; 1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 9.73 (s, 3H), 8.80-8.73 (m, 2H), 8.63 - 8.38 (m, 3H), 8.21 (dt, J=8.5, 1.7 Hz, 1H), 7.81 (dd, J=8.2, 5.2 Hz, 1H), 7.75-7.32 (m, 8H), 4.09 (q, J=5.8 Hz, 2H), 2.71 - 2.37 (m, 2H), 1.22 - 1.04 (m, 2H), 0, 74-0.58 (m, 1H), 0.48 - 0.25 (m, 2H), 0.08 - -0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.63, 120.00; MS (IER+): 553.5 (M+1); optical rotation [a] _D =(-) 2.82 [1.065, MeOH]; chiral purity was checked by chiral HPLC on a chiral AD-H column, 1 ml/min, solvent: 85% hexane, 20% EtOH, 0.1% TEA, UV=260 nm, 20°C (>99.99 ee .).

Scheme 210 (8)-2-methylpropane-2-sulfinamide

An example of the preparation of (-)-X-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (210d).

Step 1. Preparation of (+)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide (210a).

Compound (210a) was prepared from 3-cyclopropyl-1-phenylpropan-1-one (46d) (3.95 g, 22.69 mmol) using (S)-2-methylpropan-2-sulfinamide (2.5 g, 20.63 mmol) using the method described in step 1 of scheme 208 gave (+)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2sulfinamide (210a) (1.22 g, 4.40 mmol, yield 21.32%) in the form of a light brownish-yellow thick liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (d, J=7.4 Hz, 2H), 7.61 - 7.42 (m, 3H), 3.36 (m, 1H), 3.31 - 3.13 (m, 1H), 1.46 (q, J=7.4 Hz, 2H), 1.23 (s, 9H), 0.76 (m, 1H), 0.38 (m, 2H), 0.05 (m, 2H); MS (ESI+) 278.2 (M+1), 300.3 (M+Na), 555.4 (2M+1), 577.4 (2M+Na); optical rotation [a] _D =(+) 22.22 [0.27, MeOH].

Step 2. Preparation of (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2methylpropane-2-sulfinamide (210b)

Compound (210b) was prepared from (+)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2sulfinamide (210a) (2 g, 7.21 mmol) using the method described in step 2 of Scheme 208. prepared (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide (210b) (2.16 g, 5 .56 mmol, yield 77%) in the form of a light yellow thick liquid. 1H NMR (300 MHz, DMSO-d6) δ 7.36 - 7.24 (m, 4H), 7.23 -7.15 (m, 1H), 6.87 (dd, J=11.3, 8 .5 Hz, 1H), 6.71 (dd, J=8.9, 2.4 Hz, 1H), 6.48 (ddd, J=8.5, 4.3, 2.3 Hz, 1H) , 5.06 (s, 2H), 4.94 (s, 1H), 2.57 (m, 2H), 1.06 (s, 10 H), 1.05 (m, 1H), 0.87 (m, 1H), 0.45-0.24 (m, 2H), 0.04 - -0.19 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -138.17; MS (IER+) 389.3 (M+1), 777.6 (2M+1), 799.6 (2M+23), (IER-) 387.3 (M-H); optical rotation [a] _D =(+) 112.56 [0.215, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1-dimethylsulfinamido)-1phenylpropyl)-2-fluorophenylcarbamoyl)-3 -( trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (210c).

Compound (210c) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (1.473 g, 3.82 mmol) and (S )-N-((+)-1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide (210b) (1.35 g, 3.47 mmol) at Using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((8)-1,1

- 340 045731 dimethylsulfinamido)-1 -phenylpropyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (210c) (1.532 g, 2.027 mmol, 58.3% yield) as white solid matter; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.58 (s, 1H), 7.63 - 7.16 (m, 13H), 5.29 (s, 1H), 4.19 (d, J =6.2 Hz, 2H), 2.57 (m, 2H), 1.38 (s, 10H), 1.12 (s, 10H), 0.87 (m, 1H), 0.62 (m , 1H), 0.43 - 0.23 (m, 2H), -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.79, -123.61; MS (IER+) 756.6 (M+1), 778.6 (M+Na); optical rotation [a]D=(+) 72.14 [0.28, MeOH].

Step 4. Preparation of (-)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (210d).

The free base (210d) was prepared from tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((S)-1,1dimethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)- 3 -(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (210c) (1.454 g, 1.924 mmol) as described in step 4 of Scheme 208 gave the free base (-)-N-(5-( 1 -amino-3 -cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (210d) (0.830 g, 1.505 mmol, 78% yield ) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 7.55 (d, J=14.1 Hz, 3H), 7.49 - 7.31 (m, 5H), 7.30 - 7.21 (m, 3H), 7.21 - 7.09 (m, 2H), 3.81 (s, 2H), 3.34 (s, 2H), 2.73 -2, 55 (m, 2H), 2.31-2.10 (m, 2H), 1.03 (m, 2H), 0.61 (m, 1H), 0.43-0.23 (m, 2H) , -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.66, 124.51; MS (IER-) 550.4 (M-1).

Into a stirred solution of the free base (-)-N-(5-(1-amino-3-cyclopropyl-1phenylpropyl)-2-fluorophenyl)-1-(3 -(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H -pyrazole-5-carboxamide (210d) (682 mg, 1.236 mmol) in ethanol (10 ml) was added conc. HCl (0.515 ml, 6.18 mmol), water (5 ml), stirred for 10 min and concentrated to dryness in vacuo to give (-)-N-(5-(1-amino-3-cyclopropyl-1) hydrochloride salt -phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (210d) (666 mg, 1.066 mmol, 86% yield) as white solid matter; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 9.29 (s, 3H), 8.51 (s, 3H), 7.72 (dd, J=5.4 , 3.6 Hz, 2H), 7.63 (dt, J=7.2, 1.7 Hz, 1H), 7.60 - 7.47 (m, 3H), 7.47 - 7.30 ( m, 7H), 4.11 (s, 2H), 2.41 -2.55 (m, 2H), 1.22 - 0.99 (m, 2H), 0.67 (m, 1H), 0 .46 - 0.28 (m, 2H), 0.01-0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.81, 120.90; MS (ESI+) 550.4 (M-1), 586.4 (M+Cl); optical rotation [a]D=(-) 3.51 [1.025, MeOH]; analysis, calculation for C ₃₀ H ₂₉ F ₄ N ₅ O-2HCM,5H ₂ O: C: 55.36, H: 5.27, N: 10.76, Cl: 11.68; experiment: C: 55.35, H: 5.45, N: 10.63, Cl: 11.45.

Scheme 211

An example of the preparation of (+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (211d).

Step 1. Preparation of (-)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide (211a).

Compound (211a) was prepared from 3-cyclopropyl-1-phenylpropan-1-one (46d) (3.95 g, 22.69 mmol) and (R)-2-methylpropan-2-sulfinamide (2.5 g, 20 .63 mmol) using the method described in step 1 of Scheme 208 gave (-)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide (211a) (3.247 g, 11.70 mmol , yield 56.7%) in the form of a light brownish-yellow thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.89 (d, J=7.6 Hz, 2H), 7.51 (qd, J=8.7, 7.8, 3.6 Hz, 3H) , 3.45- 3.15 (m, 2H), 1.46 (m, 2H), 1.23 (s, 9 H), 0.82 - 0.67 (m, 1H), 0.43 - 0.32 (m, 2H), 0.06 (m, 2H); MS (IER+) 278.3 (M+1), 300.3 (M+Na),

577.5 (2M+Na); optical rotation [a]D=(-) 36.32 [0.76, CHCl3].

Step 2. Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide (211b).

Compound (211b) was prepared from (-)-N-(3-cyclopropyl-1-phenylpropylidene)-2-methylpropane-2-sulfinamide (211a) (3.065 g, 11.05 mmol) using the method described in step 2 of the scheme 208, prepared (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide

- 341 045731 (211b) (2.62 g, 6.74 mmol, 61.0% yield) as a light brown oily liquid; 1H NMR (300

MHz, DMSO-de) δ 7.35 - 7.25 (m, 4H), 7.22 - 7.15 (m, 1H), 6.87 (dd, J=11.3, 8.5 Hz, 1H), 6.71 (dd, J=8.8, 2.4

Hz, 1H), 6.49 (m, 1H), 5.06 (s, 2H), 4.94 (s, 1H), 2.61 - 2.52 (m, 2H), 1.14 (m , 10H), 0.97 -0.80 (m, 1H), 0.750.52 (m, 1H), 0.36 (m, 2H), -0.01 - -0.16 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^6) δ -138.17; MS (IER+) 389.4 (M+1), 777.6 (2M+1), 799.6 (2M+Na); optical rotation [a]D=(-) 100.41 [0.245, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((-)-3-cyclopronul-1-((R)-1,1-dimethylethylsulfunamido)1-phenylpropyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (211c).

Compound (211c) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (2.73 g, 7.08 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide (211b) (2.5 g, 6.43 mmol ) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)-1-phenylpropyl) was prepared -2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (211c) (1.532 g, 2.027 mmol, 31.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-de) δ 10.58 (s, 1H), 7.57 (d, J=6.9 Hz, 2H), 7.53 - 7.47 (m, 1H), 7 .42 (dd, J=5.7, 2.8 Hz, 2H), 7.39 - 7.15 (m, 9H), 5.29 (s, 1H), 4.19 (d, J=6 .3 Hz, 2H), 2.77 - 2.55 (m, 2H), 1.38 (s, 9H), 1.12 (s, 9H), 1.05 (s, 1H), 0.96 - 0.80 (m, 1H), 0.62 (m, 1H), 0.43 - 0.26 (m, 2H), -0.02 - -0.17 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -60.79, -123.62; MS (ESI+) 756.6 (M+H), 778.5 (M+Na), (ESI-) 754.5 (M-H), 790.4 (M+Cl); optical rotation [a]D=(-) 72.94 [0.255, MeOH].

Step 4. Preparation of (+)-N-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (211d).

The free base (211d) was prepared from tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)- 3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (211c) (1.49 g, 1.971 mmol) as described in step 4 of Scheme 208 gave the free base (+)-N-(5-(1-amino -3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (211d) (1.0 g, 1.813 mmol , yield 92%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.32 (s, 2H), 7.57 (d, J=5.1 Hz, 2H), 7.50 ( s, 1H), 7.47 - 7.40 (m, 2H), 7.39 - 7.30 (m, 2H), 7.29 - 7.22 (m, 2H), 7.20 - 7, 10 (m, 2H), 3.77 (s, 2H), 3.35 (s, 2H), 2.29 - 1.97 (m, 4H), 1.10 - 0.94 (m, 2H) , 0.62 (m, 1H), 0.39 - 0.28 (m, 2H), -0.09 (m, 2H); ^19F

NMR (282 MHz, DMSO-d6) δ -60.72, -124.61; MS (IER+) 552.4 (M+1), (IER-) 550.4 (M-1).

Into a stirred solution of the free base (+)-N-(5-(1-amino-3-cyclopropyl-1phenylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (211d) (0.9 g, 1.632 mmol) in ethanol (10 ml) was added conc. HCl (0.680 ml, 8.16 mmol), water (5 ml), stirred for 10 min and concentrated to dryness to give (+)-N-(5-(1amino-3-cyclopropyl-1-phenylpropyl)- hydrochloride salt 2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (211d) (700 mg, 1.121 mmol, 68.7% yield) as a white solid.

1H NMR (300 MHz, DMSO-de) δ 10.84 (d, J=4.1 Hz, 1H), 9.38 (d, J=33.2 Hz, 3H), 8.55 (s, 3H ), 7.72 (dd, J=4.6, 2.8 Hz, 2H), 7.68 - 7.61 (m, 1H), 7.60 - 7.47 (m, 3H), 7, 45- 7.31 (m, 7H), 4.10 (s, 2H), 2.3-2.6 (m, 2H), 1.09 (m, 2H), 0.68 (m, 1H) , 0.36 (m, 2H), -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.63, -120.68; MS (ESI-) 550.4, 586.4 (M+Cl); [a]D=(+) 4.77 [1.09, MeOH]; analysis, calculation for CзoH29F4N5O 2HCl 1.75H2O: C, 54.92; H, 5.30; N, 10.68; Cl, 10.81; experiment: C: 54.76, H: 5.33, N: 10.52, Cl: 11.04.

Scheme 212

- 342 045731

An example of the preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3 -(trifluoromethyl)- 1 H-pyrazole-5-carboxamide (212g).

Step 1. Preparation of (E)-4-(3-cyclopropylacryloyl)benzonitrile (212b).

To a stirred solution of 4-acetylbenzonitrile (212a) (5 g, 34.4 mmol) in ethanol (100 ml) at 0°C was added cyclopropanecarboxaldehyde (4.15 ml, 55.1 mmol), then potassium hydroxide (2M aqueous solution, 3.44 ml, 6.89 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was acidified with HCl to pH 6 and concentrated in vacuo while maintaining the bath temperature below 35°C. The resulting residue was purified by flash column chromatography (silica gel, eluted with mixtures of ethyl acetate in hexanes, 0 to 20%) to give (E)4-(3-cyclopropylacryloyl)benzonitrile (212b) (512 mg, 2.60 mmol, yield 7.54 %) in the form of a colorless liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.12 - 8.08 (m, 2H), 8.02 - 7.99 (m, 2H), 7.25 (d, J=15.0 Hz , 1H), 6.57 (dd, J=15.1, 10.4 Hz, 1H), 1.80 (dddd, J=12.4, 10.4, 7.9, 4.5 Hz, 1H ), 1.08 - 0.99 (m, 2H), 0.79 (tt, J=4.8, 2.4 Hz, 2H); MS (IER-) 196.1 (M-1).

Step 2. Preparation of 4-(3-cyclopropylpropanoyl)benzonitrile (212c).

To a stirred solution of (E)-4-(3-cyclopropylacryloyl)benzonitrile (212b) (1.1 g, 5.58 mmol) in acetonitrile (10 ml) was added tri-n-butyltin hydride (1.489 ml, 5.58 mmol ) and heated at the reverse condensation temperature for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give 4-(3-cyclopropylpropanoyl)benzonitrile (212c) (457 mg, 2.294 mmol, 41.1% yield) in in the form of a colorless oily liquid; 1H NMR (300 MHz, DMSO^) δ 8.08 - 8.03 (m, 2H), 7.98 - 7.91 (m, 2H), 3.09 (t, J=7.2 Hz, 2H ), 1.46 (q, J=7.1 Hz, 2H), 0.77 - 0.59 (m, 1H), 0.38 - 0.26 (m, 2H), 0.06 - -0 .04 (m, 2H); MS (IER-) 198.2 (M-1).

Step 3. Preparation of (+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (212d).

Compound (212d) was prepared from 4-(3-cyclopropylpropanoyl)benzonitrile (212c) (0.814 g, 4.08 mmol) and (R)-2-methylpropane-2-sulfinamide (0.45 g, 3.71 mmol) at Using the method described in step 1 of Scheme 208, (+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2sulfinamide (212d) (720 mg, 2.38 mmol, yield 64 .1%) in the form of a light yellow thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 8.11 - 7.93 (m, 4H), 3.34 (m, 2H), 1.44 (m, 1H), 1.24 (s, 10H) , 0.73 (m, 1H), 0.45-0.29 (m, 2H), 0.03 (m, 2H); optical rotation: [a] _D =(+) 16.55 [0.29, MeOH].

Step 4. Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)2-methylpropane-2-sulfinamide (212e).

Compound (212e) was prepared from (+)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (212d) (0.5 g, 1.653 mmol) using the method described in step 2 of Scheme 208, (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide was obtained (212e) (538 mg, 1.301 mmol, 79% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 - 7.66 (m, 2H), 7.61 - 7.44 (m, 2H), 6.90 (dd, J=11.3, 8.5 Hz, 1H), 6.70 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.6, 4.3, 2.4 Hz, 1H ), 5.27 (s, 1H), 5.11 (s, 2H), 2.62 - 2.55 (m, 1H), 2.46 -2.39 (m, 1H), 1.12 ( s, 9H), 1.06 (s, 1H), 0.99 - 0.80 (m, 1H), 0.64 (s, 1H), 0.36 (m, 2H), -0.02 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -137.54; MS (IER+) 414.396 (M+1); optical rotation: [a] _D =(-) 83.24 [0.185, MeOH].

Step 5. Preparation of tert-butyl-3-(5-(5-((-)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl )-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (212f).

Compound (212f) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (0.512 g, 1.330 mmol) and (R)- N-((-)-1-(3-amino-4-fluorophenyl)-1(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (212e) (0.5 g, 1.209 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((-)-1-(4-cyanophenyl)3-cyclopropyl-1-((R)-1,1 -dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (212f) (557 mg, 0.713 mmol, 59.0% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-di) δ 10.61 (s, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.58 (m, 2H), 7.49 (m , 2H), 7.42 (m, 2H), 7.38 - 7.30 (m, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.57 (s, 1H) , 4.19 (d, J=6.2 Hz, 2H), 3.102.95 (m, 1H), 2.65-2.54 (m, 1H), 2.44 (m, 1H), 1, 38 (s, 9H), 1.12 (s, 10H), 1.03 - 0.76 (m, 1H), 0.62 (m, 1H), 0.34 (m, 2H), -0, 08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.78, -122.98; MS (IER+) 803.6 (M+Na); optical rotation: [a] _D =(-) 56 [0.15, MeOH].

Step 6. Preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1(3 -(aminomethyl)phenyl)-3 -(trifluoromethyl) )-1 H-pyrazole-5-carboxamide (212g).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (212f) (0.51 g, 0.653 mmol) in ethanol (25 ml) was added conc. HCl (0.544 ml, 6.53 mmol) and

- 343 045731 heated at reverse condensation temperature for 1 hour. The reaction mixture was concentrated to dryness in vacuo, triturated with diethyl ether, stirred overnight at room temperature, collected by filtration and washed with diethyl ether. The resulting residue was dissolved in ethanol (20 ml) and concentrated to dryness in vacuo to give (+)-P-(5-(1-amino-1-(4cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1 -( hydrochloride 3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (212g) (410 mg, 0.631 mmol, 97% yield) as a white solid. 1H NMR (300 MHz, DMSO) δ 10.81 (s, 1H), 9.48 (s, 3H), 8.43 (s, 3H), 7.94 (d, J=8.0 Hz, 2H ), 7.71 (d, J=12.1 Hz, 2H), 7.66 - 7.46 (m, 6H), 7.45 - 7.28 (m, 2H), 4.12 (s, 2H), 2.60 - 2.49 (m, 2H), 1.29 - 1.08 (m, 2H), 0.67 (m, 1H), 0.46 - 0.29 (m, 2H) , 0.02-0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.79, -120.37; MS (IER+) 577.4 (M+1), (IER-) 575.5 (M-1), 611.4 (M+Cl); optical rotation: [α]π=(+) 16.43 [CH3OH, 0.28]; analysis, calculation for C31H2 ₈ P4^O-2HC1-2H2O: C, 54.31; H, 5.00; Cl, 10.34; N, 12.26; experiment: C, 53.95; H, 5.01; Cl, 9.94; N, 12.01.

Scheme 213

An example of the preparation of (-)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (213d).

Step 1. Preparation of (-)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (213a).

Compound (213a) was prepared from 4-(3-cyclopropylpropanoyl)benzonitrile (212c) (1.21 g, 6.07 mmol) and (S)-2-methylpropane-2-sulfinamide (0.743 g, 6.07 mmol) at Using the method described in step 1 of Scheme 208, (-)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2sulfinamide (213a) (1.252 g, 4.14 mmol, yield 68 .2%) in the form of a light yellow thick liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.04 - 7.89 (m, 4H), 3.47 - 3.16 (m, 2H), 1.41 (q, J=7.5 Hz , 2H), 1.21 (s, 9H), 0.80-0.60 (m, 1H), 0.40-0.27 (m, 2H), 0.08 - -0.10 (m, 2H); MS (IER+) 303.3 (M+1); (IER-) 301.3 (M-1).

Step 2. Preparation of (S)-N-((+)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (213b) .

Compound (213b) was prepared from (-)-N-(1-(4-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (213a) (1.197 g, 3.96 mmol) using the method described in step 2 of Scheme 208, (S)-N-((+)-1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide was obtained (213b) (968 mg, 2.341 mmol, 59.1% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 - 7.73 (m, 2H), 7.55 - 7.49 (m, 2H), 6.89 (dd, J=11.3, 8.5 Hz, 1H), 6.71 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.5, 4.3, 2.4 Hz, 1H ), 5.23 (s, 1H), 5.09 (s, 2H), 2.65-2.40 (m, 2H), 1.13 (s, 9H), 1.25-1.00 ( m, 1H), 1.00-0.80 (m, 1H), 0.72-0.55 (m, 1H), 0.45-0.25 (m, 2H), 0.04 --0 .21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.37; MS (IER+); 436.3 (M+Na); optical rotation: [α]π=(+) 104.62 [0.295, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((+)-1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2 -fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (213c).

Compound (213c) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (0.933 g, 2.42 mmol) and (S )-N-((+)-1-(3-amino-4-fluorophenyl)-1-(4cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (213b) (0.91 g, 2. 2 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((+)-1-(4-cyanophenyl)-3cyclopropyl-1 -((S)-1 ,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (213c) (1.126 g, 1.442 mmol, 65.5% yield) as a colorless solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.61 (s, 1H), 7.93 - 7.09 (m, 13H), 5.58 (s, 1H), 4.19 (d, J =6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s, 9H), 1.13 (s, 9H), 1.20-1.00 (m, 1H), 0.87 (d, J=23.9 Hz, 1H), 070-0.55 (m, 1H), 0.43 - 0.26 (m, 2H), -0.01 - -0 ,18 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -61.16, -122.81; MS (IER+) 781.6

- 344 045731 (M+1); (IER-) 779.5 (M-1); optical rotation: No=(+) 65.38 [0.26, MeOH].

Step 4. Preparation of (-)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-3-(trifluoromethyl) )-1H-pyrazole-5-carboxamide (213d).

Into a stirred solution of tert-butyl-3-(5-(5-((+)-1-(4-cyanophenyl)-3-cyclopropyl-1-((S)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (213c) (0.609 g, 0.78 mmol) in ethanol (6 ml) was added conc. HCl (0.65 ml, 7.8 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and purify by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA-80 in chloroform, 0-25%) to obtain the product. The product was dissolved in methanol (10 ml) and 4N was added. aqueous HCl (0.52 ml) and concentrated to dryness in vacuo to give (-)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1 hydrochloride salt -(3-(aminomethyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (213d) (330 mg, 0.508 mmol, 65.1% yield) as a white solid.

1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.48 (s, 3H), 8.42 (s, 3H), 7.94 (d, J=8.4 Hz , 2H), 7.757.66 (m, 2H), 7.64-7.46 (m, 6H), 7.40 (t, J=9.3 Hz, 1H), 7.36-7.28 ( m, 1H), 4.11 (q, J=5.8 Hz, 2H), 2.55 (d, J=9.7 Hz, 2H), 1.22-0.99 (m, 2H), 0.77-0.53 (m, 1H), 0.44-0.26 (m, 2H), -0.00 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.64, -120.16; MS (IER+) 577.5 (M+1); (IER-) 576.8 (M-1); ICS 2234 cm'¹; optical rotation: [a]D=(-) 10.84 [1.07, MeOH].

Scheme 214

An example of the preparation of (+)-H-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (214g).

Step 1. Preparation of 3-(3-cyclopropylacryloyl)benzonitrile (214b).

To a stirred solution of 3-acetylbenzonitrile (214a) (50 g, 344 mmol) in methanol (800 ml) at 0°C was added cyclopropanecarboxaldehyde (41 ml, 549 mmol), then potassium hydroxide (1 M aqueous solution, 67 ml, 67 mmol) . The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The reaction mixture was acidified with HCl to pH 6 (75 ml, 1N) and concentrated in vacuo, maintaining the bath temperature below 35°C. The residue was diluted with ethyl acetate (1200 ml) and washed with water (800 ml). The aqueous layer was extracted with ethyl acetate (800 ml) and the organic layers were combined, washed with brine, dried, filtered and concentrated in vacuo to give crude 3-(3-cyclopropylacryloyl)-benzonitrile (214b) (72.42 g) as a colorless liquid, which was used in this form in the next stage; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.19 (dp, J=7.8, 1.6 Hz, 1H), 8.11 (dddt, J=6.3, 3.7, 2, 6, 1.4 Hz, 1H), 7.80 - 7.65 (m, 2H), 7.32 (dd, J=15.1, 7.6 Hz, 1H), 6.60 (ddd, J =15.0, 11.3, 10.4 Hz, 1H), 1.91 - 1.74 (m, 1H), 1.04 (m, 2H), 0.85 - 0.75 (m, 2H ).

Step 2. Preparation of 3-(3-cyclopropylpropanoyl)benzonitrile (214c).

To a stirred solution of 3-(3-cyclopropylacryloyl)benzonitrile (214b) (65.7 g, 333 mmol) in benzene (750 ml) was added tri-n-butyltin hydride (185 ml, 666 mmol) and heated at the reflux temperature of for 14 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give 3-(3-cyclopropylpropanoyl)benzonitrile (214c) (23.3 g, 116.9 mmol, 34% yield) in the form of a colorless oily liquid; ^1H NMR

- 345 045731 (300 MHz, DMSO-d ₆ ) δ 8.41 (td, J=1.8, 0.6 Hz, 1H), 8.24 (ddd, J=7.9, 1.8, 1 ,2 Hz, 1H), 8.09 (dt, J=7.7, 1.4 Hz,

1H), 7.73 (td, J=7.8, 0.6 Hz, 1H), 3.15 (t, J=7.2 Hz, 2H), 1.52 (q, J=7.1 Hz, 2H), 0.81 - 0.64 (m, 1H), 0.46 - 0.26 (m, 2H), 0.13 - 0.00 (m, 2H); MS (IER-) 198.2 (M-1).

Step 3. Preparation of (-)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (214d)

Compound (214d) was prepared from 3-(3-cyclopropylpropanoyl)benzonitrile (214c) (22.8 g, 114 mmol) and (R)-2-methylpropane-2-sulfinamide (13.95 g, 114 mmol) using the method , described in step 1 of Scheme 208, gave (-)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2sulfinamide (214d) (21.8 g, 72.1 mmol, yield 63 %) in the form of a light yellow thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.21 - 8.12 (m, 1H), 8.01 (d, J=7.7 Hz, 1H), 7 .70 (t, J=7.9 Hz, 1H), 3.54 - 3.13 (m, 2H), 1.44 (q, J=7.5 Hz, 2H), 1.23 (s, 9H), 0.82 - 0.65 (m, 1H), 0.44 - 0.29 (m, 2H), 0.11 - 0.00 (m, 2H); MS (IER+) 303.3 (M+1); (IER-) 301.3 (M-1); optical rotation: [a] _D (-) 66.92 (0.26, MeOH).

Step 4. Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)2-methylpropane-2-sulfinamide (214e).

Into a stirred solution of (-)-M-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2sulfinamide (214d) (17.72 g, 58.6 mmol) in toluene (350 ml) at - At 20°C, a freshly prepared solution of (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (160 ml, 120 mmol, 0.75 N) was added dropwise over 30 min. The reaction mixture was stirred at -20°C for 1 hour and the reaction was quenched with 1N. aqueous KHSO ₄ (275 ml). The reaction mixture was stirred for 1 hour at room temperature, diluted with water (100 ml), basified with 2N. NaOH to pH 8 and extracted with ethyl acetate (600 ml, 300 ml). Combine the organic layers, wash with water (2x300 ml), brine (300 ml), dry and concentrate to dryness in vacuo. The crude residue was triturated with ethyl acetate and the resulting solid was collected by filtration to give, after drying in vacuo, (R)-N((-)-1 -(3-amino-4-fluorophenyl)-1 -(3-cyanophenyl)-3 - cyclopropylpropyl)-2-methylpropane-2-sulfinamide (214e) (10.4 g, 42.91% yield) as a white solid. Concentrate the filtrate in vacuo and purify by flash column chromatography (silica gel, eluting with 0 to 50% ethyl acetate in hexanes) to give (R)-N-((-)-1-(3-amino-4-fluorophenyl) -1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (214e) (4.11 g, 16.95% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.78 (t, J=1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.4 Hz, 1H), 7, 62 (dt, J=8.1, 1.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.90 (dd, J=11.3, 8.5 Hz , 1H), 6.72 (dd, J=8.7, 2.4 Hz, 1H), 6.47 (ddd, J=8.5, 4.3, 2.4 Hz, 1H), 5, 27 (s, 1H), 5.10 (s, 2H), 2.66-2.40 (m, 2H), 1.20-1.03 (m, 1H), 1.12 (s, 9H) , 1.01-0.81 (m, 1H), 0.72-0.57 (m, 1H), 0.36 (m, 2H), 0.03-0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.34; MS (ESI+): 436.4 (M+Na); ICS (KBr) 2235 cm ^-1 ; optical rotation: [a]D (-) 107.95 (0.78, MeOH); analysis, calculation for C23H28FN3OS: C, 66.80; H, 6.82; N, 10.16; experiment: C, 67.06; H, 6.82; N, 10.28.

Step 5. Preparation of tert-butyl-3-(5-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2 -fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (214f).

Compound (214f) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (9.74 g, 25.3 mmol) and (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(3cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (214e) (9.5 g, 22.97 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((-)-1-(3-cyanophenyl)-3cyclopropyl-1-((R) -1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)1H-pyrazol-1-yl)benzylcarbamate (214f) (10.00 g, 12.8 mmol, 55.7% yield) in as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 7.78 (s, 1H), 7.71 (dt, J=7.3, 1.4 Hz, 1H), 7.64 - 7.30 (m, 8H), 7.23 (d, J=7.5 Hz, 2H), 5.56 (s, 1H), 4.18 (d, J=6.2 Hz , 2H), 2.74-2.39 (m, 2H), 1.38 (s, 9H), 1.12 (s, 9H), 1.09-0.82 (m, 2H), 0. 72-0.54 (m, 1H), 0.34 (d, J=8.0 Hz, 2H), -0.01 - -0.16 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, -122.94; MS (IER+) 803.6 (M+Na), (IER-) 779.6 (M-1); optical rotation: [a] _D =(-) 75.09 (0.285, MeOH).

Step 6. Preparation of (+)-N-(5-(1-amino-1-(3-tsuanophenyl)-3-tsuklopronulnronul)-2-fluorophenyl)-1(3 -(aminomethyl)phenyl)-3-(trifluoromethyl )-1 H-πyrazole-5-carboxamide (214g).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (214f) (0.75 g, 0.960 mmol) in ethanol (7.5 ml) was added conc. HCl (0.8 ml, 9.6 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, 24 g, eluted with mixtures of CMA 80 in chloroform , from 0 to 100%) to obtain the product, which was purified again by flash column chromatography (silica gel, 24 g, eluted with mixtures of methanol in chloroform, from 0 to 50%) to obtain the free base (+)-N-(5- (1-amino-1-(3-cyanophenyl)-3cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (214g) (0 .36 g, 0.624 mmol, 65.0% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 7.86 (t, J=1.7 Hz, 1H), 7.70 - 7.55 (m, 5H) , 7.54 - 7.43 (m, 3H), 7.39 (dt, J=7.2, 2.0

- 346 045731

Hz, 1H), 7.28 (ddd, J=8.7, 4.8, 2.4 Hz, 1H), 7.18 (dd, J=10.2, 8.7 Hz, 1H), 3 .92 (s, 2H), 2.23 (t, J=8.2 Hz, 2H),

1.08 - 0.94 (m, 2H), 0.62 (qq, J=7.0, 4.7, 3.5 Hz, 1H), 0.40 - 0.27 (m, 2H), -0.08 (td, J=5.2, 4.6, 3.4 Hz, 2H); ^19F

NMR (282 MHz, DMSO) δ -60.39, -123.77; MS (IER+) 577.5 (M+1); (IER-) 575.5 (M-1); ICS (KBr) 2230 cm ^-1 ; optical rotation: [a] _D =(+) 9.18 [1.59, MeOH].

Into a stirred solution of the free base (+)-N-(5-(1-amino-1-(3-cyanophenyl)-3cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl )-III-pyrazole-5-carboxamide (214g) (0.3 g, 0.52 mmol) in methanol (10 ml) was added conc. HCl (0.217 mL, 2.60 mmol), stirred for 30 min and concentrated to dryness to give (+)-N-(5-(1-amino-1(3-cyanophenyl)-3-cyclopropylpropyl)-2- hydrochloride fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (214g) (0.31 g, 0.477 mmol, 92% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.81 (s, 1H), 9.49 (s, 3H), 8.46 (s, 3H), 7.93 - 7.80 (m, 1H ), 7.74 - 7.68 (m, 3H), 7.67 - 7.49 (m, 5H), 7.44 - 7.29 (m, 2H), 4.11 (d, J=3 .8 Hz, 2H), 2.55 (d, J=10.8 Hz, 3H), 1.37 - 1.16 (m, 1H), 0.67 (q, J=6.5 Hz, 1H ), 0.47 - 0.25 (m, 2H), 0.07 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.64, 120.22; MS (IER+) 577.4 (M+1); (IER-) 575.5 (M-1); IR (KBr) 2235 cm ^-1 .

Scheme 215

An example of the preparation of (-)-K-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (215d).

Step 1. Preparation of (+)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (215a).

Compound (215a) was prepared from 3-(3-cyclopropylpropanoyl)benzonitrile (212c) (2.33 g, 11.69 mmol) and (S)-2-methylpropane-2-sulfinamide (1.432 g, 11.69 mmol) at Using the method described in step 1 of Scheme 208, (+)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2sulfinamide (215a) (2.186 g, 7.23 mmol, yield 61 .8%) in the form of a light yellow thick liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 3.54 - 3.13 (m, 2H), 1.45 (q, J=7.5 Hz, 2H), 1, 24 (s, 9H), 0.85-0.65 (m, 1H), 0.43 - 0.27 (m, 2H), 0.13 - -0.09 (m, 2H); MC (IER+) 303.3 (M+1); 325.3 (M+Na); optical rotation: [a]D=(+) 27.74 [0.31, MeOH].

Step 2. Preparation of (S)-N-((+)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (215b) .

Compound (215b) was prepared from (+)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (215a) (0.93 g, 3.08 mmol) using the method described in step 2 of Scheme 208 gave (S)-N-((+)-1-(3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2 -sulfinamide (215b) (370 mg, 0.895 mmol, 29.1% yield) as a white solid; 1H NMR (300 MHz, DMSO-de) δ 7.78 (t, J=1.7 Hz, 1H), 7.70 (dt, J=7.5, 1.3 Hz, 1H), 7.62 (dt, J=8.2, 1.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 6.90 (dd, J=11.3, 8.5 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 1H), 6.47 (ddd, J=8.6, 4.4, 2.4 Hz, 1H), 5.26 (s, 1H), 5.10 (s, 2H), 2.65-2.40 (m, 2H), 1.30-1.00 (m, 1H), 1.12 (s, 9H), 1.00 - 0.80 (m, 1H), 0.720.56 (m, 1H), 0.42-0.28 (m, 2H), 0.06 - -0.14 (m, 2H); MS (IER+) 414.4 (M+1); 436.4 (M+Na) (IER-) 412.4 (M-1); optical rotation: [a]D=(+) 101.13 [0.265, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)propyl)-2 -fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (215c).

Compound (215c) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (321 mg, 0.833 mmol) and (S)- N-((+)-1-(3-amino-4-fluorophenyl)-1(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (215b) (313 mg, 0.757 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((+)-1-(3-cyanophenyl)3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido )propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-ul)benzylcarbamate (215c) (358 mg, 458 mmol, 60.6% yield) as a white solid

- 347 045731 substances; Ή NMR (300 MHz, DMSOL) δ 10.62 (s, 1H), 7.78 (br.B, 1H), 7.72 (dt, J=7.4, 1.4 Hz, 1H), 7.637 .32 (m,9H), 7.24 (d, J=7.6 Hz, 2H), 5.58 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2 .75-2.40 (m, 2H), 1.38 (s, 9H), 1.201.00 (m, 1H), 1.12 (s, 9H), 0.97 - 0.79 (m, 1H ), 0.70-0.55 (m, 1H), 0.42 - 0.24 (m, 2H), 0.01 - -0.17 (m, 2H); ^19F

NMR (282 MHz, DMSO-d6) δ -61.11, -122.89; MS (IER+) 781.6 (M+1); 803.6 (M+Na), (IER-) 779.6 (M-1);

optical rotation: [a] _D =(+) 75.29 [0.255, MeOH].

Step 4. Preparation of (-)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-3-(trifluoromethyl) )-III-pyrazole-5-carboxamide (215d).

Into a stirred solution of tert-butyl-3-(5-(5-((+)-1-(3-cyanophenyl)-3-cyclopropyl-1-((S)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (215c) (0.152 g, 0.195 mmol) in ethanol (15 ml) was added conc. HCl (0.16 ml, 1.917 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and triturate the residue with methyl tert-butyl ether (2x20 ml) and decant. The solid was dried in vacuo, dissolved in water (5 ml) and concentrated to dryness in vacuo to give (-)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2 hydrochloride salt -fluorophenyl)-1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (215d) (96 mg) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.78 (s, 1H), 9.40 (s, 3H), 8.35 (s, 3H), 7.92-7.82 (m, 2H ), 7.74 - 7.23 (m, 10H), 4.13 (s, 2H), 2.60-2.40 (m, 2H), 1.20-0.95 (m, 2H), 0.75-0.60 (m, 1H), 0.42-0.32 (m, 2H), 0.05-0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.64, -120.25; MS (ESI+): 599.5 (M+Na); optical rotation: [a] _D =(-) 7.84 [0.255, methanol]; analysis, calculation for C ₃₁ H ₂₈ F ₄ N ₆ O-2HCl-2.5H ₂ O: C, 53.61; H, 5.08; Cl, 10.21; N, 12.10; experiment: C, 53.49; H, 4.92; Cl, 10.21; N, 11.77.

Scheme 216

An example of the preparation of (+)-N-(5-( 1 -amino-3-cyclopropyl-1 -(pyridin-4-yl)propyl)-2-fluorophenyl)-1 -(3 (aminomethyl)phenyl)-3-( trifluoromethyl)-1 H-pyrazole-5-carboxamide (216d).

Step 1. Preparation of (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide (216a).

Compound (216a) was prepared from 3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (92d) (1.8 g, 10.27 mmol) and (R)-2-methylpropan-2-sulfinamide (1.566 g, 12.84 mmol) prepared (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2sulfinamide (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2sulfinamide ( 216a) (1.838 g, 6.57 mmol, 63.9% yield) as a yellow thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 8.76 - 8.69 (m, 2H), 7.80 - 7.73 (m, 2H), 3.49 - 3.15 (m, 2H), 1.45 (q, J=7.4 Hz, 2H), 1.24 (s, 9H), 0.84 -0.65 (m, 1H), 0.43 - 0.30 (m, 2H) , 0.10 - -0.03 (m, 2H); MS (IER+) 301.3, (M+Na); (IER-) 277.3 (M-1); optical rotation [a]D=(-) 27.61 [0.355, MeOH].

Step 2. Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)2-methylpropan-2-sulfinamide ( 216b).

Compound (216b) was prepared from (-)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide (216a) (1.7 g, 6.11 mmol) using the method described in step 2 of Scheme 208, (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl) was prepared -2-methylpropane2-sulfinamide (216b) (1.443 g, 3.7 mmol, 60.7% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 8.77 - 8.68 (m, 2H), 7.62 - 7.53 (m, 2H), 7.15 (dd, J=11.3, 8 .5 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.77 - 6.70 (m, 1H), 5.50 (s, 1H), 5.35 (s, 2H) , 2.90-2.60 (m, 2H), 1.47-1.27 (m, 1H), 1.38 (s, 9H), 1.25-1.05 (m, 1H), 0 .97-0.80 (m, 1H), 0.65-0.55 (m, 2H), 0.32-0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOL) -137.30; MS (IER+): 390.4 (M+1); chiral purity was verified by chiral HPLC on an ADH chiral column, 1 mL/min, solvent: 90% hexane, 10% EtOH, 0.1% TEA, UV=260 nm, 25°C (>99.99 ee) ; optical rotation [a] _D =(-) 78.49 [0.265, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)1-(pyridin-4-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate

- 348 045731 (216c).

Compound (216c) was prepared using 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.866 g, 2.246 mmol) and (R) -N-((-)-1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropan-2-sulfinamide (216b) (700 mg, 1.797 mmol ) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((-)3-cyclopropyl-1 -((R)-1,1-dimethylethylsulfinamido)-1 -( pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (216c) (688 mg, 0.909 mmol, 50.6% yield) as a white solid ; ^1H NMR (300 MHz, DMSO^) δ 10.60 (s, 1H), 8.53 - 8.44 (m, 2H), 7.64 - 7.19 (m, 11H), 5.57 ( s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.70-2.40 (m, 2H), 1.38 (s, 9H), 1.13 (s, 9H ), 1.05-0.80 (m, 1H), 0.70-0.50 (m, 1H), 0.39-0.29 (m, 2H), -0.01 - -0.23 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.61, -122.74; MS (IER+) 757.6 (M+1); 779.6 (M+Na), (IER-) 755.6 (M-1); optical rotation [a]D (-) 46.92 [0.26, MeOH].

Step 4. Preparation of (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (216d).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1 -(pyridin-4-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (216c) (627 mg, 0.828 mmol) in ethanol (30 ml) was added conc. HCl (0.69 ml, 8.28 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and dissolve the residue in ethanol (5 ml), triturate with methyl tert-butyl ether (2x20 ml ) and decanted. The solid was dried in vacuo, dissolved in water (20 ml) and concentrated to dryness in vacuo to give (+)-N-(5-(1-amino-3-cyclopropyl-1(πpyridin-4-yl)πpropyl) hydrochloride salt -2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-πyrazole-5-carboxamide (216d) (406 mg, 0.56 mmol, 67.6% yield) as whitish solid; 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.74 (s, 3H), 8.91 - 8.76 (m, 2H), 8.49 (d, J= 7.1 Hz, 3H), 7.75-7.60 (m, 6H), 7.56 (d, J=7.9 Hz, 1H), 7.53 - 7.44 (m, 1H) , 7.40 (dd, J=6.8, 2.3 Hz, 2H), 4.16 - 4.07 (m, 2H), 2.60 - 2.54 (m, 2H), 1.33 - 1.15 (m, 1H), 1.14 - 0.96 (m, 1H), 0.78 - 0.52 (m, 1H), 0.45 - 0.30 (m, 2H), 0 .09 - -0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.63, -119.70; MS (IER+) 554.5 (M+1), 576.5 (M+Na), (IER-) 587.5 (M+Cl); analysis, calculation for C ₂₉ H ₂₈ F ₄ N ₆ O-3HCl-3.5H ₂ O; C: 48.04, H: 5.28; N: 11.59; experiment: C: 48.06; H: 5.39; N: 11.66; optical rotation [a] _D =(+) 12.43 [0.575, MeOH].

Scheme 217

An example of the preparation of (-)-N-(5-(1 -amino-3-cyclopropyl-1 -(pyridin-4-yl)propyl)-2-fluorophenyl)-1 -(3 (aminomethyl)phenyl)-3-( trifluoromethyl)-1 H-pyrazole-5-carboxamide (217d).

Step 1. Preparation of (+)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide (217a).

Compound (217a) was prepared from 3-cyclopropyl-1-(pyridin-4-yl)propan-1-one (92d) (1.0 g, 5.71 mmol) and (S)-2-methylpropan-2-sulfinamide (0.838 g, 6.85 mmol) using the method described in step 1 of Scheme 208, prepared (+)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2sulfinamide ( 217a) (0.973 g, 3.49 mmol, 61.2% yield) as a yellow thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 9.08 - 9.01 (m, 2H), 8.08 (m, 2H), 3.78 - 3.51 (m, 2H), 1.77 ( m, 2H), 1.57 (s, 9H), 1.06 (m, 1H), 0.7-0.65 (m, 2H), 0.43 - 0.23 (m, 2H); MS (IER+) 279.3 (M+1); 301.3 (M+Na); (ES-) 277.4 (M-1); optical rotation [a]D=(+) 33.96 [0.265, MeOH].

Step 2. Preparation of (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)2-methylpropan-2-sulfinamide ( 217b).

Compound (217b) was prepared from (+)-N-(3-cyclopropyl-1-(pyridin-4-yl)propylidene)-2-methylpropane-2-sulfinamide (217a) (0.928 g, 3.33 mmol) using the method described at stage 2 of the scheme

- 349 045731

208, obtained (S)-N-((+)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(niridin-4-yl)pronyl)-2-methylpropan-2-sulfinamide ( 217b) (0.766 g, 1.966 mmol, 59% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.55-8.42 (m, 2H), 7.39 - 7.25 (m, 2H), 6.89 (dd, J=11.3, 8.5 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 1H), 6.48 (ddd, J=8.5, 4.4, 2.4 Hz, 1H ), 5.26 (s, 1H), 5.10 (s, 2H), 2.66 - 2.54 (m, 1H), 2.49 -2.36 (m, 1H), 1.13 ( s, 9H), 1.12 (m, 1H), 0.92 (m, 1H), 0.71 - 0.56 (m, 1H), 0.42 - 0.27 (m, 2H), - 0.02 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -137.32; MS (IER+) 390.4 (M+1); (IER-) 388.5 (M-1); chiral purity was checked by chiral HPLC on a chiral AD-H column, 1 ml/min, solvent: 90% hexane, 10% EtOH, 0.1% TEA, UV=260 nm, 25°C (99.355% ee) ; optical rotation No=(+) 82.4 [0.25, MeOH].

Step 3. Preparation of tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((8)-1,1-dimethylethylsulfinamido)1 -(pyridin-4-yl)propyl)- 2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (217c).

Compound (217c) was prepared using 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.61 g, 1.582 mmol) and ( S)-N-((+)-1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropan-2-sulfinamide (217b) (493 mg, 1.266 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(5-((+)3-cyclopropyl-1-((S)-1,1-dimethylethylsulfinamido)-1 -(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (217c) (637 mg, 0.841 mmol, 66.48% yield) as white semi-solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.61 (s, 1H), 8.54 - 8.44 (m, 2H), 7.63 - 7.16 (m, 11H), 5.58 (s, 1H), 4.19 (d, J=6.3 Hz, 2H), 2.70-2.40 (m, 2H), 1.38 (s, 9H), 1.30-0, 80 (m, 2H), 1.13 (s, 9H), 0.70-0.55 (m, 1H), 0.40-0.27 (m, 2H), -0.01 - -0, 20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.75, 122.85; MS (IER+) 757.6 (M+1); 779.6 (M+Na), (IER-) 755.5 (M-1); optical rotation [a] _D (+) 50.37 [0.27, MeOH].

Step 4. Preparation of (-)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (217d).

