WO2013165606A1

WO2013165606A1 - Modulators of the relaxin receptor 1

Info

Publication number: WO2013165606A1
Application number: PCT/US2013/032231
Authority: WO
Inventors: Juan Jose Marugan; Jingbo Xiao; Marc FERRER-ALEGRE; Catherine Chen; Noel Southall; Wei Zheng; Alexander AGOULNIK; Irina AGOULNIK
Original assignee: The United States Of America, As Represented By The Secretary, Department Of Health And Human Services; The Florida International University Board Of Trustees
Priority date: 2012-05-04
Filing date: 2013-03-15
Publication date: 2013-11-07
Also published as: EP2844345B1; US10125112B2; ES2929283T3; US20170144984A1; US9452973B2; US20150119426A1; EP2844345A1

Abstract

Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R¹, and R² are as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1.

Description

MODULATORS OF THE RELAXIN RECEPTOR 1

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application No. 61/642,986 filed May 4, 2012, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made in part with government support from the National Institutes of Health. The government has certain rights in this invention.

BACKGROUND

[0001] The peptide hormone relaxin was discovered in 1926 as a hormone of pregnancy, due to its effects to relax pubic ligaments and soften the cervix to facilitate parturition (Hisaw, F ., Proc. Soc. Exp. Biol. Med. 1926, 23(8), 661-663; Fevold. H.L. et al, J. Am. Chem. Soc. 1930, 52(8), 3340-3348). Since then, it has been shown that blood concentrations of relaxin rise during the first trimester of pregnancy, promoting cardiovascular and renal adjustments to meet the increased nutritional demands of the growing fetus, and the elevated requirements for renal clearance of metabolic wastes (Baylis. C, Am. J. Kidney Dis. 1999, 34, 1142-4). Relaxin induces a 20% increase in cardiac output, 30% decrease in systemic vascular resistance, 30% increase in global arterial compliance, and 45% increase in renal blood flow during pregnancy (Schrier, R. W. et al, Am. J. Kidney Dis. 1987, 9, 284-9).

Numerous clinical and nonclinical studies using this hormone have now recapitulated these cardiovascular effects in both males and females, demonstrating the pharmacological utility of relaxin in modulating cardiovascular and renal functions in humans.

[0002] The X-ray crystal structure of relaxin at 1.5 A resolution was reported for the physiologically active form of the human hormone in 1991. The physiological effects of relaxin are mediated by its interaction with a G protein-coupled receptor (RXFPl) leading to the modulation of several signal transduction pathways. Activation of RXFPl by relaxin induces: 1) up-regulation of the endothelin system which leads to vasodilation; 2)

extracellular matrix remodeling through regulation of collagen deposition, cell invasiveness, proliferation, and overall tissue homeostasis; 3) a moderation of inflammation by reducing levels of inflammatory cytokines, such as TNF-a and TGF-β; and 4) angiogenesis by activating transcription of VEGF. The understanding of the biological effects of RXFP1 activation by relaxin has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure (AHF), pre- eclampsia, and hypertensive disease. In addition, several clinical trials studied the therapeutic role of relaxin in treatment of scleroderma, cervical ripening, fibromyalgia, and orthodontics, given its function as antiinflammatory and extracellular matrix remodeler.

[0003] The latest statistics indicate that 1 of every 2.9 deaths in the United States is due to cardiovascular disease (CVD) (Roger, V.L. et al, Circulation 2011, 123(4), 459-463). Each year, ~ 795,000 people experience a new or recurrent stroke, and 1 in 9 death certificates in the United States mention heart failure. In addition, 33.5% of US adults over 20 years of age have hypertension. These statistics clearly illustrate the limitations of current therapies to address CVD in general and acute heart failure (AHF) in particular. The significant contribution of vascular dysfunction to the pathophysiology of AHF has more recently been recognized. These patients are characterized by preserved or elevated systolic blood pressure and increased vascular stiffness with less fluid overload. They are more likely to be elderly and female. Large-scale registry studies suggest that patients with vascular dysfunction causing AHF represent the majority of patients, and that this may have been underappreciated during previous development of new therapies.

[0004] Therapeutically, there is a great medical need for better approaches to treat heart failure. Currently, there are two major methodologies: a) surgery and medical devices:

coronary bypass surgery, heart valve repair or replacement, implantable cardioverter- defibrillators (ICDs), heart pumps (left ventricular assist devices, or LVADs), or heart transplant; b) medications: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), digoxin (lanoxin), beta blockers and aldosterone antagonists. Importantly, none of these approaches are able to address the development of scar heart tissue after severe heart failure, or repair it after damage. In that sense the anti-fibrotic and remodeling properties of relaxin, together with its capacity to normalize blood pressure, increase blood and renal flow, while it promotes decongestion and vascular compliance, seem to be ideal for treating these conditions. Clinical data agrees with this theory (Teichman S.L. et al, Curr. Heart Failure Rep. 2010, 7, 75-82). Relaxin relieves systemic and renal vasoconstriction and increases vascular compliance, including normalization of high blood pressure, reduction of pulmonary capillary wedge pressure, increase of cardiac output, increase renal blood flow, natriuresis, and decongestion. In addition, animal pharmacology data indicate that relaxin hormone has anti-inflammatory and cardiac protection effects, including reduction of myocardial ischemia, reduction of reperfusion injury, increase of wound healing, and reduction of ventricular fibrosis.

[0005] Recombinant relaxin hormone has produced excellent responses in clinical trials for treatment of heart failure and is about to reach commercialization. However,

administration of the peptide is difficult in chronic settings. In view of the foregoing, there is an unmet need for new small molecule agonists of the RXFP1 receptor.

SUMMARY

[0006] The invention provides a compound of the formula (I):

wherein A is 1 ,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or -CH₂CH₂-, wherein the 1 ,2-phenylenyl, 1,2-heteroarylenyl, and 1,2-heterocyclyl are optionally substituted with one or more substituents independently selected from halo, CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR⁷, -SOR⁷, -S0₂R⁷, -SCF₃, and S0₂CF₃,

Ri is -NHCOR₃, R₄, -NHR₅, or -OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, orphenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, trihalo C1-C10 alkyl, perhalo C1-C10 alkyl, trihalo C1-C10 alkyloxy, perhalo C1-C10 alkyloxy, aryl, trihalo alky laryl, perhaloalkylaryl, heterocyclylalkyl, - SR⁷, -SOR⁷, -S0₂R⁷, -SCF₃, -N0₂, -CN, and -S0₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl, arylalkyl, or phenyl, which are optionally substituted with one or more substituents independently selected from t halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, Ci-Ciohalo alkyl,

Ci-Ciohaloalkoxy, -SR⁷, -SOR⁷, -S0₂R⁷, -SCF₃, -N0₂,-CN, and -S0₂CF₃,

R₄ is phenyl optionally substituted with alkyloxy, haloalkoxy,, arylalkyl, or arylalkyloxy, R₅ is hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, or cycloalkylalkyl which are optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl,

is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl,

and R7 IS C1-C10 alkyl, Ci-Cio haloalkyl, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy.

[0007] The disclosure also provides a pharmaceutical composition comprising a compound or salt of the invention and a pharmaceutically acceptable carrier.

[0008] The disclosure further provides a method for therapeutic intervention in a facet of mammalian health that is mediated by a mammalian relaxin receptor 1 , comprising administering an effective amount of the compound on the disclosure to a mammal afflicted therewith. In some embodiments the mammal is a human and the mammalian relaxin receptor 1 is a human relaxin 1 receptor.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0009] Figure 1 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0010] Figure 2 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0011] Figure 3 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0012] Figure 4 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0013] Figure 5 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0014] Figure 6 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0015] Figure 7 depicts synthetic schemes for the preparation of compounds in accordance with embodiments of the disclosure.

[0016] Figures 1-7 depict synthetic schemes for the preparation of embodiments of the disclosure. [0017] Figure 8 depicts the cell impedence observed for representative embodiments of the disclosure.

[0018] Figure 9 depicts the results of substitution of mouse sequence with human sequence on activation of cAMP in accordance with an embodiment of the disclosure.

[0019] Figure 10 depicts the activiation of relaxin receptors from human, monkey, pig, and mouse by compound 178.

[0020] Figure 11 depicts the identification of a human RXFP1 region responsible for activation by compound 178.

DETAILED DESCRIPTION

[0021] The disclosure provides a compound of the formula (I):

wherein A is 1 ,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or -CH₂CH₂-, wherein the 1 ,2-phenylenyl, 1,2-heteroarylenyl, and 1,2-heterocyclyl are optionally substituted with one or more substituents independently selected from halo, CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and S0₂CF₃,

Ri is -NHCOR₃, R₄, -NHR₅, or -OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, or phenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, aryl, halo alky laryl, heterocyclylalkyl, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂, -CN, and -S0₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl, arylalkyl, or phenyl, each of which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy„ -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂,-CN, and -S0₂CF₃,

R₄ is phenyl optionally substituted with alkyloxy, haloalkyloxy, arylalkyl, or arylalkyloxy,

R₅ is hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, or cycloalkylalkyl which are optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl, Re is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl,

and R₇ is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, Ci-Ciohaloalkyl or Ci-Ciohaloalkoxy, with the provisos that:

(i) when R₃ is methyl, chloromethyl, or dichloromethyl, and A is 1 ,2-phenylenyl, then R₂ is not methyl, phenyl, 2-methylphenyl, 2-methoxyphenyl, or 4-methoxyphenyl; and

(ii) when R₃ is phenyl, and A is 1 ,2-phenylenyl, then R₂ is not halophenyl, methoxyphenyl, 2,6-dimethylphenyl, or 2,4,6-trimethylphenyl; and

(iii) when R₃ is phenyl substituted with alkyl, and A is 1 ,2-phenylenyl, then R₂ is not methoxyphenyl;

or a pharmaceutically acceptable salt thereof.

[0022] In accordance with certain embodiments, R₂ is phenyl substituted with a substituent selected from -S0₂CF₃, -SCF₃, and -CF3.

[0023] In accordance with certain embodiments, A is 1 ,2-phenylene optionally substituted with one or more substituents selected from hydrogen, halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0024] In accordance with certain embodiments, Rl is -NHCOR3, wherein R3 is phenyl substituted with a substituent selected from -CF₃, Ci-Cioalkyl, C₁-C₁₀ alkyloxy,

Ci-Ciohaloalkyl, Cl-Ciohaloalkoxy, alkyloxyalkyloxy, dimethylamino alkyloxy, - SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0025] In accordance with certain preferred embodiments, R₃ is

2-(Ci-Cio)alkyloxyphenyl.

[0026] In accordance with certain preferred embodiments, R2 is phenyl substituted with a substituent selected from -CF₃, Ci-Cioalkyl, C₁-C₁₀ alkyloxy, Ci-Ciohaloalkyl,

Cl-ClOhaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0027] In certain preferred embodiments, the compound is selected from the group consisting of:

[0028] In accordance with certain embodiments, Ri is R4, wherein R4 is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio) haloalkyloxyphenyl.

[0029] In accordance with certain preferred embodiments, Ri is -NHR₅, wherein R5 is aryl optionally substituted with one or more substituents selected from alkyloxy and trifluoromethyl. [0030] In accordance with certain embodiments, Ri is -OR₆, wherein R^ is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl.

[0031] In accordance with certain embodiments, A is 1 ,2-heteroarylenyl optionally substituted with one or more subsitutents independently selected from halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0032] In accordance with certain preferred embodiments, A is selected from

[0033] In accordance with certain preferred embodiments, Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from the group consisting of -CF₃, Ci-Cio alkyl, Ci-Cio alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0034] In accordance with certain preferred embodiments, R₃ is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

[0035] In certain preferred embodiments, wherein the compound is selected from the group consisting of:

[0036] In accordance with certain embodiments, A is tCH ₂CH₂-.