Into a stirred solution of tert-butyl-3-(5-(5-((+)-3-cyclopropyl-1-((8)-1,1-dimethylethylsulfinamido)-1 -(pyridin-4-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (217c) (119 mg, 0.157 mmol) in ethanol (10 ml) was added conc. HCl (0.13 ml, 1.557 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and dissolve the residue in ethanol (5 ml), triturate with methyl tert-butyl ether (30 ml) and Decanted. The solid was dried in vacuo, dissolved in water (10 ml) and concentrated to dryness in vacuo to give (-)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl) hydrochloride -2fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (217d) (78 mg, 0.141 mmol, 90% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.84 (s, 1H), 9.63 (s, 3H), 8.84-8.73 (m, 2H), 8.44 (s, 3H ), 7.75 - 7.68 (m, 2H), 7.66 - 7.31 (m, 8H), 4.12 (q, J=6.0 Hz, 2H), 2.602.40 (m, 2H), 1.35-0.93 (m, 2H), 0.79 - 0.56 (m, 1H), 0.45-0.28 (m, 2H), 0.06 - -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-66) δ -60.63, -119.88; MS (ESI+): 575.5 (M+Na); optical rotation No=(-) 10.32 [0.32, MeOH]; analysis, calculation for C ₂₉ H ₂₈ F ₄ N ₆ O-3HCl-3.25H ₂ O; C, 48.34; H, 5.25; N, 11.66; experiment: C, 48.20; H, 5.31; N, 11.59.

Scheme 218

218a (-)-isomer

An example of the preparation of (+)-N-(3-(1-amino-1-(4-cyanophenyl)-3-cyclopronylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H- pyrazol-5-carboxamide (218c).

Step 1. Preparation of (R)-N-((-)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (218a).

Compound (218a) was prepared from (+)-N-(1-(4-cyanophenyl)-3-cyclopropylpronylidene)-2-methylnpropane-2-sulfinamide (212d) (2 g, 6.64 mmol) using the method described in step 2 of Scheme 208, we obtained (R)-N-((-)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sul-350 045731 finamide (218a) (1.65 g, 4.17 mmol, 63.1% yield) as a white solid; 1H NMR (300 MHz,

DMSO-d ₆ ) δ 7.80 - 7.71 (m, 2H), 7.58 - 7.50 (m, 2H), 6.93 (t, J=7.8 Hz, 1H), 6, 50 (t, J=1.9 Hz, 1H), 6.48 - 6.43 (m, 1H), 6.41 - 6.35 (m, 1H), 5.15 (s, 1H), 5 .05 (s, 2H), 2.70-2.35 (m, 2H), 1.13 (s, 9H), 1.21-1.05 (m, 1H), 1.000.8 (m, 1H ), 0.72-0.55 (s, 1H), 0.45-0.21 (m, 2H), 0.07 - -0.22 (m, 2H); MC (IER+) 396.4 (M+1) 418.4 (M+Na); (IER-) 394.3 (M-1); optical rotation: [a] _D =(-) 103.57 [0.28, MeOH].

Step 2. Preparation of tert-butyl-3-(5-(3-((-)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl) -3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (218b).

Compound (218b) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (1.607 g, 4.17 mmol) and ( R)-N-((-)-1-(3-aminophenyl)-1-(4cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (218a) (1.5 g, 3.79 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(3-((-)-1-(4-cyanophenyl)-3cyclopropyl-1 -((R)-1,1 - dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (218b) (1.96 g, 2.57 mmol, 67.8% yield) as a colorless solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.1 Hz, 1H), 7.58 - 7.32 (m, 9H), 7.28 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 5, 39 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.37 (s, 9H), 1.13 (s , 9H), 1.20-1.00 (m, 1H), 0.97-0.77 (m, 1H), 0.70-0.55 (m, 1H), 0.40-0.27 (m, 2H), -0.01 - 0.18 (m, 2H); MS (IER+) 763.5 (M+1), 785.6 (M+Na); (IER-) 761.5 (M-1); optical rotation: No=(-) 65.96 [0.285, MeOH].

Step 3. Preparation of (+)-N-(3-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (218c).

Into a stirred solution of tert-butyl-3-(5-(3-((-)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (218b) (1.014 g, 1.329 mmol) in ethanol (15 ml) was added conc. HCl (1.10 ml, 13.2 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue twice by flash column chromatography (silica gel, 40 g, first column eluted with mixtures of 0 -50% CMA-80 in chloroform, the second column was eluted with mixtures of methanol in chloroform, 0-30%) to give free base 218c (479 mg, 0.699 mmol, 52.6% yield) as a white solid. The free base was dissolved in ethanol (5 ml), conc. HCl (0.18 ml) and concentrated to dryness in vacuo to give a white residue, which was dissolved in water (5 ml) and concentrated to dryness in vacuo to give (+)-N(3-(1-amino-1-( 4-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (218c) (276 mg, 0.417 mmol, yield 31.39 %) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.39 (s, 3H), 8.42 (s, 3H), 7.94 (d, J=8.4 Hz , 2H), 7.787.47 (m, 9H), 7.43 (t, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.18-4 .08 (m, 2H), 2.60-2.40 (m, 2H), 1.23-1.01 (m, 2H), 0.68 (s, 1H), 0.37 (dd, J =8.0, 4.1 Hz, 2H), 0.11-0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.59; MS (IER+): 559.5 (M+1); ICS (KBr) 2233 cm'¹; optical rotation: No=(+) 16.72 [0.335, MeOH]; analysis, calculation for ^^FjNiO^HCldHO: C: 54.31; H: 5.44; N: 12.26; experiment C: 54.20; H: 5.44; N: 12.11.

Scheme 219

219a (-)-isomer

An example of the preparation of (+)-N-(3 -(1 -amino-1 -(3 -cyanophenyl)-3 -cyclopropylpropyl)phenyl)-1 -(3 -(aminomethyl)phenyl)-3 -(trifluoromethyl)-1 H -pyrazole-5-carboxamide (219c).

Step 1. Preparation of (R)-N-((-)-1-(3-aminophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (219a).

Compound (219a) was prepared from (-)-N-(1-(3-cyanophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (214d) (2 g, 6.64 mmol) using the method described in step 2 of Scheme 208, we obtained (R)-N-((-)-1-(3-aminophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sul-351 045731 finamide (219a) (1.939 g, 4.9 mmol, 74.1% yield) as a white solid; 1H NMR (300 MHz, DMSO) δ 7.78 (t, J=1.6 Hz, 1H), 7.72-7.61 (m, 2H), 7.50 (t, J=7.8 Hz , 1H), 6.94 (t, J=7.8 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 6.46 (dt, J=7.9, 1, 2 Hz, 1H), 6.39 (ddd, J=8.0, 2.2, 0.9 Hz, 1H), 5.16 (s, 1H), 5.05 (s, 2H), 2, 73 2.36 (m, 2H), 1.13 (s, 9H), 1.25-1.05 (m, 1H), 0.99 - 0.79 (m, 1H), 0.73-0 .56 (m, 1H), 0.45-0.24 (m, 2H), 0.05-0.19 (m, 2H); MC (IER+) 396.4 (M+1) 418.4 (M+Na); (IER-) 394.6 (M-1) 430.4 (M+Cl); optical rotation: [a]D=(-) 117.6 [0.25, MeOH].

Step 2. Preparation of tert-butyl-3-(5-(3-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)phenylcarbamoyl) -3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (219b).

Compound (219b) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxylic acid (10d) (1.286 g, 3.34 mmol) and ( R)-N-((-)-1-(3-aminophenyl)-1-(3cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (219a) (1.2 g, 3.03 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5-(3-((-)-1-(3-cyanophenyl)-3cyclopropyl-1 -((R)-1,1 - dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (219b) (1.081 g, 1.417 mmol, 46.7% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-de) δ 10.72 (s, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.66 - 7.32 (m, 10H), 7.28 (t, J=8.0 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5, 39 (s, 1H), 4.19 (d, J=6.1 Hz, 2H), 2.73 - 2.36 (m, 2H), 1.37 (s, 9H), 1.13 (s , 9H), 1.12 (m, 1H), 1.00-0.80 (m, 1H), 0.70-0.55 (m, 1H), 0.40-0.31 (m, 2H ), -0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.58; MS (ESI+) 785.6 (M+Na); (IER-) 761.5 (M-1); optical rotation: [a]D=(-) 73.68 [0.285, MeOH].

Step 3. Preparation of (+)-N-(3-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)- 1 H-pyrazole-5-carboxamide (219c).

Into a stirred solution of tert-butyl-3-(5-(3-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)phenylcarbamoyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (219b) (0.7 g, 0.918 mmol) in ethanol (12 ml) was added conc. HCl (0.76 ml, 9.12 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and purify the resulting residue twice by flash column chromatography (silica gel, 25 g, first column eluted with mixtures of 0 -30% CMA-80 in chloroform, the second column was eluted with mixtures of methanol in chloroform, 0-10%) to give free base 219c (297 mg, 0.532 mmol, 57.9% yield) as a white solid. The free base (126 mg, 0.23 mmol) was dissolved in ethanol (5 ml), conc. HCl (0.095 ml) and concentrated to dryness in vacuo to give a white residue, which was dissolved in water (5 ml) and concentrated to dryness in vacuo to give (+)-N-(3-(1-amino-1-(3) hydrochloride salt -cyanophenyl)-3-cyclopropylpropyl)phenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (219c) (130 mg, 0.192 mmol, 83.54% yield ) as a white solid; 1H NMR (300 MHz, DMSO-de) δ 10.93 (s, 1H), 9.37 (s, 3H), 8.41 (s, 3H), 7.917.84 (m, 2H), 7.76 -7.48 (m, 9H), 7.43 (t, J=8.0 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 4.13 (lat.s, 2H), 2.60-2.40 (m, 2H), 1.19-0.99 (m, 2H), 0.77-0.60 (m, 1H), 0.46-0.30 ( m, 2H), 0.14-0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -60.60; MS (IER+): 559.5 (M+1); ICS (KBr) 2235 cm'¹; optical rotation: No=(+) 7.59 [CH3OH, 0.29]; analysis, calculation for C ₃₁ H ₂₉ F ₃ N ₆ O-2HCF2.5H ₂ O: C: 55.03; H: 5.36; N: 12.42; experiment: 55.07; H: 5.15; N: 12.30.

Scheme 220

CN

- 352 045731

An example of the preparation of (+)-M-(5-(1-amino-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-fluorophenyl)-1 -(3 -(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (220f).

Step 1. Preparation of 2-(3-cyclopropylpropanoyl)pyridine-1-oxide (220a).

In a solution of 3-cyclopropyl-1-(pyridin-2-yl)propan-1-one (59d) (2.98 g, 17.01 mmol) in CH ₂ Cl ₂ (120 ml), cooled to ~0°C , 3-chloroperoxybenzoic acid (11.43 g, 51.0 mmol) was added, stirred at ~0°C for 3 h and allowed to warm to room temperature overnight. Concentrate the reaction mixture in vacuo and purify by flash column chromatography [silica gel, eluting with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give 2-(3-cyclopropylpropanoyl)pyridine-1-oxide ( 220a) (1.115 g, 5.83 mmol, 34.3% yield) as a light brown oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.30 (dt, J=6.4, 0.8 Hz, 1H), 7.62 - 7.51 (m, 2H), 7.42 (td , J=7.7, 1.1 Hz, 1H), 3.13 - 3.06 (m, 2H), 1.48 (q, J=7.2 Hz, 2H), 0.79 - 0, 59 (m, 1H), 0.45-0.25 (m, 2H), 0.09 - -0.07 (m, 2H); MS (ESI+) 214.2 (M+Na); (IER-) 190.2 (M-1).

Step 2. Preparation of 6-(3-cyclopropylpropanoyl)picolinonitrile (220b).

In a solution of 2-(3-cyclopropylpropanoyl)pyridine-1-oxide (220a) (1.026 g, 5.37 mmol) and trimethylsilanecarbonitrile (3.22 ml, 23.66 mmol) in CH ₂ Cl ₂ (25 ml), cooled to ~0°C, dimethylcarbamic acid chloride (2.110 mL, 22.06 mmol) was added and stirred at room temperature for 86 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate ( 1:0 to 1:1)] to give 6-(3-cyclopropylpropanoyl)picolinonitrile (220b) (117 mg, 0.584 mmol, 10.89% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.34 - 8.19 (m, 3H), 3.25 (t, J=7.3 Hz, 2H), 1.54 (q, J=7 .2 Hz, 2H), 0.87 - 0.60 (m, 1H), 0.50 - 0.30 (m, 2H), 0.11 -0.01 (m, 2H); MS (IER+) 223.2 (M+Na), (IER-) 199.1 (M-1).

Step 3. Preparation of (-)-N-(1-(6-cyanopyridin-2-yl)-3-cyclopropylpropylidene)-2-methylpropane-2sulfinamide (220c).

Compound (220c) was prepared from 6-(3-cyclopropylpropanoyl)picolinonitrile (220b) (1 g, 4.99 mmol) and (R)-2-methylpropan-2-sulfinamide (608 mg, 5.02 mmol) using the method described in step 1 of Scheme 208 gave (-)-M-(1-(6-cyanopyridin-2-yl)-3-cyclopropylpropylidene)-2methylpropane-2-sulfinamide (220c) (782 mg, 2.58 mmol, yield 51.6%) as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 8.33 - 8.16 (m, 3H), 3.55-3.20 (m, 2H), 1.57 - 1.43 (m, 2H), 1 .26 (s, 9H), 0.85-0.63 (m, 1H), 0.45-0.27 (m, 2H), 0.08 - -0.01 (m, 2H); MS (IER+) 304.3, (M+1), 326.3 (M+Na); (IER-) 338.2 (M+Cl); optical rotation [a] _D =(-) 79.35 [0.31, MeOH].

Step 4. Preparation of (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(6-cyanopyridin-2-yl)-3cyclopropylpropyl)-2-methylpropane-2-sulfinamide ( 220d)

Compound (220d) was prepared from (-)-N-(1-(6-cyanopyridin-2-yl)-3-cyclopropylpropylidene)-2methylpropan-2-sulfinamide (220c) (0.695 g, 2.291 mmol) using the method described in step 2 of Scheme 208, (R)-N-((-)-1-(3-amino-4-fluorophenyl)-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-methylpropane was obtained -2-sulfinamide (220d) (0.345 g, 0.832 mmol, 36.3% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.01 - 7.88 (m, 2H), 7.61 (dd, J=7.1, 2.2 Hz, 1H), 6.90 (dd , J=11.3, 8.5 Hz, 1H), 6.66 (dd, J=8.8, 2.4 Hz, 1H), 6.49 (ddd, J=8.5, 4.2 , 2.3 Hz, 1H), 5.56 (s, 1H), 5.12 (s, 2H), 2.75-2.30 (m, 2H), 1.26 - 0.87 (m, 2H), 1.14 (s, 9H), 0.72-0.56 (m, 1H), 0.42-0.30 (m, 2H), 0.06 - -0.14 (s, 2H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.02; MS (ESI+): 437.4 (M+Na); (IER-) 413.4 (M-1), 449.4 (M+Cl); optical rotation [a] _D =(-) 7.80 [0.205, MeOH].

Step 5. Preparation of tert-butyl-3-(5-(5-((-)-1-(6-cyanopyridin-2-yl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl) -2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1yl)benzylcarbamate (220e).

Compound (220e) was prepared using 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.34 g, 0.882 mmol) and ( R)-N-((-)-1-(3-amino-4fluorophenyl)-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (220d) (323 mg , 0.779 mmol) using the method described in step 3 of Scheme 208, tert-butyl-3-(5(5-((-)-1 -(6-cyanopyridin-2-yl)-3-cyclopropyl-1 - ((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (220e) (273 mg, 0.349 mmol, 44.8% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.05-7.91 (m, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.61-7.16 (m, 9H), 5.80 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.80 - 2.54 (m, 2H) , 1.38 (s, 9H), 1.13 (s, 9H), 1.10-0.85 (m, 2H), 0.75-0.55 (m, 1H), 0.40-0 .30 (m, 2H), 0.05- -0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.62, -122.28; MS (IER+) 804.7 (M+Na); optical rotation [a] _D (-) 7.46 [0.295, MeOH].

Step 6. Preparation of (+)-M-(5-(1-amino-1-(6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2fluorophenyl)-1 -(3 -(aminomethyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (220f).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-1-(6-cyanopyridin-2-yl)-3-cyclopropyl-1-((R)1,1-dimethylethylsulfinamido)propyl) Conc. HCl (0.15 ml, 1.808 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction

- 353 045731 the mixture was dried to dryness in vacuo and the resulting residue was purified twice by flash column chromatography (silica gel, 25 g, the first column was eluted with mixtures of 0-30% CMA-80 in chloroform, the second column was eluted with mixtures of methanol in chloroform, 0-10%) to give free base 220f (41 mg, 0.071 mmol, 38.5% yield) as a white solid. The free base (41 mg, 0.071 mmol) was dissolved in ethanol (10 ml), conc. HCl (0.03 ml) and concentrated to dryness in vacuo to give a white residue, which was dissolved in water (2 ml) and concentrated to dryness in vacuo to give (+)-N-(5-(1-amino-1-) hydrochloride salt (6-cyanopyridin-2-yl)-3-cyclopropylpropyl)-2fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (220f) (50 mg, 0.071 mmol, yield 38.57%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 9.12 (s, 3H), 8.32 (s, 3H), 8.14 (s, 1H), 7, 89-7.16 (m, 10H), 4.13 (s, 2H), 1.32-1.10 (m, 1H), 1.00-0.75 (m, 1H), 0.75- 0.57 (m, 1H), 0.42-0.32 (m, 2H), 0.08 - -0.08 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.64, -119.69; MS (ESI+): 600.5 (M+Na); optical rotation [a] _D =(+) 57.39 [0.23, MeOH]; analysis, calculation for C ₃₀ H ₂₇ F ₄ N ₇ O 2HCl 3H ₂ O: C: 51.14; N: 5.01; N: 13.92; Cl: 10.06; experiment: C: 51.40; N: 4.90; N: 13.58; Cl: 10.00.

Scheme 221

An example of the preparation of (+)-5-(1-amino-1-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamido)-4-fluorophenyl)-3 -cyclopropylpropyl)picolinamide (221 i).

Step 1. Preparation of 1-(6-bromopyridin-3-yl)-3-cyclopropylprop-2-en-1-one (221b).

To a stirred solution of 1-(6-bromopyridin-3-yl)ethanone (221a) (35 g, 171 mmol) in methanol (400 ml) at 0°C was added cyclopropanecarboxaldehyde (21 ml, 281 mmol), then potassium hydroxide (1 M aqueous solution, 35 ml, 35 mmol). The reaction mixture was left to warm to room temperature and stirred for 13 hours. The reaction mixture was acidified with 1N. HCl (40 ml) to pH 6 and concentrated in vacuo while maintaining the bath temperature below 35°C. The residue was dissolved in ethyl acetate (700 ml), washed with water (300 ml), dried, filtered and concentrated in vacuo to give crude 1-(6-bromopyridin-3-yl)-3-cyclopropylprop-2-en-1-one ( 221b) (40.45 g) as a colorless liquid, which was used as such in the next step.

Step 2. Preparation of 1-(6-bromopyridin-3-yl)-3-cyclopropylpropan-1-one (221c).

To a stirred solution of crude 1-(6-bromopyridin-3-yl)-3-cyclopropylprop-2-en-1-one (221b) (40.45 g) obtained in the above step in acetonitrile (300 ml) was added tri-n-butyltin hydride (88 ml, 319 mmol) and heated at reflux temperature for 13 hours. The reaction mixture was cooled to room temperature and the layers were separated. The bottom layer was extracted with acetonitrile (150 ml), both layers were combined in acetonitrile and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with mixtures of ethyl acetate in hexanes, 0 to 100%) to give 1-(6-bromopyridin-3-yl)-3-cyclopropylpropan-1-one (221c) (11, 57 g, 45.5 mmol, 28.5% yield) as a white solid; 1H NMR (300 MHz, DMSO-th ₆ ) δ 8.94 (dd, J=2.6, 0.8 Hz, 1H), 8.22 (dd, J=8.3, 2.5 Hz, 1H ), 7.83 (dd, J=8.3, 0.8 Hz, 1H), 3.14 (t, J=7.2 Hz, 2H), 1.52 (q, J=7.1 Hz , 2H), 0.84-0.66 (m, 1H), 0.44 - 0.25 (m, 2H), 0.15- -0.17 (m, 2H); MS (IER-) 252.2 (M-1).

Step 3. Preparation of 5-(3-cyclopropylpropanoyl)picolinonitrile (221d) and 5-(3-cyclopropyl)

- 354 045731 propanoyl)picolinamide (221 e)

A mixture of 1-(6-bromopyridin-3-yl)-3-cyclopropylpropan-1-one (221c) (11.23 g, 44.2 mmol) and copper cyanide (7.92 g, 88 mmol) in DMF (150 ml) was stirred at 110°C for 45 hours. The reaction mixture was cooled to room temperature, diluted with water (200 ml) and ethyl acetate (500 ml). The mixture was filtered and the aqueous layer was separated and extracted with ethyl acetate. Combine the organic layers, wash with saturated aq. NaHCO ₃ (150 mL), brine (150 mL), dry, filter and concentrate in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with mixtures of ethyl acetate in hexanes, (1:0 to 4:1 to 1:1)] to give:

1. 5-(3-cyclopropylpropanoyl)picolinonitrile (221d) (3.642 g, 18.19 mmol, 41.2%) as a yellow oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.23 (dd, J=2.2, 0.9 Hz, 1H), 8.53 (dd, J=8.1, 2.2 Hz, 1H ), 8.22 (dd, J=8.1, 0.9 Hz, 1H), 3.20 (t, J=7.2 Hz, 2H), 1.53 (q, J=7.1 Hz , 2H), 0.91 - 0.61 (m, 1H), 0.53 - 0.23 (m, 2H), 0.15 - 0.00 (m, 2H); MS (IER+) 201.2 (M+1); (IER-) 199.2 (M-1);

2. 5-(3-cyclopropylpropanoyl)picolinamide (221e) (481 mg, 2.204 mmol, 4.99% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (dd, J=2.2, 0.9 Hz, 1H), 8.48 (dd, J=8.2, 2.2 Hz, 1H ), 8.27 (s, 1H), 8.15 (dd, J=8.2, 0.8 Hz, 1H), 7.84 (s, 1H), 3.20 (t, J=7, 2 Hz, 2H), 1.54 (q, J=7.1 Hz, 2H), 0.87 - 0.63 (m, 1H), 0.46 - 0.32 (m, 2H), 0, 13 - 0.03 (m, 2H); MC (IER+) 219.2 (M+1); 241.2 (M+Na).

Step 4. Preparation of (R)-(-)-5-(1-(tert-butylsulfinylimino)-3-cyclopropylpropyl)-picolinamide (221f).

Compound 221f was prepared from 5-(3-cyclopropylpropanoyl)picolinamide (221e) (458 mg, 2.098 mmol) and (R)-2-methylpropane-2-sulfinamide (331 mg, 2.73 mmol) using the method described in step 1 of Scheme 208, (R)-(-)-5-(1-(tert-butylsulfinylimino)-3-cyclopropylpropyl)picolinamide (221f) (393 mg, 1.223 mmol, 58.3% yield) was obtained as a light yellow thick liquid; 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.20 (s, 1H), 8.11 (d , J=8.2 Hz, 1H), 7.80 (s, 1H), 3.52 3.27 (m, 2H), 1.59 - 1.37 (m, 2H), 1.25 (s , 9H), 0.87 - 0.62 (m, 1H), 0.50 - 0.28 (m, 2H), 0.12 - -0.00 (m, 2H); MS (ESI+) 344.3 (M+Na); optical rotation: [a] _D =(+) 7.27 [0.11, MeOH].

Step 5: Preparation of 5-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)picolinamide (221g).

Compound (221g) was prepared from (R)-(-)-5-(1-(tert-butylsulfinylimino)-3-cyclopropylpropyl)picolinamide (221f) (373 mg, 1.16 mmol) using the method described in step 2 scheme 208, obtained 5-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)picolinamide (221g) (287 mg, 0.663 mmol, yield 57.2%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 8.53 - 8.49 (m, 1H), 8.08 (s, 1H), 8.00 - 7.87 (m, 2H), 7.62 ( s, 1H), 6.92 (dd, J=11.2, 8.5 Hz, 1H), 6.72 (dd, J=8.8, 2.3 Hz, 1H), 6.56-6 .46 (m, 1H), 5.42 (s, 1H), 5.12 (s, 2H), 2.62-2.38 (m, 2H), 1.30 0.77 (m, 2H) , 1.13 (s, 9H), 0.75-0.55 (m, 1H), 0.42-0.30 (d, J=8.0 Hz, 2H), 0.02 --0, 15 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -137.37; MS (ESI+) 455.4 (M+Na); optical rotation: [a] _D =(-) 78.75 [0.16, MeOH].

Step 6. Preparation of tert-butyl-3-(5-(5-((-)-1-(6-carbamoylpyridin-3-yl)-3-cyclopropyl-1-((R)1,1-dimethylethylsulfinamido)propyl )-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl)benzylcarbamate (221h).

Compound (221h) was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (290 mg, 0.751 mmol) and 5-( (-)-1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-picolinamide (221g) (260 mg, 0.601 mmol) using the method described at step 3 of Scheme 208, we obtained tert-butyl-3-(5-(5-((-)-1-(6carbamoylpyridin-3-yl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido )propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (221h) (115 mg, 0.144 mmol, 19.17% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.7 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.69 - 7.20 (m, 10H), 5.71 (s , 1H), 4.19 (d, J=6.2 Hz, 2H), 2.75-2.40 (m, 2H), 1.38 (s, 9H), 1.13 (s, 9H) , 1.15-1.13 (m, 1H), 1.00-0.80 (m, 1H), 0.70-0.55 (m, 1H), 0.40-0.27 (m, 2H), 0.00 --0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.81, -122.88; MS (IER+) 822.5 (M+Na), (IER-) 798.5 (M-1); optical rotation: [a] _D =(-) 44.71 [0.085, MeOH].

Step 7. Preparation of (+)-5-(1-amino-1-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole5-carboxamido)-4-fluorophenyl)- 3-cyclopropylpropyl)picolinamide (221i).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-1-(6-carbamoylpyridin-3-yl)-3-cyclopropyl-1((R)-1,1-dimethylethylsulfinamido)propyl) Conc. HCl (0.11 ml, 1.325 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo and suspend the resulting residue in ethanol (2 ml) and triturate with methyl tert-butyl ether (20 ml). The resulting solid was collected by filtration and washed with diethyl ether. The resulting residue was dissolved in water (1 ml) and lyophilized to give (+)-5-(1-amino-1-(3-(1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H) hydrochloride -pyrazole-5-carboxamido)-4-fluorophenyl)-3-cyclopropylpropyl)-picolinamide (221i) (42 mg, 0.059 mmol, 47.38% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.81 (s, 1H), 9.60 (s, 3H), 8.68

- 355 045731

8.62 (m, 1H), 8.43 (s, 3H), 8.18 (d, J=2.9 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.94 (dd, J=8.4, 2.4 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J=1.9 Hz, 1H), 7.68 (s , 1H), 7.61 (dt, J=7.3, 1.7 Hz, 1H), 7.58 - 7.48 (m, 3H), 7.40 (dd, J=8.5, 3 .7 Hz, 2H), 4.11 (q, J=5.8 Hz, 2H), 2.64 - 2.53 (m, 2H), 1.27 - 0.99 (m, 2H), 0 .69 (m, 1H), 0.43 - 0.32 (m, 2H), 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOC) δ -60.83, -120.35; MS (IER+) 618.462 (M+Na), (IER-) 594.458 (M1); optical rotation: [a]D=(+) 7.55 [0.265, MeOH]; analysis, calculation for C ₃₀ H ₂₉ F ₄ N7O ₂ -2HCl-2.25H ₂ O: C, 50.82; H, 5.05; Cl, 10.00; N, 13.83; experiment: C, 50.87; H, 5.41; Cl, 10.23; N, 13.44.

Scheme 222

An example of the preparation of (-)-1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (222k).

Step 1. Preparation of (R)-(-)-N-benzylidene-2-methylpropane-2-sulfinamide (222a).

To a stirred solution of benzaldehyde (259 ml, 2541 mmol) in tetrahydrofuran (2500 ml) was added (R)-2,4,6-triisopropylbenzenesulfinamide (280 g, 2310 mmol), tetraisopropoxytitanium (1382 ml, 4620 mmol) and stirred at room temperature for 36 hours. The reaction mixture was diluted with 1 L of saline with vigorous stirring, then with ethyl acetate (6 L) and stirred for 4 hours. The reaction mixture was filtered, washed with ethyl acetate (6x2 L). The organic layers were combined, washed with sodium metabisulfite solution (329 ml, 1733 mmol), water (462 ml), dried over MgSO ₄ , filtered, evaporated to dryness. The crude residue was purified by flash column chromatography (silica gel, 1.5 kg, eluted with 20% ethyl acetate in hexanes) to give (R)-()-N-benzylidene-2-methylpropane-2-sulfinamide (222a) (472.51 g , 2257 mmol, yield 98%) in the form of a pale yellow oily liquid; 1H NMR (300 MHz, DMSO-de) δ 8.57 (s, 1H), 8.03 - 7.89 (m, 2H), 7.70 - 7.48 (m, 3H), 1.19 ( s, 9H); MS (ESI+) 232.18 (M+Na); optical rotation: №=(-) 112.11 [4.155, СНС1з].

Step 2. Preparation of (R)-N-(R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222b) and (R)-N-((S) -(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222c).

Batch 1.

To a solution of (R)-(-)-N-benzylidene-2-methylpropane-2-sulfinamide (222a) (475 g, 2269 mmol) in toluene (4 L), cooled to -11°C, the freshly prepared reagent was added dropwise Grignard bromide (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium (52c) (4.75 L, 3563 mmol) for 70 min, maintaining internal temperature between -11.1 and -10°C. The reaction mixture was stirred at the indicated temperature until the completion of the reaction (completion of the reaction was checked by TLC). The reaction was quenched with 1N. KHSO4 at -10°C. The reaction mixture was warmed to room temperature for 30 minutes and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2x2 L). Combine the organic layers, wash with water (2x2 L), brine (3.5 L), dry, filter and concentrate in vacuo to obtain a crude oily liquid containing a mixture of diastereomers (R)-N-((R)-(3- amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222b) and (R)-N((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2- methylpropane-2-sulfinamide (222c) [(a.i. = 72/28), 727 g,

- 356 045731

2269 mmol]. IPA (2000 ml) was added to the crude residue in a 22 L flask and heated at reflux temperature with stirring (30 min for complete dissolution). The reaction mixture was cooled to 27°C over 5 min with gentle stirring. The resulting solid was collected by filtration, washed with IPA (5x100 ml), air dried for 24 hours to give (R)-N((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2- methylpropane-2-sulfinamide (222b) (351 g, 48.3% yield, i.d. = 94.63%) as a white crystalline solid.

Batch 2.

The above process was repeated using (R)-(-)-N-benzylidene-2-methylpropane-2-sulfinamide (222a) (0.500 kg, 2.389 mol) to give (R)-N-((R)-( 3-Amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222b) (329 g, 43% yield, i.d. = 93.58%) as a white crystalline solid.

Batch 3.

The above process was repeated using (R)-(-)-N-benzylidene-2methylpropane-2-sulfinamide (222a) (409 g, 1953 mmol) to give (R)-N-((R)-(3- amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222b) (264 g, 42% yield, i.d. = 94.33%) as a white crystalline solid.

Second crystallization. Combine the three batches obtained above in a 22 mL wide-neck rotary flask equipped with a mechanical stirrer containing a mixture of diastereomers (222b) and (222c) (batch 1, 351 g, 48.3% yield, i.d. = 94.63% ), (batch 2, 329 g, 43% yield, d.i. = 93.58%) and (batch 3, 264 g, 42% yield, d.i. = 94.33%), added IPA (4000 ml) and heated at reverse condensation temperature with stirring (50 min for complete dissolution). The reaction mixture was cooled to room temperature overnight with gentle stirring (13°C). The solid crystallized after cooling for about 1 hour, stirring continued overnight. The resulting solid was collected by filtration, washed with IPA (1x100 ml and 2x200 ml), dried under high vacuum for 24 hours to give (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl) methyl)-2-methylpropane-2-sulfinamide (222b) (872 g, 92% yield, i.d. = 99.2852%) as a white crystalline solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.40 - 7.26 (m, 4H), 7.25 - 7.15 (m, 1H), 6.90 (dd, J=11.5, 8.3 Hz, 1H), 6.75 (dd, J=8.9, 2.2 Hz, 1H), 6.57 (ddd, J=8.4, 4.4, 2.2 Hz, 1H ), 5.77 (d, J=5.4 Hz, 1H), 5.33 (d, J=5.3 Hz, 1H), 5.11 (s, 2H), 1.13 (s, 9H ); ¹⁹ F NMR (282 MHz, DMSO) δ -137.36; ¹³ C NMR (75 MHz, DMSO) δ 151.32, 148.19, 143.13, 139.74, 139.70, 128.22, 127.63, 126.93, 115.04, 114.98, 114.91, 114.82, 114.60, 114.35, 61.88, 55.42, 22.77; optical rotation: [a] _D =(-) 70.70 (MeOH, 1.065); analysis, calculation for C ₁₇ H ₂₁ FN ₂ OS: C, 63.72; H, 6.61; N, 8.74; experiment: C, 63.74; H, 6.74; N, 8.74.

Data for (R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222c); ^1H NMR (300 MHz, DMSO-d6) δ 7.41 - 7.36 (m, 2H), 7.36 - 7.27 (m, 2H), 7.26-7.18 (m, 1H) , 6.89 (dd, J=11.5, 8.3 Hz, 1H), 6.71 (dd, J=8.9, 2.2 Hz, 1H), 6.51 (ddd, J=8 ,4, 4.5, 2.2 Hz, 1H), 5.82 (d, J=5.5 Hz, 1H), 5.32 (d, J=5.5 Hz, 1H), 5.09 (s, 2H, 1H exchange with D2O), 1.14 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.32; MS (IER+) 321.3 (M+1), 343.3 (M+Na), 663.5 (2M+Na); MS (IER-) 319.3 (M-1), optical rotation: [a] _D =() 73.21 (MeOH, 2.505).

Step 3. Preparation of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (222d).

Into a mechanically stirred suspension of (R)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2methylpropane-2-sulfinamide (222b) (99.13 g, 309 mmol) in MTBE ( 600 ml) 4M HCl (in dioxane) (162 ml, 650 mmol) was added and stirred at room temperature for 11 hours. A solid began to form immediately after the addition of HCl began. TLC analysis indicated the presence of unreacted starting material, additional 4M HCl (in dioxane) (162 mL, 650 mmol) was added and stirred at room temperature for 16 hours. Excess methanol was evaporated and the mixture was basified with 3N. NaOH (455 ml) and the compound was extracted with ethyl acetate (2x750 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The solid was triturated with hexanes, stirred for 1 hour and the resulting solid was collected by filtration to give (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (222d) (38.0 g, 57% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.39 - 7.33 (m, 2H), 7.27 (ddd, J=7.6, 6.6, 1.2 Hz, 2H), 7 .21 - 7.13 (m, 1H), 6.86 (dd, J=11.5, 8.3 Hz, 1H), 6.77 (dd, J=9.0, 2.2 Hz, 1H ), 6.54 (ddd, J=8.3, 4.4, 2.2 Hz, 1H), 5.03 (s, 2H, exchange with D2O), 4.96 (s, 1H), 2, 71 (s, 2H, exchange with D ₂ O); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -138.12; MS (IER+) 217.2 (M+1); 215.1 (M-1); optical rotation: [a] _D =(+) 1.47 (0.545, MeOH).

Step 4. Preparation of (-)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222e) and (-)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f).

To a stirred solution of (+)-5-(amino(phenyl)methyl)-2-fluoroaniline (222d) (5.312 g, 24.56 mmol) in MeOH (80 mL) was added cyclopropanecarboxaldehyde (1.944 mL, 25.8 mmol) at 0°C for 10 min and stirred for 30 min. Sodium borohydride (1.859 g, 49.1 mmol) was added to the resulting mixture in several portions and stirred for 1 hour at 0°C. Excess solvent was evaporated and the residue was treated with water (100 ml) and extracted with ethyl acetate (2x100 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give:

1. (-)-N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222e) (0.663 g, 8% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.44 - 7.35 (m, 2H), 7.30 - 7.21 (m, 2H), 7.19 - 7.08 (m, 1H) , 6.96 - 6.75 (m, 2H), 6.55 (ddd, J=8.3, 4.6, 2.0 Hz, 1H), 5.26 (td, J=6.0, 2.3 Hz, 1H, exchange with D ₂ O), 4.71 (s, 1H), 2.93 (t, J=6.2 Hz, 2H), 2.27 (d, J=7.1 Hz, 3H, 1H, exchange with D2O), 1.09 - 0.84 (m, 2H), 0.39 (m, 4H), 0.25- 0.15 (m, 2H), 0.09 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 137.56; MS (IER+) 325.4 (M+1); optical rotation: [a] _D =(-) 6.67 [0.27, methanol]:

2. (-)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f) (4.84 g, 73% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 7.42 - 7.34 (m, 2H), 7.32 - 7.23 (m, 2H), 7.22 - 7.11 (m, 1H) , 6.92 - 6.78 (m, 2H), 6.55 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.04 (s, 2H, exchange with D2O) , 4.67 (s, 1H), 2.25 (td, J=9.6, 5.3 Hz, 3H; 1H exchange with D2O), 1.04 - 0.80 (m, 1H), 0, 50 - 0.28 (m, 2H), 0.11 - 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -137.92; MS (IER-) 269.3 (M-1); optical rotation: [a]D=(-) 12.24 [1.275, CHCl ₃ ]; chiral purity was checked by chiral HPLC on an ADH chiral column, 1 ml/min, solvent: 95% hexane, 5% isopropanol, UV=260 nm, 25°C (>99.99 ee).

Step 5. Preparation of 5-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (222h).

To a suspension of 5-amino-2-fluorobenzonitrile (222g) (25 g, 184 mmol) in 12N. HCl (55.1 ml, 661 mmol) was added to a solution of sodium nitrite (15.21 g, 220 mmol) in water (75 ml) at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (83 g, 367 mmol), previously dissolved in 12N, was added to the mixture. HCl (55.1 mL, 661 mmol), at a rate such that the temperature does not exceed 5°C. After stirring for 2 hours, a solution of 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (37.9 g, 184 mmol) in ethanol (305 ml) was added. and heated at 60°C for 21 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove ethanol. The aqueous layer was made basic with saturated NaHCO ₃ and extracted with ethyl acetate (3x500 ml). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 750 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] to give 5-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzonitrile (222h) (11.5 g, 35.8 mmol, 19.49% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.30 (dd, J=5.7, 2.7 Hz, 1H), 8.06 - 7.98 (m, 1H), 7.82 - 7 .70 (m, 2H), 7.34 (s, 1H), 6.59 (dd, J=3.5, 1.8 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H); MS (ESI+): MS (ESI+) 665.3 (2M+Na).

Step 6. Preparation of 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (222i).

Into a stirred solution of 5-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (222h) (11.1 g, 34.6 mmol) in acetone (200 ml ) a solution of potassium permanganate (38.2 g, 242 mmol) in water (100 ml) was added dropwise over 30 min. The resulting mixture was heated at 60°C for 2 hours, cooled to room temperature, and the reaction was quenched with 2-propanol (200 ml). The reaction mixture was stirred at room temperature overnight and filtered through Celite, washed with acetone/water (2x50 ml), methanol (2x75 ml). The organic solvent was removed by evaporation under reduced pressure. The reaction mixture was made alkaline with 1N. NaOH, washed with diethyl ether (2x150 ml). The aqueous layer was poured into crushed ice and very carefully acidified with 1N. aq. HCl with constant stirring. The resulting solid was collected by filtration, washed with hexanes (2x50 ml), dried over P ₂ O ₅ to give 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxylic acid (222i) ( 8.384 g, 81% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 14.03 (s, 1H, exchange with D2O), 8.36 (dd, J=5.7, 2.7 Hz, 1H), 8.07 (ddd , J=9.0, 4.7, 2.7 Hz, 1H), 7.72 (t, J=9.0 Hz, 1H), 7.57 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.77, -106.91; MS (IER+): MS (IER+) 300.2 (M+1); MS (IER+) 298.2 (M-1), 597.3 (2M-1).

Step 7. Preparation of (-)-1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (222j).

Compound 222j was prepared from 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (222i) (1.461 g, 4.88 mmol) and (-)-5-( (cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f) (1.1 g, 4.07 mmol) using the method described in step 3 of Scheme 208 gave (-)-1-(3cyano-4-fluorophenyl )-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (222j) (2.239 g, 100% yield) as a white solid ; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H, exchange with D2O), 8.28 (dd, J=5.7, 2.7 Hz, 1H), 8.00 (ddd , J=9.2, 4.7, 2.8 Hz, 1H), 7.76 - 7.65 (m, 2H), 7.55 (dd, J=7.5, 2.1 Hz, 1H ), 7.42 - 7.30 (m, 4H), 7.30 - 7.23 (m, 1H), 7.22 - 7.14 (m, 2H), 4.84 (s, 1H), 2.44 (s, 1H), 2.34 - 2.22 (m, 2H), 1.02 - 0.84 (m, 1H), 0.47 - 0.28 (m, 2H), 0. 08 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.82, -107.26, -123.06; MS (IER+): MS (IER-) 550.04 (M-1); optical rotation: [a] _D =(-) 5.6 [0.25, CH3OH].

Step 8. Preparation of (-)-1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (222k).

- 358 045731

(-)-1 was added to a solution of potassium tert-butoxide (1.481 g, 13.20 mmol) and acetohydroxamic acid (0.991 g, 13.20 mmol) in DMF (20 ml), which was stirred for 35 min at room temperature -(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (222j) (2.206 g, 4 mmol) in DMF (20 ml). The mixture was stirred at room temperature for 16 hours. The mixture was poured into a separatory funnel containing 100 ml of aqueous ammonium chloride and 100 ml of EtOAc. The aqueous layer was separated and extracted with EtOAc (100 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography (first column: silica gel, 40 g, eluted with mixtures of 0-100% ethyl acetate in hexanes; second column: silica gel, 40 g, eluted with mixtures of 0-50% CMA 80 in chloroform; third column: silica gel, 40 g) to obtain (-)-1-(3-aminobenzo[d]isoxazol5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5carboxamide (222k) (0.221 g, 10% yield) as a white solid; 1H NMR (300 MHz, DMSOdg) δ 10.49 (s, 1H, exchange with D ₂ O), 8.07 (d, J=2.1 Hz, 1H), 7.71 - 7.51 (m, 4H), 7.41 - 7.35 (m, 2H), 7.34 - 7.24 (m, 3H), 7.22 - 7.13 (m, 2H), 6.59 (s, 2H, exchange with D ₂ O), 4.82 (s, 1H), 2.42 (s, 1H), 2.26 (d, J=6.0 Hz, 2H), 0.89 (td, J=7 ,4, 3.8 Hz, 1H), 0.45-0.27 (m, 2H), 0.03 (dt, J=5.0, 2.7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-b6) δ 60.59, -123.45; MS (IER ⁺ ): MS (IER+) 565.5 (M+1); optical rotation: [a] _D =(-) 8.3 [0.265, CH3OH].

Scheme 223

An example of the preparation of 1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (223f).

Step 1. Preparation of 5-(amino(phenyl)methyl)-2-fluoroaniline (223b).

(R)-N-((3-Amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (223a) was obtained from the supernatant obtained from the crystallization of a mixture of diastereomers (R)-N-(( R)-(3-amino-4fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222b) and (R)-N-((S)-(3-amino-4-fluorophenyl)(phenyl) methyl)-2-methylpropane-2-sulfinamide (222c), obtained in scheme 222. Compound 223b was prepared from (R)-N-((3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2 -sulfinamide (223a) (27.8 g, 87 mmol) using the method described in step 3 of Scheme 222 gave 5-(amino(phenyl)methyl)-2fluoroaniline (223b) (14 g, 75%) as light -brown solid; 1H NMR (300 MHz, DMSOd ₆ ) δ 7.40 - 7.32 (m, 2H), 7.27 (ddd, J=7.6, 6.7, 1.2 Hz, 2H), 7.21 - 7.11 (m, 1H), 6.86 (dd, J=11.5, 8.3 Hz, 1H), 6.78 (dd, J=9.0, 2.2 Hz, 1H), 6.54 (ddd, J=8.3, 4.5, 2.2 Hz, 1H), 5.00 (s, 2H), 4.93 (s, 1H), 2.13 (s, 2H) ; ¹⁹ F NMR (282 MHz, DMSO) δ -138.30; MS (IER) 215.1 (M-1).

Step 2. Preparation of K-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (223c) and 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (223d).

Compounds 223c and 223d were prepared from 5-(amino(phenyl)methyl)-2-fluoroaniline (223b) (1.081 g, 5.00 mmol) according to the method described in step 4 of Scheme 222 to give:

1. N-(cyclopropylmethyl)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (223c) (0.194 g, 0.598 mmol, 11.96% yield) as a colorless oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.44 - 7.35 (m, 2H), 7.30 - 7.21 (m, 2H), 7.19 - 7.11 (m, 1H) , 6.94 - 6.79 (m, 2H), 6.56 (ddd, J=8.2, 4.6, 2.1 Hz, 1H), 5.29 (td, J=5.9, 2.3 Hz, 1H), 4.72 (s, 1H), 2.94 (t, J=6.2 Hz, 2H), 2.38 - 2.20 (m, 3H), 1.10 - 0.97 (m, 1H), 0.91 (m, 1H), 0.40 (m, 4H), 0.21 (m, 2H), 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -137.78; MS (IER+) 325.3 (M+1); (IER-) 323.2 (M-1);

2. 5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (223d) (0.795 g, 2.94 mmol, 58.8% yield) as a colorless oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.40 - 7.33 (m, 2H), 7.27 (tt, J=6.6, 0.9 Hz, 2H), 7.20 - 7 .12 (m, 1H), 6.90 - 6.78 (m, 2H), 6.54 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.04 (s , 2H), 4.67 (s, 1H), 2.34 - 2.22 (m, 3H), 0.91 (m, 1H), 0.44 - 0.30 (m, 2H), 0, 09 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -137.95; MS (IER+) 271.2 (M+1).

Step 3. Preparation of 1-(3-αminobenzo[d]isoxαzol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carbo

- 359 045731 new acid (223e).

Compound 223e was prepared from 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (222h) (2 g, 6.68 mmol) using the method described in step 8 Scheme 222 gave 1-(3-aminobenzo[d]isoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (223e) (1.823 g, 87% yield) as a white solid ; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.03 (d, J=2.1 Hz, 1H), 7.73 (dd, J=8.8, 2.2 Hz, 1H), 7, 63 - 7.51 (m, 2H), 6.57 (s, 2H, exchange with D2O); ¹⁹ F NMR (282 MHz, DMSOC) δ 60.63; MS (IER ⁺ ): MS (IER+) 313.2 (M+1), MS (IER-) 311.1 (M-1), 623.3 (2M-1).

Step 4. Preparation of 1-(3-aminobenzo[d]isoxazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (223f).

Compound 223f was prepared from 1-(3-aminobenzo[d]isoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (223e) (0.577 g, 1.849 mmol) and 5-((cyclopropylmethylamino)( phenyl)methyl)-2-fluoroaniline (223d) (0.5 g, 1.849 mmol) according to the method described in step 3 of Scheme 208, 1-(3aminobenzo[d]isoxazol-5-yl)-N-(5- ((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (223f) (0.171 g, 16% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.37 (t, J=2.2 Hz, 1H), 8.03 - 7.80 (m, 4H), 7.72 - 7.42 (m, 7H), 6.88 (s, 2H), 5.12 (d, J=1.8 Hz, 1H), 2.73 (m, 1H), 2.62 - 2.50 (m, 2H), 1.18 (m, 1H), 0.66 (m, 2H), 0.39 - 0.27 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.53 (d, J=2.4 Hz), -123.40; MS (IER ⁺ ): MS (IER+) 565.4 (M+1).

Scheme 224

An example of the preparation of 1-(3-amino-1H-indazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (224b).

Step 1. Preparation of 1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (224a ).

Compound 224a was prepared from 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (222h) (1.217 g, 4.07 mmol) and 5-((cyclopropylmethylamino)( phenyl)methyl)-2fluoroaniline (223d) (1.1 g, 4.07 mmol) as described in step 3 of Scheme 208 gave 1-(3-cyano-4fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl) Methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (224a) (1.38 g, 2.502 mmol, 61.5% yield) as a white solid, used as such at the next stage; MS (IER+) 552.4 (M+1); MS (IER-) 550.3 (M-1).

Step 2. Preparation of 1-(3-amino-1H-indazol-5-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (224b).

Into a stirred solution of 1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (224a ) (0.7 g, 1.269 mmol) in nbutanol (20 ml), hydrazine hydrate (1.539 ml, 31.7 mmol) was added and heated at reflux temperature overnight. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 24 g, eluted with mixtures of CMA 80 in chloroform, 0-100%] to give 1-(3-amino-1H-indazol-5-yl)-N-(5(( cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (224b) (0.197 g, 27% yield) as a light yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 10.44 (s, 1H), 7.90 (t, J=1.4 Hz, 1H), 7.65- 7.52 (m, 2H), 7.41 - 7.34 (m, 2H), 7.33 - 7.23 (m, 5H), 7.22 - 7.12 (m, 2H), 5, 54 (s, 2H), 4.81 (s, 1H), 2.43 (s, 1H), 2.25 (m, 2H), 0.97 - 0.80 (m, 1H), 0.41 - 0.30 (m, 2H), 0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.62, -123.79; MS (IER ⁺ ): MS (IER+) 564.4 (M+1); MS (IER-) 562.3 (M-1).

Scheme 225

An example of the preparation of (-)-N-(5-(1-amino-1-(3-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (225a).

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Into a stirred solution of tert-butyl-3-(5-(5-((-)-1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (214f) (7.268 g, 9.31 mmol) in ethanol (70 ml) was added conc. HCl (7.80 mL, 94 mmol) and heated at reflux temperature for 1 hour. Concentrate the reaction mixture to dryness in vacuo to give a white solid (7.173 g). The white solid was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of CMA 80 in chloroform, 0 to 100%) to give (+)-N-(5-(1-amino-1-(3-cyanophenyl )-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (214g), containing an NH ₄ Cl impurity, which was re-purified by column Flash chromatography (silica gel, 24 g, eluted with 0 to 50% methanol/chloroform mixtures) to give free base 214 g (4.567 g) as a white solid.

Free base 214g (4.45 g) was dissolved in methanol (150 ml) and 4N was added. HCl (aq, 8.0 ml), then concentrated to dryness in vacuo to give HCl salt 214g (4.622 g) as a white solid containing the impurity (-)-N-(5-(1-amino-1-( 3-carbamoylphenyl)-3-cyclopropylpropyl)-2fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (225a), which was associated with the use of dilute HCl; The solid was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of CMA 80 in chloroform, 0 to 100%) to give the free base 214g (3.8 g), then 225a (150 mg, 0.252 mmol, yield 3.64 %) as a white solid; 1H NMR (300 MHz, DMSO-de) δ 10.52 (s, 1H), 8.05-7.84 (m, 2H), 7.66 (dt, J=7.7, 1.3 Hz, 1H), 7.57 (d, J=5.3 Hz, 2H), 7.49 (d, J=8.5 Hz, 1H), 7.44 - 7.37 (m, 2H), 7. 36 - 7.22 (m, 3H), 7.18 (d, J=9.6 Hz, 1H), 3.78 (s, 2H), 2.30 - 2.17 (m, 6H), 1 .02 (m, 2H), 0.64 (m, 1H), 0.43 - 0.29 (m, 2H), -0.04 - -0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.72, -124.42; MS (IER+) 595.5 (M+1), 617.5 (M+Na), (IER-) 593.4 (M-1); analysis, calculation for C ₃₁ H ₃₀ F ₄ N ₆ O ₂ -H ₂ O: C, 61.23; H, 5.22; N, 13.82; experiment: C, 61.29; H, 5.40; N, 13.82; optical rotation: [a] _D =(-) 0.54 [1.15, methanol].

Scheme 226

An example of the preparation of 1 -(4-aminoquinazolin-6-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3 -(trifluoromethyl)-1 H-pyrazol-5-carboxamide (226a).

Into a stirred solution of 1-(3-cyano-4-fluorophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (224a ) (0.7 g, 1.269 mmol) in N,Ndimethylacetamide (20 ml), formimidamide acetate (1.321 g, 12.69 mmol) was added and heated at reflux temperature overnight. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [first column: silica gel, 24 g, eluted with mixtures of CMA 80 in chloroform, 0-100%; second column: silica gel, 24 g, eluted with ethyl acetate/methanol (9:1) in hexanes, 0-100%] to give 1-(4-aminoquinazolin-6-yl)-N-(5-((cyclopropylmethylamino)( phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (226a) (0.113 g, 15% yield) as a pale yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H, exchange with D2O), 8.47 (d, J=5.6 Hz, 2H), 7.97 (s, 2H, exchange with D2O), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.73 (d, J=9.2 Hz, 2H), 7.57 (dd, J=7, 5, 2.2 Hz, 1H), 7.38 (dt, J=6.5, 1.4 Hz, 2H), 7.35- 7.23 (m, 3H), 7.22 - 7.13 (m, 2H), 4.82 (s, 1H), 2.43 (s, 1H), 2.25 (m, 2H), 0.88 (m, 1H), 0.45-0.25 ( m, 2H), 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -60.76, -123.39; MS (IER+) 576.4 (M+1); MS (IER-) 574.4 (M-1).

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Scheme 227

An example of the preparation of (-)-1-(3-carbamidoylphenyl)-N-(5-((cyclopronylmethylamino)(phenyl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(5-((-)-((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (227a).

A solution of (-)-N-((R)-(3-amino-4-fluorophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (222b) (0.872 kg, 2.72 mol) in DMF ( 10 ml) 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (9i) (0.765 kg, 2.72 mol), N-ethyl-N-isopropylpropan-2-amine (2 .37 L, 13.61 mol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 1.4 kg, 2.99 mol) and stirred at room temperature for 24 hours. Additional 9i (153 g, 0.54 mol), Nethyl-N-isopropylpropan-2-amine (470 ml) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 280 g), DMF (500 ml) and stirred at room temperature for 24 hours. Additional 9i ( 77 g, 0.274 mol), N-ethyl-N-isopropylpropan-2-amine (470 ml) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 140 g), (DMF 500 ml) and stirred at room temperature for 24 hours After stirring for 72 hours at room temperature, the reaction mixture was diluted with ethyl acetate (8 L), washed with water (14 L), brine, dried, filtered and evaporated to dryness to give 1-(3-cyanophenyl)-N-(5- ((-)-((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227a) (3108.6 g) in as a whitish solid which was sufficiently pure for use in the next step. The sample for analysis was prepared by dissolving 1.6 g of the crude substance in isopropanol (24 ml) under heating. The mixture was cooled to room temperature overnight with stirring and the resulting solid was collected by filtration, washed with isopropanol and dried in vacuo overnight to provide 0.6 g of compound 227a as a white solid; 1H NMR (300 MHz, DMSO-de) δ 10.59 (s, 1H), 8.15-8.08 (m, 1H), 7.99 (dt, J=7.8, 1.3 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.76 - 7.68 (m, 2H), 7.51 (dd, J=6.9, 2.2 Hz, 1H), 7 .41 - 7.18 (m, 7H), 6.08 (d, J=6.2 Hz, 1H), 5.53 (d, J=6.1 Hz, 1H), 1.12 (s, 9H); ¹³ C NMR (75 MHz, DMSO) δ 156.11, 152.88, 142.57, 140.13, 140.09, 139.81, 138.41, 132.99, 130.48, 130.35, 129.27, 127.66, 127.18, 126.71, 126.61, 125.31, 123.85, 123.68, 117.76, 115.93, 115.66, 111.83, 108, 09, 61.71, 55.55, 22.75; ¹⁹ F NMR (282 MHz, DMSO) δ -60.99, -122.46; MS (IER+) 584.1 (M+1); (IER-) 582.2 (M-1); optical rotation: [a]D=(-) 49.20 (1.065, methanol); analysis, calculation for C ₂₉ H ₂₅ F ₄ N ₅ O ₂ S: C, 59.68; H, 4.32; N, 12.00; experiment: C, 59.37; H, 4.61; N, 11.96.

Step 2. Preparation of (-)-N-(5-(amino(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)3-(trifluoromethyl)-1H-pyrazole-5-carboxamide hydrochloride (227b) .

Into a solution of 1-(3-cyanophenyl)-N-(5-((-)-((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (227a) (550 g, 942 mmol) in MeOH (6 L) add hydrogen chloride (0.415 L, 1659 mmol, 4N in 1,4-dioxane) dropwise at room temperature over 30 min and stir within 30 min. Additional hydrogen chloride (70 ml, 4N in 1,4-dioxane) and (65 ml, 4N in 1,4-dioxane) were added at 30 minute intervals and stirred at room temperature. After completion of the reaction (1 h), the reaction mixture was concentrated to dryness in vacuo. The resulting residue was triturated with hexanes (2 L) and the resulting solid was collected by filtration, washed with hexanes and dried in vacuo to give (-)-N-(5(amino(phenyl)methyl)-2-fluorophenyl)-1-( hydrochloride 3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227b) (489.3 g). The sample for analysis was prepared by recrystallization from isopropanol to obtain 227b as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 9.02 (s, 3H), 8.13 (d, J=2.1 Hz, 1H), 8.00 ( dt, J=7.7, 1.3 Hz, 1H), 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.77 (s, 1H), 7.73 (t , J=8.0 Hz, 1H),

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7.67 (d, J=7.0 Hz, 1H), 7.49 - 7.36 (m, 7H), 5.70 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.99, -120.98; MS (IER+) 480.2 (M+1); (IER-) 478.2 (M-1); optical rotation: [a] _D =(-) 3.60 [1.11, CH3OH], analysis, calculation for C ₂₅ H ₁₇ F ₄ N ₅ O-HCl-1.25H ₂ O: C, 55.77; H, 3.84; Cl, 6.58; N, 13.01; experiment: C, 55.87; H, 3.98; Cl,

6.46; N, 12.91.

Step 3. Preparation of (-)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 227c).

Into a stirred solution of (-)-M-(5-(amino(phenyl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (227b) [( 50.52 g, 105 mmol) which was converted to the free base using aqueous NaHCO ₃ and cyclopropanecarbaldehyde (9.84 mL, 132 mmol) was added by extraction with ethyl acetate and drying in vacuo before use to react] in methanol (530 mL) and stirred at room temperature for 5 hours. The reaction was carefully quenched with sodium borohydride (8.14 g, 211 mmol) while cooling in ice/water (internal temperature during addition was 6°C to 10°C), then stirred at room temperature for 60 minutes. The methanol was evaporated in vacuo and the residue was treated with water (1 L) and extracted with ethyl acetate (2x1 L, 0.5 L). The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 2 kg, eluted with mixtures of ethyl acetate in hexanes, 0-60%) to give (-)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl) methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227c) (39.85 g, 71% yield) as a colorless oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H, exchange with D2O), 8.14 - 8.07 (m, 1H), 7.97 (dt, J=7.7, 1.3 Hz, 1H), 7.93 - 7.85 (m, 1H), 7.75- 7.66 (m, 2H), 7.58 (dd, J=7.6, 2.2 Hz , 1H), 7.45-7.12 (m, 7H), 4.83 (s, 1H), 2.42 (s, 1H), 2.26 (m, 2H), 0.90 (m, 1H), 0.45-0.28 (m, 2H), 0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.86, -123.17; MC (IER+): MC (IER+) 534.2 (M+1); 532.2 (M1); optical rotation: [a] _D =(-) 7.83 [0.23, MeOH].

Step 4. Preparation of (-)-1-(3-carbamidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 227d).

Into a solution of (-)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (227c) ( 1.0 g, 1.874 mmol) in THF (15 ml), add LiHMDS (1M in THF, 4.00 ml, 4.00 mmol) and stir at room temperature for 24 hours. Add additional LiHMDS (1M in THF, 4.00 ml, 4.00 mmol) and heated the reaction mixture at reflux temperature for 5.5 hours. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was acidified with 1N. KHSO4 (15 ml) and extracted with ethyl acetate (2x30 ml). The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA 80 in CHCl ₃ , from 0 to 100%) to give the free base (-)-1-(3-carbamidoylphenyl)-M-(5-( (cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d) (0.205 g, 20% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (t, J=1.8 Hz, 1H), 7.91 (dt, J=7.6, 1.5 Hz, 1H), 7, 59 (dd, J=15.0, 7.7 Hz, 4H), 7.43 - 7.36 (m, 2H), 7.35- 7.25 (m, 3H), 7.23 - 7, 14 (m, 2H), 4.83 (s, 1H), 2.26 (d, J=6.1 Hz, 2H), 0.90 (m, 1H), 0.42 - 0.32 (m , 2H), 0.07 - 0.01 (m, 2H); MS (IER+): 551.4 (M+1); 549.4 (M-1).

Preparation of HCl salt (-)-1-(3-carbamidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d ).

To a stirred solution of free base 227d (0.152 g, 0.276 mmol) in ethanol (5 ml) was added conc. HCl (0.115 mL, 1.380 mmol) and stirred at room temperature for 10 min. The solution was evaporated to dryness to obtain the hydrochloride salt of (-)-1-(3-carbamidoylphenyl)-N(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (227d) (0.165 g, 0.248 mmol, 90% yield) as a yellow solid.

1H NMR (300 MHz, DMSO- _d6 ) δ 10.84 (s, 1H, exchange with D2O), 10.20 (s, 2H, exchange with D2O), 9.53 (s, 2H, exchange with D2O) , 9.29 (s, 2H, exchange with D2O), 8.03 (t, J=1.9 Hz, 1H), 7.97 (dt, J=8.0, 1.4 Hz, 1H), 7.89 (ddd, J=9.2, 7.3, 2.1 Hz, 2H), 7.82 (s, 1H), 7.80 - 7.67 (m, 4H), 7.50 - 7.32 (m, 4H), 5.65 (t, J=6.5 Hz, 1H), 2.71 (d, J=11.3 Hz, 2H), 1.18 - 1.13 (m , 1H), 0.65-0.45 (m, 2H), 0.30 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.87, 120.21; MS (IER+) 551.4 (M+1); MS (ESI-) 549.34 (M-1), 585.36 (M+Cl); optical rotation: [a] _D =(-) 1.57 [0.51, CH3OH]; analysis, calculation for C ₂₉ H ₂₆ F ₄ N ₆ O-2HCl-2.25H2O: C, 52.46; H, 4.93; N, 12.66; experiment: C, 52.62; H, 4.89; N, 12.27.

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Scheme 228

An example of the preparation of (+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)- Ш-pyrazole-5-carboxamide (228a).

Into a stirred solution of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (212g) (80 mg, 0.123 mmol) in ethanol (10 ml) was added ammonium hydroxide (10 ml, 257 mmol), hydrogen peroxide (1 ml, 32.6 mmol) and stirred at room temperature overnight. Additional hydrogen peroxide (1 mL, 32.6 mmol) was added to the reaction mixture and stirring continued for 24 hours. The reaction mixture was concentrated in vacuo; remove remaining water by azeotroping with ethanol (50 ml). The resulting crude residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform) to give (+)N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)- 2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (228a) (32 mg, 0.054 mmol, 43.7% yield) as a white solid; Ή NMR (300 MHz, DMSO<) δ 10.52 (s, 1H), 7.90 (s, 1H), 7.79 - 7.72 (m, 2H), 7.55 (d, J=5 ,9 Hz, 2H), 7.50 (s, 1H), 7.42 (dd, J=7.9, 2.6 Hz, 4H), 7.36 - 7.24 (m, 3H), 7 .16 (t, J=9.4 Hz, 1H), 3.77 (s, 2H), 2.32 - 2.11 (m, 4H), 1.13 - 0.90 (m, 2H), 0.62 (m, 1H), 0.42 - 0.25 (m, 2H), -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.72, -124.35 (q, J=9.8, 7.8 Hz); MS (IER+) 595.5 (M+1), 617.5 (M+Na); optical rotation: [a] _D =(+) 8.57 [0.21, CH ₃ OH].

Scheme 229

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N5-(5-((cyclopropylmethylamino)phenyl)methyl)-2fluorophenyl-1H-pyrazole-3,5-dicarboxamide (229i).

Step 1. Preparation of lithium (Z)-4-tert-butoxy-1-(furan-2-yl)-3,4-dioxobut-1-en-1-olate (229b).

To LiHMDS (134 ml, 134 mmol, 1 M solution in THF) in diethyl ether (410 ml), cooled to -78°C, 1-(furan-2-yl)ethanone (229a) (14 g, 127 mmol) and stirred for 5 min. A solution of di-tert-butyl oxalate (25.7 g, 127 mmol) in diethyl ether (100 ml) was added to the resulting mixture. The reaction mixture was left to warm to room temperature overnight. Filter the mixture and wash the resulting yellow solid with diethyl ether (100 ml), dry in vacuo to give (Z)-4-tert-butoxy-1-(furan-2-yl)-3,4-dioxobut-1-ene- Lithium 1-olate (229b) (23.6 g, 97 mmol, 76% yield), which was used as such in the next step; 1H NMR (300 MHz,

DMSO-d6) δ 7.75 (dd, J=1.7, 0.8 Hz, 1H), 6.95 (dd, J=3.4, 0.9 Hz, 1H), 6.56 (dd , J=3.4, 1.7 Hz, 1H), 6.24 (s,

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1H), 1.46 (s, 9H); MS (IER-) 237.059 (M-1).

Step 2. Preparation of tert-butyl-1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (229d)

To (Z)-4-tert-butoxy-1-(furan-2-yl)-3,4-dioxobut-1-ene-1-olate lithium (229b) (21.59 g, 88 mmol) and hydrochloride 3 -hydrazinylbenzonitrile (229c) (15 g, 88 mmol) was added to AcOH (400 ml) and stirred at room temperature overnight. Concentrate the mixture in vacuo and purify the resulting residue by flash column chromatography (silica gel, 300 g, eluted with 25% ethyl acetate in hexane) to give tert-butyl-1-(3-cyanophenyl)-5-(furan-2-yl) -1H-pyrazole-3carboxylate (229d) (24.658 g, 73.5 mmol, 83% yield) as a yellow oily liquid that solidified on standing; 1H NMR (300 MHz, DMSO- _d6 ) δ 8.10 - 7.98 (m, 2H), 7.88 - 7.72 (m, 3H), 7.15 (s, 1H), 6.56 (dd, J=3.5, 1.8 Hz, 1H), 6.41 (dd, J=3.4, 0.8 Hz, 1H), 1.55 (s, 9H); MS (ESI+) 358.3 (M+Na).

Step 3. Preparation of 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic acid (229e).

To a solution of tert-butyl-1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (229d) (23 g, 68.6 mmol) in dichloromethane (250 ml) was added trifluoroacetic acid (211 ml, 2743 mmol) and stirred at room temperature for 5 hours. Concentrate the reaction mixture to dryness in vacuo to give 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazol-3 -carboxylic acid (229e) (19.0 g, 68.0 mmol, 99% yield) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 8.07 - 8.00 (m, 2H), 7.87 - 7.71 (m, 3H), 7.19 (s, 1H), 6.58 (dd, J=3.5, 1.8 Hz, 1H), 6.46 (dd, J=3.5, 0.8 Hz, 1H); MS (IER+) 280.3 (M+1); 302.2 (M+Na).

Step 4. Preparation of 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazol-3-carboxamide (229f).

To a solution of 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazol-3-carboxylic acid (229e) (13 g, 46.6 mmol) in dichloromethane (75 ml) was added oxalyl chloride (2M solution in dichloromethane, 46.6 ml, 93 mmol), then DMF (10 drops). The reaction mixture was stirred at room temperature for 5 hours and concentrated to dryness in vacuo. The resulting residue was dissolved in dichloromethane (250 ml), ammonia in dioxane (0.5 M solution, 233 ml, 116 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was poured into water. The aqueous layer was extracted with ethyl acetate (3x100 ml). Combine the organic layers, wash with brine (100 mL), dry, filter and concentrate in vacuo to give 1-(3-cyanophenyl)5-(furan-2-yl)-1H-pyrazol-3-carboxamide (229f) (10 .2 g, 36.7 mmol, 79% yield) as a brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.08 (ddd, J=2.2, 1.6, 0.6 Hz, 1H), 8.01 (dt, J=7.4, 1, 5 Hz, 1H), 7.85 - 7.72 (m, 4H), 7.52 - 7.40 (m, 1H), 7.12 (s, 1H), 6.58 (dd, J=3 ,5, 1.8 Hz, 1H), 6.44 (dd, J=3.5, 0.8 Hz, 1H); MS (IER+) 279.3 (M+1); 301.3 (M+Na); (IER-) 277.4 (M-1).

Step 5. Preparation of 3-carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g).

A solution of 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazol-3-carboxamide (229f) (7.5 g, 27.0 mmol) in water (150 ml) and t- BuOH (150 ml) was added sodium dihydrogen phosphate (5% aqueous, 105 ml, 53.6 mmol). The resulting solution was heated to 60°C and potassium permanganate (20.31 g, 129 mmol) was added in small portions over 30 min. The slurry was stirred for 30 min, cooled to 0°C, and quenched with saturated aqueous sodium bisulfite (428 ml, 2142 mmol). The resulting mixture was filtered, washed with water (300 ml) and the filtrate was acidified with conc. HCl. The resulting solid was collected by filtration to give 3-carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g) (2.48 g, 9.68 mmol, 45.2% yield) after drying. as a white solid. Concentrate the aqueous layer in vacuo to approximately 50 ml and extract with ethyl acetate (5x50 ml). Combine the organic layers, dry, filter and concentrate in vacuo to give 3-carbamoyl-1-(3cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g) (2.9 g, 11.32 mmol, 52.8% yield ) as a second fraction that was sufficiently pure for use in the next step; 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.01 - 7.86 (m, 3H), 7.72 (t, J=7.8 Hz, 1H), 7 .53 (s, 1H), 7.33 (s, 1H); MS (IER-) 255.1 (M-1).

Step 6. Preparation of 1-(3-cyanophenyl)-1H-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-3,5-dicarboxamide (229h).

Compound 229h was prepared from 3-carbamoyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylic acid (229g) (0.606 g, 2.364 mmol) and (-)-5-((cyclopropylmethylamino)(phenyl)methyl) -2-fluoroaniline (222f) (0.581 g, 2.149 mmol) as described in step 3 of Scheme 208 gave 1-(3-cyanophenyl)-1H-(5((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H -pyrazole-3,5-dicarboxamide (229h) (0.706 g, 65% yield) as a yellow thick liquid, which was used as such in the next step; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 8.10 (s, 1H), 7.95 (dt, J=7.7, 1.3 Hz, 1H), 7.87 (d, J=7.1 Hz, 2H), 7.70 (t, J=7.9 Hz, 1H), 7.62 - 7.49 (m, 3H), 7.44 - 7 .13 (m, 7H), 4.84 (s, 1H), 2.35-2.20 (m, 2H), 1.02 - 0.85 (m, 1H), 0.51 - 0.28 (m, 2H), 0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -123.18; MS (IER+): 509.4.

Step 7. Preparation of (-)-1-(3-(aminomethyl)phenyl)-1H-(5-((cyclopropylmethylamino)phenyl)methyl)2-fluorophenyl-1H-pyrazole-3,5-dicarboxamide (229i).

Compound 229i was prepared from 1-(3-cyanophenyl)-N5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-1H-pyrazole-3,5-dicarboxamide (229h) (0.681 g, 1.339 mmol) according to method of obtaining

- 365 045731 compound 15g, described in step 6 of scheme 15, gave (-)-1-(3-(aminomethyl)phenyl)-1H-(5((cyclopropylmethylamino)phenyl)methyl)-2-fluorophenyl-1H-pyrazol- 3,5-dicarboxamide (229i) (89 mg, 13% yield) as a white solid; ^1H NMR (300 MHz, DMSO-de) δ 10.42 (s, 1H, exchange with _D2O ),

7.79 (s, 1H), 7.64 - 7.55 (m, 1H), 7.49 (d, J=7.0 Hz, 2H), 7.45 - 7.36 (m, 5H) , 7.35- 7.24 (m, 4H), 7.18 (td, J=8.5,

2.3 Hz, 2H), 4.83 (s, 1H), 3.79 (s, 2H), 2.27 (m, 2H), 0.91 (m, 1H), 0.47 - 0, 27 (m, 2H), 0.04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -123.40; MS (IER+) 513.4 (M+1); MS (IER-) 511.5 (M-1); optical rotation: [a]D=(-) 4.17 [0.24, CH3OH]; analysis, calculation for: Cz^FNOrMEzO: C, 64.55; H, 5.98; F, 3.52; N, 15.57; experiment: C, 64.34; H, 5.95; F, 4.40; N, 15.62.

Scheme 230

An example of the preparation of (-)-1-(3-carbamoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (230a).

Into a stirred solution of (-)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1-pyrazole-5-carboxamide (227c) ( 1.067 g, 2.0 mmol) in ethanol (50 ml), ammonium hydroxide (19 ml, 257 mmol), hydrogen peroxide (0.700 ml, 7.92 mmol) was added and stirred at room temperature for 22 hours. Concentrate the reaction mixture to vacuum and purify the resulting crude residue by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform) to give (-)-1-(3-carbamoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl) methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (230a) (108 mg, 0.196 mmol, 9.79% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.53 (s, 1H), 8.15 (s, 1H), 8.04 - 7.97 (m, 2H), 7.70-7.52 (m, 5H), 7.42 - 7.36 (m, 2H), 7.35-7.13 (m, 5H), 4.83 (s, 1H), 2.32-2.20 (m , 2H), 0.97 - 0.78 (m, 1H), 0.44 - 0.29 (m, 2H), 0.07-0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.63, -123.40; MS (IER+): 552.4 (M+H); optical rotation: [a] _D =(-) 6.51 (0.215, methanol); analysis, calculation for C ₂₉ H ₂₅ F ₄ N ₅ O ₂ : C, 63.15; H, 4.57; N, 12.70, experiment: C, 62.97; H, 4.57; N, 12.72.

Scheme 231

NHBoc 231с NH ₂ 2:231d (+)-isomer

An example of the preparation of (+)-N ⁵ -(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-1H-pyrazole-3 ,5-dicarboxamide (231d).

Step 1. Preparation of tert-butyl-3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a).

To a solution of 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazol-3-carboxamide (229f) in methanol (100 ml), cooled in ice/water, was added nickel (II) chloride hexahydrate ) (0.322 g, 1.353 mmol) and Boscanhydride (3.14 ml, 13.53 mmol), then sodium borohydride (2.56 g, 67.6 mmol) was added portionwise over 15 min. The reaction mixture was stirred at room temperature for 2 hours and quenched with N1(2-aminoethyl)ethane-1,2-diamine (4.38 mL, 40.6 mmol), then stirred for an additional 0.5 hours. The reaction was concentrated mixture to dryness in a vacuum. The residue was treated with water (50 ml) and extracted with ethyl acetate (2x100 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, 25 g, eluted with 0 to 25% methanol/chloroform mixtures) to give tert-butyl-3-(3-carbamoyl-5-(furan-2yl)-1H-pyrazol- 1-yl)benzylcarbamate (231a) (1.8 g, 4.71 mmol, 69.6% yield) as a colorless solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.73 (dd, J=1.9, 0.8 Hz, 2H), 7.49 (dd, J=9.0, 6.4 Hz, 2H), 7.457.38 (m, 2H), 7.36 (d, J=1.8 Hz, 1H), 7.31 (dd, J=7.8, 1.7 Hz, 1H), 7, 06 (s, 1H), 6.50 (dd, J=3.5, 1.8 Hz, 1H),

6.13 (d, J=3.5 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.37 (s, 9H).

Step 2. Preparation of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-carbamoyl-1H-pyrazole-5carboxylic acid (231b).

In a solution of tert-butyl-3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a) (0.65 g, 1.70 mmol), sodium dihydrogen phosphate ( 1.02 g, 8.50 mmol) in acetonitrile (10 ml) and water (2 ml), a solution of sodium chlorite (1.537 g, 17.00 mmol) in water (10.00 ml) was added and stirred at room temperature for nights. The reaction mixture was evaporated to dryness. The rest was processed for us. NaHCO ₃ , extracted with chloroform (2x50 ml). The combined organic layers were dried, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)3-carbamoyl-1H-pyrazol- 5-carboxylic acid (231b) (225 mg, 0.624 mmol, 36.7% yield) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 (s, 1H), 7.49 (td, J=18.8, 17.7, 8.7 Hz, 3H), 7.39 7 .34 (m, 2H), 4.19 (d, J=6.3 Hz, 2H), 1.39 (s, 9H); MS (IER+) 383.3 (M+Na), (IER-) 359.3 (M-1).

Step 3. Preparation of tert-butyl-3-(3-carbamoyl-5-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl )-1H-pyrazol-1-yl)benzylcarbamate (231c).

In a solution of 1 -(3 -((tert-butoxycarbonylamino)methyl)phenyl)-3-carbamoyl-1 H-pyrazole-5-carboxylic acid (231b) (210 mg, 0.582 mmol) in N,N-dimethylformamide (4, 10 ml, 52.9 mmol) was added (R)-N-((-)1-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2- sulfinamide (212e) (219 mg, 0.529 mmol), N-ethyl-N-isopropylpropan-2-amine (0.461 ml, 2.65 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop) (296 mg, 0.635 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (2x50 ml). Combine the organic layers, wash with brine (25 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 25 g, eluted with mixtures of 0-100% ethyl acetate in hexanes) to give tert-butyl-3-(3-carbamoyl-5-(5-(1-(4cyanophenyl)-3 -cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-1Hpyrazol-1-yl)benzylcarbamate (231c) (78 mg, 0.103 mmol, 19.49% yield) as colorless solid matter; ¹ H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.64 - 7.46 (m, 2H), 7.48 - 7.27 (m, 6H), 7.21 (d, J=7.6 Hz, 2H), 5.56 (s, 1H), 4.17 (d, J=6.3 Hz, 2H), 2.71 - 2.39 (m, 2H), 1.37 (s, 9H), 1.35- 1.13 (m, 1H), 1, 12 (s, 9H), 0.98 - 0.77 (m, 1H), 0.72 - 0.51 (m, 1H), 0.42 - 0.25 (m, 2H), -0.03 - 0.19 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -122.74; MS (ESI+) 778.6 (M+Na).

Step 4. Preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1(3-(aminomethyl)phenyl)-1H-pyrazol- 3,5-dicarboxamide (231d).

Into a solution of tert-butyl-3 -(3 -carbamoyl-5-(5-( 1 -(4-cyanophenyl)-3 -cyclopropyl-1 -((R)-1,1 -dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl )-1H-pyrazol-1-yl)benzylcarbamate (231c) (70 mg, 0.093 mmol) in ethanol (5 ml) was added conc. HCl (0.077 mL, 0.924 mmol), stirred for 1 h and concentrated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel) to give free base 231d (50 mg, 0.091 mmol, 98% yield) as an off-white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.86 - 7.69 (m, 3H), 7.57 (d, J=8.1 Hz, 3H), 7.48 (s, 2H), 7.40 (dd, J=6.3, 4.1 Hz, 3H), 7.27 (ddt, J=15.5, 4.7, 2.4 Hz, 2H), 7.17 (t, J=9.4 Hz, 1H), 3.76 (s, 2H), 2.57 (m, 2H), 2.23 (m, 2 H), 1.06 - 0.89 (m, 2H), 0.5-0.6 (m, 1H), 0.44 - 0.28 (m, 2H), -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -123.86; MS (IER-) 550.4, 551.5 (M-1).

To a solution of the free base in ethanol (5 ml) was added conc. HCl (0.077 ml, 0.924 mmol), stirred for 5 min and concentrated to dryness in vacuo. The residue was dissolved in water (1 ml) and dried in vacuo to give (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3cyclopropylpropyl)-2-fluorophenyl)-1-(3-) hydrochloride (aminomethyl)phenyl)-1H-pyrazole-3,5-dicarboxamide (231d) (0.046 g, 0.074 mmol, 80% yield) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.65 (s, 1H), 9.48 (s, 3H), 8.48 (s, 3H), 7.97 - 7.91 (m, 2H ), 7.80 - 7.75 (m, 1H), 7.71 (t, J=1.8 Hz, 1H), 7.63 7.45 (m, 8H), 7.43 - 7.26 (m, 2H), 4.09 (q, J=5.7 Hz, 2H), 2.65- 2.52 (m, 2H), 1.26 - 0.95 (m, 2H), 0, 77 - 0.60 (m, 1H), 0.47 - 0.27 (m, 2H), 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -120.20; MS (IER+) 552.5 (M+1); (IER-) 550.3 (M-1); optical rotation: [a] _D =(+)18.67 [0.225, MeOH].

- 367 045731

Scheme 232

An example of the preparation of (-)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-(N-hydroxycarbamidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (232a).

Into a stirred solution of (-)-1-(3-cyanophenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227c) ( 1 g, 1.874 mmol) in ethanol (15 ml), add hydroxylamine (1.10 ml, 18.65 mmol) and heat at reflux temperature for 1 hour. Concentrate the reaction mixture in vacuo and purify the resulting crude residue by flash column chromatography [silica gel, 25 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give free base 232a (873 mg, 1.1541 mmol, 82% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.51 (s, 1H), 9.84 (s, 1H), 7.87 - 7.83 (m, 1H), 7.80 (td, J =4.4, 1.7 Hz, 1H), 7.65-7.58 (m, 2H), 7.51 - 7.48 (m, 2H), 7.41 - 7.13 (m, 7H ), 5.93 (s, 2H), 4.83 (s, 1H), 2.322.21 (m, 2H), 0.98-0.80 (m, 1H), 0.44 - 0.28 ( m, 2H), 0.10 - -0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 60.61, -123.51; MS (IER+) 567.4 (M+1), 565.3 (M-1).

To a solution of free base 232a (400 mg, 0.71 mmol) in methanol (10 ml) was added 4N. aqueous HCl (0.71 ml) and concentrated to dryness in vacuo to give (-)-N-(5((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-(N-hydroxycarbamimidoyl) hydrochloride salt phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (232a) (427 mg, 89.53%) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.81 (s, 1H), 10.14 (s, 2H), 8.98 (s, 1H), 7.94 (t, J=1.9 Hz, 1H), 7.91 - 7.80 (m, 3H), 7.80 - 7.66 (m, 5H), 7.48 - 7.31 (m, 4H ), 5.69 - 5.62 (m, 1H), 2.77-2.60 (m, 2H), 1.23 - 1.09 (m, 1H), 0.62 - 0.47 (m , 2H), 0.37 - 0.23 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.70, -120.13; MS (ESI-) 565.4 (M-1), 601.3 (M+Cl); optical rotation: [a]D=(-) 0.38 (0.52, methanol); analysis, calculation for C29H26F4N6O2-2HCl-2H2O: C: 51.56; H: 4.77; N: 12.44; experiment C: 51.21; H: 4.82; N: 12.00.

Scheme 233

227d (-)-isomer ^R = OCH2CH3 233a (-)-isomer ^{v n} R = OCH ₂ (CH ₂ )4CH3 233b (-)-isomer

R = OCH ₂ CC13 233с (-)-isomer

R = BSNgCH3 233d (-)-isomer

R = OCH(CH3)OCOCH33e (-)-isomer

An example of the preparation of (-)-ethyl-(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)( imino)methylcarbamate (233 a).

Into a solution of (-)-1-(3-carbamidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d) (200 mg, 0.363 mmol) in acetonitrile (10 ml), triethylamine (0.160 ml, 1.148 mmol), ethyl carbonochloridate (0.036 ml, 0.363 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (120 ml), washed with water (60 ml). The aqueous layer was again extracted with ethyl acetate (60 ml). The combined organic layers were washed with brine (60 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give free base 233a (130 mg, 0.209 mmol, 57.5%) as an off-white solid matter. The solid (55 mg, 0.088 mmol) was dissolved in methanol (8 ml), 4N was added. aqueous HCl (0.088 ml) and concentrated to dryness in vacuo to give (-)-ethyl-(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H -pyrazol-1-yl)phenyl)(imino)methylcarbamate (233a) (60 mg, 92.23%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 11.29 (s, 1H), 10.84 (s, 1H), 10.67 10.36 (m, 2H), 10.18 (d, 2H) , 8.05 (t, J=1.9 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.88 (dd, J=7.3, 2.2 Hz, 2H), 7.80

- 368 045731 (s, 1H), 7.78 - 7.66 (m, 4H), 7.48 - 7.31 (m, 4H), 5.68 - 5.62 (m, 1H), 4, 30 (q, J=7.1 Hz, 2H), 2.76-2.63 (m, 2H),

1.30 (t, J=7.1 Hz, 3H), 1.22 - 1.02 (m, 1H), 0.66 - 0.45 (m, 2H), 0.30 (dt, J= 6.1, 4.4 Hz, 2H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -60.86, -120.22; MS (IER+): 623.5 (M+1); optical rotation: [a] _D =(-) 13 [0.2,

CH3OH]; analysis, calculation for C ₃₂ H ₃₀ F ₄ N ₆ O ₃ -2HCl-2.25H2O: C, 52.22; H, 5.00; Cl, 9.63; N, 11.42; experiment

C: 52.29; H: 4.85 N: 11.66; Cl 9.27.

An example of the preparation of (-)-hexyl-(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)phenyl)(imino )methylcarbamate (233b).

In a solution of (-)-1-(3-carbamidoylphenyl)-M-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d) (150 mg, 0.27 mmol) in anhydrous acetonitrile (10 ml) was added triethylamine (88 mg, 0.87 mmol), followed by a solution of hexyl chloroformate (45 mg, 0.27 mmol) in anhydrous acetonitrile (3.0 ml). The reaction mixture was stirred for 11 hours at room temperature, diluted with EtOAc (40 ml) and washed with water (20 ml). The aqueous layer was again extracted with EtOAc (20 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 12 g, eluted with 0-50% (ethyl acetate/MeOH (9:1, v/v)) in hexanes] to give the free base 233b. The free base was dissolved in MeOH, 3N was added. HCl in MeOH (5.0 ml), stirred for 4 hours at room temperature and concentrated in vacuo to give (-)-hexyl-(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)- hydrochloride 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (233b) (126 mg, 59% yield) as a white solid. 1H NMR (300 MHz, DMSO^) δ 10.85 (s, 1H), 10.23 (d, J=23.1 Hz, 2H), 8.05 (t, J=2.0 Hz, 1H) , 7.98 - 7.69 (m, 7H), 7.53 - 7.27 (m, 4H), 5.65 (s, 1H), 4.23 (s, 2H), 2.69 (s , 2H), 1.66 (s, 2H), 1.46 - 1.22 (m, 6H), 0.93 - 0.79 (m, 3H), 0.62 - 0.47 (m, 2H ), 0.30 (d, J=5.1 Hz, 2H), 0.00 (s, 2H); MS (IER+) 304.9 (M/22H2O), 340.4 (M/2+1), 679.5 (M+1); optical rotation: [a] _D =(-) 7.77 [0.515, CH3OH]; analysis, calculation for C ₃ 6H3 ₈ F4N6O ₃ -2HCl-2H2O: C, 54.89; H, 5.63; Cl, 9.00; N, 10.67; experiment: C, 54.92; H, 5.51; Cl, 8.80; N, 10.60.

An example of the preparation of (-)-2,2,2-trichloroethyl-(3-(5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)(imino)methylcarbamate (233c).

In a solution of (-)-1-(3-carbamidoylphenyl)-M-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d) (150 mg, 0.27 mmol) in anhydrous acetonitrile (10 ml) was added triethylamine (88 mg, 0.87 mmol), then a solution of 2,2,2-trichloroethyl chloroformate (57.6 mg, 0.27 mmol) in anhydrous acetonitrile (3.0 ml). The resulting reaction mixture was stirred for 11 hours at room temperature. Workup, purification and conversion to the hydrochloride salt, which were carried out according to the description of the method for the preparation of compound 233b, resulted in the preparation of (-)-2,2,2-trichloroethyl-((3-(5-((5-((((-)-2,2,2-trichloroethyl-((3-(5-((5-((((5-((((-)-2,2,2-trichloroethyl-((3-(5-((5-(((((-)-2,2,2-trichloroethyl )amino)(phenyl)methyl)-2fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methyl)carbamate (233c) (106 mg, 54% yield) as white solid matter. 1H NMR (300 MHz, DMSO-d6, one drop of D2O) δ 8.22 7.96 (m, 2H), 7.87 (dq, J=6.1, 3.0 Hz, 1H), 7.83 - 7.60 (m, 6H), 7.40 (dt, J=13.3, 7.7 Hz, 4H), 5.64 (s, 1H), 4.99 (s, 1H), 4, 90 (s, 1H), 2.70 (d, J=7.0 Hz, 2H), 1.19 - 1.02 (m, 1H), 0.67 - 0.41 (m, 2H), 0 .37 - 0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.63, -60.65, -120.48; MS (IER+) 727.4 (M+1); optical rotation: [a]D=(-) 12.63 [0.285, CH3OH]; analysis, calculation for C3 ₂ H ₂ 7ClC ₄ ^Oz-1.8HC1-2H ₂ O: C, 46.44; H, 3.99; Cl, 20.56; N, 10.15; experiment: C, 46.39; H, 4.0; Cl, 20.60; N, 10.16.

An example of the preparation of (-)-S-ethyl-((3-(5-((5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole -1-yl)phenyl)(imino)methyl)-carbamothioate (233d).

Compound 233d was prepared from (-)-1-(3-carbamidoylphenyl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 227d) (220.0 mg, 0.40 mmol) and ethyl chlorothioformate (49.8 mg, 0.40 mmol) according to the method described for the preparation of compound 233b, the hydrochloride salt of (-)-S-ethyl-((3- (5-((5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methyl)carbamothioate (233d) (120 mg, 47% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.90 (s, 1H), 10.89 (s, 1H), 10.29 (br.s, 2H), 8.13 - 7.98 (m , 2H), 7.92 - 7.62 (m, 7H), 7.49 - 7.30 (m, 4H), 5.77 - 5.52 (m, 1H), 2.87 (m, 2H ), 2.77 - 2.59 (m, 2H), 1.29 - 1.22 (m, 3H), 1.22 - 1.11 (m, 1H), 0.64 - 0.42 (m , 2H), 0.40 - 0.17 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.66, -60.68, -120.13; MS (IER+) 639.4 (M+1); optical rotation: [a] _D =(-) 5.44 [0.515, CH3OH]; analysis, calculation for C ₃₂ H ₃₀ F ₄ N ₆ O ₂ S-2HCl-2H ₂ O: C, 51.41; H, 4.85; Cl, 9.48; N, 11.24; S, 4.29; experiment: C, 51.33; H, 4.76; Cl, 9.21; N, 11.41; S, 4.15.

An example of the preparation of (-)-1-((3-(5-(5-((-)(cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)(imino)methylcarbamoyloxy)ethyl acetate (233e).

K (-)-1-(3-carbamidoylphenyl)-M-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (227d) (245 mg, 0.445 mmol) NaOH (0.1N, 5.3 ml) was added and the resulting mixture was stirred for 10 min at room temperature. Concentrate the reaction mixture in vacuo and dissolve the resulting residue in HMPA (10 ml). 1((4-nitrophenoxy)-carbonyloxy)ethyl acetate was added to the solution [prepared as described by Rahmathullah, Syed M. et al.,

- 369 045731

Journal of Medicinal Chemistry, 42(19), 3994-4000; 1999, 240 mg, 0.89 mmol] and stirred at room temperature overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (3x30 ml). Combine the organic layers, wash with brine (20 mL), dry and concentrate in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with mixtures of 0-100% EtOAc in hexane) to give (-)-1-((3-(5-(5-((-)(cyclopropylmethylamino)(phenyl)methyl )-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamoyloxy)ethyl acetate (233e) (212 mg, 0.311 mmol, 70.0% yield) as a white solid ; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.54 (s, 1H), 9.47 - 9.34 (m, 2H), 8.21 -8.08 (m, 2H), 7.82 - 7.54 (m, 4H), 7.39 (d J=7.0 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 7.24 - 7.14 (m , 2H), 6.77 (q, J=5.4 Hz, 1H), 4.84 (s, 1H), 2.27 (m, 2H), 2.02 (s, 3H), 1.43 (d, J=5.4 Hz, 3H), 0.88 (m, 1H), 0.43 - 0.26 (m, 2H), 0.04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.64, -123.32; MS (IER+) 681.5 (M+1); optical rotation: No=(-) 5.37 [0.335, MeOH].

Scheme 234

An example of the preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-cyano-1H- pyrazole-5-carboxamide (234d).

Step 1. Preparation of tert-butyl-3-(3-cyano-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (234a).

Dropwise into a solution of tert-butyl-3-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (231a) (200 mg, 0.523 mmol) in THF (4 ml). pyridine (0.085 ml, 1.046 mmol), 2,2,2trifluoroacetic anhydride (0.089 ml, 0.628 mmol) were added and stirred at room temperature for 30 minutes. The reaction was quenched with water (1 ml) and the mixture was concentrated to dryness in vacuo. Saturated aqueous NaHCO ₃ (20 ml) was added to the residue and extracted with chloroform (2x30 ml). The combined chloroform layers were washed with brine (30 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 12 g, eluted with 0 to 100% ethyl acetate in hexane mixtures) to give tert-butyl-3-(3-cyano-5-(furan-2-yl)-1Hpyrazol- 1-yl)benzylcarbamate (234a) (120 mg, 0.329 mmol, 63.0%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.79 (dd, J=1.8, 0.8 Hz, 1H), 7.57-7.42 (m, 4H), 7.40 - 7.31 (m, 2H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 6.15 (d, J=3.5 Hz, 1H), 4.20 (d , J=6.2 Hz, 2H), 1.37 (s, 9H); MS (ESI+): 387.3 (M+Na).