[0037] In accordance with certain embodiments, wherein Ri is -NHCOR3, wherein R₃ is phenyl substituted with a substituent independently selected from -CF₃, C₁-C₁0 alkyl, C₁-C₁0 alkyloxy, Ci-Ciohalo alkyl, Ci-Ciohaloalkoxy„ -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0038] In accordance with certain embodimenst, R₃ is 2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

[0039] In accordance with a particular embodiment, the compound is:

[0040] The disclosure provides compounds and pharmaceutically acceptable thereof, having the formula (Formula X)

is a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, each of which A ring is optionally fused to a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, to form a bicylic ring system; and the A ring and 3 Qo 8--membered carbocyclic or heterocyclic ring to which A is optionally fused are each substituted with R₁₀; , and p are integers independently chosen from 0, 1, and 2 and each

n ,

, and P , is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, Ci-C₂alkyl, and Ci-C₂alkoxy;

X and Y are independently chosen from O and S;

Rs and R9 are independently chosen from hydrogen and Ci-C₄alkyl;

Rio, R21 , and R31 are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂₀ is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Ciocarbyhdryl or Ci-Ciohaloalkyl;

R30 is hydrogen or R₃₀ is Ci-Cscarbhydryloxy or Ci-Cscarbhydrylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci-C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy. [0041] In another embodiment the disclosure includes a compound or salt of Formula X

where

is a phenyl or 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently chosen from N, O, and S, each of which A ring is optionally fused to 5- or 6-membered carbocyclic or heterocyclic ring to form a bicylic ring system; and the A ring and 5- or 6-membered carbocyclic or heterocyclic ring to which A is optionally fused are each substituted with R₁₀.

[0042] The disclosure includes compounds or salts for Formula X where

is a group of formula

each of which is substituted with R₁₀.

[0043] The disclosure includes compounds or salts for Formula X, wherein m, n, o, and p are all 0 and X and Y are both O.

The disclosure includes compounds or pharmaceutically salts for Formula XI

(Formula XI) where:

Rio, R₂₁, and R₃i are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, d-Gtalkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, d-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂₀ is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Cioalkyl or Ci-Ciohaloalkyl; R30 is hydrogen or R₃₀ is Ci-Csalkoxy or Ci-Csalkylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci- C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0044] The disclosure includes compounds and salts of Formula XI, wherein R₂o is Ci- Cehaloalkyl, -S(Ci-C₆haloalkyl), or SO ₂(Ci-C₆haloalkyl).

[0045] The disclosure includes compounds and salts of Formula XI, wherein Rio, R₂₁, and R31 are each 0 substituents.

[0046] The disclosure includes compounds and salts of Formula XI, wherein Rio, R₂₁, and R31 are each 0 substituents; R₂₀ is CF₃, SCF₃, or S0₂CF_3i and R30 is C₂-C₆alkoxy or C₂- Cealkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and STF 3.

[0047] The disclosure includes compounds and salts of Formula XI, wherein R₂o is

[0048] The disclosure includes compounds and salts of Formula XII

(Formula XII) where:

Rio and R₃₁ are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy; and

R₂ is (phenyl)Co-C₂alkyl- or (5- or 6-membered heteroaryl)Co-C₂alkyl, each of which is substituted with 0 or 1 or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-Cealkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇Cycloalkyl)Co-C₂alkyl, 5- and 6-membered heterocycloalkyl, thienyl, phenyl, phenyl substituted with CF₃, mono- and di-Ci-Cealkylamino, Ci -Cealkylthio, Ci-Cealkylsulfonyl Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy, -SR7, -SOR₇, and -SO₂R₇, where R₇ is Ci-Ciocarbhydryl or Ci-Ciohaloalkyl; or

R₂ is dihydroindenyl, benzo[<i][l,3]dioxolyl, or indolyl, each of which is substituted with 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- or di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and - C₂haloalkoxy.

[0049] The disclosure includes compounds and salts of Formula XII, wherein R₁₀ and R31 are both 0 substituents.

[0050] The disclosure includes compounds and salts of Formula XII, wherein

R₂ is phenyl substituted with one or two substituents independently chosen from hydroxyl, halogen, nitro, SCF₃, SO₂CF₃, Ci-Cealkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 5- and 6- membered heterocycloalkyl, thienyl, phenyl, phenyl substituted with CF₃, mono- and di-Ci- Cealkylamino, Ci-Cealkylthio, Ci-Cealkylsulfonyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci- C₂haloalkoxy.

[0051] The disclosure includes compounds and salts of Formula XII, wherein R₂ is phenyl substituted in the meta position with CF₃, SCF₃, or S0₂CF₃.

[0052] The disclosure includes compounds and salts of Formula XII, wherein

R₂ is 2,3-dihydro-lH-indenyl, benzo[<i][l,3]dioxolyl, or indolyl, each of which is unsubstituted.

[0053] The disclosure includes compounds and pharmaceutically acceptable salts of Formul

(Formula XIII); where:

Rio and R₂₁ are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂₀ is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Ciocarbhydryl or Ci-Ciohaloalkyl;_; and

R₃ is cyclohexyl; or

R₃ is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SC>₂CF₃, Ci-Cealkyl, C₂-Cealkenyl, C₂- Cealkynyl, phenyl mono- and di-Ci-Cealkylamino, Ci-Cealkylthio, Ci-Cealkylsulfonyl Ci- C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy. [0054] The disclosure includes compounds and salts of Formula XIII, wherein R₁₀ and

R21 are both 0 substituents and R₃ is phenyl substituted with one meta-position substituent.

[0055] The disclosure includes compounds and salts of Formula XIII, wherein R₁₀ and

R21 are both 0 substituents and R20 is CF₃, SCF₃, or S0₂CF₃.

[0056] The disclosure includes compounds and salts of Formula XIII, wherein R₂o is

CF₃; and

R₃ is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, S0₂CF₃, Ci-Cealkyl, C₂-C₆alkenyl, C₂- C₆alkynyl, phenyl mono- and di-Ci-Cealkylamino, Ci-C₆alkylthio, Ci-Cealkylsulfonyl Ci- C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0057] The disclosure includes compounds and salts of Formula XIII, wherein R₂o is

S0₂CF₃; and

R₃ is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SC>₂CF₃, Ci-Cealkyl, C₂-Cealkenyl, C₂- Cealkynyl, phenyl mono- and di-Ci-Cealkylamino, Ci-Cealkylthio, Ci-Cealkylsulfonyl Ci- C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

he disclosure includes compounds and salts of Formula X, wherein

is a group of formula

each of which is substituted with R₁₀.

[0058] Additionally in certain embodiments where the A-ring is a thienyl or pyridyl

Rio, R21, and R₃i are each 0 substituents.

[0059] The disclosure also includes compounds and salts where the A ring is a thienyl or pyridyl, wherein each of m, n, o, and p are 0 and X and Y are both O.