Step 2. Preparation of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylic acid (234b).

Compound 234b was prepared from tert-butyl-3-(3-cyano-5-(furan-2-yl)-1H-pyrazol-1-yl)benzylcarbamate (234a) (115 mg, 0.316 mmol) as described in step 5 of scheme 229 1-(3-((tertbutoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylic acid (234b) (135 mg) was obtained as a yellow solid, which was used as such in the next step; MS (IER-) 341.3 (M-1), 683.3 (2M-1).

Step 3. Preparation of tert-butyl-3-(3-cyano-5-(5-((-)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl) -2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate (234c).

Compound 234c was prepared from 1-(3-((tert-butoxycarbonylαamino)methyl)phenyl)-3-cyano-1Hpyrazole-5-carboxylic acid (234b) (0.117 g, 0.341 mmol) and (R)-N-((- )-1-(3-amino-4-fluorophenyl)-1-(4cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (212e) (0.103 g, 0.249 mmol) as described in step 3 of scheme 208, was prepared tert-butyl-3-(3-cyano-5-(5-((-)-1-(4-cyanophenyl)-3cyclopropyl-1 -((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl )-1 H-pyrazol-1 yl)benzylcarbamate (234c) (90 mg, 0.122 mmol, 49.0%) as an off-white solid; 1H NMR (300 MHz, DMSO-06) δ 10.64 (s, 1H), 7.81 - 7.32 (m, 11H), 7.23 (d, J=7.5 Hz, 2H), 5 .55 (s, 1H), 4.18 (d, J=6.1 Hz, 2H), 2.65-2.40 (m, 2H), 1.38 (s, 9H), 1.12 ( s, 9H), 1.08 - 0.76 (m, 2H), 0.63 (s, 1H), 0.39-0.30 (m, 2H), -0.02 - 0.21 (m , 2H); MS (ESI+): 760.6 (M+Na); optical rotation: No=(-) 43.81 [0.105, MeOH].

Step 4. Preparation of (+)-N-(5-(1-αmino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1

- 370 045731 (3-(aminomethyl)phenyl)-3-cyano-1H-nirazole-5-carboxamide (234d).

Into a solution of tert-butyl-3-(3-cyano-5-(5-((-)-1-(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl) -2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate (234c) (78 mg, 0.106 mmol) in ethanol (10 ml) was added conc. HCl (0.090 mL, 1.078 mmol), heated at reflux temperature for 1 h and concentrated to dryness in vacuo. The residue was purified twice by flash column chromatography [silica gel, first column eluted with chloroform/CMA 80 (1:0 to 3:1), second column eluted with chloroform/methanol (1:0 to 9:1)] to give free base 234d (25 mg, 0.047 mmol, 44.3% yield) as an off-white solid; the free base (25 mg, 0.047 mmol) was dissolved in ethanol (3 ml), conc. HCl (aq, 0.020 ml) and concentrated to dryness in vacuo. The residue was dissolved in 3 ml of water and concentrated to dryness in vacuo to obtain the hydrochloride salt of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-( 3-(aminomethyl)phenyl)-3-cyano-1H-nirazole-5-carboxamide (234d) (28 mg, 95.69%) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.83 (s, 1H), 9.33 (s, 3H), 8.31 (s, 3H), 7.96 (d, J=8.3 Hz, 2H ), 7.90 - 7.20 (m, 10H), 4.17-4.07 (m, 2H), 2.60-2.40 (m, 2H), 1.35-0.93 (m , 2H), 0.75-0.60 (m, 1H), 0.42-0.32 (m, 2H), 0.04- -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -120.21; MS (IER+): 534.5 (M +1); optical rotation: [a] _D =(+) 15.85 [0.265, MeOH]. Scheme 235

An example of the preparation of (-)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclononylmethylamino)(phenyl)methyl)2-fluorophenyl)-3 -(trifluoromethyl)-1 H-pyrazol-5- carboxamide (235 g).

Step 1. Preparation of (E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (235b).

A mixture of 2-methyl-5-nitrobenzonitrile (235a) (5 g, 30.8 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck reagent) (10.19 ml, 49, 3 mmol) in dry DMF (10 ml) was heated at 70°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo; the crude product was triturated with 120 ml of hexanes/ethyl acetate (5:1) and stirred for 10 minutes. The resulting solid was collected by filtration, washed with hexanes (2x75 ml), dried in vacuo to give (E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (235b) (6.07 g, 91% yield) as a light brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.35 (d, J=2.5 Hz, 1H), 8.06 (ddd, J=9.2, 2.6, 0.7 Hz, 1H ), 7.93 (d, J=13.0 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 5.29 (d, J=12.9 Hz, 1H), 3.04(s, 6H); MS (ESI-) 252.1 (M+Cl).

Step 2. Preparation of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinoline-1(2H)-imine (235c).

A mixture of (E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (235b) (6.01 g, 27.7 mmol) and (2,4dimethoxyphenyl)methanamine (5.45 ml, 34.6 mmol ) in 1,3-dimethyltetrahydropyrimidin-2(1H)-one (DMPU) (10 mg, 80 mmol) was heated at 140°C for 3 hours. The solvent was removed by vacuum distillation and the resulting residue was purified by flash column chromatography [silica gel , 120 g, eluted with mixtures of methanol in chloroform, 0-100%] to obtain 2-(2,4-dimethoxybenzyl)-7-nitroiso-371 045731 quinoline-1(2H)-imine (235c) (4.26 g, yield 45%) as a brown solid; 1H NMR (300

MHz, DMSO-d ₆ ) δ 9.07 (d, J=2.4 Hz, 1H), 8.26 (dd, J=8.7, 2.3 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.38 (d, J=7.4

Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.4, 2 ,4 Hz, 1H), 6.22 (d, J=7.4 Hz, 1H),

4.96 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H); MS (IER+): MS (IER+) 340.27 (M+1).

Step 3. Preparation of 2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinoline-7-amine (235d).

To a solution of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinoline-1(2H)-imine (235c) (4.18 g, 12.32 mmol) in methanol (50 ml) was added palladium (10% Pd on carbon substrate; 0.787 g). The reaction mixture was hydrogenated at 60 psi (414 kPa) for 4 hours at room temperature. The reaction mixture was filtered through a small pad of Celite, washed with methanol (2x75 ml) and concentrated under reduced pressure to give 2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinoline-7-amine (235d) (3.786 g, 99% yield) as a brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.21 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.87 - 6.75 (m, 2H), 6.58 (d, J=2.4 Hz, 1H), 6.44 (dd, J=8.4, 2.4 Hz, 1H ), 5.97 (d, J=7.4 Hz, 1H), 5.32 (s, 2H, exchange with D2O), 4.94 (s, 2H), 3.82 (s, 3H), 3 .72 (s, 3H), 3.17 (d, J=4.9 Hz, 1H); MS (IER ⁺ ): MS (IER+) 310.3 (M+1).

Step 4. Preparation of 2-(2,4-dimethoxybenzyl)-7-hydrazinyl isoquinoline-1(2H)-imine hydrochloride (235e).

To a suspension of 2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinoline-7-amine (235d) (3.21 g, 10.38 mmol) in conc. HCl (9.51 ml, 114 mmol) at 0°C, a solution of sodium nitrite (0.716 g, 10.38 mmol) in water (15 ml) was added dropwise. The reaction mixture was stirred for 30 min at 0°C and a solution of tin(II) chloride dihydrate (7.02 g, 31.1 mmol) in 12N was added at 0°C. HCl (6.05 ml, 72.6 mmol). The reaction mixture was stirred at 0°C for 10 min and placed in the refrigerator overnight. The resulting solid was collected by filtration, washed with cold brine, cold water and hexanes. The solid was dried over P ₂ O ₅ to obtain 2-(2,4dimethoxybenzyl)-7-hydrazinyl isoquinoline-1(2H)-imine hydrochloride (235e) as a light brown solid, which was used as such in the next step; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.30 (s, 3H, exchange with D2O), 9.15 (d, J=29.9 Hz, 3H, exchange with D2O), 8.32 (d , J=2.2 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.7, 2.0 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.67 (d , J=2.3 Hz, 1H), 6.55 (dd, J=8.4, 2.4 Hz, 1H), 5.33 (s, 2H), 3.79 (s, 3H), 3 .77 (s, 3H); MS (IER ⁺ ): MS (IER+) 325.3 (M+1).

Step 5. Preparation of 2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1yl)isoquinoline-1(2H)-imine (235f) .

A solution of 2-(2,4-dimethoxybenzyl)-7-hydrazinyl-isoquinoline-1(2H)-imine hydrochloride (235e) (3.59 g, 11.07 mmol) in ethanol (50 ml) and conc. HCl (2.77 ml, 33.2 mmol) added 4,4,4-trifluoro-1(furan-2-yl)butan-1,3-dione (2.509 g, 12.17 mmol) and stirred at room temperature during the night. The reaction mixture was concentrated in vacuo and the residue was treated with us. NaHCO ₃ , extracted with chloroform (2x150 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness to give 2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)1H-pyrazol-1-yl )isoquinoline-1(2H)-imine (235f) (2.582 g, 47% yield) as a dark yellow waxy solid; 1H NMR (300 MHz, DMSO^) δ 8.43 (s, 1H), 8.32 (s, 1H), 7.77 (dd, J=1.8, 0.7 Hz, 1H), 7, 61 (d, J=1.3 Hz, 2H), 7.31 (s, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 6.47 (dd, J=8 ,4, 2.4 Hz, 1H), 6.32 - 6.19 (m, 2H), 4.99 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H) ; ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.60; MS (IER ⁺ ): MS (IER+) 495.3 (M+1).

Step 6. Preparation of 1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (235e).

Into a suspension of 2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3 -(trifluoromethyl)-1H-pyrazol-1 -yl)isoquinolin-1(2H)-imine (235f) (15.13 g, 30.6 mmol) in tert-BuOH (200 ml) containing 5% aqueous sodium dihydrogen phosphate (6.98 g, 58.2 mmol) in water (140 ml), solid permanganate was added slowly piecemeal potassium permanganate (4.84 g, 30.6 mmol) and stirred at room temperature for 4 hours. Additional potassium permanganate (4.84 g, 30.6 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction was quenched 2 -propanol (250 ml), stirred for 6 hours, filtered through a pad of Celite, washed with 2-propanol and acetone. Excess solvents were evaporated and the aq. was acidified. layer of 1M KHSO4, the crude product was extracted with ethyl acetate (2x300 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 120 g, eluted with mixtures of CMA 80 in chloroform, 0-100%] to give 235e (1.103 g, 2.335 mmol, 7.63% yield) as a yellow solid. Compound 235e was dissolved in chloroform (50 ml) and treated with 30 ml 1M KHSO4, the resulting solid was collected by filtration and dried in vacuo to give 1-(2-(2,4dimethoxybenzyl)-1-imino-1,2-dihydroisoquinoline-7 -yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (235e) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.39 (s, 2H, exchange with D ₂ O), 8.83 (d, J=1.9 Hz, 1H), 8.19 - 7.96 (m, 2H), 7.67 (d, J=7.3 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.22 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.56 (dd, J=8.5, 2.4 Hz, 1H), 5 .33 (s, 2H), 3.81 (s, 3H), 3.77 (s,

- 372 045731

3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.67; MS (IER ⁺ ): MS (IER+) 473.3 (M+1); MS (IER-) 471.3 (M1); analysis, calculation for: 0^^404-0.5^804-1.5^0: C, 48.68; H, 4.00; N, 9.87; experiment: C, 48.96;

N, 4.09; N, 9.91.

Step 7. Preparation of N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl )-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (235f).

Compound 235f was prepared from 1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (235e) (0.269 g, 0.569 mmol) and (-)-5((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f (0.185 g, 0.683 mmol) using the method described in step 3 of Scheme 208 gave N-(5- ((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-3-(trifluoromethyl)-1Hpyrazole-5 -carboxamide (235f) (0.118 g, 0.163 mmol, 28.6% yield) as a yellow waxy solid, which was used as such in the next step; MS (ESI+): 725.5 (M+1); MS (IER-): 723.3 (M-1).

Step 8. Preparation of (-)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (235g).

Into a solution of N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (235f) (0.113 g, 0.156 mmol) in anisole (2 ml) was added with trifluoroacetic acid (0.120 ml, 1.559 mmol) and heated at 90°C for 6 hours. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was suspended in water (50 ml) and made alkaline. aqueous NaHCO ₃ to pH 8.0 and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [first column: silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform; second column: silica gel, 12 g, eluted with ethyl acetate/methanol (9:1) in hexanes, 0-100%] to give (-)-1-(1-aminoisoquinolin-7-yl)-N-(5-( (cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (235g) (4 mg, 4% yield) as a colorless solid; 1H NMR (300 MHz, CD3OD) δ 8.35 (d, J=2.4 Hz, 1H), 7.82 (d, J=6.2 Hz, 2H), 7.78 - 7.69 (m , 2H), 7.45 (s, 1H), 7.39 - 7.31 (m, 2H), 7.31 - 7.22 (m, 3H), 7.22 - 7.02 (m, 3H ), 4.86 (s, 1H), 2.34 (d, J=6.9 Hz, 2H), 1.03 0.84 (m, 1H), 0.53 - 0.35 (m, 2H ), 0.04 (m, 2H), ¹⁹ F NMR (282 MHz, DMSO-de) δ -64.53, -128.12; MS (IER ⁺ ): MS (IER+) 575.4 (M+1); MS (ESI-) 573.3 (M-1), 609.3 (M+Cl); optical rotation: [a] _D =(-) 0.21 [0.095, MeOH].

Scheme 236

An example of the preparation of (+)-1-(3-carbamidoylphenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 236h).

Step 1. Preparation of (-)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (236a).

To a stirred solution of 3-formylbenzonitrile (45.4 g, 347 mmol) in tetrahydrofuran (460 ml) was added (R)-2,4,6-triisopropylbenzenesulfinamide (35 g, 289 mmol), tetraisopropoxytitanium (173 ml, 578 mmol) and heated at the reverse condensation temperature for 10 hours. Treatment was carried out according to the description of stage 1 of scheme 222 to obtain, after column chromatography (silica gel, 1.5 kg, eluted with mixtures of 20% ethyl acetate in hexane) (-)-N-(3-cyanobenzylidene) -2-methylpropane-2- 373 045731 sulfinamide (236a) (37.4 g, 160 mmol, 55.3% yield) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 8.42 (dd, J=1.9, 1.3 Hz, 1H), 8.28 (dt, J=7 ,9, 1.4 Hz, 1H), 8.07 (dt, J=7.7,

1.4 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 1.21 (s, 9H); MS (ESI+) 257.2 (M+Na); optical rotation: [a] _D =(-)

83.21 [2.55, CHCl ₃ ].

Step 2. Preparation of (R)-N-((R)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2sulfinamide (236b) and (R)-N-((S )-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2sulfinamide (236c).

Compound 236b was prepared from (-)-N-(3-cyanobenzylidene)-2-methylpropane-2-sulfinamide (236a) (72 g, 307 mmol) and bromide (3-(bis(trimethylsilyl)amino)-4-fluorophenyl) magnesium (52c) (430 ml, 430 mmol) according to the description of the preparation of compounds 222d and 222e in step 2 of scheme 222, a mixture of diastereomers 236b and 236c was obtained. The crude mixture was purified by flash column chromatography [silica gel, 4.5 kg, eluted with mixtures of ethyl acetate in hexanes, 0-60%] to give:

1. (R)-N-((R)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide (236b) (47.32 g, 45% yield) , which was isolated as a whitish solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.83 (t, J=1.6 Hz, 1H), 7.76 - 7.64 (m, 2H), 7.54 (t, J=7 .7 Hz, 1H), 6.93 (dd, J=11.4, 8.3 Hz, 1H), 6.73 (dd, J=8.8, 2.2 Hz, 1H), 6.57 (ddd, J=8.4, 4.4, 2.2 Hz, 1H), 6.01 (d, J=6.0 Hz, 1H), 5.48 (d, J=6.0 Hz, 1H), 5.15 (s, 2H), 1.13 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO) δ -136.86; MS (IER+): MS (IER+) 346.3 (M+1), 368.3 (M+Na); MS (ESI-) 725.3 (M+Cl); chiral HPLC method: AD-H column; solvent 90:10:1.0 hexane/isopropanol/TEA, 25°C, 1.0 ml/min, UV=260 nm; R _t =26.207 (peak 1, corresponding to compound 236b) >99.99% ee; optical rotation: [a] _D =(-) 52.31 [0.845, MeOH]; analysis, calculation for C ₁₈ H ₂₀ FN ₃ OS: C, 62.59; H, 5.84; N, 12.16; experiment: C, 62.44; H, 5.90; N, 11.93;

2. (R)-N-((S)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide (236c) (13.51 g, 13% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.88 (t, J=1.7 Hz, 1H), 7.77 - 7.65 (m, 2H), 7.54 (t, J=7 .7 Hz, 1H), 6.92 (dd, J=11.5, 8.3 Hz, 1H), 6.69 (dd, J=8.9, 2.2 Hz, 1H), 6.50 (ddd, J=8.4, 4.4, 2.2 Hz, 1H), 6.07 (d, J=6.5 Hz, 1H), 5.44 (d, J=6.4 Hz, 1H), 5.15 (s, 2H), 1.15 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -136.88; MS (IER+): MS (IER+) 346.3 (M+1), 368.2 (M+Na), MS (IER-) 344.2 (M1); HPLC: chiral HPLC method: AD-H column; solvent 90:10:1.0 hexane/isopropanol/TEA, 25°C, 1.0 ml/min, UV=260 nm; R _t =26.497 (peak 1, corresponding to compound 236b, 2.5953%), R _t =28.253 (peak 2, corresponding to compound 236c, 97.4047%); 94.8094% e.i. Optical rotation: [a] _D =(-) 77.82 [1.19, MeOH]; analysis, calculation for C ₁₈ H ₂₀ FN ₃ OS: C, 62.59; H, 5.84; N, 12.16; S, 9.28; experiment: C, 62.58; H, 5.71; N, 12.15; S, 9.20.

Step 3. Preparation of (+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (236d).

Compound (236d) was prepared from (R)-N-(R)-(3-amino-4-fluorophenyl)(3-cyanophenyl)methyl)-2-methylpropane-2-sulfinamide (236b) according to the method for preparation of compound 222d described Step 3 of Scheme 222 provided (+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile hydrochloride salt (236d) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.39 - 9.10 (m, 3H), 7.57 - 7.49 (m, 2H), 7.45 - 7.34 (m, 3H) , 7.26 (d, J=5.8 Hz, 1H), 7.15 (dd, J=8.0, 2.0 Hz, 1H), 5.58 (d, J=5.5 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -129.75; MS (IER-) 240.2 (M-1). The above solid was dissolved in water, made basic by adding NaOH (3N), extracted with ethyl acetate. The organic layer was washed with brine, dried, filtered and concentrated in vacuo to give (+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile free base (236d) as a brown oil; 1H NMR (300 MHz, DMSO-d6) δ 7.84 (t, J=1.7 Hz, 1H), 7.66 (ddt, J=7.7, 6.2, 1.4 Hz, 2H) , 7.48 (t, J=7.7 Hz, 1H), 6.88 (dd, J=11.5, 8.3 Hz, 1H), 6.76 (dd, J=9.0, 2 ,2 Hz, 1H), 6.55 (ddd, J=8.4, 4.5, 2.2 Hz, 1H), 5.06 (s, 2H), 5.00 (s, 1H), 2 .27 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -138.23; ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.59; purity according to chiral HPLC 99.8838% ee; MS (ESI-) 240.3 (M-1), 276.1 (M+Cl); optical rotation: [a] _D =(+) 27.99 [1.665, MeOH].

Step 4. Preparation of (+)-3-((cyclopropylmethylamino)(3-(cyclopropylmethylamino)-4-fluorophenyl)methyl)benzonitrile (236e) and (+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino) )methyl)benzonitrile (236f)

To a stirred solution of (+)-3-(amino(3-amino-4-fluorophenyl)methyl)benzonitrile (236d) free base (8.321 g, 34.5 mmol) in MeOH (20 ml) was added cyclopropanecarboxaldehyde (3.25 ml , 43.1 mmol) at 0°C and stirred for 30 min. Sodium borohydride (2.61 g, 69.0 mmol) was added to the resulting mixture and stirred at 0°C for 1 hour. Concentrate the reaction mixture in vacuo to remove methanol and dissolve the residue in ethyl acetate (200 ml), wash with water (2x50 ml), saline (50 ml), dried and concentrated. The crude residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%) to give:

1. (+)-3-((cyclopropylmethylamino)(3-(cyclopropylmethylamino)-4-fluorophenyl)methyl)-benzonitrile (236e) (1.087 g, 3.11 mmol, 9.02% yield) as a colorless thick liquid ; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.88 (t, J=1.7 Hz, 1H), 7.75 (dt, J=7.9, 1.5 Hz, 1H), 7, 64 (dt, J=7.7, 1.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.90 (dd, J=11.9, 8.2 Hz , 1H), 6.84 (dd, J=8.9, 2.1 Hz, 1H), 6.57 (ddd, J=8.2, 4.5, 2.0 Hz, 1H), 5, 34 (td,

- 374 045731

J=6.0, 2.4 Hz, 1H), 4.81 (d, J=4.2 Hz, 1H), 2.96 (t, J=6.3 Hz, 2H), 2.59 ( m, 1H), 2.27 (m, 2H), 1.03 (m, 1H), 0.98

- 0.84 (m, 1H), 0.40 (m, 4H), 0.26 - 0.17 (m, 2H), 0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -137.04; MS (IER-) 348.4 (M-1); optical rotation: No=(+) 17.96 [0.245, MeOH];

2. (+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile (236f) (7.891 g, 26.7 mmol, 77% yield) as a colorless thick liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.84 (t, J=1.6 Hz, 1H), 7.71 (dt, J=7.9, 1.5 Hz, 1H), 7 ,68 - 7.63 (m, 1H), 7.49 (t, J=7.7 Hz, 1H), 6.88 (dd, J=11.5, 8.3 Hz, 1H), 6, 81 (dd, J=9.0, 2.2 Hz, 1H), 6.56 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.08 (s, 2H) , 4.76 (d, J=2.8 Hz, 1H), 2.48 (m, 1H), 2.26 (m, 2H), 0.91 (m, 1H), 0.42 - 0, 34 (m, 2H), 0.09 - 0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -137.18; MS (IER+) 296.3 (M+1), (IER-) 294.3 (M-1); optical rotation: №=(+) 22.05 [0.88, СНС1з].

Step 5. Preparation of 1-(3-carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (236g).

To a stirred solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.0 g, 3.55 mmol) in THF (10 ml) was added LiHMDS (14 ml , 1 M in THF) and heated at reflux temperature overnight. The reaction mixture was cooled to room temperature and the pH was adjusted to 2~3 using KHSO4 (1N aqueous solution). The organic solvent was removed in vacuo and the aqueous layer was extracted with EtOAc (5x50 ml). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with 0-100% CMA-80 in chloroform, then 0-100% chloroform in CMA 50) to give 1-(3-carbamidoylphenyl)-3-(trifluoromethyl) -1Hpyrazole-5-carboxylic acid (236g) (250 mg, 23%) as a white solid; ¹ H NMR (300 MHz, DMSO-d6) δ 10.63 - 8.88 (m, 4H), 8.03 - 7.92 (m, 2H), 7.87 (dt, J=8.1, 1.3 Hz, 1H), 7.74 (t, J=7.9 Hz, 1H), 7.03 (d, J=0.6 Hz, 1H); MS (IER+) 299.3 (M+1); 297.3 (M-1).

Step 6. Preparation of (+)-1-(3-carbamidoylphenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (236h).

To a solution of 1-(3-carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid hydrochloride (236g) (200 mg, 0.671 mmol) in DMF (10 ml) was added bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop, 375 mg, 0.805 mmol), pyridine (265 mg, 3.35 mmol) and stirred at room temperature for 10 min. (+)-3-((3-amino-4fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile (236f) (198 mg, 0.671 mmol) was added to the reaction mixture and stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched with aqueous HCl (6N, 20 ml) and washed with ethyl acetate (4x50 ml). The aqueous layer was made alkaline to pH 9 with 1N. NaOH and extracted with ethyl acetate (4x40 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with mixtures of 0-100% CMA-80 in chloroform) to give the free base 236h. The free base was dissolved in dioxane (5 ml), HCl (4N in dioxane, 4 ml) was added and stirred at room temperature for 1 hour. The solution was concentrated and dried in vacuo to give the hydrochloride salt (+)-1-(3- carbamidoylphenyl)-X-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (236h) (74 mg, 0.129 mmol, yield 19 .17%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.87 (s, 1H), 10.43 (s, 2H), 9.51 (s, 2H), 9.31 (s, 2H), 8. 28 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.01 - 7.69 (m, 6H ), 7.65 (t, J=7.8 Hz, 1H), 7.41 (t, J=9.4 Hz, 1H), 5.97 - 5.59 (m, 1H), 2.80 - 2.60 (m, 2H), 1.32 - 1.01 (m, 2H), 0.99 - 0.72 (m, 1H), 0.66 - 0.43 (m, 2H), 0 .41 - 0.16 (m, 2H); MS (IER+): MS (IER+) 576.4 (M+1); optical rotation: [a] _D =(+) 2.31 [0.26, MeOH].

Scheme 237

An example of the preparation of (+)-H-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (237a).

Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrop, 563 mg, 1.207 mmol), pyridine (398 mg, 5.03 mmol), stirred at room temperature for 10 min and added (R)-N-((-)-1-(3-amino-4-fluorophenyl) -1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (214e) (416 mg, 1.006 mmol). The reaction mixture was stirred at room temperature overnight, quenched with aqueous HCl (6N, 20 ml) and washed with ethyl acetate (4x30 ml). The aqueous layer was made alkaline to pH 9 with 1N. NaOH and extracted with ethyl acetate

- 375 045731 (4x40 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, eluted with mixtures of 0-100% CMA-80 in chloroform) to give free base 237a as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.67 (s, 1H), 9.64 - 9.38 (m, 2H), 9.22 (s, 2H), 8.01 (m, 1H ), 7.95 (m, 1H), 7.92 - 7.85 (m, 2H), 7.79 - 7.64 (m, 4H), 7.54 (m, 2H), 7.37 - 7.16 (m, 2H), 2.39 -2.19 (m, 2H), 1.150.90 (m, 2H), 0.72 - 0.55 (m, 1H), 0.41 - 0, 28 (m, 2H), -0.01 - -0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ 60.84, -123.70; MS (IER+) 590.5 (M+1); ICS (KBr) 2235 cm ^-1 ; optical rotation: [a] _D =(+) 6.53 (0.245, methanol); The free base was dissolved in dioxane (5 ml), HCl (4N in dioxane, 10 eq.) was added and stirred at room temperature for 1 hour. Concentrate the solution and dry in vacuo to give (+)-N-(5-( 1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (237a) (60 mg) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.85 (s, 1H), 9.54 (s, 5H), 9.33 (s, 3H), 8.12 -7.06 (m, 12H), 3 .77 3.58 (m, 2H), 2.74-2.21 (m, 2H), 0.78 - 0.51 (m, 1H), 0.47 - 0.22 (m, 2H), -0.00(s,2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.84, -123.62; MS (IER+) 590.5 (M+1), (IER-) 624.5 (M+Cl); IR (KBr) 2232 cm ^-1 .

Scheme 238

An example of the preparation of 1-(3-carbamidoylphenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238c).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(5-((-)-3-cyclononyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238a).

Compound 238a was prepared from 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) and (R)-N-((-)-1-(3-amino-4- fluorophenyl)-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2methylpropane-2-sulfinamide (209b) (3 g, 7.70 mmol) according to the method described in step 3 of scheme 208, after column flash chromatography [silica gel, 80 g, eluted with mixtures of 0-50% ethyl acetate/methanol (9:1) in hexanes] gave 1-(3-cyanophenyl)-N-(5-((-)-3-cyclopropyl-1-( (R)-1,1dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (238a) (3.518 g, 69.9% yield) as a white solid; ¹ H NMR (300 MHz, DMSOd ₆ ) δ 8.55-8.45 (m, 1H), 8.40 (td, J=5.0, 1.5 Hz, 2H), 10.58 (s, 1H), 8.11 (t, J=1.9 Hz, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7.92 - 7.85 (m, 1H ), 7.75 - 7.67 (m, 3H), 7.55 (d, J=7.0 Hz, 1H), 7.39 - 7.18 (m, 3H), 5.57 (s, 1H), 2.70 2.50 (m, 2H), 1.12 (s, 9H), 0.98-0.78 (m, 1H), 0.73-0.51 (m, 1H), 0.35 (m, 2H), -0.10 (m, 2H); ¹⁹ F NMR (282

MHz, DMSO) δ -60.78, -122.81; MS (IER+) 653.5 (M+1); (IER-) 651.5 (M-1); optical rotation [a] _D =(-) 21.82 [0.55, MeOH].

Step 2. Preparation of 1-(3-carbamidoylphenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238c).

Into a solution of 1-(3-cyanophenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1(pyridin-3-yl)propyl)-2 -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238a) (490 mg, 0.751 mmol) in ethanol (50 ml) was added hydroxylamine (124 mg, 3.75 mmol) and heated at the reflux temperature during the night. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue N-(5-(3-cyclopropyl-1-((-)-1,1-dimethylethylsulfinamido)-1(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-(N-hydroxycarbamimidoyl) )phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (238b) was dissolved in acetic acid (50 ml) and Ac ₂ O (10 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, Pd/C (200 mg) was added and hydrogenated at 65 psi (448 kPa) for 12 hours at room temperature. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with CMA80/CHCl ₃ mixtures, 0-100%)

- 376 045731 to obtain 1-(3-carbamidoylphenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl) propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238c) (256 mg, 0.382 mmol, 50.9% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.78 (s, 4H), 8.48 (d, J=2.4 Hz, 1H), 8.41 (dd, J=4.8, 1 .5 Hz, 1H), 8.01 - 7.96 (m, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.81 - 7.74 (m, 1H), 7 .73 - 7.62 (m, 3H), 7.59 - 7.53 (m, 1H), 7.37 - 7.18 (m, 3H), 5.55 (s, 1H), 2.76 - 2.54 (m, 2H), 1.12 (s, 9H), 0.92 (m, 2H), 0.63 (m, 1H), 0.34 (m, 2H), -0.09 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ 60.65, -122.63; MS (IER+) 670.5 (M+1), (IER-) 668.5 (M-1); optical rotation No=(-) 63.85 [0.26, MeOH].

Preparation of (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-1-(3-carbamidoylphenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (238d).

Into a solution of 1-(3-carbamidoylphenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238c) (100 mg, 0.149 mmol) in MeOH (5 ml) was added HCl (0.070 ml, 0.280 mmol, 4N in 1,4- dioxane) and stirred at room temperature for 2 hours. Additional HCl (4N in 1,4-dioxane, 0.12 ml) was added and stirring continued until reaction was complete. Concentrate the reaction mixture to dryness and purify twice by flash column chromatography [silica gel, eluting with chloroform/CMA 80 (1:0 to 0:1)] to give free base 238d (30 mg, 0.053 mmol, 35.5%) in in the form of an oily liquid. The free base (30 mg, 0.053 mmol) was dissolved in methanol (8 ml), 4N was added. HCl (aq, 0.053 mL) and concentrated in vacuo to give (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl) hydrochloride salt. -1-(3carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (238d) (35 mg, 92.8%) as a white solid; 1H NMR (300 MHz, DMSO-06) δ 10.85 (s, 1H), 9.58 (s, 3H), 9.52 (s, 3H), 9.27 (s, 2H), 8.70 -8.60 (m, 2H), 8.06 - 7.93 (m, 3H), 7.92 - 7.85 (m, 1H), 7.80 (s, 1H), 7.76 (m , 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.47 - 7.32 (m, 2H), 2.75-2.40 (m, 2H), 1, 12 (m, 2H), 0.77-0.57 (m, 1H), 0.44-0.30 (m, 2H), 0.08 - -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.50, -119.76; MS (IER-): 564.5 (M-1); optical rotation [a]D=(+) 2.22 [0.18, MeOH].

Scheme 239

An example of the preparation of (+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)1-(3-(aminomethyl)phenyl)-3-cyano-1H- pyrazole-5-carboxamide (239c).

Step 1. Preparation of 4-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)benzamide (239a).

Into a solution of (R)-N-((-)-(3-amino-4-fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (212e) (1.41 g, 3.41 mmol) in ethanol (80 ml) was added conc. NH4OH (30 mL), hydrogen peroxide (1.200 mL, 13.59 mmol) and stirred at room temperature for 22 hours. Concentrate the reaction mixture to dryness in vacuo and purify by flash column chromatography [silica gel, elute with chloroform/methanol mixtures (1: 0 to 9:1)] to give 4-(()-1 -(3-amino-4-fluorophenyl)-3-cyclopropyl-1 -((R)-1,1-dimethylethylsulfinamido)propyl)-benzamide (239a ) (335 mg, 22.77%) as a brown solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 7.93 (s, 1H), 7.82 - 7.72 (m, 2H), 7.43 - 7.36 (m, 2H), 7.33 (s, 1H), 6.88 (dd, J=11.2, 8.5 Hz, 1H), 6.70 (dd, J=8.8, 2.3 Hz, 1H), 6.48 ( ddd, J=8.5, 4.2, 2.3 Hz, 1H), 5.14-4.98 (m, 3H), 2.65-2.40 (m, 2H), 1.20- 1.05 (m, 1H), 1.13 (s, 9H), 0.97-0.80 (m, 1H), 0.72-0.55 (m, 1H), 0.42-0, 29 (m, 2H), 0.07 - -0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -137.75; MS (IER+): 432.4 (M+1); optical rotation: No=(-) 77.82 [0.275, MeOH].

Step 2. Preparation of tert-butyl-3-(5-(5-((-)-1-(4-carbamoylphenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl )-3-cyano-1H-pyrazol-1-yl)benzylcarbamate

- 377 045731 (239b).

Compound 239b was prepared from 4-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)benzamide (239a) (275 mg, 0.636 mmol ) and 1-(3-((tertbutoxycarbonylamino)methyl)phenyl)-3-cyano-1H-pyrazole-5-carboxylic acid (234d) (240 mg, 0.7 mmol) using the method described in step 3 of scheme 208 , after purification by flash column chromatography [silica gel, eluted with chloroform/methanol mixtures (1:0 to 19:1)], tert-butyl-3-(5-(5-((-)-1 -(4-carbamoylphenyl)-3 -cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)2-fluorophenylcarbamoyl)-3-cyano-III-pyrazol-1-yl)benzylcarbamate (239b) (188 mg, 39.1%) as whitish solid. 1H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 7.93 (s, 1H), 7.81 - 7.70 (m, 3H), 7.61 - 7.14 (m, 11H), 5.39 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.60-2.40 (m, 2H), 1.38 (s, 9H), 1.12 (s, 9H), 1.18-1.02 (m, 1H), 0.98-0.78 (m, 1H), 0.72-0.55 (m, 1H), 0. 40-0.25 (m, 2H), 0.08 - -0.20 (s, 2H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -123.20; MS (IER+): 756.6 (M +1); optical rotation: No=(-) 62.04 [0.245, MeOH].

Step 3. (+)-N-(5-(1-Amino-1-(4-carbamoylphenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3(aminomethyl)phenyl)-3-cyano-1H -pyrazole-5-carboxamide (239c).

Into a solution of tert-butyl-3-(5-(5-((-)-1-(4-carbamoylphenyl)-3-cyclopronyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl )-3-cyano-1H-pyrazol-1-yl)benzylcarbamate (239b) (161 mg, 0.213 mmol) in ethanol (15 ml) was added conc. HCl (0.180 mL, 2.162 mmol), heated at reflux temperature for 1 h, cooled to room temperature and concentrated to dryness in vacuo. The residue was purified twice by column chromatography [silica gel, first column eluted with chloroform/CMA 80 (1:0 to 2:1), second column eluted with chloroform/methanol (1:0 to 3:1)] to give the free base 239c (50 mg, 33.7%) as a white solid. The free base (46 mg, 0.083 mmol) was dissolved in ethanol (5 ml), conc. HCl (aq, 0.035 ml) and concentrated to dryness in vacuo. The residue was dissolved in 5 ml of water and concentrated to obtain the hydrochloride salt of (+)-N-(5-(1-amino-1-(4-carbamoylphenyl)-3cyclopropylπpropyl)-2-fluorophenyl)-1-(3-(aminomethyl )phenyl)-3-cyano-1H-πyrazole-5-carboxamide (239c) (58 mg, 91.85%) as a white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.84 (s, 1H), 9.25 (s, 3H), 8.36 (s, 3H), 8.06 (s, 1H), 7. 91 (d, J=8.2 Hz, 2H), 7.82 (s, 1H), 7.73 (s, 1H), 7.64 - 7.25 (m, 9H), 4.12 (q , J=5.9 Hz, 2H), 2.70-2.40 (m, 2H), 1.20-0.95 (m, 2H), 0.75-0.60 (m, 1H), 0.49 - 0.28 (m, 2H), 0.03 - 0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -120.45; MS (ESI+): 574.5 (M+Na); optical rotation: [a]D=(+) 12.5 [0.24, MeOH].

Scheme 240

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-3-cyano-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-pyrazole-5-carboxamide (240b ).

Step 1. Preparation of tert-butyl-3-(3-cyano-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenylcarbamoyl)-1H-πyrazol-1-yl)benzylcarbamate (240a).

Compound 240a was prepared from (-)-5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluoroaniline (222f) (147 mg, 0.545 mmol) and 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)- 3-cyano-1H-pyrazole-5-carboxylic acid (234b) (205 mg, 0.6 mmol) using the method described in step 3 of scheme 208, after purification by flash column chromatography [silica gel, eluted with chloroform/methanol mixtures (from 1:0 to 19:1)] prepared tert-butyl-3-(3-cyano-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate (240a) (161 mg, 49.6%) as a yellow viscous substance. 1H NMR (300 MHz, DMSO^) δ 10.59 (s, 1H), 7.73 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.53 - 7, 12 (m, 12H), 4.83 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.32-2.20 (m, 2H), 1.38 (s , 9H), 0.97-0.83 (m, 1H), 0.44 - 0.29 (m, 2H), 0.08 - -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -123.61; MS (IER+): 595.5 (M +1).

Step 2. Preparation of (-)-1-(3-(aminomethyl)phenyl)-3-cyano-P-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1H-πyrazole-5-carboxamide (240b).

Into a solution of tert-butyl-3-(3-cyano-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazol-1-yl)benzylcarbamate (240a) (150 mg, 0.252 mmol) in ethanol (15 ml) was added conc. HCl (0.210 mL, 2.52 mmol), heated at reflux temperature for 1 h, cooled to room temperature and concentrated to dryness in vacuo. The residue was purified twice by column chromatography [silica gel, first column eluted with chloroform/CMA 80 mixtures (1:0 to 2:1), second column eluted with chloroform/methanol mixtures (1:0 to 9:1)] to obtain free

- 378 045731 base (-)-1-(3-(aminomethyl)phenyl)-3-cyano-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenyl)-1H-pyrazole-5-carboxamide (240b ) (44 mg, 35.3%) as a white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 7.71 (s, 1H), 7.65-7.12 (m, 12H), 4.83 (s, 1H), 3.77 (s, 2H ), 2.26 (m, 2H), 0.90 (s, 1H),

0.44 - 0.29 (m, 2H), 0.12 - -0.06 (m, 2H); (IER+): 517.5 (M+Na); ICS 2244 cm ^-1 ; optical rotation:

[a]D=(-) 7.62 [0.105, CH3OH].

Scheme 241

An example of the preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (241a).

Compound 241a was prepared from 1-(3-carbamidoylphenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxylic acid hydrochloride (236g) (500 mg, 1.677 mmol) and (R)-N-((-)-1-( 3-amino-4-fluorophenyl)-1-(4cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (212e) (693 mg, 1.677 mmol) according to the method for the preparation of compound 237a described in Scheme 237, after purification Flash column chromatography (silica gel, eluted with mixtures of 0-100% CMA-80 in chloroform) provided the free base of 241a (235 mg, 0.399 mmol, 23.77% yield) as a white solid; 1H NMR (300 MHz, DMSO-d^ δ 8.91 (s, 4H), 8.26 (s, 1H), 8.20 (d, J=7.7 Hz, 1H), 8.04 - 7 .81 (m, 8H), 7.55 (m, 1H), 7.45 (t, J=9.4 Hz, 1H), 2.60 (s, 2H), 2.55- 2.45 ( m, 2H), 1.42 - 1.19 (m, 2H), 0.90 (m, 1H), 0.70 - 0.46 (m, 2H), 0.19 (m, 2H). the base was dissolved in dioxane (5 ml), HCl (4N in dioxane, 0.4 ml) was added and stirred at room temperature for 1 hour. The solution was concentrated and dried in vacuum to obtain the hydrochloride salt (+)-N-(5 -(1-amino-1-(4-cyanophenyl)-3cyclopropylpropyl)-2-fluorophenyl)-1-(3-carbamidoylphenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (241a) as white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 9.50 (s, 3H), 9.22 (s, 2H), 8.10 - 7.68 ( m, 7H), 7.54 (t, J=7.6 Hz, 3H), 7.33 (s, 2H), 1.20 - 0.94 (m, 2H), 0.71 - 0.57 (m, 1H), 0.36 (d, J=7.4 Hz, 2H), -0.00 - -0.14 (m, 2H); MS (IER+): 590.5 (M+1 ); IR (KBr) 2233 cm ^-1 ; optical rotation (+) 14.81 (0.27, methanol).

Scheme 242

An example of the preparation of (-)-ethyl-(3 -(5-(5-(1 -amino-3 -cyclopropyl-1 -(pyridin-3 -yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H -pyrazol-1-yl)phenyl)(imino)methylcarbamate (242c).

Step 1. Preparation of ethyl-(3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1(pyridin-3-yl)propyl)-2 -fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242a).

Compound 242a was prepared from 1-(3-karbamidoylphenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (238c) (109 mg, 0.163 mmol) and ethyl carbonochloridate (0.016 ml, 0.163 mmol) according to the method for preparing compound 233a described in Scheme 233, after purification by column flash chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] gave ethyl-(3-(5-(5-((-)-3-cyclopropyl-1-((R )-1,1 -dimethylethylsulfinamido)-1 -(pyridin-3 -yl)propyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)phenyl)(imino)methylcarbamate (242a) (50 mg, 0.067 mmol, 41.4%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.59

- 379 045731 (s, 1H), 9.20 (s, 2H), 8.51 - 8.47 (m, 1H), 8.41 (dd, J=4.7, 1.5 Hz, 1H) , 8.15 (t, J=1.9 Hz, 1H), 8.11 (d, J=7.8 Hz,

1H), 7.74 - 7.53 (m, 5H), 7.32 (dd, J=8.0, 4.7 Hz, 1H), 7.28-7.16 (m, 2H), 5 .55 (s, 1H), 4.06 (q, J=7.1 Hz, 2H),

2.75-2.40 (m, 2H), 1.20-1.00 (m, 1H), 1.21 (t, J=7.1 Hz, 3H), 1.11 (s, 9H) , 0.97 - 0.81 (m, 1H), 0.70-0.52 (m,

1H), 0.40 - 0.22 (m, 2H), -0.02 - -0.18 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.62, -122.82; MS (IER+):

742.6 (M+1); optical rotation: [a] _D =(-) 68.09 [0.235, MeOH].

Step 2. Preparation of (-)-ethyl-(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl) -1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242c).

Into a solution of ethyl-(3 -(5-(5-((-)-3-cyclopropyl-1 -((R)-1,1-dimethylethylsulfinamido)-1 -(pyridin-3yl)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242a) (48 mg, 0.065 mmol) in MeOH (5 ml) was added HCl (0.065 ml, 0.259 mmol, 4N in 1 ,4-dioxane), stirred at room temperature and concentrated to dryness in vacuo. The residue was purified by flash column chromatography [silica gel, eluted with chloroform/CMA 80 (1:0 to 2:1)] to give 242c free base (24 mg, 0.038 mmol) as a white thick liquid. The free base was dissolved in methanol (8 ml), 4N was added. HCl (aq, 0.038 ml) and concentrated to dryness in vacuo to give (-)-ethyl-(3-(5-(5-(1-amino-3cyclopropyl-1-(pyridin-3-yl)propyl)-hydrochloride 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242c) (38 mg) as a white solid; ^1H NMR (300 MHz, DMSOd6) δ 11.44 (s, 1H), 10.88 (s, 1H), 10.60 (s, 1H), 9.61 (s, 3H), 8.73 - 8.56 (m, 2H), 8.06 - 7.85 (m, 4H), 7.80 (s, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 7 .57 - 7.51 (m, 1H), 7.46 - 7.36 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 2.65-2.40 (m , 2H), 1.31 (t, J=7.1 Hz, 3H), 1.13 (m, 2H), 0.75-0.60 (m, 1H), 0.37 (m, 2H) , 0.05- -0.04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.71, -119.86; MS (IER+): 638.5 (M+1); optical rotation: [a] _D =(-) 9.78 [0.225, MeOH].

An example of the preparation of (-)-hexyl-(3-(5-(5-(1-amino-3-cyclopropyl-1 -(pyridin-3-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole -1-yl)phenyl)(imino)methylcarbamate (242d).

Step 1. Preparation of hexyl-(3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1(pyridin-3-yl)propyl)-2 -fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242b).

Compound 242b was prepared from 1-(3-carbamidoylphenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (238c) (80 mg, 0.119 mmol) and hexyl chloroformate (19.7 mg, 0.119 mmol) according to the preparation of compound 233b described in scheme 233, after purification by flash column chromatography (silica gel, 12 g, eluted with mixtures of CMA 80/CHC13, 0-60%), hexyl-(3-(5-(5((-)-3-cyclopropyl-1-((R)-1, 1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242b) (88 mg, yield 92.68%) as a whitish solid; 1H NMR (300 MHz, CDC13) δ 8.54 (s, 3H), 8.33 - 8.15 (m, 1H), 8.16 7.88 (m, 2H), 7.86 - 7.62 (m, 2H), 7.20 - 6.99 (m, 2H), 4.24 (td, J=7.0, 5.1 Hz, 2H), 4.17 (d, J=8.7 Hz, 1H), 2.74 (m, 2H), 1.87 - 1.69 (m, 2H), 1.50 - 1.22 (m, 16H), 1.07 - 0.92 (m, 6H), 0.80 - 0.63 (m, 1H), 0.47 (m, 2H), -0.00 (m, 2H); ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -62.20, -129.62; MS (IER+): MS (IER+) 798.6 (M+1); optical rotation: [a] _D =(-) 59.59 [0.245, CH3OH].

Step 2. Preparation of (-)-hexyl-(3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl) -1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242d).