[0060] The disclosure also includes compounds and salts where the A ring is a thienyl or pyridyl R₂₀ is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Cioalkyl or Ci-Ciohaloalkyl; and R30 is hydrogen or R₃₀ is Ci-Csalkoxy or Ci-Csalkylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci- C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0061] The disclosure also includes compounds and salts where the A ring is a thienyl or pyridyl, wherein R₂o is Ci-Cehaloalkyl, -S(Ci-C₆haloalkyl), or SO ₂(Ci-C₆haloalkyl).

[0062] The disclosure also includes compounds and salts where the A ring is a thienyl or pyridyl, wherein R₁₀, R21 , and R31 are each 0 substituents; R₂o is CF₃, SCF₃, or S0₂CF_3i and R30 is C₂-C₆alkoxy or C₂-C₆alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and HEF 3.

[0063] The disclosure also includes compounds and salts where the A ring is a thienyl or pyridyl, wherein R₂o is S0₂CF₃.

[0064] The disclosure further includes compounds and salts of Formula XIV

m, n, o, and p are integers independently chosen from 0, 1, and 2 and each of V^{/ n} , ^{V / o} , and ^; P P , is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, Ci-C₂alkyl, and Ci-C₂alkoxy;

X and Y are independently chosen from O and S;

R8 and R9 are independently chosnen from hydrogen and Ci-C₄alkyl;

Rio, R21 , and R31 are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy; R₂₀ is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Ciocarbyhdryl or Ci-Ciohaloalkyl;

R30 is hydrogen or R₃₀ is Ci-Cscarbhydryloxy or Ci-Cscarbhydrylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci-C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

[0065] The disclosure includes compounds and salts of Formula XIV, wherein m, n, o, and p are all 0 and X and Y are both O.

[0066] The disclosure includes compounds and salts of Formula XV

( Formula XV) where:

Rio, R₂₁, and R₃i are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂₀ is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Cioalkyl or Ci-Ciohaloalkyl;

R₃o is hydrogen or R₃₀ is Ci-Csalkoxy or Ci-Csalkylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci- C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

The disclosure includes compounds and salts of Formula XVI

(Formula XVI) where:

[0067] The disclosure includes compounds of Formula XV and XVI, wherein R₂o is

Ci-Cehaloalkyl, -S(d-C₆haloalkyl), or SO ₂(Ci-C₆haloalkyl).

[0068] The disclosure includes compounds of Formula XV and XVI, wherein R₂₁, and

R31 are both 0 substituents.

[0069] The disclosure includes compounds of Formula XV and XVI, wherein R₂i and

R31 are both 0 substituents; R₂o is CF₃, SCF₃, or S0₂CF_3i and R30 is C₂-C₆alkoxy or C₂- C₆alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and STF 3.

[0070] The disclosure includes compounds of Formula XV and XVI, wherein R₂₀ is S0₂CF₃.

[0071] Any of the variable definitions set forth herein (e.g. Rio, R₂o, R₂i, R30, R31, Rs, R9, X, Y, m, n, o, and p) may be combined so long as a stable compound results, and all such combinations which result in a stable compound are included as compounds within the scope of the disclosure.

[0072] Any of the genuses, subgenuses, and compounds in the scope of the disclosure, including compounds and salts of Formula X to Formula XVI, can be used for treating any of the conditions, disorders, diseases, or other facets of mammalian health listed in this application.

[0073] Any of the genuses, subgenuses, and compounds of the disclosure, including compounds and salts of Formula X to XI can be used for the manufacture of a medicament for any of the conditions, disorders, diseases, or other facets of mammalian health listed in this application.

[0074] Referring now to terminology used generically herein, the term HlkylChieans a straight-chain or branched alkyl substituent containing from, for example, 1 to about 10 carbon atoms, preferably from 1 to about 4 carbon atoms, more preferably from 1 to 2 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, and the like.

[0075] The term alkenyl, Cas used herein, means a linear or branched alkenyl substituent containing at least one carbon-carbon double bond and from, for example, linear alkenyl of about 2 to about 10 carbon atoms (branched alkenyls are about 3 to about 6 carbons atoms), preferably from about 2 to about 5 carbon atoms (branched alkenyls are preferably from about 3 to about 5 carbon atoms), more preferably linear alkenyl of about 3 to about 4 carbon atoms. Examples of such substituents include vinyl, propenyl, isopropenyl, n-butenyl, sec- butenyl, isobutenyl, tert-butenyl, pentenyl, isopentenyl, hexenyl, and the like.

[0076] The term alkynyl, Cas used herein, means a linear or branched alkynyl substituent containing at least one carbon-carbon triple bond and from, for example, linear alkynyl of 2 to about 10 carbon atoms (branched alkynyls are about 3 to about 6 carbons atoms), preferably from 2 to about 5 carbon atoms (branched alkynyls are preferably from about 3 to about 5 carbon atoms), more preferably linear alkynyl of about 3 to about 4 carbon atoms. Examples of such substituents include ethynyl, propynyl, isopropynyl, n-butynyl, sec- butynyl, isobutynyl, tert-butynyl, pentynyl, isopentynyl, hexynyl, and the like.

[0077] [Carbhydryl Os a hydrocarbon group that is straight, branched or cyclic (including (cycloalkyl)alkyl) and contains any combination of single, double, and triple covalent bonds. For example a carbhydryl group may be an alkyl, alkenyl, or alkynyl group. When the term carbhydryl is used in conjuction with BxyCcarbhydryl is a group as defined covalently bound to the group it substitutes through an oxygen, -0-, bridge. Similarly, carbhydrylthio is a carbhydryl group as defined covalently bound to the group it substitutes through a sulfur, - S-, bridge.

[0078] The term BycloalkyLCas used herein, means a cyclic alkyl substituent containing from, for example, about 3 to about 8 carbon atoms, preferably from about 4 to about 7 carbon atoms, and more preferably from about 4 to about 6 carbon atoms. Examples of such substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The cyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.

[0079] The term fbicycloalkyl^as used herein, means a bicyclic alkyl substituent containing from, for example, about 4 to about 12 carbon atoms, preferably from about 4 to about 7 carbon atoms, and more preferably from about 6 to about 10 carbon atoms.

Examples of such substituents include bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl,

bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, and the like. The bicyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like. [0080] The term tricycloalkylQas used herein, means a tricyclic alkyl substituent containing from, for example, about 6 to about 18 carbon atoms, preferably from about 8 to about 16 carbon atoms. Examples of such substituents include adamantyl and the like. The tricyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.

[0081] Halo alkyl indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0082] Halo alkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical). The term [heterocyclyl, Cor [heterocyclic Cas used herein, refers to a monocyclic or bicyclic 3- to 8-membered ring system containing one or more heteroatoms selected from O, N, S, and combinations thereof. The heterocyclyl group can be any suitable heterocyclyl group and can be an aliphatic heterocyclyl group, an aromatic heterocyclyl group, or a combination thereof. The heterocyclyl group can be a monocyclic heterocyclyl group or a bicyclic heterocyclyl group. Suitable bicyclic heterocyclyl groups include monocylic heterocyclyl rings fused to a C₆-Cio aryl ring. When the heterocyclyl group is a bicyclic heterocyclyl group, both ring systems can be aliphatic or aromatic, or one ring system can be aromatic and the other ring system can be aliphatic as in, for example, dihydrobenzofuran. Preferably, the heterocyclyl group is an aromatic heterocyclyl group. Non-limiting examples of suitable heterocyclyl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-2-yl, 5-methyl-l,3,4- oxadiazole, 3-methyl-l,2,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl, benzothiazolinyl, and quinazolinyl. The heterocyclyl group is optionally substituted with 1, 2, 3, 4, or 5 substituents as recited herein such as with alkyl groups such as methyl groups, ethyl groups, and the like, or with aryl groups such as phenyl groups, naphthyl groups and the like, wherein the aryl groups can be further substituted with, for example halo, dihaloalkyl, trihaloalkyl, nitro, hydroxy, alkoxy, aryloxy, amino, substituted amino, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, thio, alkylthio, arylthio, and the like, wherein the optional substituent can be present at any open position on the heterocyclyl group.

[0083] The term [heteroaryl, Cas used herein, refers to a monocyclic or bicyclic 5- or 6-membered ring system containing one or more heteroatoms selected from O, N, S, and combinations thereof. The heteroaryl group can be any suitable heteroaryl. The heteroaryl group can be a monocyclic heteroaryl group or a bicyclic heteroaryl group. Suitable bicyclic heteroaryl groups include monocylic heteroaryl rings fused to a C₆-Cio aryl ring. When the heteroaryl group is a bicyclic heteroaryl group, both ring systems are preferably aryl.

Non-limiting examples of suitable heteroaryl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzo furanyl, benzo thiopheneyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolinyl, benzo thiazolinyl, and quinazolinyl. The heteroaryl group is optionally substituted with 1, 2, 3, 4, or 5 substituents as recited herein, wherein the optional substituent can be present at any open position on the heteroaryl group.

[0084] The terms fieteroarylalkylCand Iheterocyclylalkyl, Cas used herein, refers to a heteroaryl or heterocyclyl group as defined herein having an alkyl linker group attached thereto, wherein the heteroarylalkyl and heterocyclylalkyl groups are attached to the rest of the molecule via the alkyl linker group.

[0085] The terms [1,2-phenylenylCand [[,2-heteroarylenyl, Cas used herein, refer to a phenyl group or a heteroaryl group having attached to the ring two groups positioned at adjacent positions on the phenyl or heteroaryl group, i.e., forming an ortho substitution on the phenyl or heteroaryl group.

[0086] The term Hrylalkyl, as used herein, refers to an alkyl group linked to a C ₆-Cio aryl ring and further linked to a molecule via the alkyl group. The term Hlkylaryl, Cas used herein, refers to a C₆-Cio aryl ring linked to an alkyl group and further linked to a molecule via the aryl group.

[0087] The term Hlkylcarbonyl, Cas used herein, refers to an alkyl group linked to a carbonyl group and further linked to a molecule via the carbonyl group, e.g., alkyl-C(=0)-. The term Hlkoxycarbonyl, Cas used herein, refers to an alkoxy group linked to a carbonyl group and further linked to a molecule via the carbonyl group, e.g., alkyl-0-C(=0)-. [0088] Whenever a range of the number of atoms in a structure is indicated (e.g., a C1-C12, Ci-C₈, Ci-C₆, C1-C4, or C2-C12, C₂-C₈, C₂-C₆, C₂-C₄ alkyl, alkenyl, alkynyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1- 8 carbon atoms (e.g., Ci-Cs), 1-6 carbon atoms (e.g., Ci-C₆), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C₂-Cs) as used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3- 6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms, and/or 4- 12 carbon atoms, etc., as appropriate). Similarly, the recitation of a range of 6-10 carbon atoms (e.g., C₆-Cio) as used with respect to any chemical group (e.g., aryl) referenced herein encompasses and specifically describes 6, 7, 8, 9, and/or 10 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 6-10 carbon atoms, 6-9 carbon atoms, 6-8 carbon atoms, 6-7 carbon atoms, 7-10 carbon atoms, 7-9 carbon atoms, 7-8 carbon atoms, 8-10 carbon atoms, and/or 8-9 carbon atoms, etc., as appropriate).

[0089] The term Halo Cor [halogen, as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.

[0090] The term Hryl refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art, and the term HE 6-Cio arylOncludes phenyl and naphthyl. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 π electrons, according to HuckelH Rule. The term BarbocyclicQefers to an aliphatic or aromatic ring containing only carbon ring atoms.

[0091] The phrase pharmaceutically acceptable saltOs intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington^ Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of ^'Pharmaceutical Science, 66, 2-19 (1977).

[0092] Suitable bases include inorganic bases such as alkali and alkaline earth metal bases, e.g., those containing metallic cations such as sodium, potassium, magnesium, calcium and the like. Non-limiting examples of suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acids, long chain fatty acids, and the like. Preferred pharmaceutically acceptable salts of inventive compounds having an acidic moiety include sodium and potassium salts. Preferred pharmaceutically acceptable salts of inventive compounds having a basic moiety (e.g., a dimethylaminoalkyl group) include hydrochloride and hydrobromide salts. The compounds of the present disclosure containing an acidic or basic moiety are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof.