Into a solution of hexyl-(3 -(5-(5-((-)-3-cyclopropyl-1 -((R)-1,1-dimethylethylsulfinamido)-1 -(pyridin-3 yl)propyl)-2-fluorophenylcarbamoyl )-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242b) (70.0 mg, 0.09 mmol) in anhydrous dioxane (3.0 ml) was added with HCl at room temperature (0.1 ml, 4N in dioxane). The resulting mixture was stirred for 1 hour and concentrated in vacuo. The resulting residue was purified twice by flash column chromatography (silica gel, first column (12 g) eluted with mixtures of CMA-80 in CHCl3, 0-100%, second column (4 g) eluted with mixtures of MeOH in chloroform, 0-40%) to obtain free base 242b. The free base was dissolved in MTBE (4 ml), HCl (4N HCl in dioxane, 0.5 ml) was added and stirred for 30 min at room temperature. The slurry was concentrated in vacuo and dried to give (-)-hexyl-(3-(5-(5(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3 - (trifluoromethyl)-1 H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (242d) (45 mg, 74%) as an off-white solid.

1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.87 (s, 1H), 10.59 (s, 1H), 9.60 (s, 3H), 8.66 (m, 2H), 8.06 - 7.96 (m, 3H), 7.95 - 7.86 (m, 2H), 7.80 (m, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 7.58 - 7.50 (m, 1H), 7.41 (m, 2H), 4.27 (m, 2H), 2.56 (m, 2H), 1 .67 (m, 2H), 1.44 - 1.21 (m, 8H), 1.20 - 1.03 (m, 3H), 0.68 (s, 1H), 0.49 - 0.31 (m, 2H), 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.63, -119.82; MS (IER+) 694.6 (M+1); optical rotation: [a] _D =(-) 10.0 [0.26, MeOH].

- 380 045731

Scheme 243

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1 -(pyridin-3 -yl) propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (243a).

Compound 243a was prepared from 1-(3-cyanophenyl)-N-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-3-yl)propyl )-2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (238a) (40 mg, 0.061 mmol) according to the method for preparing compound 15g described in step 6 of Scheme 15, after purification by flash column chromatography [silica gel, eluted with mixtures of chloroform/methanol (1:0 to 9:1)] gave 1-(3-(aminomethyl)phenyl)-N-(5-((-)-3-cyclopropyl-1-(( R)-1,1dimethylethylsulfinamide)-1-(pyrudin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (243a) (13 mg, 32.3%) as whitish solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.41 (dd, J=4.8, 1 .5 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.62 - 7.18 (m, 9H), 5.57 (s, 1H), 3.77 (s , 2H), 2.75-2.40 (m, 2H), 1.20-1.00 (m, 1H), 1.12 (s, 9H), 0.98 - 0.79 (m, 1H ), 0.70-0.55 (m, 1H), 0.40-0.28 (m, 2H), 0.02 - -0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.54, -122.96; MS (IER+):

679.7 (M+Na); optical rotation [a]D=(-) 81.90 [0.105, MeOH]. Scheme 244

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-C-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (244g).

Step 1. Preparation of (-)-tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzylcarbamate (244a).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1 -(pyridin-3-yl)propyl)- 2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (209c) (1.603 g, 2.118 mmol) in methanol (18 ml), cooled to 0°C, added 4N. hydrochloric acid in dioxane (1.60 ml, 6.40 mmol) and stirred at 0°C for 2.5 hours. The reaction was quenched with triethylamine (1.10 ml, 7.89 mmol) and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give (-)-tert-butyl-3-(5-(5-( 1-Amino-3-cyclopropyl-1(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (244a) (658 mg, 47.6% ) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.46 - 8.38 (m, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.71 -7.60 (m, 2H), 7.59 - 7.32 (m, 8H), 7.25 (t, J=9.5 Hz, 1H), 4.29 - 4.19 ( m, 2H), 2.42 (s, 2H), 2.37 - 2.22 (m, 2H), 1.44 (s, 9H), 1.19 - 1.02 (m, 2H), 0 .78 - 0.61 (m, 1H), 0.50 0.34 (m, 2H), 0.04 - -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.60, -123.99; MS (IER+) 653.3 (M+1), (IER-) 651.5 (M-1); optical rotation: [a]D=(-) 1.45 [0.275, CH ₃ OH].

Step 2. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (244b).

Into a solution of (-)-tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl

- 381 045731 carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (244a) (132 mg, 0.202 mmol) in pyridine (5 ml) was added N,N-dimethylpyridin-4-amine (30, 0 mg, 0.246 mmol), pivaloyl chloride (0.030 ml, 0.243 mmol) and stirred at room temperature for 5 hours. Add additional pivaloyl chloride (0.060 ml) and stir at room temperature for 22 hours. Add additional pivaloyl chloride (0.060 ml ) and heated at 70°C for 15 hours. The reaction mixture was cooled to room temperature, quenched with methanol (5 ml) and concentrated to dryness in vacuo. The residue was diluted with ethyl acetate (150 ml), washed with water (75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(5-(3-cyclopropyl-1-pivalamido-1 -(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (244b) (29 mg, 19.5%) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.49 (s, 1H), 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.67 - 7.16 (m, 12H), 4.18 (d, J=6.2 Hz, 2H), 2.70-2.40 (m, 2H), 1.38 (s, 9H) , 1.11 (s, 9H), 1.00-0.80 (m, 2H), 0.70-0.55 (m, 1H), 0.40-0.27 (m, 2H), - 0.05- -0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.60, -123.86; MS (ESI+) 759.7 (M+Na).

Step 3. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin3 -yl)propyl)-2-fluorophenyl)-3- (trifluoromethyl)-1 H-pyrazole-5-carboxamide (244g).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (244b) (26 mg, 0.035 mmol) in ethanol (6 ml) was added conc. HCl (0.030 mL, 0.360 mmol) and heated at reflux temperature for 1 h. The solution was cooled to room temperature and concentrated to dryness in vacuo to give (-)-1-(3-(aminomethyl)phenyl)-N-(5 -(3-cyclopropyl-1-pivalamido-1-(pyridin-3-yl)propyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244g) (24 mg, 0.034 mmol, 96% ) as a white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.69 (s, 1H), 8.65-8.58 (s, 2H), 8.33 (s, 3H), 8.11 (s, 1H ), 7.75-7.45 (m, 8H), 7.32 - 7.18 (m, 2H), 4.12 (q, J=5.8 Hz, 2H), 2.65-2, 40 (m, 2H), 1.11 (s, 9H), 1.02-0.84 (m, 2H), 0.70-0.56 (m, 1H), 0.40 - 0.28 ( m, 2H), -0.06 - -0.16 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.62, -123.06; MS (IER+): 637.5 (M +1); optical rotation: [a] _D =(-) 0.39 [1.55, CH3OH].

An example of the preparation of (-)-N-(5-(1 -acetamido-3-cyclopropyl-1 -(pyridin-3-yl)propyl)-2-fluorophenyl)-1 (3 -(aminomethyl)phenyl)-3 -( trifluoromethyl)-1 H-pyrazole-5-carboxamide (244h).

Step 1. Preparation of tert-butyl-3-(5-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (244c).

Into a solution of (-)-tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzylcarbamate (244a) (170 mg, 0.260 mmol) in pyridine (5 ml) was added N,N-dimethylpyridin-4-amine (38.0 mg, 0.311 mmol), acetic anhydride (0.030 ml, 0.313 mmol) and stirred at room temperature for 5 hours. Added additional acetic anhydride (0.060 ml) and stirred at room temperature for 22 hours. Added additional acetic anhydride (0.060 ml) and stirred at room temperature for 15 hours. The reaction was quenched with methanol (5 ml) and the mixture was concentrated to dryness in vacuo. The residue was diluted with ethyl acetate (150 ml), washed with water (75 ml), brine (75 ml), dried over MgSO4, filtered and concentrated to dryness in vacuo. The residue was purified by flash column chromatography [silica gel, eluted with chloroform/methanol (1:0 to 19:1)] to give tert-butyl-3-(5-(5-(1-acetamido-3-cyclopropyl-1 -(pyridin-3-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (244c) (53 mg, 29.3%) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.38 (dd, J=4.8, 1 .5 Hz, 1H), 8.31 (s, 1H), 7.69 - 7.17 (m, 11H), 4.19 (d, J=6.2 Hz, 2H), 2.65-2 .40 (m, 2H), 1.89 (s, 3H), 1.38 (s, 9H), 1.05-0.80 (m, 2H), 0.70-0.50 (m, 1H ), 0.40-0.25 (m, 2H), -0.05- -0.17 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.62, -123.29; MS (IER-): 693.6 (M-1).

Step 2. Preparation of (-)-N-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenyl)1-(3-(aminomethyl)phenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (244h).

Compound 244h was obtained from tert-butyl-3-(5-(5-(1-acetamido-3-cyclopropyl-1-(pyridin-3yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (244c) (45 mg, 0.065 mmol) and conc. HCl (0.054 ml, 0.648 mmol) using the method for compound 244g described in step 3 of scheme 244, (-)-N-(5-(1-acetamido-3-cyclopropyl-1(pyridin-3-yl) hydrochloride salt )propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (244h) (44 mg) as an off-white solid. 1H NMR (300 MHz, DMSO- _d6 ) δ 10.72 (s, 1H), 8.70 - 8.62 (m, 2H), 8.55 (s, 1H), 8.39 (br.s , 3H), 8.22 (d, J=8.2 Hz, 1H), 7.83 - 7.21 (m, 9H), 4.12 (q, J=5.7 Hz, 2H), 2 .60-2.40 (m, 2H), 1.91 (s, 3H), 1.11 - 0.77 (m, 2H), 0.70-0.54 (m, 1H), 0.41 - 0.23 (m, 2H), -0.04 - 0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.63, -122.26; MS (IER+): 595.4 (M+1); optical rotation: [a] _D =(-) 1.51 [0.265, CH3OH].

An example of the preparation of (-)-1-(3 -(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-propionamido-1-(pyridin3 -yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl )-1 H-pyrazole-5-carboxamide (244i).

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Step 1. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzylcarbamate (244d).

Into a solution of (-)-tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)- DMAP (33.0 mg, 0 .27 mmol), then isobutyryl chloride (142.8 mg, 1.34 mmol, 5.0 eq.) in anhydrous THF (2.0 ml). The resulting reaction mixture was stirred for 11 hours at room temperature and concentrated to dryness in vacuo. The residue was dissolved in EtOAc (100 ml), washed with water (2x50 ml), brine, dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with EtOAc/MeOH (9:1) and hexane, 0-50%) to give tert-butyl-3-(5(5-(3-cyclopropyl- 1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (244d) (150 mg, 78.47% yield) in as a white solid; 1H NMR (300 MHz, CD3OD) δ 8.52 (d, J=2.4 Hz, 1H), 8.36 (dd, J=4.9, 1.5 Hz, 1H), 7.81 (dt , J=7.8, 2.2 Hz, 2H), 7.48 - 7.29 (m, 5H), 7.26 - 7.10 (m, 3H), 4.29 (s, 2H), 2.74 - 2.53 (m, 2H), 2.28 (q, J=7.6 Hz, 2H), 1.43 (s, 9H), 1.05 (m, 3H), 0.95 - 0.82 (m, 2H), 0.69 - 0.61 (m, 1H), 0.42 - 0.34 (m, 2H), -0.03 - -0.12 (m, 2H) ; MS (IER+) 709.5 (M+1).

Step 2. Preparation of (-)-1-(3-(aminomethyl)phenyl)-C-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244i).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-propionamido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (244d) (150 mg, 0.211 mmol) in ethanol (20 ml) was added with HCl (4N in dioxane, 0.35 ml, 10 eq.) and heated at reflux temperature for 2 hours. Concentrated reaction mixture in vacuo, purify the resulting residue by flash column chromatography (silica gel, 12 g, eluted with mixtures of CHCl ₃ in CMA-80, 0-60%) to give free base 244i (71 mg) as a white solid. The free base was dissolved in methanol (5 ml), HCl (0.2 ml, 4N in dioxane) was added at room temperature and concentrated to dryness in vacuo. The residue was dissolved in water (2 ml) and two drops of acetonitrile, lyophilized to obtain (-)-1-(3-(aminomethyl)phenyl)-K-(5-(3-cyclopropyl-1propionamido-1-(pyridin- 3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244i) (72 mg, 84%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.82 (s, 1H), 8.80 8.66 (brs, 2H), 8.60 (brs, 3H), 8.39 ( d, J=8.1 Hz, 1H), 7.91 (m, 1H), 7.73 (m, 2H), 7.65 (d, J=7.2 Hz, 1H), 7.59 - 7.48 (m, 4H), 7.35- 7.20 (m, 3H), 4.10 (d, J=5.8 Hz, 2H), 2.54 (m, 2H), 2.24 (q, J=7.4 Hz, 2H), 0.92 (m, 5H), 0.70 - 0.55 (m, 1H), 0.33 (m, 2H), -0.07 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.77, -122.21; MS (IER+): MS (IER+) 609.5 (M+1); optical rotation: [a] _D =(-) 1.57 [0.255, CH3OH].

An example of the preparation of (-)-1 -(3 -(aminomethyl)phenyl)-K-(5-(3-cyclopropyl-1-isobutyramido-1 -(pyridin-3-yl)propyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (244j).

Step 1. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzylcarbamate (244e).

Compound 244e was prepared from (-)-tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl )-1H-pyrazol-1-yl)benzylcarbamate (244a) (175 mg, 0.27 mmol) and isobutyryl chloride (142.8 mg, 1.34 mmol, 5.0 eq.) using the method for 244d described Scheme 244, after purification by flash column chromatography [silica gel, 12 g column, eluted with mixtures of EtOAc/MeOH (9:1) and hexane, 0-50%] gave tert-butyl-3-(5-(5-( 3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)benzylcarbamate (244e) (150 mg, 76.86% yield) in as a white solid; MS (IER+) 723.5 (M+1); (IER-) 721.5 (M-1).

Step 2. Preparation of (-)-1-(3-(aminomethyl)phenyl)-C-(5-(3-cyclopropyl-1-isobutyramido-1-(pyridin-3-yl)propyl)-2-fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244j).

Free base 244j was prepared from tert-butyl-3-(5-(5-(3-cyclopropyl-1-isobutyramido-1(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzylcarbamate (244e) (150 mg, 0.208 mmol) and HCl (4N in dioxane, 0.35 mL, 10 eq.) using the method for free base 244i described in Scheme 244, after purification by Flash column chromatography (silica gel, 12 g, eluted with mixtures of CHCl3 in CMA-80, 0-60%) gave free base 244j (63 mg) as a white solid. The free base was converted to the hydrochloride salt according to the description of the preparation of the hydrochloride salt of compound 244i from the free base in Scheme 244, giving the hydrochloride salt of (-)-1-(3-(aminomethyl)phenyl)-K-(5-(3-cyclopropyl-1isobutyramido- 1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244j) (64 mg) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 8.68 (m, 2H), 8.48 (m, 3H), 8.28 (d, J=8.1 Hz, 1H), 7.83 (t, J=7.1 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.67 - 7.47 (m, 4H), 7.42 (s, 1H), 7.31 - 7.21 (m, 3H), 7.08 (s, 1H), 4.11 (d, J=5.8 Hz, 2H), 2.75 - 2, 63 (m, 1H), 2.58 (m, 2H), 0.93 (t, J=7.2 Hz, 8H), 0.64 (m, 1H), 0.39 - 0.29 (m , 2H), -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.79, -122.69; MS (IER+) 623.5 (M+1); 621.9 (M-1); optical rotation: [a] _D =(-) 0.73 [0.055, CH3OH]; analysis, calculation for

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C ₃₃ H ₃ 4E4^Og3,5HC1-3.5H2O: C, 48.73; H, 5.51; Cl, 15.26; N, 10.33; experiment: C, 48.32; H, 5.79; Cl,

15.29; N, 10.73.

An example of the preparation of (-)-1 -(3 -(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1 (pyridin-3-yl)propyl)-2-fluorophenyl) -3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (244k).

Step 1. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1-(pyridin-3yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)- 1 H-pyrazol-1-yl)benzylcarbamate (244f).

Compound 244f was prepared from (-)-tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-3yl)propyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)- 1 H-pyrazol-1-yl)benzylcarbamate (244a) (175 mg, 0.27 mmol) and isovaleric acid chloride (139 mg, 1.149 mmol) using the method for compound 244d described in Scheme 244, tert-butyl- 3-(5-(5-(3-cyclopropyl-1-(3methylbutanamido)-1 -(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1 yl) benzylcarbamate (244f) (190 mg); MS (IER+) 737.6 (M+1), (IER-) 735.5 (M-1).

Step 2. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(3-methylbutanamido)-1(pyridin-3-yl)propyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244k).

Free base 244k was prepared from tert-butyl-3-(5-(5-(3-cyclopropyl-1-(3-methylbutanamido)1 -(pyridin-3-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl )-1 H-pyrazol-1-yl)benzylcarbamate (244f) (190 mg) and HCl (4N in dioxane, 0.35 ml) using the method for free base 244i described in Scheme 244, after purification by flash column -chromatography (silica gel, 12 g, eluted with mixtures of CHC13 in CMA-80, 0-60%) provided 44 g of 244k free base as a white solid. The free base was converted to the hydrochloride salt according to the description of the preparation of the hydrochloride salt of compound 244i from the free base in scheme 244, giving the hydrochloride salt of (-)-1 -(3 -(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1 - (3-methylbutanamido)-1-(pyridin-3 yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (244k) (46 mg, 31% in 2 steps) as white solid; 1H NMR (300 MHz, DMSO-d^ δ 10.73 (s, 1H), 8.72 - 8.62 (m, 2H), 8.51 (s, 1H), 8.43 (br.s, 3H), 8.25 (d, J=8.2 Hz, 1H), 7.87 - 7.77 (m, 1H), 7.73 (t, J=1.7 Hz, 1H), 7, 68 (s, 1H), 7.62 (m, 1H), 7.57 - 7.46 (m, 3H), 7.40 - 7.01 (m, 3H), 4.11 (q, J= 5.8 Hz, 2H), 2.60 - 2.54 (m, 2H), 2.17 - 2.05 (m, 2H), 1.88 (m, 1H), 0.97 (m, 2H ), 0.79 (m, 6H), 0.61 (m, 1H), 0.44 - 0.28 (m, 2H), -0.05- -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, -122.48; MS (ESI+) 637.6 (M+1); optical rotation: [a] _D =(-) 2.61 [0.23 , CH3OH]; analysis, calculation for C ₃₄ H ₃₆ FN ₆ O ₂ -2HC1-2.5H ₂ O: C, 54.11; H, 5.74; Cl, 9.40; N, 11.14; experiment : C, 53.98; H, 5.70; Cl, 9.78; N, 11.09.

Scheme 245

An example of the preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1(pyridin-4-yl)propyl)-2-fluorophenyl)-3 -(trifluoromethyl)-1H-pyrazole-5-carboxamide (245c).

Step 1. Preparation of tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzylcarbamate (245a).

Into a solution of tert-butyl-3 -(5-(5 -((-)-3 -cyclopropyl-1 -((R)-1,1 -dimethylethylsulfinamido)-1 -(pyridin4-yl)propyl)-2-fluorophenylcarbamoyl )-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (216c) (893 mg, 1.180 mmol) in MeOH (15 ml), cooled to 0°C, added HCl (0.89 ml, 3 .56 mmol, 4N in 1,4dioxane) and stirred at approximately 0°C for 2 hours. The reaction was quenched with triethylamine (0.610 ml, 4.38 mmol) at 0°C and the mixture was concentrated to dryness in vacuo. The residue was purified by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1), then chloroform/CMA 80, 1:1] to give tert-butyl-3-(5 -(5-(1-amino-3-cyclopropyl-1(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (245a) (140 mg , 18.2%) in the form of a colorless viscous substance; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.55 (s, 1H), 8.48 - 8.40 (m, 2H), 7.64 - 7.25 (m, 10H), 7.18 (t, J=9.4 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.21 (m, 2H), 1.38 (s, 9H), 1.15 -0.90 (m, 2H), 0.70-0.55 (m, 1H), 0.42 - 0.26 (m, 2H), -0.04 - -0.12 (m, 2H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.63, -123.81; MS (IER+): 653.5 (M+1).

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Step 2. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H -pyrazol-1-yl)benzylcarbamate (245b)

Into a solution of tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (245a) (126 mg, 0.193 mmol) in pyridine (5 ml) was added N,N-dimethylpyridin-4-amine (24.00 mg, 0.196 mmol), methanesulfonyl chloride (0.018 ml, 0.232 mmol) and stirred at room temperature for 19 hours. Additional amounts of methanesulfonyl chloride (0.03 ml, 0.03 ml, 0.08 ml, 0.15 ml, 0.15 ml) were added each day for five consecutive days and continued to heat at 70°C overnight. The reaction mixture was diluted with ethyl acetate (120 ml), washed with water (2x50 ml), brine (50 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-(5-(3-cyclopropyl- 1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (245b) (30 mg, 21.3%) in as a whitish solid; 1H NMR (300 MHz, DMSO-dg) δ 10.64 (s, 1H), 8.54 - 8.50 (m, 2H), 7.85 (s, 1H), 7.65 - 7.17 ( m, 11H), 4.18 (d, J=6.2 Hz, 2H), 2.65-2.35 (m, 2H), 2.28 (s, 3H), 1.38 (s, 9H ), 1.15-0.90 (m, 1H), 0.93 - 0.71 (m, 1H), 0.64-0.48 (m, 1H), 0.39 - 0.20 (m , 2H), -0.03 - -0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.80, -121.96; MS (IER+): 753.4 (M+23).

Step 3. Preparation of (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1(pyridin-4-yl)propyl)-2-fluorophenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (245c).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (245b) (27 mg, 0.037 mmol) in ethanol (6 ml) was added conc. HCl (0.03 mL, 0.366 mmol) and heated at reflux temperature for 45 min. The reaction mixture was cooled to room temperature and concentrated to give (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridine-4- yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (245c) (23 mg, 88%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.77 (s, 1H), 8.75 (s, 2H), 8.39 (s, 3H), 8.10 (s, 1H), 7, 77 - 7.45 (m, 8H), 7.33 (t, J=9.3 Hz, 1H), 7.29 - 7.20 (m, 1H), 4.12 (d, J=5, 6 Hz, 2H), 2.76-2.25 (m, 2H), 2.38 (s, 3H), 1.15-0.95 (m, 1H), 0.90-0.70 (m , 1H), 0.65-0.50 (m, 1H), 0.40-0.25 (m, 2H), -0.01 --0.20 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.79, -121.16; MS (IER+): 631.4 (M+1); optical rotation: [a]D=(-) 7.62 [0.105, CH ₃ OH]; analysis, calculation for C ₃₀ H ₃₀ F ₄ N ₆ O ₃ S-2HCl-2H ₂ O: C, 48.72; H, 4.91; N, 11.36; experiment: C, 48.61; H, 4.91; N, 10.99.

Scheme 246

245 _e 246f (+)-isomer

An example of the preparation of (+)-1-(3 -(aminomethyl)phenyl)-5 -(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylic acid (246f).

Step 1. Preparation of methyl 4-(furan-2-yl)-4-hydroxy-2-oxobut-3-enoate (246a).

Sodium methoxide (25% in methanol, 29.7 g, 137 mmol). The resulting suspension was stirred at room temperature for 18 hours. The resulting solid was collected by filtration, washed with diethyl ether to give methyl 4-(furan-2-yl)-4hydroxy-2-oxobut-3-enoate (246a ) (11.7 g, 59.6 mmol, 47.7% yield) as a brown solid, which was used as such in the next step; 1H NMR (300 MHz, DMSO- _d6 ) δ 8.33 (d,

J=2.2 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.56 (dd, J=8.6, 2.2 Hz, 1H), 5.19 (d, J =13.2 Hz, 1H), 2.95 (s, 3H).

Step 2. Preparation of methyl 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate (246b).

To methyl 4-(furan-2-yl)-4-hydroxy-2-oxobut-3-enoate (246a) (4 g, 20.39 mmol) and 3hydrazinylbenzonitrile hydrochloride (229c) (2.94 g, 17. 33 mmol) AcOH (40 ml) was added and stirred at room temperature overnight. Concentrate the mixture in vacuo and purify the resulting residue by flash column chromatography (silica gel, 300 g, eluted with 25% ethyl acetate in hexane) to give methyl 1-(3-cyanophenyl)-5-(furan-2-yl)-1H -pyrazole-3-carboxylate (246b) as a yellow oily liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 8.10 - 8.01 (m, 2H), 7.89 - 7.82 (m, 1H), 7.81 - 7.71 (m, 2H) , 7.27 (s, 1H), 6.59 (dd, J=3.5, 1.8 Hz, 1H), 6.50 (dd, J=3.5, 0.8 Hz, 1H), 3.87(s, 3H); MS (IER+) 294.2 (M+1), 316.2 (M+Na).

Step 3. Preparation of 1-(3-cyanophenyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid (246c).

Compound 246c was prepared by oxidation of methyl 1-(3-cyanophenyl)-5-(furan-2-yl)-1H-pyrazole-3carboxylate (246b) (2 g, 6.82 mmol) according to the method described in step 5 of the scheme 229, after purification by flash column chromatography (silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) gave 1-(3-cyanophenyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid (246c) (0.753 g, 41% yield) as a yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 8.02 (s, 1H), 7.94 - 7.77 (m, 2H), 7.72 - 7.59 (m, 1H), 7.01 (s, 1H), 3.83 (s, 3H); MS (IER+): MS (IER+) 272.2 (M+1), 294.2 (M+Na), 565.3 (2M+Na); MS (IER-) 270.2 (M-1), 541.3 (2M-1).

Step 4. Preparation of methyl 1-(3-cyanophenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246d).

Compound 246d was prepared from 1-(3-cyanophenyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acid (246c) (0.706 g, 2.60 mmol) and (-)-5-((cyclopropylmethylamino)( phenyl)methyl)-2-fluoroaniline (222f) (0.844 g, 3.12 mmol) as described in step 3 of Scheme 208 gave methyl 1-(3-cyanophenyl)-5(5-((cyclopropylmethylamino)(phenyl)methyl )-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246d), which was used as such without further purification in the next step; MS (IER+) 524.4 (M+1); MS (IER-) 522.5 (M-1).

Step 5. Preparation of methyl 1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246e).

Compound 246e was prepared from methyl 1-(3-cyanophenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246d) (1.66 g, 3.17 mmol) according to the method for preparing compound 15g described in step 6 of Scheme 15, after purification by flash column chromatography (silica gel, eluted with mixtures of CMA 80 in chloroform, 0-100%) gave methyl-1-(3(aminomethyl)phenyl) -5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246e) (0.126 g, 8% yield) as a white solid; MS (IER+): MS (IER+) 528.4 (M+1); MS (IER-) 526.5 (M-1).

Step 6. Preparation of (+)-1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylic acid (246f).

In a solution of methyl 1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylate (246e) (0.119 g, 0.226 mmol) in methanol (2.4 ml) and THF (2.4 ml) at room temperature was added aq. sodium hydroxide (2.256 ml, 2.256 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with acetic acid (0.155 ml, 2.71 mmol), stirred for 10 minutes and evaporated to dryness. The resulting residue was purified twice by flash column chromatography [silica gel, 25 g, eluted with mixtures of CMA 80 in chloroform, 0-100%, second column: silica gel, 12 g, eluted with mixtures of methanol in chloroform, 0-100%] to give (+ )-1-(3-(aminomethyl)phenyl)-5-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenylcarbamoyl)-1H-pyrazole-3-carboxylic acid (246f) (19 mg, yield 16 %) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H, exchange with D2O), 8.13 (s, 1H), 7.58 (dd, J=7.4, 2.2 Hz , 1H), 7.44 - 7.09 (m, 12H), 4.81 (s, 1H), 4.15 (s, 2H), 2.26 (d, J=6.7 Hz, 2H) , 0.90 (dq, J=13.0, 6.9, 6.0 Hz, 1H), 0.42 0.28 (m, 2H), 0.03 (dt, J=5.0, 2 .7 Hz, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -123.25; MS (IER+): MS (IER+) 514.4 (M+1); MS (IER-) 512.4 (M-1); optical rotation: [a] _D =(+) 2.86 [0.07, MeOH].

- 386 045731

Scheme 247

-(3 -(aminomethyl)phenyl)-N-(3 -(3-cyclopropyl-1 -(2-oxopyridin-1 (2H)-yl)pro Example of preparation of pyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (247c).

Step 1. Preparation of N-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (247a).

In a solution of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-hydroxynponyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (89e) (200 mg, 0.440 mmol) in dichloromethane (12 ml) at 0°C, add sulfuric acid chloride (0.070 ml, 0.946 mmol) and leave to warm to room temperature for 2 hours. Concentrate the reaction mixture in vacuo to give K-(3-(1-chloro-3-cyclopropylpropyl) phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-nirazole-5-carboxamide (247a), which was used as such without further purification.

Step 2. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-πyrazole -5-carboxamide (247b).

To a solution of pyridin-2-ol (216 mg, 2.200 mmol) in THF (5 ml) was added lithium bis(dimethylsilyl)amide (2.20 ml, 2.200 mmol, 1 M in THF), stirred at room temperature for 0.5 h and concentrated to dryness in vacuo. A solution of N-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (247a) in DMF (10) was added to the resulting mixture ml) and heated at 70°C for 14 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1(2 -oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (247b) (49 mg, 21%) as an off-white solid. 1H NMR (300 MHz, DMSO-d^) δ 10.70 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1 ,4 Hz, 1H), 7.91 (m, 1H), 7.79 - 7.60 (m, 4H), 7.55 (t, J=1.8 Hz, 1H), 7.41 - 7 .30 (m, 2H), 7.17 (d, J=7.8 Hz, 1H), 6.44 - 6.38 (m, 1H), 6.23 (td, J=6.7, 1 .5 Hz, 1H), 6.13 - 6.05 (m, 1H), 2.30-2.14 (m, 2H), 1.29 - 0.92 (m, 2H), 0.80 - 0.61 (m, 1H), 0.42 - 0.26 (m, 2H), 0.06 - -0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOd ₆ ) δ -60.76; MS (IER+): 532.5 (M+1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)phenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (247c).

Compound 247c was prepared from 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (247b) (44 mg, 0.083 mmol) according to the preparation of compound 89f described in step 6 of Scheme 89, after purification by flash column chromatography [silica gel, eluted with chloroform/methanol mixtures (1:0 to 9:1 )] obtained the free base 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (247c) (25 mg, 56.4%) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.75 (s, 1H), 7.67 - 7.54 (m, 4H), 7.52 (s, 1H), 7.47 - 7.27 (m , 5H), 7.19 - 7.12 (m, 1H), 6.43 - 6.37 (m, 1H), 6.27 - 6.20 (m, 1H), 6.08 (t, J =8.1 Hz, 1H), 3.77 (s, 2H), 2.30-2.10 (m, 2H), 1.27 - 0.93 (m, 2H), 0.77-0, 60 (m, 1H), 0.37 (m, 2H), -0.05- -0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.51; MS (IER+) 536.5 (M+1).

Free base 247c (18 mg, 0.034 mmol) was dissolved in methanol (1 ml), 4N was added. HCl (aq, 0.034 ml) and concentrated to dryness in vacuo. The residue was dissolved in water (0.5 ml), then lyophilized to give 1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopi) hydrochloride

- 387 045731 ridin-1(2H)-yl)propyl)phenyl)-3-(trifluoromethyl)-III-pyrazole-5-carboxamide (247c) in the form of a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 8.31 (s, 3H), 7.71 (t, J=1.7 Hz, 1H), 7.66 ( s, 2H), 7.65-7.51 (m, 5H), 7.41 - 7.29 (m, 2H), 7.18 (d, J=7.8 Hz, 1H), 6.39 (dd, J=9.0, 1.4 Hz, 1H), 6.23 (td, J=6.7, 1.5 Hz, 1H), 6.08 (t, J=8.0 Hz, 1H), 4.13 (q, J=5.8 Hz, 2H), 2.21 (m, 2H), 1.09 (m, 2H), 0.71 (m, 1H), 0.37 ( m, 2H), -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.60; MC (IER+) 536.5 (M+1), (IER-) 534.5 (M1), 570.5 (M+Cl).

An example of the preparation of 1 -(3 -(aminomethyl)phenyl)-N-(3 -(3 -cyclopropyl-1 -(2-oxopyrrolidin-1 -yl)propyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazol- 5-carboxamide (247e).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3 -(trifluoromethyl)-1 H-pyrazole-5 -carboxamide (247d).

Compound 247d was prepared from N-(3-(1-chloro-3-cyclopropylpropyl)phenyl)-1-(3-cyanophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (247a) (0.44 mmol) and pyrrolidin-2-one (0.169 ml, 2.200 mmol) according to the method for preparing compound 247b described above in step 2 of the above scheme, after purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate mixtures (1:0 to 1: 1)] obtained 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 247d) (11 mg, 4.8%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.18 (t, J=1.9 Hz, 1H), 8.01 (dt, J=7.9, 1 ,3 Hz, 1H), 7.95-7.89 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H ), 7.65 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.36 - 7.28 (m, 1H), 7.07 (d, J=7, 6 Hz, 1H), 5.09 (t, J=8.0 Hz, 1H), 2.39 - 2.16 (m, 2H), 2.07 - 1.70 (m, 6H), 1, 24 0.98 (m, 2H), 0.73 (m, 1H), 0.51 - 0.24 (m, 2H), 0.12 - -0.15 (m, 2H); MS 522.4 (M+1), 544.5 (M+Na); (IER-) 520.4 (M-1).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-X-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5 -carboxamide (247e).

Compound 247e was prepared from 1-(3-cyanophenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 247d) (10 mg, 0.019 mmol) according to the preparation of compound 89f described in step 6 of scheme 89, after purification by flash column chromatography [silica gel, eluted with chloroform/methanol mixtures (1:0 to 9:1)] gave 1 (3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-(2-oxopyrrolidin-1-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (247e ) (3 mg) as a whitish solid; 1H NMR (300 MHz,

MeOD) δ 7.55 - 7.35 (m, 6H), 7.33 - 7.27 (m, 2H), 7.10 (m, 1H), 5.24 - 5.13 (m, 1H) , 3.60 (s, 2H), 3.45- 3.30 (m, 1H), 3.05 (m, 1H), 2.49 - 2.32 (m, 2H), 2.09 -1 .84 (m, 2H), 1.26 - 1.05 (m, 3H), 0.86 (m, 1H), 0.80 - 0.65 (m, 1H), 0.41 (m, 2H ), 0.06 - -0.02 (m, 2H); ¹⁹ F NMR (282 MHz, MeOD) δ -64.55; MS (IER+) 526.4 (M+1).

Scheme 248

SiMsg

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (248j).

Step 1. Preparation of (E)-ethyl-3-cyclopropylacrylateα (248b).

To a solution of 1-(triphenylphosphoranylidene)pentan-2-one (248a) (994 g, 2853 mmol) in dichloromethane (3000 ml) was added cyclopropanecarbaldehyde (200 g, 2853 mmol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated. to 1/3 volume, diluted with hexane (1000 ml) and concentrated in vacuo. The reaction mixture was diluted with hexane (3000 ml) and stirred for 10 minutes. The resulting solid triphenylphosphine oxide was removed by filtration. The filtrate was concentrated to give (E)-ethyl-3-cyclopropylacrylate (248b) (410 g, 2925 mmol, 103% yield) as a colorless oil, which was used as such in the next step without purification; ¹ H NMR (300 MHz, DMSO-d,) δ 6.38 (dd, J=15.4, 10.2 Hz, 1H), 5.93 (d, J=15.4 Hz, 1H), 4 .08(q,

J=7.1 Hz, 2H), 1.64 (dtt, J=10.2, 8.0, 4.6 Hz, 1H), 1.19 (td, J=7.1, 1.0 Hz , 3H), 0.98 - 0.82 (m, 2H), 0.75 - 0.62 (m, 2H).

Step 2. Preparation of ethyl 3-cyclopropylpropanoate (248c).

To a solution of (E)-ethyl-3-cyclopropylacrylate (248b) (290 g, 2069 mmol) in methanol (2000 ml), cooled to 5°C, was added cobalt (II) chloride hexahydrate (24.61 g, 103 mmol) , then a solution of sodium tetrahydroborate (157 g, 4138 mmol) in DMF (500 ml) was added dropwise at such a rate that the internal temperature did not exceed 10°C. The reaction mixture was stirred for 1 hour at 5°C, poured into water (5000 ml) and stirred for 15 minutes. The resulting black suspended solution was filtered through a pad of celite, washed with dichloromethane (3x800 ml). The aqueous layer was separated and extracted with dichloromethane (2x600 ml). Combine the layers in dichloromethane, wash with water (2x1500 ml), brine, dry over MgSO ₄ , filter and concentrate in vacuo in a bath below 40°C to give ethyl 3-cyclopropylpropanoate (248c) (260 g, 88% yield ) in the form of a colorless liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.03 (q, J=7.1 Hz, 2H), 2.33 (t, J=7.3 Hz, 2H), 1.41 (q , J=7.2 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H), 0.75-0.59 (m, 1H), 0.40 - 0.31 (m, 2H), 0.06 - -0.06 (m, 2H).

Step 3. Preparation of 3-cyclopropyl-N-methoxy-N-methylpropanamide (248d).

To a solution of ethyl 3-cyclopropylpropanoate (248c) (260 g, 1828 mmol) in THF (2000 ml), cooled to -10°C, was added N,Ο-dimethylhydroxylamine hydrochloride (268 g, 2743 mmol), then added dropwise isopropylmagnesium chloride (2743 ml, 5485 mmol, 2M in THF). The mixture was stirred at -10°C for 2 hours and quenched. NH ₄ Cl solution (4000 ml) and left to warm to room temperature. Separate the layer in THF and extract the aqueous layer with EtOAc (2x1000 ml). Combine the organic layers, wash with brine, dry over MgSO ₄ , filter and concentrate in vacuo to give 3-cyclopropyl-N-methoxy-N-methylpropanamide (248d) (240 g, 1527 mmol, 83% yield) as an orange liquid; ¹ H NMR (300 MHz, DMSO-d,) δ 3.66 (s, 3H), 3.07 (s, 3H), 2.44 (t, J=7.6 Hz, 2H), 1.39 (q, J=7.3 Hz, 2H), 0.76 - 0.62 (m, 1H), 0.42 - 0.31 (m, 2H), 0.08 - -0.09 (m, 2H).

Step 4. Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e).

A freshly prepared solution of bromide (3(bis(trimethylsilyl)amino) )-4-fluorophenyl)magnesium (52c) (1908 ml, 1527 mmol, 1M in THF), maintaining the internal temperature at approximately 5°C during addition. The reaction mixture was stirred at 5°C for 2 hours, quenched with 3N. HCl (1000 ml) and stirred for 2 hours. The mixture was made basic with solid NaHCO ₃ and extracted with ethyl acetate (2x500 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude 248e. The crude material was dissolved in isopropanol (150 ml) and stirred overnight. The resulting solid was collected by filtration, washed with isopropanol and dried to give 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e) (90 g, 28.46%, first batch) as white solid matter. Concentrate the filtrate, keep at room temperature for 6 hours and collect the resulting solid by filtration to give 1-(3amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e) (50 g, 15.81%, second batch) as a white solid; I NMR (300 MHz, DMSO-d,) δ 7.38 (dd, J=8.9, 2.2 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 2, 2 Hz, 1H), 7.09 (dd, J=11.1, 8.4 Hz, 1H), 5.41 (s, 2H), 2.98 (t, J=7.3 Hz, 2H) , 1.48 (q, J=7.2 Hz, 2H), 0.82 - 0.65 (m, 1H), 0.41 - 0.33 (m, 2H), 0.10 - -0, 02 (m, 2H); MS (IER+) 208.2 (M+1), (IER-) 206.2 (M-1); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -128.24.

Step 5. Preparation of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f).

In a solution of 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e) (13.63 g, 65.8 mmol) in THF (150 ml) and methanol (300 ml) at 0° C sodium borohydride (5.08 g, 132 mmol) was added and stirred at 0°C for 1 hour. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate (800 ml), neutralized with acetic acid, washed with water (2x300 ml), brine (300 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 4:1)] to give 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f) (11.47 g 53.8 mmol, 83% yield) as a white solid; I NMR (300 MHz, DMSO-d ₆ ) δ 6.86 (dd, J=11.5, 8.2 Hz, 1H), 6.72 (dd, J=9.1, 2.1 Hz, 1H ), 6.42 (ddd, J=8.3, 4.5, 2.1 Hz, 1H), 5.03 (s, 2H), 4.98 (d, J=4.1 Hz, 1H) , 4.40 - 4.30 (m, 1H), 1.71 - 1.48 (m, 2H), 1.26 - 1.01 (m, 2H), 0.73 - 0.54 (m, 1H), 0.45-0.24 (m, 2H), 0.02 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -138.16; MS (IER+) 210.1 (M+1); (IER-) 208.1 (M-1).

Step 6. Preparation of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (248g).

In a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.419 g, 8.60

- 389 045731 mmol) in DMF (40 ml) was added 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-ol (248f) (1.5 g, 7.17 mmol), N-ethyl- N-isopropylpropan-2-amine (7.50 mL, 43.1 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrOP, 4.02 g, 8.60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 19 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (2x100 ml). Combine the organic layers, wash with brine (50 mL), dry, filter and concentrate to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with hexanes/ethyl acetate (1:0 to 4:1)] to give 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl- 1-Hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (248g) (2.22 g, 66%) as a yellow solid. 1H NMR (300 MHz, DMSO^) δ 10.54 (s, 1H), 8.13 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.79 - 7.68 (m, 2H), 7.49 (d, J=7.4 Hz, 1H), 7.27 - 7.16 (m, 2H), 5.22 (d, J=4.4 Hz, 1H), 4.52 (q, J=5.8 Hz, 1H), 1.73 - 1.55 ( m, 2H), 1.16 (m, 2H), 0.72 - 0.54 (m, 1H), 0.41 - 0.28 (m, 2H), -0.02 - 0.09 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.94, -124.07; MS (IER-) 471.5 (M-1).

Step 7. N-(5-(1-chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxamide (248h).

In solution of 1-(3-cyanophenyl)-N(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (248g) (645 mg, 1.365 mmol) in dichloromethane (36 ml) at 0°C, add sulfuric acid chloride (0.220 ml, 2.98 mmol) and leave to warm to room temperature for 2 hours. Concentrate the reaction mixture in vacuo to give N-(5-(1- chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (248h), which was used as such without further purification.

Step 8. Preparation of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (248f).

To a solution of pyridin-2-ol (669 mg, 6.83 mmol) in THF (15 ml) was added lithium bis(dimethylsilyl)amide (6.90 ml, 6.90 mmol, 1 M in THF), stirred at room temperature in for 0.5 h and concentrated to dryness in vacuo. A solution of N-(5-(1-chloro-3cyclopropylpropyl)-2-fluorophenyl)-1 -(3-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (248h) (1.365) was added to the resulting mixture mmol) in DMF (10 ml) and heated at 70°C for 14 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated in a vacuum. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridine- 1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)1H-pyrazol-5-carboxamide (248i) (81 mg, 0.147 mmol, 10.8%) as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.13 (s, 1H), 8.00 (dt, J=7.8, 1.3 Hz, 1H), 7 .90 (d, J=8.4 Hz, 1H), 7.77 - 7.67 (m, 3H), 7.51 (d, J=7.1 Hz, 1H), 7.41 - 7, 23 (m, 3H), 6.42-6.37 (m, 1H), 6.24 (td, J=6.7, 1.5 Hz, 1H), 6.06 (t, J=8, 1 Hz, 1H), 2.22 (m, 2H), 1.32 - 0.92 (m, 2H), 0.75-0.60 (m, 1H), 0.43-0.30 (m , 2H), -0.05- -0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-di) δ -60.95, -121.40; MS (IER+) 550.3 (M+1), 572.3 (M+Na), 548.3 (M-1).

Step 9. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) )-1H-pyrazole-5-carboxamide (248j).

Compound 248j was prepared from 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (248i) (45 mg, 0.082 mmol) according to the method for preparation of compound 89f described in step 6 of scheme 89, after purification by flash column chromatography [silica gel, eluted with mixtures of chloroform/methanol (1:0 to 9:1)] gave the free base 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)-2-fluorophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (248j) (28 mg, 0.051 mmol, 61.8%) as a colorless viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.74 - 7.66 (m, 1H), 7.54 (d, J=18.6 Hz, 3H), 7.45 - 7.38 (m , 2H), 7.37 - 7.32 (m, 2H), 7.32 -7.27 (m, 2H), 6.43 - 6.35 (m, 1H), 6.23 (td, J =6.7, 1.4 Hz, 1H), 6.05 (t, J=8.0 Hz, 1H), 3.77 (s, 2H), 2.31 - 2.07 (m, 2H) , 1.21 - 0.90 (m, 2H), 0.77 - 0.59 (m, 1H), 0.44 - 0.22 (m, 2H), 0.10 --0.12 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.72, -121.87.

The free base was dissolved in methanol (5 ml), 4N was added. HCl (aq, 0.050 ml) and concentrated in vacuo to give 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2oxopyridin-1(2H)-yl)propyl) hydrochloride -2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (248j) (29 mg, 89%) as an off-white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.74 (s, 1H), 8.44 (s, 3H), 7.80 - 7.26 (m, 10H), 6.43 (d, J =9.1 Hz, 1H), 6.28 (t, J=6.7 Hz, 1H), 6.08 (t, J=8.0 Hz, 1H), 4.15 (q, J=5 ,9 Hz, 2H), 2.25 (q, J=8.2, 6.8 Hz, 2H), 1.25-0.95 (m, 2H), 0.80-0.65 (m, 1H), 0.45-0.35 (m, 2H), 0.13 - -0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.63, -121.38; MS (IER+): 554.4 (M+1).

An example of the preparation of (+)-1 -(3 -(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1 -(2-oxopyridin-1 (2H)yl)propyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide(248k), (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridine-1 (2H )-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxamide (248l).

Racemate 1 -(3 -(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1 -(2-oxopyridin-1 (2H)-yl)propyl)-2- 390 045731 fluorophenyl)-3-(trifluoromethyl )-1H-pyrazole-5-carboxamide (248j) (350 mg) was separated using the preparative SFC method. Column: 2.1 x 25 cm ChiralPak AD-H from Chiral Technologies; CO2 co-solvent (solvent B) isopropanol with 1% isopropylamine; isocratic method: 25% co-solvent, flow rate 80 g/min; system pressure 100 bar (10 MPa); column temperature 40°C; sample diluent methanol, we obtained:

1. 1 peak corresponding to (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin1(2H)-yl)propyl)-2-fluorophenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (2481) (91.4 mg, >99.99% ee), as a white solid. 1H NMR (300 MHz, MeOD) δ 7.76 (d, J=7.4 Hz, 1H), 7.59 (dd, J=7.0, 1.9 Hz, 1H), 7.51 (s , 1H), 7.48 - 7.36 (m, 4H), 7.32 (s, 1H), 7.26 (m, 1H), 7.16 (t, J=9.5 Hz, 1H) , 6.52 (ddd, J=9.1, 1.4, 0.7 Hz, 1H), 6.35 (td, J=6.8, 1.4 Hz, 1H), 6.19 (t , J=8.0 Hz, 1H), 3.84 (s, 2H), 2.35-2.13 (m, 2H), 1.36 - 0.97 (m, 2H), 0.79 - 0.62 (m, 1H), 0.49 - 0.31 (m, 2H), 0.01 - -0.10 (m, 2H); ¹⁹ F NMR (282 MHz, MeOD) δ 64.56, -126.36; MS (IER+) 554.3 (M+1); (IER-) 552.3 (M-1); optical rotation: [a]D=(-) 138.95 (MeOH, 0.535). Free base (2481) (87 mg, 0.157 mmol) was dissolved in methanol (10 ml), filtered, 4N was added. HCl (aq, 0.16 ml) and concentrated to dryness in vacuo. The residue was dissolved in water (5 ml) and lyophilized to give HCl salt (59 mg) as a white solid. ^1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.30 (s, 3H, exchange with D2O), 7.77 - 7.65 (m, 3H), 7.64 - 7.48 (m, 4H), 7.35 (m, 3H), 6.39 (dd, J=9.2, 1.4 Hz, 1H), 6.24 (td, J=6.7 , 1.5 Hz, 1H), 6.05 (t, J=8.1 Hz, 1H), 4.13 (d, J=5.8 Hz, 2H), 2.22 (m, 2H), 1.06 (m, 2H), 0.69 (m, 1H), 0.37 (m, 2H), -0.01 - -0.07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.83, -121.63; MS (IER+): MS (IER+) 554.3 (M+1); MS (ESI-) 588.3 (M+Cl); chiral purity >99.99% ee;

2. 2 peak corresponding to (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxoniridin1(2H)-yl)propyl)-2-fluorophenyl) -3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (248k) (89.4 mg, 98.2% ee); 1H NMR (300 MHz, MeOD) δ 7.75 (s, 1H), 7.59 (d, J=6.9 Hz, 1H), 7.52 (s, 1H), 7.49 - 7.23 (m, 6H), 7.17 (t, J=9.5 Hz, 1H), 6.57 -6.48 (m, 1H), 6.39 - 6.30 (m, 1H), 6, 24 - 6.13 (m, 1H), 3.86 (s, 2H), 2.43 - 2.15 (m, 2H), 1.35- 1.16 (m, 1H), 1.14 - 0.99 (m, 1H), 0.96 - 0.65 (m, 1H), 0.47 - 0.26 (m, 2H), -0.04 --0.09 (m, 2H); ¹⁹ F NMR (282 MHz, MeOD) δ -64.57, -126.35; optical rotation: [a] _D =(+) 144.61 (MeOH, 0.52); free base (248k) (82 mg, 0.148 mmol) was dissolved in methanol (10 ml), filtered, added 4N. HCl (aq, 0.16 ml) and concentrated to dryness in vacuo. The residue was dissolved in water (5 ml) and lyophilized to give HCl salt (65 mg) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (s, 1H), 8.36 (s, 3H), 7.75-7.66 (m, 3H), 7.64 - 7.48 (m, 4H), 7.41 - 7.25 (m, 3H), 6.39 (dd, J=9.1, 1.3 Hz, 1H), 6.24 (td, J=6.7 , 1.4 Hz, 1H), 6.05 (t, J=8.1 Hz, 1H), 4.13 (t, J=5.5 Hz, 2H), 2.30 - 2.14 (m , 2H), 1.25 - 0.91 (m, 2H), 0.77 - 0.59 (m, 1H), 0.46 - 0.28 (m, 2H), 0.05 - -0, 12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.82, -121.62; chiral purity 98.87% ee.

To verify the chiral purity of compounds 248k and 248l, the following analytical method was used: column: ChiraCel AD-H, 250 mm/5 μm, 4.6 mm; solvent system: 80:20 hexane/ethanol with 0.1% TEA; flow rate: 1.0 ml/min; column temperature: 25°C; sample volume: 5 µm; UV detection: 260 nm.

Scheme 249

NiCI ₂ 6Н ₂ О №ВН ₄

LiHMDS

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) -1 H-pyrazole-5-carboxamide (249b).

Step 1. Preparation of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxonirazin-1(2H)-yl)nropyl)-2fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (249a).

To a solution of pyrazin-2-ol (431 mg, 4.40 mmol) in THF (10 ml) was added LiHMDS (4.40 ml, 4.40 mmol, 1 M in THF), stirred at room temperature for 0.5 h and concentrated to dryness in vacuo. A solution of N-(5-(1-chloro-3-cyclopropylpropyl)-2-fluorophenyl)-1(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (248h) (0 .88 mmol) in DMF (18 ml) and heated at 70°C for 14 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2x75 ml), brine (75 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate (1:0 to 1:1)] to give 1-(3-cyanophenyl)-N-(5-(3-cyclopronyl-1-( 2oxopyrazin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-carboxamide (249a) (141 mg, 0.256 mmol, 29.1%) as an off-white solid substances; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.62 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.02 (d, J=1.1 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.90 (dd, J=8.9, 1.8 Hz, 1H), 7.77 (dd,

- 391 045731

J=4.6, 1.2 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.55 (d, J=6.8 Hz, 1H), 7.40 - 7.27 (m, 3H), 5.88 (t, J=8.0 Hz, 1H), 2.352.15 (m, 2H), 1.15-0.96 (m, 2H), 0.75-0, 60 (m, 1H), 0.44 - 0.25 (m, 2H), 0.05 - -0.17 (m, 2H); ¹⁹ F NMR (282

MHz, DMSO-d ₆ ) δ -60.79, -120.66; MS (IER+) 551.4 (M+1); 573.4 (M+Na).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl )-III-pyrazole-5-carboxamide (249b).

Compound 249b was prepared from 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-III -pyrazole-5-carboxamide (249a) (124 mg, 0.225 mmol) according to the preparation of compound 89f described in step 6 of scheme 89, after purification by flash column chromatography [silica gel, eluted with mixtures of chloroform/methanol (1:0 to 9:1)] gave free base 249b (20 mg, 0.036 mmol, 16.01%) as a brown solid. The free base was dissolved in methanol (5 ml), 4N was added. HCl (aq, 0.050 ml) and concentrated in vacuo to give 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2oxopyrazin-1(2H)-yl)propyl) hydrochloride -2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (249b) (21 mg, 92.19%) as an off-white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.72 (s, 1H), 8.41 (s, 3H), 8.02 (d, J=1.1 Hz, 1H), 7.79 ( dd, J=4.5, 1.2 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.68 (s, 1H), 7.65- 7.48 (m , 4H), 7.40 - 7.28 (m, 3H), 5.88 (dd, J=9.1, 7.0 Hz, 1H), 4.12 (q, J=5.8 Hz, 2H), 2.37 - 2.13 (m, 2H), 1.21 - 0.96 (m, 2H), 0.78 - 0.60 (m, 1H), 0.45 - 0.27 ( m, 2H), 0.02 - -0.07 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.84, -121.00; MS (IER+) 555.4 (M+1), (IER-) 553.4 (M-1).

Scheme 250

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- carboxamide (250c).

Step 1. Preparation of N-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (250a).

To a solution of triphenylphosphine (0.833 g, 3.18 mmol) in dichloromethane (30 ml) at 0°C, bromine (0.131 ml, 2.54 mmol) was added over 2 min. A previously prepared solution of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole was added dropwise to the reaction mixture at 0°C -5-carboxamide (0.6 g, 1.270 mmol) and imidazole (0.216 g, 3.18 mmol) in dichloromethane (30 ml). The reaction mixture was stirred at 0°C for 15 min, allowed to warm to room temperature for 1 hour and diluted with dichloromethane (100 ml). The solution was passed through a silica gel pad, eluting with mixtures of ethyl acetate in hexanes (20 to 30%), to give N-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenyl)-1-(3-cyanophenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (250a) (680 mg, 1.270 mmol, 100% yield) as a colorless semi-solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.15 (t, J=1.9 Hz, 1H), 8.01 (dt, J=7.7, 1 ,4 Hz, 1H), 7.92 (dt, J=8.5, 1.3 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.71 - 7.66 (m, 1H), 7.41 (m, 1H), 7.31 (m, 1H), 5.32 (t, J=7.5 Hz, 1H), 2.39 - 2.09 (m, 2H), 1.37 - 1.20 (m, 2H), 0.70 (m, 1H), 0.38 (m, 2H), 0.03 - -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.97, -119.88, -122.84.

Step 2. Preparation of 1-(3-cyanophenyl)-K-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5 -carboxamide (250b).

To a solution of pyridin-2-ol (604 mg, 6.35 mmol) in acetonitrile (25 ml) was added potassium carbonate (913 mg, 6.60 mmol) and heated to reflux temperature for 1 hour. The reaction mixture was cooled to room temperature temperature and added a solution of N-(5-(1-bromo-3-cyclopropylpropyl)2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (250a) (680 mg , 1.27 mmol) in acetonitrile (15 ml) and heated at 70°C for 8 hours. The reaction mixture was suspended in water (50 ml) and extracted with ethyl acetate (3x100 ml). Combine the layers in ethyl acetate, wash with water (2x25 ml), brine (25 ml), dry, filter and concentrate in vacuo. The resulting crude residue was purified by flash column chromatography [silica gel, 12 g, eluted with 9:1 mixtures of ethyl acetate and methanol in hexanes (0 to 60%)] to give 1-(3-cyanophenyl)N- (5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (250b) (151 mg, 0.275 mmol, yield 21 .64%) in the form of a thick liquid; 1H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 8.13 (s, 1H), 8.05 (ddd, J=5.0, 2.0, 0.8 Hz, 1H) , 8.00 (dt, J=7.7, 1.3 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.69 - 7.64 (m, 1H), 7.57 (d, J=7.0 Hz, 1H), 7.38 - 7.18 (m, 2H), 6.91 (ddd, J= 7.1, 5.1, 0.9 Hz, 1H), 6.84 (dd, J=8.3, 1.0 Hz, 1H), 6.06 (dd, J=8.0, 5, 3 Hz, 1H), 1.99 (s, 1H), 1.87 (s, 1H), 1.34 - 1.20 (m, 2H), 0.66 (s, 1H), 0.36 ( m, 2H), -0.01 - -0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.94, 120.42 - -124.83.

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (250c).

Into a solution of 1-(3-cyanophenyl)-N-(5-(3-cyclopropyl-1-(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 250b) (145 mg, 0.264 mmol) in methanol (5 ml), cooled in ice/water, nickel (II) chloride hexahydrate (16.12 mg, 0.068 mmol) was added portionwise with sodium borohydride (64.4 mg, 1.669 mmol), then stirred at room temperature for 1 hour. The reaction was quenched with N1-(2-aminoethyl)ethane-1,2-diamine (0.064 ml, 0.609 mmol) and the mixture was stirred at room temperature for 0.5 hour The reaction mixture was concentrated in vacuo to remove methanol. The mixture was suspended in water (20 ml). The resulting solid was collected by filtration and purified by flash column chromatography (silica gel, 4 g, eluted with mixtures of CMA 80 in chloroform, 0 to 100%) to give 1-(3-(aminomethyl)phenyl)-N-(5- (3-cyclopropyl-1(pyridin-2-yloxy)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (250c) (61 mg, 0.110 mmol, 41.8% yield ) as a light yellow solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.56 (s, 1H), 8.14 - 8.00 (m, 1H), 7.72 - 7.64 (m, 1H), 7.62 (d, J=7.1 Hz, 1H), 7.55 (d, J=17.3 Hz, 2H), 7.48 7.37 (m, 2H), 7.33 (d, J=7 ,1 Hz, 1H), 7.30 - 7.16 (m, 2H), 6.91 (ddd, J=7.2, 5.0, 0.9 Hz, 1H), 6.84 (dd, J=8.3, 0.9 Hz, 1H), 6.05 (dd, J=8.2, 5.4 Hz, 1H), 3.78 (s, 2H), 1.98 (m, 1H ), 1.86 (m, 1H), 1.25 (m, 2H), 0.79 - 0.56 (m, 1H), 0.41 - 0.24 (m, 2H), -0.02 - -0.08 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73, -123.02; MS (IER+) 554.3 (M+1), (IER-) 552.3 (M-1).

Scheme 251

1-(3 -(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1 -(4-methyl-1,4-diazepane-1 Example of preparation of yl)propyl)-2-fluorophenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (251 e).

Step 1. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (251a) .

A solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (4.42 g, 11.47 mmol) in DMF (25 ml) 1-(3-amino-4-fluorophenyl)-3cyclopropylpropan-1-ol (248f (2 g, 9.56 mmol), N-ethyl-N-isopropylpropan-2-amine (8.32 ml, 47 .8 mmol) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP) (4.92 g, 10.51 mmol) at room temperature. The reaction mixture was stirred at room temperature for 48 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 ml ), washed with water (2x75 ml), brine (75 ml), dried, filtered and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give tert-butyl 3-(5-(5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (251a) (4.04 g, 7.01 mmol, 73.3% yield as white foam; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.56 (s, 1H), 7.60 (s, 1H), 7.51 ( dd, J=14.3, 7.0 Hz, 2H), 7.46 - 7.32 (m, 4H), 7.23 - 7.16 (m, 2H), 5.21 (d, J= 4.4 Hz, 1H), 4.51 (q, J=5.8 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.71-1.53 (m, 2H), 1.38 (s, 9H), 1.34 - 1.07 (m, 2H), 0.74 - 0.56 (m, 1H), 0.43 - 0.24 (m, 2H) , 0.03 - -0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.80, -124.41; MS (ESI+) 599.3 (M+Na); (IER-) 575.2 (M-1).

- 393 045731

Step 2. Preparation of tert-butyl-3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate (251b).

Into a cooled (ice-water bath) solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-hydroxypropyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1-yl)benzylcarbamate ( 251a) (2.04 g, 3.54 mmol) in THF (20 ml) was added PBr ₃ (0.112 ml, 1.185 mmol). The resulting mixture was stirred for 40 min at 0°C and the reaction was quenched with water (50 ml). The reaction mixture was extracted with ethyl acetate (2x25 ml). Combine the organic layers, wash with water and brine (50 mL), dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give tert-butyl-3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl )-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (251b) (1.4 g, 2.189 mmol, 61.9% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.61 (s, 1H), 7.53 - 7.47 (m, 1H), 7.46 7.36 (m, 5H), 7.28 (d, J=9.0 Hz, 1H), 5.32 (t, J=7.5 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.37 - 2.07 (m, 2H), 1.37 (s, 9H), 1.34 - 1.16 (m , 2H), 0.79 - 0.57 (m, 1H), 0.47 - 0.29 (m, 2H), 0.07 - -0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.82, -121.25; MS (ESI+) 661.2, 663.2 (M+Na).

Step 3. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzylcarbamate (251d).

In a solution of tert-butyl 3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (251b) (200 mg , 0.313 mmol) and N-methylhomopiperazine (251c) (143 mg, 1.251 mmol) in N,N-dimethylformamide (2 ml) was added K2CO3 (173 mg, 1.251 mmol). The reaction mixture was stirred at room temperature for 12 hours, quenched with water (10 ml) and extracted with EtOAc (3x50 ml). Combine the organic layers, wash with water (50 ml), brine (25 ml), dry over MgSO ₄ , filter and concentrate. The residue was purified by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-90% EtOAc in hexanes, then 0-40% CMA 80 in CHCl ₃ ) to give tert-butyl-3-(5-(5-(3 -cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (251d) (160 mg, 0.238 mmol , yield 76%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.56 (s, 1H), 7.60 (s, 1H), 7.54 - 7.29 (m, 6H), 7.26 - 7.10 (m, 2H), 4.19 (d, J=6.3 Hz, 2H), 3.34 (s, 2H), 2.69 - 2.53 (m, 4H), 2.46 - 2, 31 (m, 2H), 2.19 (s, 3H), 1.98 - 1.80 (m, 1H), 1.71-1.53 (m, 2H), 1.38 (s, 9H) , 1.31 - 1.16 (m, 2H), 1.19 - 0.97 (m, 2H), 0.88 - 0.76 (m, 1H), 0.40 - 0.29 (m, 2H), -0.01 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.80, 124.05.

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1yl)propyl)-2-fluorophenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (251e).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzylcarbamate (251d) (156 mg, 0.232 mmol) in MeOH (3 mL), add HCl (3N in MeOH, 1.546 mL, 4.64 mmol), stir at room temperature overnight and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-80% CMA 80 in CHCl ₃ ), then by reverse phase column chromatography (C ₁₈ column, eluted with mixtures of 0-50% MeOH in H2O) to give the free base 251e (110 mg, 0.192 mmol, 83% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.58 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.49 - 7.40 (m, 3H ), 7.41 - 7.32 (m, 2H), 7.27 - 7.09 (m, 2H), 3.82 (s, 2H), 3.59 (t, J=7.2 Hz, 1H), 3.33 - 3.03 (m, 2H), 2.68 - 2.54 (m, 3H), 2.18 (s, 3H), 1.95 - 1.81 (m, 1H) , 1.76 - 1.47 (m, 4H), 1.33 - 0.92 (m, 5H), 0.70 - 0.57 (m, 1H), 0.41 - 0.22 (m, 2H), -0.01 - 0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.75, -124.00.

To a solution of free base 251e (89 mg, 0.155 mmol) in MeOH (10 mL) was added HCl (3N in MeOH, 0.389 mL, 1.554 mmol), stirred at room temperature for 2 h and concentrated in vacuo. The residue was dissolved in H2O/ACN (10 ml, 9.5:0.5, v/v) and lyophilized to give 1 -(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl) hydrochloride -1-(4-methyl-1,4-diazepan-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (251e) (72 mg, 0.126 mmol, yield 81%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 12.30 - 11.90 (m, 1H), 11.68 - 11.29 (m, 1H), 11.07 - 10.81 (m, 1H) , 8.58 (s, 3H), 7.88 (t, J=6.8 Hz, 1H), 7.82 - 7.70 (m, 3H), 7.69 - 7.50 (m, 4H ), 7.52 - 7.36 (m, 1H), 4.54 (s, 1H), 4.12 (d, J=5.3 Hz, 2H), 3.97 - 3.48 (m, 4H), 3.47 - 3.20 (m, 3H), 2.82 - 2.62 (m, 3H), 2.45 - 2.04 (m, 3H), 1.09 - 0.89 ( m, 1H), 0.81 - 0.51 (m, 2H), 0.38-0.27 (m, 2H), -0.04-0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.81, -119.00; MS (IER+): MS (IER+) 573.3 (M+1).

- 394 045731

Scheme 252

An example of the preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-phenylprop-1-enyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (252c).

Step 1. Preparation of tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (252a).

Into a stirred solution of tert-butyl-3-(5-(5-((-)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-1H-nirazol-1-yl)benzylcarbamate (211c) (1.603 g, 2.118 mmol) in methanol (18 ml), cooled to 0°C, added 4N. hydrochloric acid in dioxane (1.6 ml, 6.40 mmol) and stirred at 0°C for 2.5 hours. The reaction was quenched with triethylamine (1.100 ml, 7.89 mmol) and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography [silica gel, eluted with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] to give tert-butyl-3-(5-(5-(1-amino- 3-cyclopropyl-1-phenylpropyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (252a) (658 mg, 47.6%) as a white solid; 1H NMR (300 MHz, DMSO) δ 10.52 (s, 1H), 7.62 - 7.07 (m, 12H), 4.19 (d, J=6.2 Hz, 2H), 2.31 - 2.07 (m, 4H), 1.38 (s, 9H), 1.11 - 0.90 (m, 2H), 0.91 - 0.74 (m, 1H), 0.71 - 0 .53 (m, 1H), 0.40 0.26 (m, 2H), -0.05- -0.16 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d^) δ -60.79, -123.62; MS (IER+) 652.4 (M+1), (IER-) 650.4 (M-1).

Step 2. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-phenylpropyl)2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzylcarbamate (252b).

In a solution of tert-butyl-3-(5-(5-(1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (252a) (145 mg, 0.222 mmol) in dichloromethane (10 ml) and pyridine (70.4 mg, 0.890 mmol) was added methanesulfonic acid anhydride (78 mg, 0.445 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature overnight. Additional amounts of DIPEA (0.078 ml, 0.445 mmol) and methanesulfonic acid anhydride (78 mg, 0.445 mmol) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), extracted with dichloromethane (3x10 ml). Combine the organic layers, dry over MgSO4, filter and concentrate. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with EtOAc/hexane, 0-50%) to give tert-butyl-3(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-phenylpropyl )-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (252b) (86 mg) as a white solid; MS (IER+) 752.4 (M+23), (IER-) 728.5 (M-1).

Step 3. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-phenylnpon-1-enyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-πyrazole-5 -carboxamide (252c).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-phenylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (252b) (86 mg, 0.118 mmol) in methanol (20 mL) was added with HCl (3N anhydrous in MeOH, 2 mL) and heated at reflux temperature for 30 min. Concentrate the reaction mixture in vacuo and purify the resulting residue by flash column chromatography (silica gel, 12 g, eluted with mixtures of CHCl ₃ in CMA-80, 060%) to give free base 252c (40 mg) as a white solid. The free base was dissolved in methanol (10 ml) and HCl (3N anhydrous in MeOH, 2 ml) was added at room temperature. Concentrate the solution to dryness in vacuo and dissolve the residue in water (2 ml) and two drops of acetonitrile, lyophilize to obtain the hydrochloride salt of 1-(3-(aminomethyl)phenyl)-N-(5(3-cyclopropyl-1-phenylprop-1- enyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (252c) (42 mg, 0.079 mmol, 35.3% yield over 2 steps) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.68 (2s, 1H), 8.38 (br.e, 3H), 7.75-7.64 (m, 2H), 7.66 - 7 .56 (m, 1H), 7.56 - 7.21 (m, 7H), 7.20 - 7.09 (m, 2H), 7.11 - 7.00 (m, 1H), 6.17 (dt, J=15.1, 7.5 Hz, 1H), 3.36 (s, 2H), 1.94 (q, J=7.4 Hz, 2H), 0.87 0.68 (m , 1H), 0.49 - 0.29 (m, 2H), 0.14 - -0.01 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.63, -60.64, -122.32, - 395 045731

122.64, (mixture of E- and Z-); MS (IER+): MS (IER+) 535.4 (M+1); 533,3,4 (M-1); analysis, calculation for

C30H26F4N4O-HC1-H2O: C; 61.17, H; 4.96, N; 9.51; experiment: C; 61.39, H; 5.02, N; 9.52.

Scheme 253

An example of the preparation of (+)-N-(5-( 1 -amino-3-cyclopropyl-1 -(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1 aminoisoquinolin-7-yl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxamide (253e).

Step 1. Preparation of 7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-amine (253a).

Solution of 2-(2,4-dimethoxybenzyl)-7-(5-(furan-2-yl)-3-(trifluoromethyl)-III-pyrazol-1-yl)isoquinolin-1(2H)-imine (235f) ( 2.88 g, 5.82 mmol) in TFA (10 ml) and anisole (5 ml) were heated at 90°C for 19 hours, cooled to room temperature and concentrated in vacuo. The residue was taken up twice in MeOH (50 ml) and evaporated. The residue was adjusted to pH 8.0 with saturated aqueous NaHCO3, diluted with water (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and evaporated to dryness. The resulting residue was purified by flash column chromatography [silica gel, 40 g, eluted with ethyl acetate/methanol in hexanes, 0-100%] to give 7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)isoquinolin-1-amine (253a) (0.994 g, 49% yield) as a pale yellow solid; ¹ H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=2.1 Hz, 1H), 7.97 - 7.83 (m, 2H), 7.79 - 7.72 (m , 1H), 7.67 (dd, J=8.7, 2.0 Hz, 1H), 7.34 (s, 1H), 7.03 (d, J=5.8 Hz, 1H), 6 .98 (s, 2H, exchange with D2O), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 6.20 (dd, J=3.6, 0.8 Hz, 1H ); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.73; MS (IER ^- ): MS (IER+) 345.2 (M+1); MS (ESI-) 379.2 (M+Cl).

Step 2. Preparation of di-tert-butyl-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-yliminodicarbonate (253b).

A solution of 7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-amine (253a) (12.177 g, 35.4 mmol) in acetonitrile (150 ml) DIPEA (14.83 ml, 85 mmol), (Boc) _2O (61.6 ml, 265 mmol) and DMAP (1.080 g, 8.84 mmol) were added. The mixture was heated at 50°C overnight, cooled to room temperature and concentrated in vacuo. The residue was treated with saline/water (100 ml/400 ml) and extracted with ethyl acetate (2x750 ml). The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-80%) to give di-tert-butyl-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole -1-yl)isoquinolin-1-yliminodicarbonate (253b) (13.621 g, 71% yield) as a brown solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.56 (d, J=5.7 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.10 - 7, 99 (m, 2H), 7.91 (dd, J=8.8, 2.1 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.37 (s, 1H ), 6.54 (dd, J=3.5, 1.8 Hz, 1H), 6.39 (d, J=3.5 Hz, 1H), 1.27 (s, 18H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.99. MS (ESI ⁺ ): MS (ESI ⁺ ): 567.2 (M+Na).

Step 3. Preparation of 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (253c) and 1-(1-(tert- butoxycarbonylamino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253f).

In a solution of di-tert-butyl-7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinoline-1-yliminodicarbonate (253b) (5.70 g, 10.47 mmol) in t-BuOH (220 ml) was added 5% aq. Sodium dihydrogen phosphate (2.387 g, 19.90 mmol) in water (50 ml), then potassium permanganate (3.31 g, 20.94 mmol). The reaction mixture was stirred at room temperature for 13 hours, quenched with 2-propanol (350 ml) and stirred at room temperature overnight. The reaction mixture was filtered through Celite and washed with 2-propanol. The filtrate was evaporated to dryness and purified by flash column chromatography (silica gel, 80 g, eluted with mixtures of CMA 80 in chloroform, 0-100%) to give compounds 253c and 253f. Each compound was individually acidified with 1N. KHSO4 (10 ml), extracted with ethyl acetate (2x30 ml), dried over anhydrous MgSO ₄ , filtered, concentrated in vacuo and dried over P ₂ O ₅ to obtain:

1. 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazol-5-carbo-

- 396 045731 new acid (253 c) (1.161 g, 2.222 mmol, 21% yield) as a yellow solid; 1H NMR (300

MHz, DMSO-de) δ 8.53 (d, J=5.7 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 8.09 - 7.97 (m, 3H ), 7.59 (s, 1H), 1.29 (s,

18H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.97; MS (IER ⁺ ): MS (IER+) 545.3 (M+Na); MC (IER-) 521.3 (M-1);

2. 1-(1-(tert-butoxycarbonylamino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253f) (0.481 g, 11% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-de) δ 8.36 (t, J=2.8 Hz, 1H), 8.29 (d, J=3.5 Hz, 1H), 8.10 (dd, J =8.8, 4.3 Hz, 1H), 7.99 (dd, J=8.5, 2.1 Hz, 1H), 7.76 7.66 (m, 1H), 7.60 (s , 1H), 1.46 (d, J=1.7 Hz, 9H); MS (IER-) 421.2 (M-1), 843.2 (2M-1).

Step 4. Preparation of di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)1 -(pyridin-4-yl)propyl)-2- fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)isoquinoline-1 ylcarbamate (253d).

Compound 253 d was prepared from 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253c) (0.261 g, 0.500 mmol) and (R)-N-((-)-1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (216b) (0.234 g, 0.599 mmol) according to the method for preparing compound 208c described in step 3 of scheme 208, after workup, crude compound 253 d was obtained, which was used as such in the next step; MS (IER ⁺ ): MS (IER+) 916.6 (M+Na); MS (IER-) 892.6 (M-1).

Step 5. Preparation of (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1(1-aminoisoquinolin-7-yl)- 3 -(trifluoromethyl)-1 H-pyrazole-5-carboxamide (253e).

Into a stirred solution of di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate (253d) (0.671 g, 0.751 mmol) in methanol (10 ml) added 3M HCl (in MeOH, 3.75 ml) and heated at reverse condensation temperature for 1 hour. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in water (25 ml), washed with MTBE (2x50 ml), the aqueous layer was basified with 1N. NaOH and extracted with ethyl acetate (2x50 ml). Combine the layers in ethyl acetate, dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The resulting residue was purified by flash chromatography [silica gel, 12 g (4 separate columns), eluted with mixtures of CMA 80 in chloroform, 0-50%] to give free base 253e (9 mg, 2% yield) as a light brown solid ; 1H NMR (300 MHz, DMSO-d _e ) δ 10.50 (s, 1H, exchange with D ₂ O), 8.50 8.34 (m, 3H), 7.88 (d, J=5.8 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.55 (dd, J=7.4, 2.4 Hz , 1H), 7.39 -7.32 (m, 2H), 7.28 (ddd, J=8.7, 4.8, 2.3 Hz, 1H), 7.16 (dd, J=10 ,1, 8.7 Hz, 1H), 7.03 - 6.90 (m, 3H, exchange with D ₂ O, 2H), 2.32 (s, 2H), 2.19 (m, 2H), 1.02 (m, 2H), 0.61 (m, 1H), 0.39 - 0.19 (m, 2H), -0.11 (m, 2H); 1H NMR (300 MHz, DMSO-d6, D2O) δ 8.38 (td, J=5.6, 5.1, 1.8 Hz, 3H), 7.90 - 7.75 (m, 2H), 7.71 - 7.59 (m, 2H), 7.49 (dd, J=7.2, 2.2 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.25 ( ddd, J=9.0, 4.8, 2.4 Hz, 1H), 7.14 (t, J=9.4 Hz, 1H), 7.00 (d, J=5.8 Hz, 1H ), 2.26 - 2.07 (m, 2H), 0.97 (m, 2H), 0.57 (m, 1H), 0.41 - 0.14 (m, 2H), -0.15 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d _e ) δ -60.71, -123.61; MS (IER ⁺ ): MS (IER+): MS (IER+) 590.4 (M+1); (IER-) 588.4 (M-1).

Compound 253e was treated with 3H. a solution of HCl in methanol, which after evaporation and lyophilization led to the production of the hydrochloride salt of (+)-A5-(1-amino-3-cyclopropyl-1-(pyridin-4yl)propyl)-2-fluorophenyl)-1-(1- aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (253e) as a white solid; 1H NMR (300 MHz, DMSO-d _e ) δ 13.74 (s, 1H, exchange with _D2O ), 11.02 (s, 1H, exchange with D2O), 9.80 (s, 3H, exchange with D2O), 9.42 (s, 3H, exchange with D2O), 8.95 (s, 1H), 8.87 (m, 2H), 8.13 (d, J=1.8 Hz, 2H), 7.85 (d, J=7.0 Hz, 1H), 7.72 (m, 3H), 7.46 (d, J=7.8 Hz, 2H), 7.37 (d, J=7 .0 Hz, 1H), 2.60 (m, 2H), 1.17 (m, 2H), 0.69 (m, 1H), 0.34 (m, 2H), -0.00 (m, 2H); 1H NMR (300 MHz, DMSO/E> ₂ O^) δ 8.91 (s, 1H), 8.87 - 8.80 (m, 2H), 8.15 (d, J=1.5 Hz, 2H), 7.89 (s, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.66 (m, 3H), 7.49 (t, J=9.4 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.35 (m, 1H), 2.56 (m, 2H), 1.14 (m, 2H), 0.73 ( m, 1H), 0.38 (m, 2H), 0.12 - -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d _e ) δ -60.89, -119.82; analysis, calculation for C ₃ iH ₂₇ F4N7O-3HCl-3.5H ₂ O: C, 48.86; H, 4.89; Cl, 13.96; N, 12.87; experiment; C, 48.62; H, 4.90; Cl, 14.37; N, 12.97; optical rotation: [a] _D =(+) 19.31 [0.29, MeOH].

Scheme 254

An example of the preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1aminoisoquinolin-7-yl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (254c).

Step 1. Preparation of 1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (254a).

Compound 254a was prepared from 7-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)isoquinolin-1amine (253a) (0.275 g, 0.799 mmol) according to the method for preparation of compound 9i, described in step 2 of Scheme 10 gave 1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (254a) (0.077 g, 0.239 mmol, 29.9% yield) as a white solid; MS (IER+) 323.2 (M+1), 321.1 (M-1).

Step 2. Preparation of 1-(1-aminoisoquinolin-7-yl)-N-(5-(1-(4-cyanophenyl)-3-cyclopropyl-1-((R)1,1-dimethylethylsulfinamido)propyl)-2 -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (254b).

Compound 254b was prepared from 1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (254a) [322 mg, 0.999 mmol, which was converted to HCl salt using HCl (3N in MeOH, 3 ml) and concentrated to dryness in vacuo before use] and (R)-N-((-)-1-(3-amino-4fluorophenyl)-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2- Methylpropane-2-sulfinamide (212e) (248 mg, 0.600 mmol) according to the preparation of compound 237a described in Scheme 237, after workup, crude compound 254b was obtained, which was used as such in the next step.

Step 3. Preparation of (+)-N-(5-(1-amino-1-(4-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1(1-aminoisoquinolin-7-yl)-3 -( trifluoromethyl)-1 H-pyrazole-5-carboxamide (254c).

Into a solution of the crude residue obtained above containing 1-(1-aminoisoquinolin-7-yl)-N(5-(1 -(4-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido) propyl)-2-fluorophenyl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (254b), HCl (4N in dioxane, 2 ml) was added to dioxane (5 ml) and heated to reflux temperature for 15 min. Concentrate the solution in vacuo and place the residue in water, washing with EtOAc (50 ml) to remove organic impurities. The aqueous layer was made basic with NaOH (1N) and extracted with EtOAc (2x50 ml). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% CMA-80 in chloroform) to give the free base (+)-N-(5-(1-amino-1-(4-cyanophenyl )-3-cyclopropylpropyl)-2fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (254c) (17 mg, 0.028 mmol, yield 2.77 %) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.45-8.38 (m, 1H), 7.88 (d, J=5.8 Hz, 1H), 7.81 - 7.69 (m, 4H), 7.66 (dd, J=8.7, 2.0 Hz, 1H), 7.59 - 7.48 (m, 3H), 7.30 - 7.13 (m, 2H), 7.03 - 6.93 (m, 3H), 2.31 - 2.17 (m, 2H), 1.13 - 0.79 (m, 2H), 0. 74 - 0.51 (m, 1H), 0.42 - 0.23 (m, 2H), -0.01 - -0.24 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.74, -123.59; ICS (KBr) 2230 cm ^-1 ; optical rotation: [a] _D =(+) 11.61 (0.155, methanol).

Scheme 255

An example of the preparation of (+)-N-(5-( 1 -amino-3-cyclopropyl-1 -phenylpropyl)-2-fluorophenyl)-1-(1 -aminoisoquinolin-7 -yl)-3 -(trifluoromethyl)-1 H -pyrazole-5-carboxamide (255a).

To a solution of 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole5-carboxylic acid (253c) (60 mg, 0.115 mmol) in DMF (5 ml ) (R)-N-((-)-1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-phenylpropyl)-2-methylpropane-2-sulfinamide (211b) (53.5 mg, 0.138 mmol) was added ), N-ethyl-N-isopropylpropan-2-amine (30.1 μL, 0.172 mmol) and bromo-trispyrrolidinophosphonium hexafluorophosphate (PyBrop, 64.2 mg, 0.138 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours and diluted with ethyl acetate (100 ml), washed with water (2x50 ml), brine (50 ml), dried, filtered and concentrated to dryness in vacuo to obtain a crude residue. The residue was dissolved in anhydrous dioxane (5 ml), HCl (4N in dioxane, 2 ml) was added and heated at 60°C for 50 minutes. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in water, washed with EtOAc (50 ml). The aqueous layer was made basic with NaOH (1N) and extracted with EtOAc (2x50 ml). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% CMA-80 in chloroform) to give free base 255a, which was converted to the HCl salt to give (+)-N-(5-) hydrochloride salt (1-amino-3-cyclopropyl-1-phenylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3 (trifluoromethyl)-1H-pyrazole-5-carboxamide (255a) (22 mg, 0.037 mmol, yield 32.5%) as a white solid; 1H NMR (300 MHz, DMSO^) δ 10.84 (s, 1H), 9.22 (s, 4H), 8.86 (s, 1H), 8.07 (s, 2H),

- 398 045731

7.87 (s, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.53 (dd, J=7.0, 2.0 Hz, 2H), 7.49 - 7 .22 (m, 8H), 2.44 (d, J=8.3 Hz, 2H),

1.17 - 1.00 (m, 2H), 0.72 - 0.53 (m, 1H), 0.38 -0.23 (m, 2H), -0.03 - -0.09 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.70, -120.69; MS (IER+): MS (IER+) 589.4 (M+1); 587.4 (M-1); optical rotation: [a]D=(+) 8.42 (0.285, methanol); analysis, calculation for: C ₃₂ H ₂₈ F ₄ N ₆ O-2HCl-3H ₂ O; C, 53.71; H, 5.07; N, 11.74; experiment: C,

53.63; H, 4.98; N, 11.65.

Scheme 256

An example of the preparation of (+)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1 aminoisoquinolin-7-yl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (256a).

To a solution of 1-(1-(bis(tert-butoxycarbonyl)αmino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole5-carboxylic acid (253c) (40 mg, 0.077 mmol) in DMF (5 ml ) added (R)-N-((-)-1-(3-amino-4fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (214e) (31.7 mg, 0.077 mmol), N-ethyl-N-isopropylpropan-2-αmin (13.37 µl, 0.077 mmol) and bromotris-pyrrolidinophosphonium hexafluorophosphate (PyBrop, 35.7 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours, diluted with ethyl acetate (100 ml), washed with water (2x50 ml), brine (50 ml), dried, filtered and concentrated to dryness in vacuo to give a crude residue. The residue was dissolved in anhydrous dioxane (5 ml), HCl (4N in dioxane, 2 ml) was added and heated at 60°C for 50 min. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% CMA-80 in chloroform) to give free base 256a, which was converted to the HCl salt to give (+)N-(5-(1) hydrochloride -amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1-(1-aminoisoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamideα (256a) (7 mg, 0.011 mmol, yield 14.90%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 13.37 (s, 1H), 10.81 (s, 1H), 9.36 (s, 3H), 9.16 (s, 3H), 8. 83 (d, J=1.5 Hz, 1H), 8.07 (d, J=1.2 Hz, 2H), 7.92 - 7.81 (m, 3H), 7.79 (d, J =6.9 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.56 - 7.51 (m, 1H), 7.42 (dd, J=10.0, 8.7 Hz, 1H), 7.31 (dd, J=7.4, 4.0 Hz, 2H), 2.61 - 2.38 (m, 2H), 1.07 (m, 2H), 0.65 (m, 1H), 0.31 (m, 2H), -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.69, -120.30; MS (IER+): MS (IER+) 614.4 (M+1); 612.4 (M-1); optical rotation: [a] _D =(+) 15.38 (0.13, methanol).

Scheme 257

An example of the preparation of (+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (257b).

Step 1. Preparation of di-tert-butyl-(7-(5-((5-((3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2fluorophenyl)carbαmoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)isoquinolin-1-yl)carbamate (257a).

Compound 257a was prepared from 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3-(trifluoromethyl)-1P-pyrazole-5-carboxylic acid (253c) (0.839 g, 1.60 mmol ) and (+)-3-((3-amino-4-fluorophenyl)(cyclopropylmethylamino)methyl)benzonitrile (236f (0.569 g, 1.927 mmol) according to the method for preparation of compound 208c described in step 3 of scheme 208, after workup obtained the crude compound 257a, which was used as such in the next step; MS (ESI+) 800.4 (M+1), 822.4 (M+Na); MS (ESI-) 798.4 (M-1).

Step 2. Preparation of (+)-1-(1-aminoisoquinolin-7-yl)-X-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrαzole-5-carboxamide (257b).

Into a stirred solution of di-tert-butyl-(7-(5-((5-((3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)carbamoyl)-3 -(trifluoromethyl)-1 H- pyrazol-1-yl)isoquinolin-1-yl)carbamate (257a) (2.58 g, 3.23 mmol) in dioxane (30 ml) was added 4M HCl (in dioxane) (4.84 ml, 19.35 mmol ) and heated at the reverse condensation temperature for 1 hour. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in water (10 ml), washed with MTBE (2x50 ml),

- 399 045731 the aqueous layer was made alkaline with 1N. NaOH and extracted with ethyl acetate (2x50 ml). Combine the layers in ethyl acetate, dry over anhydrous MgSO ₄ , filter and evaporate to dryness. The residue was purified by flash chromatography [first column: silica gel, 24 g, eluted with mixtures of ethyl acetate/methanol (9:1) in hexanes, 0-100%, second column: silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100% 100%, third column: silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-40%] to give free base 257b (0.10 g, 0.167 mmol, 5.17% yield) as a white solid; 1H NMR (300 MHz, DMSO-dg) δ 10.52 (s, 1H, exchange with D2O), 8.42 (d, J=2.0 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.79 (d, J=8.7 Hz, 1H), 7.75-7.63 (m, 4H), 7.59 (dd, J=7.5, 2.2 Hz, 1H ), 7.49 (t, J=7.7 Hz, 1H), 7.34 (m, 1H), 7.21 (dd, J=10.3, 8.6 Hz, 1H), 6.98 (m, 3H, exchange with D ₂ O, 2H), 4.91 (s, 1H), 2.69 (br.s, 1H), 2.24 (m, 2H), 0.88 (m, 1H ), 0.52 0.23 (m, 2H), 0.09 - -0.06 (m, 2H); 1H NMR (300 MHz, DMSO-d6 D2O) δ 8.41 (d, J=2.0 Hz, 1H), 7.92 - 7.80 (m, 3H), 7.69 (m, 4H), 7.62 - 7.56 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.35 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 7.21 (dd, J=10.2, 8.6 Hz, 1H), 7.10 - 7.00 (m, 1H), 4.92 (s, 1H), 2.24 (m , 2H), 0.89 (m, 1H), 0.49 -0.27 (m, 2H), 0.05-0.02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.73, -122.79; MS (IER+): MS (IER+) 600.3 (M+1); MS (IER-) 598.3 (M-1).

To a stirred solution of free base 257b (0.093 g, 0.155 mmol) in methanol (10 ml) was added HCl (3 M in methanol) (0.517 ml, 1.551 mmol), stirred at room temperature for 1 h, evaporated to dryness, triturated with MTBE ( 50 ml), filtered, washed with MTBE and dried. The residue was dissolved in water, filtered, lyophilized to dryness to obtain the hydrochloride salt of (+)-1-(1-aminoisoquinolin-7-yl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl) -3(trifluoromethyl)-1H-pyrazole-5-carboxamide (257b) (0.070 g, 0.117 mmol, 75% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.84 (s, 1H, exchange with D2O), 10.24 (s, 2H, exchange with D2O), 9.09 (s, 2H, exchange with D2O) , 8.83 (s, 1H), 8.22 (s, 1H), 8.07 (s, 2H), 8.01 (d, J=7.9 Hz, 1H), 7.92 (dd, J=7.2, 2.3 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.80 (d, J=6.9 Hz, 1H), 7.67 (q, J =7.4 Hz, 2H), 7.42 (dd, J=10.2, 8.6 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H), 5.74 (s , 1H), 2.70 (m, 2H), 1.13 (d, J=11.9 Hz, 1H), 0.63 - 0.47 (m, 2H), 0.29 (h, J= 4.1 Hz, 2H); 1H NMR (300 MHz, DMSO-d ₆ D ₂ O) δ 8.81 (d, J=1.3 Hz, 1H), 8.13 (t, J=1.7 Hz, 1H), 8.07 (d, J=1.4 Hz, 2H), 7.98 - 7.82 (m, 4H), 7.78 (d, J=6.9 Hz, 1H), 7.72 - 7.57 ( m, 2H), 7.50 - 7.39 (m, 1H), 7.31 (d, J=6.9 Hz, 1H), 5.73 (s, 1H), 2.72 (m, 2H ), 1.08 (m, 1H), 0.63 - 0.48 (m, 2H), 0.28 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -60.88, -119.84; MS (IER+): MS (IER+) 600.3 (M+1); MS (ESI-) 598.3 (M-1), 634.2 (M+Cl); optical rotation: (+) 0.73 [0.275, MeOH]; analysis, calculation for C ₃₂ H ₂₅ F ₄ N ₇ O-2HCl-2H ₂ O: C, 54.24; H, 4.41; Cl, 10.01; N, 13.84; experiment: C, 54.37; H, 4.45; Cl, 9.79; N, 13.87.

Scheme 258

An example of the preparation of 1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (258g).

Step 1. Preparation of methyl 5-(3-cyclopropylpropanoyl)-2-fluorophenylcarbamate (258a).

Pyridine (0.121 mL, 1.5 mmol) and methyl chloroformate (0.077 ml, 1 mmol). The reaction mixture was slowly warmed to room temperature overnight and evaporated to dryness. The residue was treated with water (25 ml) and extracted with ethyl acetate (2x50 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness to give methyl 5-(3-cyclopropylpropanoyl)-2-fluorophenylcarbamate (258a) (0.254 g, yield 96%) in the form of a clear oily liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H, exchange with D2O), 8.30 (dd, J=7.9, 2.2 Hz, 1H), 7.85- 7 .72 (m, 1H), 7.37 (dd, J=10.6, 8.6 Hz, 1H), 3.69 (s, 3H), 3.06 (t, J=7.3 Hz, 2H), 1.51 (q, J=7.2 Hz, 2H), 0.85-0.65 (m, 1H), 0.47 - 0.33 (m, 2H), 0.12 - 0 .02 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -117.74; MS (IER+): 266.1 (M+1); MS (IER-) 264.2 (M-1).

Step 2. Preparation of methyl 5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamate (258b).

Compound 258b was prepared from methyl 5-(3-cyclopropylpropanoyl)-2-fluorophenylcarbamate (258a) (2.51 g, 9.46 mmol) according to the method for preparation of compound 248f described in step 5 of scheme 248.

- 400 045731 after purification by flash column chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-50%] gave methyl 5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamate (258b) (2.387 g, yield 94%) in the form of a colorless oily liquid; 1H NMR (300 MHz, DMSO-de) δ 9.32 (s, 1H, exchange with D ₂ O), 7.70 - 7.51 (m, 1H), 7.18 (dd, J=10.6 , 8.4 Hz, 1H), 7.09 (ddd, J=8.4, 4.9, 2.1 Hz, 1H), 5.21 (d, J=4.4 Hz, 1H, exchange with D2O), 4.60 - 4.43 (m, 1H), 3.69 (s, 3H), 1.68 (m, 2H), 1.21 (m, 2H), 0.79 - 0.57 (m, 1H), 0.39 (m, 2H), 0.11 - -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-eb) δ -127.49; MS (ESI+): 290.2 (M+Na); MS (IER-) 266.2 (M-1).

Step 3. Preparation of methyl 5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c).