[0093] It should be recognized that the particular counterion forming a part of any salt of this disclosure is usually not of a critical nature, so long as the salt as a whole is

pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[0094] It is further understood that the above compounds and salts may form solvates, or exist in a substantially uncomplexed form, such as the anhydrous form. As used herein, the term "solvate" refers to a molecular complex wherein the solvent molecule, such as the crystallizing solvent, is incorporated into the crystal lattice. When the solvent incorporated in the solvate is water, the molecular complex is called a hydrate. Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms. [0095] The compounds of the disclosure can be synthesized using any suitable synthetic route. Referring to Figure 1, methyl 2-aminobenzoate 500 can be reacted with an acid chloride in the presence of a base such as triethylamine in a solvent such as

dichloromethane to provide amide 501. Amide 501 can be reacted with an amine in the presence of a catalyst such as trimethylaluminum in a solvent such as toluene to provide bis-amide 502. Compound 503 can be reacted with a boronic acid in the presence of a catalyst such as Pd(PPh₃)₄, a base such as sodium carbonate, in a solvent such as

dimethylformamide under microwave irradiation to give the coupled product 504. Arylthiol compound 505 can be oxidized with an agent such as m-chloroperoxybenzoic acid in a solvent such as dichloromethane to give sulfone 506. The cyano compound 507 can be reacted with ammonium chloride in the presence of a catalyst such as trimethylaluminum in a solvent such as toluene to give amidine 508. Reaction of amidine 508 with an azide such as sodium azide in the presence of a catalyst such as zinc bromide in a solvent such as water gives tetrazole 510.

[0096] Referring to Figure 2, carboxylic acid 511 can be reacted with an amine such as

1,3-trilfuoromethylaniline in the presence of a coupling agent such as EDC and a basic catalyst such as dimethylaminopyridine in a solvent such as dichloromethane, followed by deprotection with an agent such as trifluoro acetic acid in a solvent such as dichloromethane to give free amine 513. Reaction of amine 513 with a carboxylic acid in the presence of coupling agentssuch as EDC or HATU in the presence of a basic catalyst such as

dimethylaminopyridine in a solvent such as dimethylformamide gives amide 514.

Alternatively, reaction of amine 513 with an acid chloride or an acid bromide in the presence of a base such as triethylamine in a solvent such as dichloromethane provides amide 514.

[0097] Referring to Figure 3, reaction of aryl iodide 515 with an alcohol in the presence of a catalyst such as 1,10-phenanthroline and a base such as cesium carbonate in a solvent such as toluene gives aryl ether 516. Reaction of 2-bromobenzoyl chloride or 2-iodobenzoyl chloride 517 with 3-trifluoromethylaniline in the presence of a base such as triethylamine in a solvent such as dichloromethane provides amide 518. Amide 518 reacts with a boronic acid in the presence of a catalyst such as Pd(PPh₃)₄, a base such as sodium carbonate, in a solvent such as dimethylformamide under microwave irradiation gives alkylated/arylated compound

519. Reaction of compound 518 with a primary amine in the presence of a catalyst such as cuprous chloride in a solvent such as dimethylformanide provides arylamine 520. Reaction of 518 with an alcohol in the presence of catalysts such as copper (I) iodide and 1,10-phenanthroline in the presence of a base such as cesium carbonate in a solvent such as toluene gives aryl ether 521.

[0098] Referring to Figure 4, reaction of amide 522 with an alkylating agent such as iodomethane in the presence of a base such as NaH in a solvent such as dimethylformamide gives N-methylamide 523. Compound 523 reacts with an arylamine such as compound 524 in the presence of a catalyst such as trimethylaluminum in a solvent such as toluene to give bis-amide 525. Oxidation of alcohol 526 with an oxidant such as Dess-Martin periodinane in a solvent such as dichloromethane gives aldehyde 527. Reductive amination of aldehyde 527 with an amine such as 528 in the presence of a catalyst such as Ti(Oz^'Pr)4 and a reductant such as sodium borohydride gives amine 529. Deprotection of Boc compound 529 with an agent such as trifluoro acetic acid in a solvent such as dichloromethane gives arylamine 530.

Coupling of arylamine 530 with an acyl chloride such as 531 in the presence of a base such as triethylamine in a solvent such as dichloromethane gives amine-amide 532. Sulfonamides can be prepared by reaction of methyl 2-aminobenzoate 533 with sulfonyl chloride 534 in the presence of a base such as triethylamine in a solvent such as dichloromethane to give sulfonamide 535. Reaction of 535 with 3-trifluoromethylsulfonylaniline in the presence of a catalyst such as trimethylaluminum in a solvent such as toluene gives compound 536.

[0099] Referring to Figure 5, aniline derivative 537 can be reacted with an acyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane to provide amide 538. Reaction of 538 with 3-trifluoromethylaniline in the presence of a catalyst such as trimethylaluminum in a solvent such as toluene gives bis-amide 539. The same chemistry can be performed substituting hetero eye lic/hetero aryl analogs of compound 537.

[0100] Referring to Figure 6, cyclization of amino amide 543 in a solvent such as acetic acid at room temperature provides benzimidazole 544. Cyclization at 70° C gives a mixture of isomeric tetracyclic compounds 545 and 546. Reaction of bis-amine compound 547 with an acid chloride such as 2-ethoxybenzoyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane gives amino amide 548. Cyclization of

548 in a solvent such as acetic acid gives benzimidazole 549. Amidation of 549 with

3-trifluoromethylsulfonylaniline in the presence of a catalyst such as trimethylaluminum in a solvent such as toluene gives compound 550. Reaction of amine 551 with 3-iodotrifluorobenzene in the presence of a catalyst such as 1,2-methylaminocyclohexane in the presence of a catalyst such as copper (I) iodide and a base such as potassium carbonate in a solvent such as toluene gives the coupled product 553. Reaction of 553 with

2-ethoxybenzoyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane gives amide 554.

[0101] Referring to Figure 7, reaction of aryl iodide 555 with an alcohol or a thiol in the presence of catalysst such as copper (I) iodide chloride and 1,10-phenanthroline in the presence of base such as cesium carbonate in a solvent such as toluene gives aryl ether 556.

[0102] The present disclosure is further directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound or salt described herein.

[0103] It is preferred that the pharmaceutically acceptable carrier be one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.

[0104] The choice of carrier will be determined in part by the particular compound of the present disclosure chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the

pharmaceutical composition of the present disclosure. The following formulations for oral, aerosol, nasal, pulmonary, parenteral, subcutaneous, intravenous, intramuscular,

intraperitoneal, intrathecal, intratumoral, topical, rectal, and vaginal administration are merely exemplary and are in no way limiting.

[0105] The pharmaceutical composition can be administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. Thus, the disclosure provides compositions for parenteral administration that comprise a solution or suspension of the inventive compound or salt dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous isotonic sterile injection solutions.

[0106] Overall, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill in the art. See, e.g., Banker and

Chalmers, eds., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company,

Philadelphia, pp. 238-250 (1982), and Toissel, ASHP Handbook on Injectable Drugs, 4th ed., pp. 622-630 (1986). Such solutions can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound or salt of the present disclosure may be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose,

hydro xypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0107] Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

[0108] Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfo succinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.

[0109] The parenteral formulations can contain preservatives and buffers. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0110] Topical formulations, including those that are useful for transdermal drug release, are well-known to those of skill in the art and are suitable in the context of the disclosure for application to skin. Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels. Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa. In some embodiments, the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant. The carrier can be a liquid, solid or semi-solid. In embodiments, the composition is an aqueous solution. Alternatively, the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components. In one embodiment, the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral. The liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site. In embodiments of the disclosure, the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.

[0111] Formulations suitable for oral administration can consist of (a) liquid solutions, such as a therapeutically effective amount of the inventive compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules, (c) powders, (d) suspensions in an appropriate liquid, and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a

pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, micro crystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

[0112] The compound or salt of the present disclosure, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.

The compounds are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of active compound are 0.01%-20% by weight, preferably

1%-10%. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1%-20% by weight of the composition, preferably 0.25%-5%.

The balance of the composition is ordinarily propellant. A carrier can also be included as desired, e.g., lecithin for intranasal delivery. These aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations may be used to spray mucosa.

[0113] Additionally, the compound or salt of the present disclosure may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0114] It will be appreciated by one of ordinary skill in the art that, in addition to the aforedescribed pharmaceutical compositions, the compound or salt of the present disclosure may be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. Liposomes serve to target the compounds to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of the inventive compound. Liposomes useful in the present disclosure include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. In these preparations, the active agent to be delivered is incorporated as part of a liposome, alone or in conjunction with a suitable chemotherapeutic agent. Thus, liposomes filled with a desired inventive compound or salt thereof, can be directed to the site of a specific tissue type, hepatic cells, for example, where the liposomes then deliver the selected compositions. Liposomes for use in the disclosure are formed from standard vesicle-forming lipids, which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of, for example, liposome size and stability of the liposomes in the blood stream. A variety of methods are available for preparing liposomes, as described in, for example, Szoka et al, Ann. Rev. Biophys. Bioeng., 9, 467 (1980), and U.S. Patents 4,235,871, 4,501,728, 4,837,028, and 5,019,369. For targeting to the cells of a particular tissue type, a ligand to be

incorporated into the liposome can include, for example, antibodies or fragments thereof specific for cell surface determinants of the targeted tissue type. A liposome suspension containing a compound or salt of the present disclosure may be administered intravenously, locally, topically, etc. in a dose that varies according to the mode of administration, the agent being delivered, and the stage of disease being treated.

[0115] The disclosure further provides a method for therapeutic intervention in a facet of mammalian health that is mediated by a mammalian relaxin receptor 1 comprising

administering to a mammal in need thereof a therapeutically effective amount of a compound or salt thereof represented by Formula (I):

wherein A is 1 ,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or -CH₂CH₂-, wherein the 1 ,2-phenylenyl, 1,2-heteroarylenyl, or 1,2-heterocyclyl are optionally substituted with one or more substituents independently selected from halo, CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and S0₂CF₃,

Ri is -NHCOR₃, R₄, -NHR₅, or -OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, or phenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C₁-C₁₀ alkyl, C₂-Cio alkenyl, C₁-C₁₀ alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy aryl, , halo alky laryl, heterocyclylalkyl, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂, -CN, and -S0₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl, arylalkyl, or phenyl, which are optionally substituted with one or more substituents selected from halo, CF₃, C₁-C₁₀ alkyl, C₂-Cio alkenyl, C₁-C₁₀ alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂,-CN, and -S0₂CF₃,

R₅ is hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, or cycloalkylalkyl which are optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl,

Re is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl,

and R₇ is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, Ci-Ciohaloalkyl, or Ci-Ciohaloalkoxy.

[0116] In accordance with certain embodiments, R₂ is phenyl substituted

with -S0₂CF₃, -SCF₃, or -CF₃.

[0117] In accordance with certain embodiments, A is 1 ,2-phenylene optionally substituted with one or more substituents independently selected from halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0118] In accordance with certain embodiments, Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from -CF₃, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloxy,

Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, alkyloxyalkyloxy, dimethylaminoalkyloxy, -

SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0119] In accordance with certain preferred embodiments, R₃ is

2-(Ci-Cio)alkyloxyphenyl. [0120] In accordance with certain preferred embodiments, R₂ is phenyl substituted with a substituent selected from -CF₃, Ci-Cio alkyl, Ci-Cio alkyloxy, Ci-Ciohaloalkyl,

Ci-Ciohaloalkoxy -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0121] In certain preferred embodiments, the compound is selected from the group consisting of:

[0122] In accordance with certain embodiments, Ri is R4, wherein R4 is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

[0123] In accordance with certain preferred embodiments, Ri is -NHR₅, wherein R5 is aryl optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl.

[0124] In accordance with certain embodiments, Ri is -OR₆, wherein R^ is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl.

[0125] In accordance with certain embodiments, A is 1 ,2-heteroarylenyl optionally substituted with one or more subsitutents independently selected from halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0126] In accordance with certain preferred embodiments, A is selected from

[0127] In accordance with certain preferred embodiments, Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from independently -CF3, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloxy, Ci-Ciohalo alkyl, Cl-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0128] In accordance with certain preferred embodiments, R3 is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

[0129] In certain preferred embodiments, wherein the compound is selected from the group consisting of:

[0130] In accordance with certain embodiments, A is [CH ₂CH₂-.