Compound 258c was prepared from methyl 5-(3-cyclopropyl-1-hydroxypropyl)-2-fluorophenylcarbamate (258b) (2.303 g, 8.62 mmol) according to the method for compound 251b described in step 2 of Scheme 251, after purification by column Flash chromatography [silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-100%] gave methyl 5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c) (1.289 g, 3.90 mmol, yield 45.3%) in the form of a colorless oily liquid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H, exchange with D2O), 7.78 (dd, J=7.7, 2.0 Hz, 1H), 7.36 - 7.11 (m, 2H), 5.29 (dd, J=8.1, 6.9 Hz, 1H), 3.67 (s, 3H), 2.41 - 2.06 (m, 2H) , 1.39 - 1.09 (m, 2H), 0.71 (m, 1H), 0.39 (m, 2H), 0.11 - -0.09 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -124.45; MS (IER-) 328.1 (M-2).

Step 4. Preparation of methyl 5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (258d).

Pyridin-2(1H)-one (0.418 g, 4.40 mmol), cesium carbonate (1.791 g, 5.50 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2x75 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 24 g, eluted with mixtures of ethyl acetate in hexanes, 0-50%] to give methyl 5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)- 2-fluorophenylcarbamate (258d) (0.606 g, 48.0% yield) as a colorless oily liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 9.37 (s, 1H, exchange with D2O), 7.76 - 7.58 (m, 2H), 7.36 (m, 1H), 7.28 - 7.09 (m, 2H), 6.44 - 6.34 (m, 1H), 6.23 (td, J=6.7, 1.5 Hz, 1H), 6.06 (t, J =8.0 Hz, 1H), 3.65 (s, 3H), 2.20 (m, 2H), 1.26 - 0.92 (m, 2H), 0.80 - 0.63 (m, 1H), 0.46 - 0.30 (m, 2H), 0.01 - -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -125.28; MS (ESI+) 367.3 (M+Na); MC (IER-) 343.3 (M-1).

Step 5. Preparation of 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one (258e)

2, 5M NaOH (6.48 ml, 16.20 mmol) and refluxed for 13 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2x50 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 12 g, eluted with mixtures of ethyl acetate in hexanes, 0-25%] to give 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyridine-2(1H )-she (258e) (0.409 g, 88% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO-d6) δ 7.59 (ddd, J=6.9, 2.1, 0.7 Hz, 1H), 7.35 (ddd, J=8.8, 6.5 , 2.0 Hz, 1H), 6.95 (dd, J=11.4, 8.3 Hz, 1H), 6.75 (dd, J=8.8, 2.2 Hz, 1H), 6 .53 (ddd, J=8.4, 4.3, 2.3 Hz, 1H), 6.44 - 6.33 (m, 1H), 6.21 (td, J=6.7, 1, 5 Hz, 1H), 5.99 (dd, J=9.0, 7.0 Hz, 1H), 5.20 (s, 2H), 2.14 (m, 2H), 1.14 - 1, 07 (m, 1H), 1.05-0.92 (m, 1H), 0.70 (m, 1H), 0.47 - 0.30 (m, 2H), 0.00 - -0.10 (m, 2H); MS (ESI+): 309.2 (M+Na), MS (ESI-) 285.2 (M-1), 321.2 (M+Cl).

Step 6. Preparation of di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H -pyrazol-1-yl)isoquinolin-1-ylcarbamate (258f).

Compound 258f was prepared from 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253c) (281 mg, 0.538 mmol) and 1 -(1-(3-amino-4fluorophenyl)-3-cyclopropylpropyl)pyridin-2(1H)-one (258e) (0.154 g, 0.538 mmol) according to the method for preparation of compound 208c described in step 3 of scheme 208, after workup received crude di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazole -1-yl)isoquinolin-1-ylcarbamate (258f) as a brown waxy substance, which was used as such in the next step; MS (IER+): 813.5 (M+1).

Step 7. Preparation of 1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)-2-fluorophenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (258g).

Into a stirred solution of di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)isoquinolin-1-ylcarbamate (258f) (0.801 g, 1.013 mmol) in methanol (10 ml) was added with HCl (3M in methanol) (2.026 ml, 6.08 mmol) and heated at ref. condensation for 1 hour. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by flash chromatography [silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%]. The sample was dissolved in a minimal amount of methanol/1 N mixture. HCl and purified by reverse phase flash chromatography [C18 column, eluted with mixtures of water (0.1% TFA) in methanol, 0-100%]. The isolated compound was triturated with 3N. a solution of HCl in methanol and treated with ultrasound and evaporated to dryness. The residue was dissolved in a minimum amount of acetonitrile and water, lyophilized to obtain the hydrochloride salt of 1-(1aminoisoquinolin-7-yl)-X-(5-(3-cyclopropyl-1-(2-oxopyridin-1(2H)-yl)propyl) -2-fluorophenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxamide (258g) (10 mg, 2% yield) as a white solid; ^1H NMR (300 MHz, DMSO- _d6 ) δ 13.38 (s, 1H, exchange with D2O), 10.71 (s, 1H, exchange with D2O), 9.20 (s, 3H, exchange with D2O ), 8.84 (s, 1H), 8.09 (s, 2H), 7.85-7.75 (m, 2H), 7.70 (dd, J=7.0, 2.0 Hz, 1H), 7.54 (s, 1H), 7.34 (dd, J=8.9, 4.8 Hz, 3H), 6.39 (d, J=9.0 Hz, 1H), 6, 23 (t, J=6.6 Hz, 1H), 6.04 (t, J=8.0 Hz, 1H), 2.20 (m, 2H), 1.05 (m, 2H), 0, 76 - 0.62 (m, 1H), 0.42 - 0.31 (m, 2H), -0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -60.70, -121.04; MS (IER+): 591.3 (M+1); MS (ESI-) 625.3 (M+Cl); analysis, calculation for C31VD4^O2'2NSG2H2O: C, 53.23; H, 4.61; N, 12.01; experiment: C, 53.18; H, 4.56; N, 12.38.

Scheme 259

An example of the preparation of 1 -(1 -aminoisoquinolin-7-yl)-N-(5 -(3 -cyclopropyl-1 -(2-oxopyrazin-1 (2H)yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (259d).

Step 1. Preparation of methyl 5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2-fluorophenylcarbamate (259a).

Pyrazin-2(1H)-one (0.323 g, 3.36 mmol), cesium carbonate (0.867 g, 2.66 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2x75 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered and evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 24 g, eluted with ethyl acetate/methanol (9:1) in hexanes, 0-75%] to give methyl 5-(3-cyclopropyl-1-(2-oxopyrazine-1 (2H )-yl)propyl)-2-fluorophenylcarbamate (259a) (0.304 g, 31% yield) as a colorless waxy substance. MS (IER+): 368.3 (M+Na), MC (IER-) 344.2 (M-1).

Step 2. Preparation of 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrazin-2(1H)-one (259b)

Compound 259b was prepared from methyl 5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2fluorophenylcarbamate (259a) (301 mg, 0.872 mmol) according to the method for preparation of compound 258e described in step 5 of Scheme 258, after purification by flash column chromatography [silica gel, 12 g, eluted with ethyl acetate/methanol (9:1) in hexanes, 0-75%] gave 1-(1-(3-amino-4-fluorophenyl) 3-cyclopropylpropyl)pyrazin-2(1H)-one (259b) (61 mg, 24% yield) as a yellow solid; ^1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=1.2 Hz, 1H), 7.65 (d, J=4.6 Hz, 1H), 7.33 (d, J=4.5 Hz, 1H), 6.97 (dd, J=11.4, 8.3 Hz, 1H), 6.76 (dd, J=8.8, 2.3 Hz, 1H), 6.57 (dt, J=7.3, 3.4 Hz, 1H), 5.81 (t, J=8.0 Hz, 1H), 5.22 (s, 2H, exchange with D2O), 2 .18 (m, 2H), 1.08 (m, 2H), 0.69 (m, 1H), 0.43 - 0.29 (m, 2H), -0.02 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -135.69; MS (ESI+): 310.2 (M+Na), MS (ESI-) 286.3 (M-1), 322.2 (M+Cl).

Step 3. Preparation of tert-butyl-7-(5-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole -1-yl)isoquinolin-1-ylcarbamate (259c).

Compound 259c was prepared from 1-(1-(tert-butoxycarbonylamino)isoquinolin-7-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253f) (0.102 g, 0.242 mmol) and 1-(1 -(3-amino-4-fluorophenyl)-3cyclopropylpropyl)pyrazin-2(1H)-one (259b) (58 mg) according to the method for preparation of compound 208c described in step 3 of Scheme 208, after workup, crude tert-butyl-7 was obtained -(5-(5-(3cyclopropyl-1 -(2-oxopyrazin-1 (2H)-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)isoquinoline-1 -ylcarbamate (259c) (359 mg) as a brown waxy substance, which was used as such in the next step; MS (IER+) 692.2 (M+1).

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Step 4. Preparation of 1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)yl)propyl)-2-fluorophenyl)-3-( trifluoromethyl)-III-pyrazole-5-carboxamide (259d).

Into a solution of crude tert-butyl-7-(5-(5-(3-cyclopropyl-1-(2-oxopyrazin-1(2H)-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)isoquinolin-1-ylcarbamate (259c) (0.338 g, crude reaction mixture) in methanol (10 ml), add 3M HCl in methanol (0.977 ml, 2.93 mmol) and heat at reflux temperature for 1 .5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was made alkaline with aq. Ammonium hydroxide and evaporated to dryness. The residue was purified by flash chromatography [silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-100%] to give free base 259d (12 g, 4% yield) as a colorless solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 10.65 (s, 1H, exchange with D2O), 8.57 - 8.38 (m, 1H), 8.07 (d, J=1.1 Hz , 1H), 7.94 (d, J=5.7 Hz, 1H), 7.88 - 7.69 (m, 4H), 7.66 - 7.58 (m, 1H), 7.44 - 7.30 (m, 3H), 7.10 - 6.94 (m, 3H), 5.92 (dd, J=9.0, 6.9 Hz, 1H), 2.41 - 2.17 ( m, 2H), 1.12 (m, 2H), 0.73 (m, 1H), 0.49 - 0.31 (m, 2H), 0.04 - -0.04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.73, -120.86; MS (IER+) 592.3 (M+1), 614.2 (M+Na); MS (ESI-) 590.3 (M-1), 626.3 (M+Cl).

Scheme 260

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (260b).

Step 1. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (260a).

Compound 260a was prepared from tert-butyl 3-(5-(5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (251b) ( 0.7 g, 1.09 mmol) and pyrrolidine-2,5-dione (0.217 g, 2.19 mmol) according to the preparation of compound 258d described in step 4 of Scheme 258, after purification by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-50%) to obtain tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1 -yl)propyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (260a) (0.19 g, 0.29 mmol, 26.4% yield) as a colorless foam; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.60 (s, 1H), 7.59 (m, 2H), 7.53 - 7.14 (m, 7H), 5.07 (dd, J =9.5, 6.4 Hz, 1H), 4.20 (d, J=6.2 Hz, 2H), 2.70 - 2.57 (m, 4H), 2.47 - 2.31 ( m, 1H), 2.16 (m, 1H), 1.37 (s, 11H), 0.66 (s, 1H), 0.37 (m, 2H), -0.01- -0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -60.85, -121.00; MS (ESI+) 680.3 (M+Na).

Step 2. Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (260b).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2,5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl)benzylcarbamate (260a) (0.15 g, 0.23 mmol) in methanol (5 ml) was added 3M hydrogen chloride in methanol (0.76 ml, 2.28 mmol) and stirred at room temperature for 20 h The solution was concentrated in vacuo and the resulting residue was separated in a solution of NaHCO ₃ (40 ml) and EtOAc (30 ml). The layers were separated; the aqueous layer was extracted with EtOAc (25 ml). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, eluted with mixtures of 0-100% CMA 80 in chloroform) to give 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1(2, 5-dioxopyrrolidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (260b) (0.105 g, 0.188 mmol, 83% yield) as a colorless foam; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.59 (s, 1H), 8.32 (s, 1H), 7.71 - 7.14 (m, 9H), 5.07 (dd, J =9.5, 6.4 Hz, 1H), 3.80 (s, 2H), 2.70 - 2.57 (m, 4H), 2.43 (m, 1H) 2.16 (m, 1H ), 1.10 (m, 2H), 0.64 (m, 1H), 0.37 (m, 2H), -0.00 (m, 2H), ¹⁹ F NMR (282 MHz, DMSO) δ 60 .75, -122.08; MS (IER+) 558.3 (M+1).

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Scheme 261

An example of the preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (261k).

Step 1. Preparation of N-(1-(3-amino-4-fluorophenyl)-3-cyclopronylpropylidene)-2-methylnponan-2sulfinamide (261a).

Compound 261a was prepared from 1-(3-amino-4-fluorophenyl)-3-cyclopropylpropan-1-one (248e) (19.5 g, 94 mmol) and 2-methylpropan-2-sulfinamide (14.83 g, 122 mmol) according to the method for preparing compound 208a described in step 1 of scheme 208, (reaction time 62 hours), after purification by flash column chromatography [silica gel, eluted with hexanes/ethyl acetate mixtures (1:0 to 4:1, then 2: 1, 1:1)] gave N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylnponan-2sulfinamide (261a) (14.26 g, 49.9%) as yellow viscous substance; 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.33 (d, J=8.9 Hz, 1H), 7.10 - 7.03 (m, 2H), 5.39 (s, 2H), 3.32-3.04 (m, 2H), 1.54 - 1.36 (m, 2H), 1.21 (s, 9H), 0.82-0.66 (m, 1H), 0. 53 - 0.27 (m, 2H), 0.15- -0.05 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -129.99; MS (ESI+): 333.2 (M+Na).

Step 2. Preparation of N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (261b).

Compound 261b was prepared from N-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropylidene)-2-methylpropane-2-sulfinamide (261a) (4 g, 12.89 mmol) according to the method for preparation of compound 248f described Step 5 of Scheme 248 (reaction temperature -78°C) gave N-(1-(3-amino-4-fluorophenyl)3-cyclopropylpropyl)-2-methylpropane-2-sulfinamide (261b) (4.15 g) in the form of a light yellow thick substance, which was used as such in the next step.

Step 3. Preparation of methyl 5-(3-cyclopropyl-1-(1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate (261c).

In a biphasic solution of N-(1-(3-amino-4-fluorophenyl)-3-cyclononylpronyl)-2-methylpropane-2sulfinamide (261b) (4.5 g, 14.40 mmol) in ethyl acetate (100 ml) and saturated aqueous NaHCO ₃ (100 ml) was added methyl chloroformate (1.673 ml, 21.60 mmol) and stirred at room temperature for 16 hours. The aqueous layer was separated, extracted with ethyl acetate (2x150 ml) and the combined organic layers were washed with brine, dried over MgSO ₄ , filtered, concentrated and purified by flash column chromatography to give methyl 5-(3-cyclopropyl-1-(1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamate (261c) (4.86 g, 13.12 mmol, yield 91%) as a viscous solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 9.30 (s, 1H), 7.69 - 7.52 (m, 1H), 7.256.98 (m, 2H), 5.60 (d, J =8.2 Hz, 1H), 4.12 (m, 1H), 3.66 (s, 3H), 1.97 - 1.79 (m, 1H), 1.68 (m, 1H), 1 .08 (m, 11H), 0.63 (m, 1H), 0.42 - 0.26 (m, 2H), -0.01 - -0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -127.03 (d, J=44.3 Hz).

Step 4. Preparation of methyl 5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (261 d).

To a stirred solution of methyl 5-(3-cyclopropyl-1-(1,1-dimethylethylsulfinamido)propyl)-2fluorophenylcarbamate (261c) (4.85 g, 13.09 mmol) in methanol (100 ml) was added 4N. water chloride solution

- 404 045731 native acid in 1,4-dioxane (16.36 ml, 65.5 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo, the residue was dissolved in water (100 ml), made basic with saturated sodium bicarbonate solution and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with water (2x50 ml), brine (50 ml), dried, filtered and concentrated in vacuo to give methyl 5-(1-amino-3-cyclopropylpropyl)-2fluorophenylcarbamate (261d) (3.57 g, 13.41 mmol, yield 102%) as a thick liquid, which was used as such in the next step; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 7.75-7.39 (m, 1H), 7.30 - 6.85 (m, 2H), 3.65 (s, 3H), 3.37 (m, 1H), 2.04 (s, 2H), 1.59 (m, 2H), 1.27 - 1.13 (m, 1H), 1.08 - 0.91 (m, 1H), 0.73 - 0.51 (m, 1H), 0.41 - 0.24 (m, 2H), -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -127.68.

Step 5. Preparation of methyl 5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (261e).

To a stirred solution of methyl 5-(1-amino-3-cyclopropylpropyl)-2-fluorophenylcarbamate (261d) (3.2 g, 12.02 mmol) in dichloromethane (70 ml) was added dihydro-2H-pyran-2,6 (3H)-dione (1.508 g, 13.22 mmol). The reaction mixture was stirred at room temperature for 30 minutes, acetic acid chloride (17.09 ml, 240 mmol) was added and heated at reflux temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica gel, 40 g , eluted with mixtures of ethyl acetate in hexanes, from 0 to 100%) to give methyl 5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (261e) (4.078 g, 11.25 mmol, yield 94%) as a colorless solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.25-6.90 (m, 2H), 5.71 (dd, J=9.2, 6.5 Hz, 1H), 3.65 (s, 3H), 2.62 (m, 4H), 2.37 - 2.12 (m, 2H) , 1.88 -1.75 (m, 2H), 1.20 - 0.99 (m, 2H), 0.68 (m, 1H), 0.47 - 0.32 (m, 2H), 0 .05- 0.00 (m, 1H), -0.01 - -0.07 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO^) δ -127.01.

Step 6. Preparation of methyl 5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2fluorophenylcarbamate (261f).

Into a stirred solution of methyl 5-(3-cyclopropyl-1-(2,6-dioxopiperidin-1-yl)propyl)-2fluorophenylcarbamate (261e) (3.55 g, 9.80 mmol) in dichloromethane (200 ml) at -78°C, diisobutylaluminum hydride (29.4 ml, 29.4 mmol) was added and stirred at -78°C for 1 hour. The reaction was quenched with methanol (3 ml) and the mixture was warmed to room temperature. The reaction mixture was diluted with 2N. sodium hydroxide (4 ml), washed with saturated disodium tartrate solution. The layers were separated and the aqueous layer was extracted with dichloromethane (2x150 ml). Combine the organic layers, wash with brine (100 mL), dry, filter and concentrate to give methyl 5-(3-cyclopropyl-1(2-hydroxy-6-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamate (261f ) (3.204 g, 8.79 mmol, 90% yield), which was used as such in the next step; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.51 9.07 (m, 1H), 7.68 - 7.41 (m, 1H), 7.37 - 6.95 (m, 2H), 5.58 (dd, J=30.4, 6.5 Hz, 1H), 5.45 (m, 0.5H), 4.96 (m, 0.5H), 4.87 (m, 0. 5 H), 4.62 (m, 0.5 H), 3.65 (2s, 3H), 2.35- 1.99 (m, 4H), 1.81 - 1.59 (m, 2H) , 1.59 - 1.36 (m, 2H), 1.27 - 1.06 (m, 2H), 0.70 (m, 1H), 0.45 - 0.25 (m, 2H), 0 .05- -0.18 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -126.93.

Step 7. Preparation of methyl 5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2fluorophenylcarbamate (261g).

Into a stirred solution of methyl 5-(3-cyclopropyl-1-(2-hydroxy-6-oxopiperidin-1-yl)propyl)2-fluorophenylcarbamate (261f) (3.2 g, 8.78 mmol) in dichloromethane (100 ml), cooled to 0°C, triethylamine (7.34 ml, 52.7 mmol) and methanesulfonyl chloride (1.369 ml, 17.56 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was diluted with dichloromethane (200 ml) and water (50 ml). The aqueous layer was separated and extracted with dichloromethane (2x50 ml). Combine the organic layers, wash with water (2x25 mL), brine (25 mL), dry and concentrate. The crude residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0 to 50 to 100% ethyl acetate in hexanes) to give methyl 5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridine- 1 (2H)-yl)propyl)-2-fluorophenylcarbamate (261g) (2.35 g, 6.78 mmol, 77% yield) as a clear thick liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 7.58 (dd, J=8.0, 2.1 Hz, 1H), 7.18 (dd, J=10 ,6, 8.5 Hz, 1H), 7.06 (m, 1H), 6.15 (dt, J=7.9, 1.6 Hz, 1H), 5.64 (dd, J=9, 9, 6.2 Hz, 1H), 5.17 (dt, J=8.4, 4.4 Hz, 1H), 3.66 (s, 3H), 2.43 (m, 2H), 2, 20 (m, 2H), 2.08 - 1.80 (m, 2H), 1.25-1.00 (m, 2H), 0.71 (m, 1H), 0.45-0.31 ( m, 2H), 0.05 (m, 1H), 0.00 - -0.08 (m, 1H); ¹⁹ F NMR (282 MHz, DMSOL) δ -126.28.

Step 8. Preparation of 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-3,4-dihydropyridin2(1H)-one (261h).

Compound 261h was prepared from methyl 5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)yl)propyl)-2-fluorophenylcarbamate (261g) (1.2 g, 3.46 mmol) according to the method for preparing compound 258e described in step 5 of scheme 248, 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)3,4-dihydropyridin-2(III)-one (261h) was obtained (0.89 g, 3.09 mmol, 89% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 6.91 (dd, J=11.5, 8.4 Hz, 1H), 6.69 (dd, J=8.8, 2.3 Hz, 1H) , 6.44 (m, 1H), 6.09 (dt, J=7.8, 1.6 Hz, 1H), 5.56 (dd, J=10.1, 5.9 Hz, 1H), 5.20 - 5.06 (m, 3H), 2.48 - 2.35 (m, 2H), 2.27 - 2.12 (m, 2H),

- 405 045731

1.98 - 1.77 (m, 2H), 1.16 - 0.93 (m, 2H), 0.78 - 0.63 (m, 1H), 0.44 - 0.33 (m, 2H ), 0.10 - -0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -137.03.

Step 9. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2-oxo-3,4-dihydroniridin-1(2H)yl)propyl)-2-fluorophenylcarbamoyl)-3 - (trifluoromethyl)-1 H-pyrazol-1-yl)benzylcarbamate (261i).

Compound 261i was prepared from 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)1H-pyrazole-5-carboxylic acid (10d) (0.53 g, 1.38 mmol) and 1- (1-(3-amino-4-fluorophenyl)-3cyclopropylpropyl)-3,4-dihydropyridin-2(1H)-one (261h) (0.4 g, 1.39 mmol) according to the method for the preparation of compound 208c described at step 3 of scheme 208, after purification by flash column chromatography (silica gel, 40 g, eluted with mixtures of ethyl acetate in hexanes, 0-40%) gave tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2-oxo- 3,4-dihydropyridin-1(2H)-yl)propyl)-2-fluorophenylcarbamoyl)3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (261i) (0.48 g, 0.73 mmol, yield 52.8%) in the form of colorless foam; ¹ H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.60 (s, 1H), 7.44 (ddd, J=26.7, 13.8, 5.9 Hz , 6H), 7.31 - 7.15 (m, 2H), 6.17 (d, J=7.9 Hz, 1H), 5.71 - 5.57 (m, 1H), 5.25- 5.08 (m, 1H), 4.19 (d, J=6.2 Hz, 2H), 2.49 - 2.35 (m, 2H), 2.27 - 2.12 (m, 2H) , 2.05-1.88 (m, 2H), 1.37 (s, 9H), 1.27 (m, 1H), 1.16 - 1.01 (m, 1H), 0.71 (m , 1H), 0.38 (m, 2H), -0.00 (m, 2H), ¹⁹ F NMR (282 MHz, DMSO-d6) δ -122.72, -60.80.

Step 10. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1 H-pyrazole-1 -yl)benzylcarbamate (261j).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2-oxo-3,4-dihydropyridin-1(2H)-yl)propyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl) -1H-pyrazol-1-yl)benzylcarbamate (261i) (0.15 g, 0.23 mmol) in ethyl acetate (5 ml), palladium (II) hydroxide (6.43 mg, 0.023 mmol) was added and the mixture was hydrogenated under atmosphere H ₂ for 36 hours. Filter the mixture through a pad of celite, wash with EtOAc (2x10 ml), concentrate in vacuo and purify by flash column chromatography (silica gel, 24 g, eluted with mixtures of ethyl acetate in hexanes, 0-40%) to give tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2oxopiperidin-1 -yl)propyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazol-1 -yl)benzylcarbamate (261j) (0.09 g, 0.137 mmol, 59.8% yield) as a viscous mass; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 7.60 (s, 1H), 7.42 (m, 6H), 7.23 (dt, J=13.4 , 6.7 Hz, 2H), 5.77 (t, J=8.0 Hz, 1H), 4.19 (d, J=6.3 Hz, 2H), 3.16 - 3.00 (m , 1H), 2.82 - 2.64 (m, 1H), 2.39 - 2.18 (m, 2H), 1.99 (m, 3H), 1.74 - 1.43 (m, 3H ), 1.37 (s, 9H), 1.30 (m, 1H), 1.08 (m, 1H), 0.72 (m, 1H), 0.38 (m, 2H), -0, 00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ 123.10, -60.81.

Step 11. Preparation of (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2-oxopiperidin-1yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) )-1H-pyrazole-5-carboxalamideα (261k).

Into a solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzylcarbamate (261j) (0.09 g, 0.137 mmol) in methanol (4 ml), add HCl (0.46 ml, 1.37 mmol, 3M in methanol), stir at room temperature for 20 h and concentrate in vacuum. The residue was partitioned in a solution of NaHCO ₃ (40 ml) and EtOAc (30 ml). The layers were separated, the aqueous layer was extracted with EtOAc (25 ml) and the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash column chromatography [silica gel, 12 g, eluted with mixtures of CMA 80 and chloroform, 0-30%] to give (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3- cyclopropyl-1-(2-oxopiperidin-1-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (261k) (0.06 g, 0.11 mmol, yield 79 %) in the form of colorless foam; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.59 (s, 1H), 7.58 (s, 1H), 7.54 - 7.38 (m, 4H), 7.38 - 7.10 (m, 3H), 5.76 (t, J=8.0 Hz, 1H), 3.78 (s, 2H), 3.16 - 3.00 (m, 1H), 2.72 (dd, J=12.2, 6.2 Hz, 1H), 2.29 (q, J=6.8 Hz, 2H), 1.95 (dd, J=15.5, 8.1 Hz, 2H), 1.76 - 1.43 (m, 4H), 1.34 - 0.96 (m, 3H), 0.91 - 0.65 (m, 2H), 0.38 (m, 2H), 0. 11 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -123.14, -60.74; MS (IER+) 558.3 (M+1); MS (ESI-) 556.3 (M-1), 592.3 (M+Cl). Optical rotation: [α]ρ=(+) 49.12 [0.285, MeOH].

Scheme 262

- 406 045731

An example of the preparation of (-)-1-(1 -aminoisoquinolin-7-ul)-N-(5-(3-cyclopropyl-1 -(methylsulfonamido)-1 (pyridin-4-yl)propyl)-2-fluorophenyl)- 3-(trifluoromethyl)-III-pyrazole-5-carboxamide (262f).

Step 1. Preparation of 5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4yl)propyl)-2-fluorophenylcarbamate (262a).

Compound 262a was prepared from (R)-N-((-)-1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4yl)propyl)-2-methylpropane-2-sulfinamide (216b ) (0.5 g, 1.284 mmol) according to the method for the preparation of compound 258a described in step 1 of scheme 258, 5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridine- 4-yl)propyl)-2-fluorophenylcarbamate (262a) (0.573 g, 100% yield) as a yellow solid, which was used as such in the next step; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.53 - 8.45 (m, 2H), 7.67 (d, J=7.5 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.21 - 7.08 (m, 2H), 5.51 (s, 1H), 3.64 (s, 3H), 2.71 - 2, 40 (m, 2H), 1.15 (s, 9H), 1.10 - 0.85 (m, 2H), 0.73 - 0.55 (m, 1H), 0.43 - 0.29 ( m, 2H), -0.02 - -0.11 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOL) δ -126.83; MS (IER ⁺ ): MS (IER+) 448.3 (M+1); MS (ESI-) 446.3 (M-1), 482.3 (M+Cl).

Step 2. Preparation of methyl 5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate (262b).

Into a stirred solution of 5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4yl)propyl)-2-fluorophenylcarbamate (262a) (0.551 g, 1.231 mmol) in methanol ( 12 ml) a 3M solution of HCl in methanol (2.462 ml, 7.39 mmol) was added and heated at the reverse condensation temperature. The reaction mixture was cooled to room temperature, concentrated in vacuo, made basic with saturated aqueous NaHCO ₃ and extracted with ethyl acetate (2x30 ml). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness to give methyl 5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamate (262b) (0.418 g, 1.217 mmol , yield 99%) in the form of a yellow thick liquid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 8.53 - 8.35 (m, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.25 - 7.04 (m, 2H), 3.63 (s, 3H), 2.35 (s, 2H), 2.20 (t, J=8.1 Hz, 2H), 1.12 - 0.91 (m, 2H), 0.73 - 0.56 (m, 1H), 0.41 - 0.29 (m, 2H), - 0.03 - -0.10 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -127.63; MS (IER ⁺ ): MS (IER+) 344.2 (M+1); MS (IER-) 342.2 (M-1).

Step 3. Preparation of methyl 5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2fluorophenylcarbamate (262c).

To a stirred solution of methyl 5-(1-amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2fluorophenylcarbamate (262b) (0.401 g, 1.168 mmol) in dichloromethane (20 ml) at 0°C was added pyridine (0.471 ml, 5.84 mmol), methanesulfonic acid anhydride (0.407 g, 2.336 mmol). The resulting mixture was left to warm to room temperature overnight. Additional amounts of pyridine (0.471 mL, 5.84 mmol) and methanesulfonic acid anhydride (0.407 g, 2.336 mmol) were added and the mixture was stirred for an additional 3 hours at room temperature. The reaction mixture was diluted with brine (20 ml), extracted with dichloromethane (2x30 ml), the combined organic layers were dried over anhydrous MgSO ₄ , filtered, evaporated to dryness. The residue was purified by flash column chromatography [silica gel, 12 g, eluted with mixtures of CMA 80 in chloroform, 0-75%] to give methyl 5-(3cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl )-2-fluorophenylcarbamate (2c26) (0.489 g, 1.160 mmol, 99% yield), which was used as such in the next step; MS (IER ⁺ ): MS (IER+) 444.2 (M+Na); MS (IER-) 456.2 (M+Cl).

Step 4. Preparation of (+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)methanesulfonamide (262d).

Compound 262d was prepared from methyl 5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4yl)propyl)-2-fluorophenylcarbamate (262c) (0.483 g, 1.146 mmol) according to the method for preparation of compound 258e described at Step 5 of Scheme 258 gave (+)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1(pyridin-4-yl)propyl)methanesulfonamide (262d) (0.311 g, 0.856 mmol, yield 74.7%) as a white solid; 1H NMR (300 MHz, DMSO^) δ 8.61 - 8.30 (m, 2H), 7.67 (s, 1H), 7.37 - 7.18 (m, 2H), 6.95 (dd , J=11.2, 8.5 Hz, 1H), 6.82 (dd, J=8.9, 2.4 Hz, 1H), 6.50 - 6.36 (m, 1H), 5, 21 (s, 2H), 2.66 - 2.54 (m, 1H), 2.35 - 2.24 (m, 1H), 2.21 (s, 3H), 1.15 - 0.97 ( m, 1H), 0.87 - 0.67 (m, 1H), 0.64 - 0.47 (m, 1H), 0.40 - 0.20 (m, 2H), -0.02 - - 0.20 (m, 2H); MS (IER ⁺ ): MS (IER-) 362.2 (M-1), 725.3 (2M-1); optical rotation: [α]η=(+) 21.0 [0.2, MeOH].

Step 5. Preparation of di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)- 1 H-pyrazol-1 -yl)isoquinolin-1 -ylcarbamate (262e).

Compound 262e was prepared from 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253c) (0.519 g, 0.994 mmol) and ( +)-N-(1-(3-amino-4fluorophenyl)-3-cyclopropyl-1-(pyridin-4-yl)propyl)methanesulfonamide (262d) (0.301 g, 0.828 mmol) according to the method for preparing compound 208c described at step 3 of Scheme 208, we obtained di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl )-1H-pyrazol-1-yl)isoquinolin-1-ylcarbamate (262e), the crude reaction mixture was used as such in the next step; MS (IER+): 868.3 (M+1).

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Step 6. Preparation of (-)-1-(1-aminoisoquinolin-7-yl)-K-(5-(3-cyclopropyl-1-(methylsulfonamido)-1-(pyridin-4-yl)propyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (262f).

Compound 262f was prepared from di-tert-butyl-7-(5-(5-(3-cyclopropyl-1-(methylsulfonamido)-1(pyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl) -1 H-pyrazol-1 -yl)isoquinolin-1 -ylcarbamate (262e) (1.439 g, 1.658 mmol) according to the preparation of compound 258f described in step 7 of Scheme 258, after purification, free base 262f (78 mg, yield 7 %) as a yellow solid; 1H NMR (300 MHz, DMSO^) δ 10.61 (s, 1H), 8.69 - 8.45 (m, 2H), 8.43 (s, 1H), 7.98 7.51 (m, 6H), 7.40 - 7.14 (m, 3H), 7.10 - 6.84 (m, 3H), 2.31 - 2.22 (m, 2H), 2.27 (s, 3H) , 1.21 -0.93 (m, 2H), 0.90 - 0.71 (m, 1H), 0.65 - 0.48 (m, 1H), 0.38 - 0.20 (m, 2H), -0.05- -0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSOd ₆ ) δ -60.70, -121.52.

To a solution of free base 262f (0.069 g, 0.103 mmol) in methanol (10 ml) was added HCl (3M in methanol) (0.207 ml, 0.620 mmol), evaporated to dryness, dissolved in a minimum amount of water and lyophilized to give the hydrochloride salt (-) -1-(1-aminoisoquinolin-7-yl)-N-(5-(3cyclopropyl-1 -(methylsulfonamido)-1 -(pyridin-4-yl)propyl)-2-fluorophenyl)-3 -(trifluoromethyl)- 1 Hpyrazole-5-carboxamide (262f) (34 mg, 49% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H, exchange with D2O), 10.90 (s, 1H, exchange with D2O), 9.33 (s, 2H, exchange with D2O), 8.99 - 8.85 (m, 1H), 8.78 (d, J=6.0 Hz, 2H), 8.19 - 8.03 (m, 3H), 7.89 (s, 1H) , 7.90 - 7.67 (m, 3H), 7.67 - 7.55 (m, 1H), 7.39 - 7.21 (m, 3H), 2.76 - 2.41 (m, 2H), 2.39 (s, 3H), 1.11 - 0.95 (m, 1H), 0.88 - 0.69 (m, 1H), 0.65 - 0.50 (m, 1H) , 0.38-0.19 (m, 2H), -0.02 - -0.21 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -60.90, -120.70; 1H NMR (300 MHz, DMSO-d6/D2O) δ 8.97 (s, 1H), 8.91 - 8.83 (m, 2H), 8.30 -8.14 (m, 2H), 8, 00 - 7.84 (m, 4H), 7.76 (dd, J=7.2, 2.4 Hz, 1H), 7.54 - 6.79 (m, 3H), 2.86 - 2, 58 (m, 2H), 2.55 (s, 3H), 1.26 - 1.04 (m, 2H), 1.05 - 0.83 (m, 1H), 0.80 0.62 (m , 1H), 0.53 - 0.32 (m, 2H), 0.11 - -0.08 (m, 2H); MS (ESI+): MS (ESI+) 668.2 (M+1), 702.2 (M+Cl); optical rotation: [a] _D =(-) 2.0 [0.1, MeOH]; analysis, calculation for: C ₃₂ H ₂₉ F ₄ N ₇ O ₃ S-2.25HCl-4.25H2O: C, 46.51; H, 4.85; Cl, 9.65; N, 11.87; experiment: C, 46.66; H, 4.56; Cl, 9.27; N, 12.03.

Scheme 263

An example of the preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2- fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (263d).

Step 1. Preparation of methyl (5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)carbamate (263a).

To a suspension of uracil (1 g, 8.92 mmol) in acetonitrile (60 ml) was added H,O-bis(trimethylsilyl)acetamide (BSA, 4.54 g, 22.30 mmol) and stirred for 30 min. Methyl 5-(1-bromo-3-cyclopropylpropyl)-2-fluorophenylcarbamate (258c) (3.54 g, 10.71 mmol), iodine (0.226 g, 0.892 mmol) was added to the reaction mixture and heated at reflux temperature until all starting materials are used up. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with ethyl acetate (100 ml) and washed with H2O (50 ml). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-90% EtOAc in hexane) to give methyl (5(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidine-1( 2H)-yl)propyl)-2-fluorophenyl)carbamate (263 a) (785 mg, 0.498 mmol, 24.4% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 9.40 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.65 ( d, J=6.2 Hz, 1H), 7.29 - 7.16 (m, 1H), 7.19 - 7.09 (m, 1H), 5.58 (t, J=7.5 Hz , 2H), 3.66 (s, 3H), 2.24 - 2.05 (m, 2H), 1.24 -1.02 (m, 2H), 0.75 - 0.64 (m, 1H ), 0.46 - 0.32 (m, 2H), 0.05- -0.03 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO^) δ -125.34; MS (IER+) 362.2 (M+1), 360.2 (M-1).

Step 2. Preparation of 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)pyrimidine-2,4(1H,3H)dione (263b).

- 408 045731

Compound 263b was prepared from methyl (5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin1(2H)-yl)pronyl)-2-fluorophenyl)carbamate (263a) (765 mg, 2.117 mmol) according to the method for preparing compound 258e, described in step 5 of scheme 258, after purification by flash column chromatography [silica gel, 12 g, eluted with mixtures of 0-60% ethyl acetate in hexanes] gave 1-(1-(3amino-4-fluorophenyl)- 3-cyclopropylpropyl)pyrimidine-2,4(1H, 3H)-dione (263b) (450 mg, 1.484 mmol, 70.1% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-dg) δ 11.31 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 6.96 (dd, J=11.2, 8 .5 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.56 - 6.48 (m, 1H), 5.57 (d, J=6.3 Hz, 1H ), 5.49 (t, J=7.7 Hz, 1H), 5.21 (s, 2H), 2.21 - 1.97 (m, 2H), 1.21-1.00 (m, 2H), 0.76 - 0.59 (m, 1H), 0.42-0.32 (m, 2H), 0.10 - -0.12 (m, 2H); ¹⁹ F NMR (282 MHz,

DMSO-dg) δ -136.17.

Step 3. Preparation of tert-butyl-3-(5-((5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin1(2H)-yl)propyl)-2-fluorophenyl)carbamoyl )-3-(trifluoromethyl)-1H-pyrazol-1-ul)benzylcarbamate (263c).

Compound 263c was prepared from 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-pyrimidine2,4(1H,3H)-dione (263b) (410 mg, 1.352 mmol) and 1-(3- ((tert-butoxycarbonylamino)methyl)phenyl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (781 mg, 2.027 mmol) according to the method for preparing compound 208c described in step 3 of scheme 208, after purification by Flash column chromatography [silica gel, 24 g, eluted with mixtures of 0-90% EtOAc/MeOH (9:1, v/v) in hexane] gave tert-butyl-3-(5-((5 -(3-cyclopropyl- 1 -(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pronyl)-2fluorophenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (263c) (325 mg, 0.485 mmol, yield 35.9%) as a white solid; 1H NMR (300 MHz, DMSO-dg) δ 11.35 (s, 1H), 10.64 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.64 - 7 .25 (m, 9H), 5.59 (d, J=8.0 Hz, 2H), 4.20 (d, J=6.1 Hz, 2H), 2.30 - 2.04 (m, 2H), 1.37 (s, 9H), 1.24 - 1.00 (m, 2H), 0.77 - 0.61 (m, 1H), 0.43 - 0.31 (m, 2H) , 0.08 - -0.06 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.82, -121.69; MS (IER ⁺ ) 693.2 (M+Na); (IER ^- ) 669.3 (M-1).

Step 4. Preparation of 1-(3-(aminomethyl)phenyl)-K-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)nropyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (263d).

Into a solution of tert-butyl-3-(5-((5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrumidin-1(2H)-yl)propyl)-2-fluorophenyl)carbamoyl )-3-(trifluoromethyl)-1H-pyrazol-1-ul)benzylcarbamate (263 c) (300 mg, 0.447 mmol) in MeOH (15 ml) added HCl (3N in MeOH) (1.193 ml, 3.58 mmol ) and heated at reverse condensation temperature for 40 min. The solution was cooled to room temperature, concentrated in vacuo and the residue purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-60% CMA 80 in CHCl ₃ ) to give 1-(3-(aminomethyl)phenyl)-I- (5-(3-cyclopropyl-1-(2,4dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide ( 263d) (140 mg, 0.245 mmol, 54.9% yield) as a white solid; 1H NMR (300 MHz,

DMSO-dg) δ 7.74 (d, J=8.0 Hz, 1H), 7.63 - 7.48 (m, 3H), 7.48 - 7.39 (m, 2H), 7.38 - 7.25 (m, 3H), 5.60 (m, 2H), 3.78 (s, 2H), 2.26 - 2.05 (m, 2H), 1.22 - 0.98 (m , 2H), 0.77 - 0.62 (m, 1H), 0.45 - 0.32 (m, 2H), 0.00 (m, 2H); ^19F

NMR (282 MHz, DMSO-dg) δ -60.75, -121.72; MS (IER+) 571.3 (M+1), 569.3 (M-1). Scheme 264

An example of the preparation of (+)-1-(1-aminoisoquinoline-7-ηλ)-Ν-(5-((cyclopropylmethylamino)-(pyridin-4yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (264g).

Step 1. Preparation of (R)-2-methyl-N-(pyridin-4-ulmethylene)pronan-2-sulfinamide (264a).

Compound 264a was prepared from isonicotinaldehyde (11.67 g, 109 mmol) and (R)-2,4,6-triisopro

- 409 045731 pilbenzenesulfinamide (12 g, 99 mmol) according to the method for the preparation of compound 222a described in step 1 of scheme 222, after purification by flash column chromatography (silica gel, 120 g, eluted with mixtures of ethyl acetate in hexanes, 0-70%) gave ( R)-2-methyl-N-(pyridin-4-ylmethylene)propan-2sulfinamide (264a) (15.60 g, 75% yield) as a crystalline pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 8.84 - 8.77 (m, 2H), 8.63 (s, 1H), 7.94 - 7.81 (m, 2H), 1.21 ( s, 9H); MS (IER ⁺ ): MS (IER ⁺ ): 211.2 (M+1); optical rotation: [a] _D =(-) 99.25 [0.935, MeOH].

Step 2. Preparation of (R)-N-((S)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropan-2sulfinamide (264b) and (R)-N-( (R)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropan-2sulfinamide (264c).

Compounds 264b and 264c were prepared from (R)-2-methyl-N-(pyridin-4-ylmethylene)propan-2-sulfinamide (264a) (10.73 g, 51 mmol) and freshly prepared bromide (3-(bis(trimethylsilyl) )amino)-4fluorophenyl)magnesium (52c) (107 ml, 81 mmol) according to the preparation of compounds 222b and 222c described in step 2 of scheme 222, after purification by flash column chromatography [silica gel, 120 g, eluted with mixtures of CMA 80 in chloroform, 0-100%] received:

1. (R)-N-((S)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropan-2-sulfinamide (264b) (6.979 g, 43% yield) as a light red solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 8.42 (m, 2H), 7.43 - 7.26 (m, 2H), 6.93 (dd, J=11.5, 8 ,3 Hz, 1H), 6.80 - 6.66 (m, 1H), 6.64 - 6.50 (m, 1H), 6.02 (d, J=6.1 Hz, 1H), 5 .40 (d, J=6.1 Hz, 1H), 5.15 (s, 2H, exchange with D2O), 1.14 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -136.78; MS (IER ⁺ ): MS (IER+) 322.2 (M+1), 344.2 (M+Na); MS (IER-) 320.3 (M-1); optical rotation: [a] _D =(-) 27.41 [0.54, MeOH];

2. (R)-N-((R)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropan-2-sulfinamide (264c) (5.26 g, yield 32 %) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 - 8.44 (m, 2H), 7.48 - 7.31 (m, 2H), 6.92 (dd, J=11.4, 8.3 Hz, 1H), 6.69 (dd, J=8.9, 2.2 Hz, 1H), 6.58 - 6.41 (m, 1H), 6.10 (d, J=6 .3 Hz, 1H), 5.36 (d, J=6.2 Hz, 1H), 5.14 (s, 2H, exchange with D2O), 1.14 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOd6) δ -136.73; MS (IER ⁺ ): MS (IER+) 322.2 (M+1), 344.2 (M+Na); MS (IER-) 320.3 (M-1), 356.2 (M+Cl); optical rotation: [a]D=(-) 77.2 [0.5, MeOH].

Step 3. Preparation of (+)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (264d).

Compound 264d was prepared from (R)-N-((S)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropan-2-sulfinamide (264b) (2.26 g, 7.03 mmol) according to the method for preparing compound 222d described in step 3 of scheme 222, after purification by flash column chromatography [silica gel, 40 g, eluted with mixtures of methanol in chloroform, 0-100%] gave (+)-5-( amino(pyridin-4-yl)methyl)-2fluoroaniline (264d) (0.344 g, 22% yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.55-8.38 (m, 2H), 7.44 - 7.23 (m, 2H), 6.88 (dd, J=11.5, 8.3 Hz, 1H), 6.74 (dd, J=8.9, 2.2 Hz, 1H), 6.62 - 6.48 (m, 1H), 5.06 (s, 2H, exchange with D2O), 4.92 (s, 1H), 2.26 (s, 2H, exchange with _D2O ); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -137.67; MS (IER ⁺ ): MS (IER+) 218.2 (M+1); MS (IER-) 216.1 (M-1); optical rotation: [a]D=(+) 47.55 [0.235, MeOH].

Step 4. Preparation of (+)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline (264e).

Compound 264e was prepared from (+)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (264d) (0.331 g, 1.524 mmol) according to the method for preparation of compound 222f described in step 4 of Scheme 222, after purification flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-50% CMA 80 in chloroform in hexanes) gave (+)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2fluoroaniline (264e) ( 0.326 g, 1.201 mmol, 79% yield) as a yellow oily liquid; ^1H NMR (300 MHz, DMSO-d6) δ 8.53 - 8.41 (m, 2H), 7.48 - 7.32 (m, 2H), 6.96 - 6.73 (m, 2H) , 6.63 - 6.45 (m, 1H), 5.10 (s, 2H, exchange with D2O), 4.69 (s, 1H), 2.50 - 2.39 (m, 1H), 2 .34 - 2.17 (m, 2H), 0.98 - 0.83 (m, 1H), 0.48 - 0.31 (m, 2H), 0.10 - -0.01 (m, 2H ); ¹⁹ F NMR (282 MHz, DMSO^) δ -137.28; MS (IER ⁺ ): MS (IER+) 272.2 (M+1), MS (IER-) 270.2 (M-1); optical rotation: [a]D=(+) 41.65 [0.485, MeOH].

Step 5. Preparation of bis-di-tert-butyl-7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )isoquinolin-1-ylcarbamate (264f).

Compound 264f was prepared from 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253c) (0.595 g, 1.139 mmol) and ( +)-5((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline (264e) (0.309 g, 1.139 mmol) according to the method for compound 208c described in step 3 of scheme 208, bis-di-tert -butyl-7(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)isoquinolin-1-ylcarbamate (264f) in as a brown waxy solid, which was used as such in the next step.

Step 6: (+)-1-(1-Aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)2-fluorophenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide (264g).

Compound 264g was prepared from bis-di-tert-butyl-7-(5-(5-((cyclopropylmethylamino)(pyridin-4yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )isoquinolin-1-ylcarbamate (264f) (1.4202 g, 1.831 mmol) according to the method for preparation of compound 258f described in step 7 of Scheme 258, after purification, the free base 264g was obtained. The free base was converted into the hydrochloride salt; after lyophilization, the hydrochloride salt (+)-1-(1-aminoisoquinolin-7-yl)-N-(5((cyclopropylmethylamino)(pyridin-4-yl)methyl)- 2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (264g) (64 mg, 6% yield) as a white solid.

1H NMR (300 MHz, DMSO-dg) δ 13.74 (s, 1H, exchange with D2O), 10.96 (s, 1H, exchange with D2O), 10.76 (s, 1H, exchange with D2O), 9.55 - 9.18 (m, 2H, exchange with D2O), 8.99 - 8.74 (m, 3H), 8.29 - 8.13 (m, 2H), 8.10 (s, 1H ), 8.00 (d, J=6.6 Hz, 1H), 7.93 (s, 1H), 7.88 - 7.66 (m, 2H), 7.42 (t, J=9, 4 Hz, 1H), 7.39 - 7.22 (m, 1H), 5.93 (s, 1H), 2.73 (s, 2H), 1.36 - 1.06 (m, 1H), 0.53 (m, 2H), 0.43 - 0.10 (m, 2H); Ή NMR (300 MHz, DMSO/D ₂ Od ₆ ) δ 8.92 8.74 (m, 3H), 8.10 (s, 2H), 7.94 (d, J=5.6 Hz, 2H) , 7.94 - 7.84 (m, 1H), 7.81 (s, 1H), 7.75 (d, J=6.9 Hz, 1H), 7.66 - 7.55 (m, 1H ), 7.44 (t, J=9.4 Hz, 1H), 7.36 (d, J=7.1 Hz, 1H), 5.85 (s, 1H), 2.98 - 2.68 (m, 2H), 1.19-1.00 (m, 1H), 0.71 - 0.52 (m, 2H), 0.31 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dg) δ -60.86, -118.92; MS (ESI+): MS (ESI+) 576.2 (M+1), 610.2 (M+Cl); HPLC (reversed phase, UV absorption 260 nm; Rt= 3.010 min (98.17%)]; optical rotation: [a] _D =(+) 23.40 [0.265, MeOH]; analysis, calculation for:

C ₃ 0H25F4N7O-3HCi-4H2O: C, 47.60; H, 4.79; Cl, 14.05; N, 12.95; experiment: C, 47.41; H, 4.80; Cl, 13.88; N, 12.87.

Scheme 265

Г ² Y °' ^NH Yu PyBrOP

HCl i| J fl I o Λ | DIPEA

ΥΎ gn —- dmf ^N t _n --------* II Ί [I

264c (-)-isomer 265a (-)-isomer ^NaBH 4 F 253c

NH2

An example of the preparation of (-)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)-(pyridin-4yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole -5-carboxamide (265d).

Step 1. Preparation of (-)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (265a).

Compound 265a was prepared from (R)-N-((R)-(3-amino-4-fluorophenyl)(pyridin-4-yl)methyl)-2-methylpropan-2-sulfinamide (264c) (2.61 g, 8.12 mmol) according to the method for preparing compound 222d, described in step 3 of scheme 222, after purification by flash column chromatography [silica gel, 40 g, eluted with mixtures of methanol in chloroform, 0-100%] gave (-)-5-( amino(pyridin-4-yl)methyl)-2fluoroaniline (265a) (1.736 g, 98% yield) as a reddish-yellow oily liquid, which was used as such in the next step; MS (IER+): MS (IER+) 218.2 (M+1); MS (IER-) 216.1 (M-1); optical rotation: [a] _D =(-) 62.35 [0.51, MeOH].

Step 2. Preparation of (-)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline (265b).

Compound 265b was prepared from (-)-5-(amino(pyridin-4-yl)methyl)-2-fluoroaniline (265a) (1.79 g, 8.24 mmol) according to the method for preparation of compound 222f described in step 4 of the scheme 222, after purification by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-100% CMA 80 in chloroform) gave (-)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline (265b) (0.089 g, 4% yield) as a yellow oily liquid; 1H NMR (300 MHz, DMSO- _d6 ) δ 8.68 - 8.35 (m, 2H), 7.52 - 7.28 (m, 2H), 6.99 - 6.74 (m, 2H) , 6.64 - 6.44 (m, 1H), 5.09 (s, 2H), 4.68 (s, 1H), 2.51 - 2.36 (m, 1H), 2.37 2, 18 (m, 2H), 1.00 - 0.81 (m, 1H), 0.48 - 0.32 (m, 2H), 0.11 - 0.00 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ 137.26; MC (IER+): MC (IER+) 272.3 (M+1); MC (IER-) 270.3 (M-1).

Step 3. Preparation of bis-di-tert-butyl-7-(5-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl )isoquinolin-1-ylcarbamate (265c).

Compound 265c was prepared from 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-3(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253c) (81 mg, 0.155 mmol) and ( -)-5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluoroaniline (265b) (50 mg, 0.186 mmol) according to the method for compound 208c described in step 3 of scheme 208, crude bis-di -tert-butyl-7(5-(5-((cyclopropylmethylamino)-(pyridin-4-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl)isoquinolin-1-ylcarbamate ( 265c), which was used in this form in the next stage.

Step 4. Preparation of (-)-1-(1-aminoisoquinolin-7-yl)-N-(5-((cyclopropylmethylamino)-(pyridin-4yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (265d).

Into a solution of crude bis-di-tert-butyl-7-(5-(5-((cyclopropylmethylamino)-(pyridin-4yl)methyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-1 H-pyrazole-1 - yl)isoquinolin-1-ylcarbamate (265c) obtained in the above step in anhydrous dioxane (5 ml) was added with HCl (4N in dioxane, 2 ml) and heated at 60°C for 50 minutes. The reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% CMA-80 in chloroform) to give the free base 265d, which was converted to the HCl salt to give (-)-1-(1aminoisoquinolin-7-yl) hydrochloride )-and-(5-((cyclopropylmethylamino)(pyridin-4-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (265d) (25 mg, 0.043 mmol, yield 28.0%) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 13.50 (s, 1H), 10.87 (s, 1H), 10.48 (s, 2H), 9.26 (s, 2H), 8, 76 - 8.69 (m, 2H), 8.09 (m, 2H), 8.01 - 7.84 (m, 5H), 7.80 (d, J=7.0 Hz, 1H), 7 .77 - 7.71 (m, 1H), 7.42 (dd, J=10.3, 8.6 Hz, 1H), 7.33 (d, J=7.0 Hz, 1H), 5, 80 (d, J=7.2 Hz, 1H), 2.83 - 2.62 (m, 2H), 1.26 - 1.05 (m, 1H), 0.65 - 0.44 (m, 2H),

0.42 - 0.21 (m, 2H); MS (IER+) 576.4 (M+1); 574.4 (M-1); optical rotation: [a] _D = (-) 16 [0.25,

MeOH]; analysis, calculation for C ₃₀ H ₂₅ F ₄ N ₇ O-3HCl-3.5H ₂ O: C, 48.17; H, 4.72; N, 13.11; experiment: C, 48.29;

H, 4.70; N, 12.88.

Scheme 266 n ₃ s

Bu

Example

266j (+)-isomer of (+)-N-(5-(1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-1-(3- (aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (266j).

Step 1. Preparation of 2-methylisonicotinic acid (266b).

Potassium permanganate (294.97 g, 1866.489 mmol) was added portionwise to a solution of 2,4-dimethylpyridine (266a) (100 g, 933.245 mmol) in water (1000 ml) for 2 hours. The resulting reaction mixture was heated at 80 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to 250 ml at 50°C. The resulting solution was cooled to 0°C and the pH was adjusted to 3 using 1N. HCl (temperature 0°C to 5°C). The resulting solid was collected by filtration, washed with ice water and dried to obtain 2-methylisonicotinic acid (266b) (22.3 g, yield: 17.42%); 1H NMR (D2O) δ 8.52 (s, 1H), 7.94-7.90 (m, 2H), 2.69 (s, 3H); MS (+) 138.1 (M+1).

Step 2. Preparation of N-methoxy-N,2-dimethylisonicotinamide (266c).

To a stirred solution of 2-methylisonicotinic acid (266b) (17.8 g, 129.798 mmol) in N,Ndimethylformamide (180 mL) was added N,N-diisopropylethylamine (67.105 g, 519.192 mmol) and 1-ethyl-3-(3 -dimethylaminopropyl)carbodiimide (EDCI, 40.299 g, 259.596 mmol) and hydroxybenzotriazole (HOBt, 39.753 g, 259.596 mmol) at room temperature. The resulting reaction mixture was stirred for 0.5 h at room temperature, then N,Odimethylhydroxylamine hydrochloride (13.8 g, 141.479 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, quenched with water (500 ml), and extracted with ethyl acetate (5x500 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to give N-methoxy-N,2-dimethylisonicotinamide (266c) (23 g, 98.4% yield) as a reddish viscous solid; 1H NMR (CDCl ₃ ) δ 8.29-8.27 (d, 1H), 7.08 (s, 1H), 7.02-7.01 (d, 1H), 3.27 (s, 3H) , 3.07 (s, 3H), 2.32 (s, 3H); MS (IER+) 181.1 (M+1).

Step 3. Preparation of 1-(2-methylpyridin-4-yl)ethanone (266d).

To a stirred solution of N-methoxy-N,2-dimethylisonicotinamide (266c) (26 g, 144.281 mmol) in THF (520 ml) was added MeLi (6.342 g, 288.562 mmol, 1 M solution in THF) under a nitrogen atmosphere at -78°C . The reaction mixture was heated to room temperature for 1 hour, the reaction was quenched with saturated

- 412 045731 NH ₄ Cl solution at 0°C. The resulting reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to obtain 1-(2methylpyridin-4-yl)ethanone (266d) (11 g, 56.4% yield) as a reddish thick liquid; 1H NMR ( _CDCl3 ) δ 8.61-8.59 (d, 1H), 7.51-7.45 (d, 1H), 7.45-7.44 (m, 1H), 2.56 ( s, 3H), 2.53 (s, 3H); MS (IER+) 136.1 (M+1).

Step 4. Preparation of 3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one (266e).

Cyclopropanecarboxaldehyde (10.039 g, 143.234 mmol), aqueous potassium hydroxide (1N. , 0.911 g, 16.276 mmol) and stirred at room temperature for 12 hours. The reaction mixture was cooled to 0°C, 1N was added. hydrochloric acid (20.5 ml) and concentrated to remove methanol. The resulting residue was partitioned in ethyl acetate and water (75:75 ml). The aqueous layer was separated and extracted with ethyl acetate (2x75 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to give 3-cyclopropyl-1-(2-methylpyridin-4-yl)prop2-en-1-one (266e) (4.5 g, 29.5% yield) as a reddish liquid; MS (IER+) 188.1 (M+1).

Step 5. Preparation of 3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (266f).

Compound 266f was prepared from 3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one (266e) (8 g, 42.726 mmol) according to the method for preparation of compound 212c described in step 2 of scheme 212 Purification by column chromatography gave 3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1one (266f) (5.5 g, 68.1% yield) as a yellow liquid; 1H NMR ( _CDCl3 ) δ 8.61-8.59 (d, 1H), 7.53 (s, 1H), 7.47-7.46 (dd, 1H), 3.02-2.97 ( m, 2H), 2.58 (s, 3H), 1.60-1.53 (m, 2H), 0.71-0.66 (m, 1H), 0.41-0.37 (m, 2H), 0.05-0.01 (m, 2H); MS (IER+) 190.2 (M+1).

Step 6. Preparation of (R)-N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2-methylpropane2-sulfinamide (266g).

Compound 266g was prepared from 3-cyclopropyl-1-(2-methylpyridin-4-yl)propan-1-one (266f) (5.5 g, 29.062 mmol) and (R)-2-methylpropan-2-sulfinamide (4.209 g, 34.729 mmol) according to the method for preparing compound 208a described in step 1 of scheme 208, after purification by column chromatography, (R)-N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2 was obtained -methylpropane-2-sulfinamide (266g) (7 g, 82.44% yield) as a yellow liquid; 1H NMR (CDCl ₃ ) δ 8.51-8.49 (d, 1H), 7.51-7.33 (m, 2H), 3.35-3.05 (m, 2H), 2.54 ( s, 3H), 1.54-1.49 (m, 2H), 1.24 (s, 9H), 0.75-0.61(m, 1H), 0.41-0.31 (m, 2H), 0.05-0.01 (m, 2H); MS (IER+) 293.2 (M+1).

Step 7. Preparation of (R)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-methylpropan-2-sulfinamide (266h ).

Compound 266h was prepared from (R)-N-(3-cyclopropyl-1-(2-methylpyridin-4-yl)propylidene)-2methylpropane-2-sulfinamide (266g) (5.5 g, 29.062 mmol) and (R) -2-methylpropane-2-sulfinamide (2 g, 6.839 mmol) and freshly prepared (3-(bis(trimethylsilyl)amino)-4-fluorophenyl)magnesium bromide (52c) (19.10 ml, 15.28 mmol) according to method preparation of compound 208b described in step 2 of Scheme 208, after purification by column chromatography gave (R)-N-(1-(3-amino-4-fluorophenyl)-3cyclopropyl-1-(2-methylpyridin-4-yl)propyl )-2-methylpropane-2-sulfinamide (266h) (0.8 g, 29.0% yield) as a reddish thick liquid; 1H NMR (DMSO- _d6 ) δ 8.36-8.34 (d, 1H), 7.24 (s, 1H), 7.127.10 (d, 1H), 6.95-6.91 (m, 1H), 6.76-6.72 (m,1H),6.59-6.50 (m, 1H), 5.38-5.32 (m, 1H), 5.11 (s, 2H) , 2.49 (s, 3H), 2.05-2.01 (m, 2H), 1.55-1.51 (m, 2H), 1.16 (s, 9H), 0.9-0 .85 (m, 1H), 0.39-0.37 (m, 2H), 0.03-0.09 (m, 2H); MC (IER+) 404.3 (M+1).

Step 8. Preparation of tert-butyl-3-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1(2-methylpyridin-4-yl)propyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-III-pyrazol-1yl)benzylcarbamate (266i).

Compound 266i was prepared from (R)-N-(1-(3-amino-4-fluorophenyl)-3-cyclopropyl-1-(2-methylpyridin4-yl)propyl)-2-methylpropane-2-sulfinamide (266h) ( 0.5 g, 1.238 mmol) and 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.573 g, 1.2 mmol) according to The method for preparing compound 208c described in step 3 of Scheme 208, after purification by column chromatography, gave tert-butyl-3-(5-(5-(3-cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)-1-( 2-methylpyridin-4-yl)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate (266i) (0.25 g, 26.2% yield) as a reddish thick liquids; 1H NMR (DMSO-d ₆ ) δ 10.66 (s, 1H), 8.42-8.40 (d, 1H), 7.65-7.49 (m, 2H), 7.48-7, 28 (m, 8H), 7.14 (s, 1H), 5.54 (s, 1H), 4.27-4.25 (d, 2H), 2.58 (s, 3H), 1.47 -1.45 (m, 2H), 1.5 (s, 9H), 1.34-1.31 (m, 2H) 1.2 (s, 9H), 0.85-0.71 (m, 1H), 0.45-0.35 (m, 2H), 0.03-0.01 (m, 2H); MS (IER+) 771.4 (M+1).

Step 9. Preparation of (+)-N-(5-(1-amino-3-cyclopropyl-1-(2-methylpyridin-4-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (266j).

Into a stirred solution of tert-butyl-3-(5-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(2-methylpyridin-4-yl)propyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)ben

- 413 045731 zylcarbamate (266i) (0.25 g, 0.324 mmol) in ethanol (5 ml) was added HCl (4N in MeOH, 20 ml) at room temperature. The resulting reaction mixture was heated to reflux temperature for 1 hour, cooled to room temperature and concentrated in vacuo. The resulting residue was purified twice by flash chromatography (silica, 12 g, eluted with mixtures of 0-100% CMA 80 in CHCl ₃ ) to give the free base (+)-N-(5-(1-amino-3-cyclopropyl-1 -(2-methylpyridin-4yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (266j) (65 mg, yield 35, 5%) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.53 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.57 (m, 2H), 7.50 ( m, 1H), 7.42 (m, 2H), 7.29 (m, 3H), 7.19 (d, J=9.6 Hz, 1H), 7.12 (d, J=6.6 Hz, 1H), 3.77 (s, 2H), 2.40 (s, 3H), 2.31 - 2.08 (m, 4H), 1.09 - 0.78 (m, 2H), 0 .70 - 0.52 (m, 1H), 0.40 - 0.27 (m, 2H), 0.03 - -0.14 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.73, -124.10; MC (IER+) 567.3 (M+1); 565.3 (M-1); optical rotation [a]D=(+) 12.38 [0.21, MeOH]. To a solution of free base 266j (50 mg, 0.088 mmol) in MeOH (3 mL) was added HCl (3N in MeOH) (0.588 mL, 1.765 mmol), stirred for 3 h at room temperature and concentrated to dryness in vacuo. The residue was taken up in water/ACN and lyophilized to give (+)-N-(5-(1-amino-3-cyclopropyl-1-(2methylpyridin-4-yl)propyl)-2-fluorophenyl)-1- hydrochloride salt. (3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxamide (266j) (56 mg, 94% yield) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.78 (s, 3H), 8.77 (d, J=5.9 Hz, 1H), 8.52 (s , 3H), 7.83 - 7.77 (m, 1H), 7.74 (m, 2H), 7.71 - 7.58 (m, 3H), 7.58 - 7.47 (m, 2H ), 7.40 (dd, J=7.0, 1.5 Hz, 2H), 4.11 (d, J=5.8 Hz, 2H), 2.65 (s, 3H), 2.63 - 2.50 (m, 2H), 1.32 - 0.94 (m, 2H), 0.67 (m, 1H), 0.48 - 0.24 (m, 2H), 0.01 (m , 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ 60.82, -119.73. MS (IER+) 567.3 (M+1), (IER-) 565.4 (M-1).

Scheme 267

An example of the preparation of (-)-N-(5-( 1 -amino-1 -(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1 -(3carbamoylphenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (267c).

Step 1. Preparation of 1-(3-(N-(tert-butoxycarbonyl)carbamidoyl)phenyl)-3-(trifluoromethyl)-1Hpyrazole-5-carboxylic acid (267a).

A solution of 1-(3-carbamidoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (236g) (1.2 g, 4.02 mmol) in MeOH-H ₂ O (50 ml, ratio : 1:2) (Boc) _2O (1.121 g, 4.83 mmol) and sodium hydroxide (0.322 g, 8.05 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. Additional (Boc) _2O (0.878 g, 4.02 mmol) was added and the resulting mixture was stirred for 8 hours, diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml) . The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0100% CMA-80 in chloroform) to give 1-(3-(N-(tert-butoxycarbonyl)carbamidoyl)phenyl)-3(trifluoromethyl)-1H -pyrazole-5-carboxylic acid (267a) (205 mg, 0.515 mmol, 12.79% yield) as a white solid; 1H NMR (300 MHz, DMSOL) δ 9.18 (s, 1H), 8.12 - 7.94 (m, 2H), 7.77 - 7.65 (m, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.13 (s, 1H), 1.45 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -60.45; MS (IER+): 399.4 (M+1), (IER-) 397.3 (M-1).

Step 2. Preparation of tert-butyl-(3-(5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl) -3-(trifluoromethyl)-1H-pyrazol-1yl)phenyl)(imino)methylcarbamate (267b).

In a solution of 1-(3-(N-(tert-butoxycarbonyl)carbamidoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5carboxylic acid (267a) (150 mg, 0.377 mmol) in THF (20 ml) at 0 °C, NMO (44.1 mg, 0.377 mmol), isobutyl chloroformate (153 mg, 1.125 mmol) was added and stirred at 0 °C for 1 h. (R)-N-((-)-1- (3-amino-4-fluorophenyl)-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2methylpropane-2-sulfinamide (214e) (156 mg, 0.377 mmol), lithium chloride (23.95 mg, 0.565 mmol) , re

- 414 045731 stirred at 0°C for 2 hours, quenched with water (10 ml) and extracted with ethyl acetate (3x20 ml). The organic layers were combined, dried, filtered and concentrated to dryness in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 12 g, eluted with mixtures of 0-100% EtOAc in hexanes) to give tert-butyl-(3-(5-(5-(1-(3-cyanophenyl)-3- cyclopropyl-1-((R)-1,1dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)(imino)methylcarbamate (267b) (88 mg, 0.111 mmol , yield 29.4%) as a white solid; ¹ H NMR (300 MHz, chloroform-d) δ 8.09 (m, 1H), 7.90 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.47 (m, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.20 (m, 1H), 7.04 (m, 1H), 6.99 - 6.92 (m, 1H), 2.58 (m, 2H), 1.49 (s, 9H), 1 .19 (s, 9H), 0.97 - 0.85 (m, 2H), 0.59 (m, 1H), 0.36 (m, 2H), -0.12 (m, 2H); MS (IER+): 794.6 (M+1); IR (KBr) 2232 cm ^-1 .

Step 3. Preparation of (-)-N-(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)-2-fluorophenyl)-1(3-carbamoylphenyl)-3-(trifluoromethyl)-1H -pyrazole-5-carboxamide (267c).

Into a solution of tert-butyl-(3-(5-(5-(1-(3-cyanophenyl)-3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)propyl)-2-fluorophenylcarbamoyl)-3 -(trifluoromethyl)-III-pyrazol-1-yl)phenyl)(imino)methylcarbamate (267b) (70 mg, 0.088 mmol) in EtOH (10 ml) added HCl (4N in dioxane) (0.220 ml, 0.882 mmol) and heated at reverse condensation temperature for 10 minutes. Concentrate the solution to dryness in vacuo and purify the resulting residue by flash column chromatography (silica gel, eluting with mixtures of 0-100% CMA 80 in chloroform) to give free base 267c (17 mg, 0.029 mmol) as a white solid. The free base was converted to the HCl salt using HCl (4N in dioxane, 0.1 ml) and lyophilization to give (-)-No(5-(1-amino-1-(3-cyanophenyl)-3-cyclopropylpropyl)2 -fluorophenyl)-1-(3-carbamoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (267c) (17 mg, 0.027 mmol, 30.7% yield) as a white solid; 1H NMR (300 MHz, DMSO- _d6 ) δ 10.73 (s, 1H), 9.26 (s, 3H), 8.16 (s, 1H), 8.04 - 7.98 (m, 2H ), 7.89 (dt, J=7.3, 1.4 Hz, 1H), 7.83 (s, 1H), 7.71 - 7.54 (m, 7h), 7.42 (dd, J=10.1, 8.8 Hz, 1H), 7.29 - 7.19 (m, 1H), 2.50 (dp, J=39.9, 1.8 Hz, 2H), 1.06 (tt, J=12.3, 5.3 Hz, 2H), 0.77 0.59 (m, 1H), 0.48 - 0.29 (m, 1H), -0.02 (s, 2H ); ¹⁹ F NMR (282 MHz, MeOH-d4) δ -64.55, -128.38; MS (IER+) 613.5 (M+Na); ICS (KBr) 2235 cm ^-1 ; analysis, calculation for C ₃₁ H ₂₆ F ₄ N ₆ O ₂ -HCl-2.75H ₂ O; C, 55.03; H, 4.84; N,

12.42; experiment: C, 55.30; H, 4.81; N, 12.00; optical rotation: [a]D=(-) 3.2 [0.125, MeOH]. Scheme 268

An example of the preparation of (+)-N-(5-( 1 -amino-3-cyclopropyl-1 -(pyridin-4-yl)propyl)-2-fluorophenyl)-1-( 1 aminoisoquinolin-7-yl)-5- (trifluoromethyl)-1H-pyrazole-3-carboxamide (268g).

Step 1. Preparation of ethyl 1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7-yl)-5(trifluoromethyl)-1H-pyrazole-3-carboxylate (268b) .

Copper complex (268a) (prepared according to Russian Chemical Bulletin, 1990, 1273-1277) (10.79 g, 41.4 mmol). The resulting mixture was cooled to 0°C, conc. HCl (15.10 g, 414 mmol) and stirred at room temperature overnight. Additional HCl (7.02 g, 193 mmol) was added and the reaction mixture was heated at reflux overnight, cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, eluted with mixtures of CMA 80 in chloroform, 0-70%) to give ethyl 1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole 3-carboxylate ( 268c) (1.90 g, 5.42 mmol, 13.10% yield) and ethyl 1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2dihydroisoquinolin-7-yl)-5- (trifluoromethyl)-1H-pyrazole-3-carboxylate (268b) (4.1 g, 8.19 mmol, 19.78% yield). 1H NMR (300 MHz, DMSO-de) δ 8.45 (s, 1H), 7.76 - 7.55 (m, 3H), 7.27 (d, J=7.4 Hz, 1H), 7 .06 (d, J=8.4 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.48 (dd, J=8.4, 2.3 Hz, 1H) , 6.21 (d, J=7.4 Hz, 1H), 4.97 (s, 2H), 4.35 (q,

- 415 045731

J=7.1 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 1.32 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -56.85.

Step 2. Preparation of ethyl 1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (268c).

Compound 268c was prepared from ethyl 1-(2-(2,4-dimethoxybenzyl)-1-imino-1,2-dihydroisoquinolin-7yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (268b) (4 .1 g, 8.19 mmol) according to the method for preparing compound 253a, described in step 1 of scheme 253, after purification by column chromatography (silica gel, eluted with mixtures of CMA 80 in chloroform, 0-40%) gave ethyl-1-(1- aminoisoquinolin7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (268c) (2.4 g, 6.85 mmol, 84% yield) as an off-white solid; 1H NMR (300 MHz, chloroform-d) δ 8.49 (s, 1H), 7.86 (q, J=8.6 Hz, 2H), 7.52 (d, J=6.5 Hz, 1H ), 7.36 (s, 1H), 7.02 (d, J=6.1 Hz, 1H), 4.38 (q, J=7.0 Hz, 2H), 1.34 (t, J =7.0 Hz, 3H).

Step 3. Preparation of ethyl 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (268d).

To a solution of ethyl 1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (268c) (1.90 g, 5.42 mmol) in acetonitrile (75 ml) was added DIPEA (4.74 ml, 27.1 mmol), Boc anhydride (3.55 g, 16.27 mmol), DMAP (0.066 g, 0.542 mmol) and stirred at room temperature overnight. Additional Boc anhydride (2.368 g, 10.85 mmol) was added and the reaction mixture was heated at 60°C for 4 hours. The reaction mixture was cooled to room temperature, Boc anhydride (1.776 g, 8.14 mmol) was added and heated at 50 °C overnight. The reaction mixture was evaporated to dryness, treated with brine (100 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over MgSO ₄ , filtered, evaporated to dryness and the resulting residue was purified by flash column chromatography (silica gel, 40 g, eluted with mixtures of 0-40% ethyl acetate in hexanes) to give ethyl-1-(1-(bis(tert) -butoxycarbonyl)amino)isoquinolin-7-yl)-5-(trifluoromethyl)1H-pyrazole-3-carboxylate (268d) (647 mg, 1.175 mmol, 21.67% yield) as a white semi-solid. ¹ H NMR (300 MHz, chloroform-d) δ 8.57 (d, J=5.7 Hz, 1H), 8.16 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.87 (dd, J=8.8, 2.0 Hz, 1H), 7.78 (d, J=5.7 Hz, 1H), 7.42 (s, 1H), 4, 48 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H), 1.32 (s, 18H).

Step 4. Preparation of 1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (268e).

In a solution of ethyl 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (268d) (544 mg, 0.988 mmol) in To a mixture of THF/H ₂ O (30 ml, ratio: 3:1) at room temperature, lithium hydroxide monohydrate (415 mg, 9.88 mmol) was added and heated at 67°C overnight. The reaction mixture was diluted with EtOAc (35 ml), the organic layer was separated and the aqueous layer was acidified with conc. HCl to pH 2. The resulting white precipitate was collected by filtration, washed with water (2x5 ml), dried in vacuum to give 1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3carboxylic acid (268e ) (295 mg, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 7.98 - 7.86 (m, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.61 (s, 1H), 7.25 (s, 2H), 7.06 (d, J=5.7 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -56.71; MS (IER+) 323 (M+1), (IER-) 321 (M-1).

Step 5. Preparation of 1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-((R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl )-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide (268f).

Compound 268f was prepared from 1-(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1H-pyrazole-3carboxylic acid (268e) (100 mg, 0.310 mmol) and (R)-N-((-)- 1-(3-amino-4-fluorophenyl)-3-cyclopropyl1-(pyridin-4-yl)propyl)-2-methylpropan-2-sulfinamide (216b) (121 mg, 0.310 mmol) using the method described in step 3 of Scheme 208, after purification by column chromatography (silica gel, eluted with mixtures of 0-40% CMA 80 in CHCl ₃ ), 1-(1-aminoisoquinolin-7-yl)-K-(5-(3-cyclopropyl-1-( (R)-1,1-dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-5-(trifluoromethyl)1H-pyrazole-3-carboxamide (268f) (120 mg) which was used in this form without additional purification.

Step 6: (+)-N-(5-(1-Amino-3-cyclopropyl-1-(pyridin-4-yl)propyl)-2-fluorophenyl)-1-(1 aminoisoquinolin-7-yl)-5 -(trifluoromethyl)-1H-pyrazole-3-carboxamide (268g).

Into a solution of 1-(1 -aminoisoquinoline-7 -ul)-N-(5-(3 -cyclopropyl-1 -((R)-1,1 -dimethylethylsulfinamido)-1-(pyridin-4-yl)propyl)- 2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide (268f) (120 mg, 0.173 mmol) in ethanol (10 ml) was added with HCl (32 mg, 0.865 mmol) and heated at the reflux temperature in for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and purified by flash column chromatography (silica gel, eluted with mixtures of chloroform in CMA 80, 0-40%) to give (+)-N-(5-(1- amino-3-cyclopropyl-1-(pyridin-4yl)propyl)-2-fluorophenyl)-1 -(1-aminoisoquinolin-7-yl)-5-(trifluoromethyl)-1 H-pyrazole-3-carboxamide (268g) (7 mg, 0.012 mmol, 6.86% yield) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 8.54 (d, J=2.3 Hz, 1H), 8.49 - 8.41 (m, 2H), 7.96 -7.89 (m, 2H), 7.86 - 7.76 (m, 1H), 7.68 (s, 1H), 7.63 (dd, J=7.5, 2.4 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.32 (m, 1H), 7.19 (dd, J=10.2, 8.6 Hz, 1H), 7.03 (d, J=5.1 Hz, 3H), 2.34 (s, 2H), 2.23 (m, 2H), 1.06 (m, 2H), 0.64 (m, 1H), 0 .44 - 0.31 (m, 2H), -0.01 - -0.15 (m, 2H); ¹⁹ F NMR

- 416 045731 (282 MHz, DMSO) δ -56.82, -124.34; MS (IER+) 590.3 (M+1); (IER-) 588.3 (M-1); optical rotation:

[a]D=(+) 10.67 [0.225, MeOH].

Scheme 269

269a ^269b

An example of the preparation of 1 -(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopronyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2 -fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (269b).

Step 1. Preparation of 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-N-(5-(3-cyclopropyl-1 -(2,4-dioxo-3,4-dihydropyrimidine- 1 (2H)-yl)propyl)-2-fluorophenyl)-3 -(trifluoromethyl)-1Hpyrazol-5-carboxamide (269a).

Compound 269a was prepared from 1-(1-(3-amino-4-fluorophenyl)-3-cyclopropylpropyl)-pyrimidine2,4(1H,3I)-dione (263b) (163 mg, 0.537 mmol) and 1-(1- (bis(tert-butoxycarbonyl)amino)isoquinolin-7yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (253c) (337 mg, 0.645 mmol) according to the method for preparation of compound 208c described in step 3 of scheme 208 , after purification by flash column chromatography [silica gel, 40 g, eluted with mixtures of 0-90% EtOAc/MeOH (9:1, v/v) in hexane] gave 1-(1-(bis(tert-butoxycarbonyl)amino) isoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl) -1H-pyrazole-5-carboxamide (269a) (55 mg, 0.068 mmol, 12.7% yield) as a white solid; MS (IER ⁺ ) 830.4 (M+Na); (IER ^- ) 806.4 (M-1).

Step 2. Preparation of 1-(1-aminoisoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl) -2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (269b).

Into a solution of 1-(1-(bis(tert-butoxycarbonyl)amino)isoquinolin-7-yl)-N-(5-(3-cyclopropyl-1-(2,4dioxo-3,4-dihydropyrimidine-1 (2H) -yl)nponyl)-2-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (269a) (55 mg, 0.068 mmol) in MeOH (15 ml) was added HCl (3N in MeOH) ( 0.45 ml, 1.36 mmol) and stirred at room temperature overnight. Concentrate the reaction mixture in vacuo and purify the resulting residue by flash column chromatography (silica gel, 24 g, eluted with mixtures of 0-40% CMA 80 in CHCl ₃ ) to give 1-(1-aminoisoquinolin-7-yl)-K-(5 -(3cyclonropyl-1-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)1H-nirazole-5-carboxamide (269b) ( 9.0 mg, 0.015 mmol, 41.4% yield) as a white solid; 1H NMR (300 MHz, DMSO-d ₆ ) δ 11.36 (s, 1H), 10.60 (s, 1H), 8.42 (s, 1H), 7.88 (d, J=5.7 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.74 - 7.63 (m, 3H), 7.52 (d, J=7.2 Hz, 1H), 7.29 (d, J=7.9 Hz, 2H), 6.98 (m, 3H), 5.57 (m, 2H), 2.31-1.98 (m, 2H), 1.32 - 0.95 (m, 2H), 0.78 - 0.57 (m, 1H), 0.47 - 0.29 (m, 2H), 0.13 - -0.12 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.73, -121.27.

Scheme 270

42b (-)-isomer 270a (-)-isomer

An example of the preparation of (-)-N-(5-((cyclopropylmethylamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-((ethylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-carboxamide (270a).

Into a solution of (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopronylmethylamino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (42b) (0.25 g, 0.46 mmol) in MeOH (10 mL) was added with acetaldehyde (0.16 mL, 2.8 mmol) and stirred at room temperature for 10 min. Sodium borohydride (0.035 g, 0.93 mmol) was added to the reaction mixture and stirring continued at room temperature for 6 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2x40 ml). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography [silica gel, 24 g, eluted with mixtures of 0-30% CMA 80 in chloroform] to give free base 270a (0.11 g, 0.194 mmol, 41.8% yield) as a white solid; 1H NMR (300 MHz, DMSO

- 417 045731 d ₆ ) δ 10.53 (s, 1H), 7.63 (d, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.50 - 7.24 (m , 9H), 7.22 - 7.14 (m, 2H), 4.83 (s, 1H), 3.73 (s, 2H), 2.45 (m, 2H), 2.26 (d, J=6.6 Hz, 2H), 0.96 (m, 4H), 0.43 - 0.30 (m, 2H), 0.04 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -60.54, -123.79; MS (IER+) 566.4 (M+1); MS (ESI-) 564.4 (M-1), 600.3 (M+Cl); The free base (0.7 g) was converted to the HCl salt using 3N. HCl (5 eq.) to give (-)-N-(5-((cyclopropylmethylαamino)(phenyl)methyl)-2-fluorophenyl)-1-(3-((ethylamino)methyl)phenyl)-3-( trifluoromethyl)-1H-pyrazole-5-carboxamide (270a) as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.16 (s, 2H), 9.20 (s, 2H), 7.94 (d, J=7.2 Hz , 1H), 7.80 - 7.11 (m, 12H), 5.75- 5.57 (m, 1H), 4.21 (t, J=5.8 Hz, 2H), 3.05- 2.83 (m, 2H), 2.70 (m, 2H), 1.18 (m, 4H), 0.60 - 0.50 (m, 2H), 0.29 (m, 2H); optical rotation: [a] _D =(-) 3.57 [0.28, MeOH].

Example 271.

Study of plasma kallikrein activity. The effect of the compounds of the present invention on human plasma kallikrein activity was determined using chromogenic substrates (DiaPharma Group, Inc., West Chester, OH, USA). In these experiments, 2 nM kallikrein (Enzyme Research Laboratories, South Bend, IN, USA) was co-incubated with 80 µM S2302 (HD-Pro-Phe-Arg-p-nitroaniline) together with the compounds of the present invention in increasing concentrations or without them in Tris-HCl buffer (200 mM NaCl; 2.5 mM CaCl ₂ ; 50 mM TrisHCl, pH 7.8) with a final volume of 200 μl.

After incubation at 30°C, kallikrein activity was measured by the change in absorbance at OD 405 nm using a BioTek PowerWave X340 microplate analyzer (Winooski, VT, USA). Data were analyzed using SigmaPlot software (Systat Software, Inc., San Jose, CA, USA) (four-parameter logistic curve). Ki values for inhibitors were determined using the Cheng-Prusow equation (Biochem. Pharmacol. 1973, 22, 3099).

The compounds provided herein had Ki values for the plasma kallikrein enzyme of less than 1 micromolar (μM). See table.

Measured Ki values of connections

Compound Ki (nM) 161e >100 162s >100 163g >100 17d >100 18f >100 19d >100 20d >100 18g >50-100 22b >100

Compound Ki (nM) 23c >100 24c >100 25b >50-100 25c >100 26f >100 18i >50-100 18h >50-100 21e >100 18j >100

Compound Ki(nM) 18k 0.1-50 27f >50-100 28f >100 29e 0.1-50 30g >100 31f >100 32f >50-100 33e >100 33f >100

- 418 045731

34d >100 35g >50-100 34c 0.1-50 18e >100 81c >100 39e >100 40b >100 41e 0.1-50 74a 0.1-50 75a >50-100 38d 0.1-50 76h >100 36d 0.1-50 77e 0.1-50 43f 0.1-50 44c 0.1-50 78d 0.1-50 79f 0.1-50 80h 0.1-50 87f 0.1-50 88b 0.1-50 82f 0.1-50 83c 0.1-50 46g 0.1-50 205f >100 89g 0.1-50 91a 0.1-50 86g 0.1-50 45g 0.1-50 47f 0.1-50 92g 0.1-50 84h 0.1-50 85c 0.1-50 93b >100 94b 0.1-50 95i 0.1-50 96f 0.1-50 48f 0.1-50 164e 0.1-50 97f >100 98b 0.1-50 99g 0.1-50 lOOe 0.1-50 lOle 0.1-50 102b 0.1-50 103b 0.1-50 104f 0.1-50 105g 0.1-50 49h 0.1-50

106a 0.1-50 5 Of 0.1-50 107f 0.1-50 108e 0.1-50 109f 0.1-50 IlOf 0.1-50 lllf 0.1-50 H2g 0.1-50 113f 0.1-50 114f 0.1-50 115e >50-100 116e 0.1-50 117e 0.1-50 118f 0.1-50 119e 0.1-50 120e 0.1-50 122g 0.1-50 121f 0.1-50 123g 0.1-50 124f 0.1-50 51f 0.1-50 125g 0.1-50 126g 0.1-50 127f 0.1-50 128g 0.1-50 129f 0.1-50 130g 0.1-50 131b 0.1-50 132f 0.1-50 133g 0.1-50 134f 0.1-50 135c 0.1-50 136a >100 137a 0.1-50 137b >100 138f 0.1-50 52h 0.1-50 139b 0.1-50 140e 0.1-50 167f >100 141e 0.1-50 142f 0.1-50 1431 0.1-50 144d 0.1-50 145c >100 146g 0.1-50 147e 0.1-50 148b 0.1-50 149b 0.1-50

53f 0.1-50 150f 0.1-50 153b 0.1-50 151g 0.1-50 152d 0.1-50 154e 0.1-50 155c 0.1-50 156c 0.1-50 54e 0.1-50 55b 0.1-50 58c 0.1-50 56c 0.1-50 68c 0.1-50 61e 0.1-50 59c 0.1-50 57e 0.1-50 60e 0.1-50 71a 0.1-50 71b 0.1-50 65a 0.1-50 65b 0.1-50 192f 0.1-50 168b 0.1-50 169b >100 170b >100 171b >100 172b >100 173b >100 174b >100 175b >100 176b >100 177b >100 178b >100 179b >100 180b >100 181b >100 182b >100 183b >100 184b >100 185b >100 186b >100 187b >100 188b 0.1-50 189b >100 190b >100 193f 0.1-50 191b >100 195f 0.1-50 196f 0.1-50

- 419 045731

197f 0.1-50 198f 0.1-50 194f 0.1-50 199f 0.1-50 200f 0.1-50 201f 0.1-50 202f 0.1-50 203f >100 157a >100 158a >100 159a >100 160a >100 207j 0.1-50 247c 0.1-50 247e 0.1-50 248) 0.1-50 249b 0.1-50 250c 0.1-50 252c 0.1-50 251e >50-100 260b 0.1-50 262f 0.1-50 263d 0.1-50 15g >100 16b >100 90f >100 166e 0.1-50 165e 0.1-50 50g 0.1-50 50h 0.1-50 43g 0.1-50 43h 0.1-50 44d 0.1-50 44e 0.1-50 47g 0.1-50 47h 0.1-50 46h 0.1-50 46i 0.1-50 48g 0.1-50 48h 0.1-50 51g 0.1-50 51h 0.1-50 64a 0.1-50 64b 0.1-50 49i 0.1-50 49j 0.1-50 42b 0.1-50 42a 0.1-50 67a 0.1-50

67b 0.1-50 70a 0.1-50 70b 0.1-50 69a 0.1-50 69b 0.1-50 68d 0.1-50 68e 0.1-50 63a 0.1-50 63b 0.1-50 73a 0.1-50 73b 0.1-50 72s 0.1-50 72d 0.1-50 66a 0.1-50 66b 0.1-50 37b 0.1-50 37a 0.1-50 206d 0.1-50 205d 0.1-50 205e 0.1-50 208d 0.1-50 209d 0.1-50 210d 0.1-50 211d 0.1-50 212g 0.1-50 214g 0.1-50 213d 0.1-50 222k >100 223f >100 220f 0.1-50 224b >100 225a 0.1-50 226a >100 227d 0.1-50 228a 0.1-50 229i 0.1-50 230a >100 231d 0.1-50 232a >100 246f 0.1-50 234d >100 235g 0.1-50 218c 0.1-50 219c 0.1-50 239d >100 267c >100 240b 0.1-50 23 6h 0.1-50 237a 0.1-50

238c 0.1-50 241a 0.1-50 215d >100 238d 0.1-50 221i 0.1-50 216d 0.1-50 243a 0.1-50 217d >50-100 244g 0.1-50 244h 0.1-50 244i 0.1-50 244j 0.1-50 244k 0.1-50 253e 0.1-50 245c 0.1-50 257b 0.1-50 254c 0.1-50 255a 0.1-50 265d 0.1-50 256a 0.1-50 268g >50-100 258g 0.1-50 2481 0.1-50 248k 0.1-50 264g 0.1-50 261k 0.1-50 259d 0.1-50 266j 0.1-50 269b 0.1-50 270a >50-100

Equivalents

The above description is considered to be sufficient to enable the invention to be practiced by those skilled in the art. The scope of the present invention is not limited to the examples provided, as the examples are offered solely as an illustration of one aspect of the invention, and other functionally equivalent embodiments are included within the scope of the invention. Various modifications of the invention other than those shown and described in the present invention will be apparent to those skilled in the art upon examination of the foregoing description and are included within the scope of the appended claims. The advantages and objectives of the invention need not be covered in every embodiment of the invention.

Claims (16)

1. The compound or a pharmaceutically acceptable salt thereof represented by formula XXVI (XXVI) - 420 045731 where X represents CH, -C(NH2) or -C(NR ^a R ^b ); -YR ⁴ is -((C1-C6)alkyl)-R ⁴ , -NH-R ⁴ or -NHCH2-R ⁴ , where the (C1-C ₆ )alkyl moiety is -((C ₁ -C ₆ )alkyl )-R ⁴ is optionally substituted; Z represents halogen; R ^1c represents -NH2; R2 is fluoro(C ₁ -C ₆ )alkyl; R ³ represents optionally substituted aryl or heteroaryl; R ^3a is absent or cyano; And R ⁴ is an optionally substituted (C ₃ -C ₈ )cycloalkyl or (C ₃ -C ₈ )cycloalkyl (C ₁ -C ₆ )alkyl; R ^a and R ^b are independently H or -S(O)2R ^c ; R ^c represents (C ₁ -C ₈ )alkyl; and any chiral center has an R-, S- stereochemical configuration or a mixture of R- and S-; wherein aryl is an aromatic ring selected from the group consisting of phenyl, naphthyl, anthracenyl and phenanthrenyl; and heteroaryl is a monocyclic aromatic ring containing one or more heteroatoms in the ring, selected from the group consisting of N, O and S; and wherein any optional substituent is selected from halogen, (C ₁ -C ₈ )alkyl, aryl (C ₁ -C ₈ )alkyl, hydroxyl, (C ₁ -C ₈ )alkoxy, amino, oxo (=O) and cyano. 2. A compound according to claim 1, characterized in that X represents CH or -C(NH2). 3. A compound according to claim 1, characterized in that Z represents fluorine. 4. A compound according to claim 1, characterized in that R ^c represents (C ₁ )alkyl. 5. The compound according to claim 1, characterized in that R ² represents CF ₃ . 6. A compound according to claim 1, characterized in that R ³ represents optionally substituted phenyl or pyridinyl. 7. A compound according to claim 1, characterized in that R ^3a is cyano. 8. A compound according to claim 1, characterized in that -YR ⁴ is -((C ₁ -C ₆ )alkyl)-R ⁴ or -NHCH2-R ⁴ . 9. A compound according to claim 1, characterized in that R ⁴ represents an optionally substituted (C ₃ -C ₈ )cycloalkyl. 10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from the group consisting of - 421 045731 11. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of 12. A pharmaceutical composition containing a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease or condition characterized by undesirable plasma kallikrein activity. 14. Use according to claim 13, characterized in that the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, condition caused by fibrinolytic treatment, angina pectoris , edema, angioedema, hereditary angioedema, sepsis, arthritis, bleeding, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin secretion, macroalbuminuria and nephropathy. 15. Use according to claim 13, characterized in that the disease or condition characterized by the undesirable activity of plasma kallikrein is angioedema. 16. Use according to claim 13, characterized in that the disease or condition characterized by the undesirable activity of plasma kallikrein is hereditary angioedema.