[0131] In accordance with certain embodiments, wherein Ri is -NHCOR3, wherein R₃ is phenyl substituted with a substituent selected from -CF₃, C₁-C₁0 alkyl, C₁-C₁0 alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

[0132] In accordance with certain embodimenst, R3 is 2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

[0133] In accordance with a particular embodiment, the compound is:

[0134] The facet of mammalian health can be any disease, disorder, or aspect of mammalian health that is mediated by a mammalian relaxin receptor 1. Examples of facets of mammalian health, wherein the mammal is a human, that are mediated by a mammalian relaxin receptor 1, wherein the mammalian relaxin receptor 1 is a human relaxin receptor 1, are disclosed in, e.g., E.T. Van Der Westhuizen et al, Current Drug Targets 2007, 8, 91-104; U.S. Patent 8,053,411; and U.S. Patent Application Publication 2011/0177998, the discloses of which are incorporated herein.

[0135] The mammal can be any suitable mammal. Examples of suitable mammals include, but are not limited to, the order Rodentia, such as mice, and the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human. Furthermore, the subject can be the unborn offspring of any of the forgoing hosts, especially mammals (e.g., humans), in which case any screening of the subject or cells of the subject, or administration of compounds to the subject or cells of the subject, can be performed in utero.

[0136] The mammalian relaxin receptor 1 can be any suitable mammalian relaxin receptor 1. Typically, the mammalian relaxin receptor 1 is a relaxin receptor 1 that exists in the particular mammal being treated.

[0137] In some embodiments, the facet of mammalian health is a facet of human health. In these embodiments, the mammalian relaxin receptor 1 is a human relaxin receptor 1.

[0138] In an embodiment, the facet of mammalian health is cardiovascular disease. Non-limiting examples of cardiovascular disease include acute heart failure, myocardial ischemia-reperfusion injury, cardiac fibrosis, acute congestive heart failure, cerebrovascular disease and stroke, post-infarction heart, cardiac anaphylaxis, cerebral ischemia (stroke), intestinal ischemia-reperfusion injury, systemic and pulmonary hypertension, vascular inflammation, hypertension, high blood pressure; left ventricular hypertrophy (LVH);

vasodilation; renal hypertension; diuresis; nephritis; natriuresis; scleroderma renal crisis; angina pectoris (stable and unstable); myocardial infarction; heart attack; coronary artery disease; coronary heart disease; cardiac arrhythmias; atrial fibrillation; portal hypertension; raised intraocular pressure; vascular restenosis; chronic hypertension; valvular disease;

myocardial ischemia; acute pulmonary edema; acute coronary syndrome; hypertensive retinopathy; hypertensive pregnancy sickness; Raynaud's phenomenon; erectile dysfunction, glaucoma, and preeclampsia. [0139] In an embodiment, the facet of mammalian health is dyspnea associated with acute heart failure in a human subject, wherein said subject has dyspnea associated with acute heart failure and is in a hypertensive or normotensive state at the onset of said administering.

[0140] In an embodiment, the facet of mammalian health is acute decompensated heart failure, wherein the method is effective to reduce in-hospital worsening of said acute decompensated heart failure in said subject. In a preferred embodiment, the in-hospital worsening of said acute decompensated heart failure comprises one or more of worsening dyspnea, need for additional therapy to treat said heart failure, need for mechanical support of breathing, and need for mechanical support of blood pressure. In another preferred embodiment, the method further comprises a reduction in the risk of death or

rehospitalization of said subject.

[0141] In an embodiment, the facet of mammalian health is fibrotic disease. In selected embodiments, the fibrotic disease is selected from the group of but not limited to pulmonary fibrosis, renal tubulo interstitial fibrosis, mesangial proliferative nephritis, hepatic fibrosis (cirrhosis) alcohol and non-alcohol related (including viral infection such as HAV, HBV and HCV); fibromatosis; granulomatous lung disease; glomerulonephritis, myocardial scarring following infarction; endometrial fibrosis and endometriosis, polycystic kidney disease, scleroderma and systemic sclerosis, keloids, arthritis, autoimmune disorder, inflammatory condition associated with infection, skeletal muscle injuries, conditions involving tissue remodeling following inflammation or ischemia-reperfusion injury and is selected from endomyocardial and cardiac fibrosis; mediastinal fibrosis; retroperitoneal fibrosis; fibrosis of the spleen; fibrosis of the pancreas; wound healing whether by injury or surgical procedures, diabetes related wound fibrosis.

[0142] In an embodiment, the facet of mammalian health is respiratory disease selected from asthma, bronchial disease, lung diseases, chronic obstructive pulmonary disease (COPD), Acute Respiratory Distress Syndrome (ARDS), severe acute respiratory syndrome (SARS), Fibrosis related Asthma, and cystic fibrosis.

[0143] In an embodiment, the facet of mammalian health is skin disease selected from dermal repair, wound healing; burns, erythemas, lesions, wound healing following surgical procedures; skin or tissue lesions including lesions induced by Psoriasis, Lupus and Kaposhi Sarcoma; Scleroderma, and collagenous diseases of the skin and skin tumors. [0144] In an embodiment, the facet of mammalian health is female reproduction. In selected embodiments, the facet of female reproduction is selected from in vitro fertilization, abnormal implantation, pre-term birth and induction of labor, mammary functions and lactation disorders;, plasma osmolarity during pregnancy, uterine fibroids, abnormal endometrial angiogenesis; placental development defects; cervical ripening (softening); nipple development and disfunction; pregnancy related remodeling of the uterine tissue; endometriosis; preeclampsia; estrogenic and non-estrogenic related hormonal disorders; preterm labor; post term labor; and labor complications.

[0145] In an embodiment, the facet of mammalian health is male reproduction. In particular embodiments, the facet of male reproduction is selected from sperm functions and fertilization.

[0146] In an embodiment, the facet of mammalian health is surgical transplantation of a liver.

[0147] In an embodiment, the facet of mammalian health is a cancer selected from colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, pancreatic cancer, ovarian cancer, kidney cancer, testicular cancer, bone cancer, osteosarcoma, liver cancer, melanoma, glioma, sarcoma, leukemia, or lymphoma, and wherein the cancer is invasive or metastatic.

[0148] In an embodiment, the facet of mammalian health is enhancement of drug delivery in the treatment of a solid cancer, in combination with a chemotherapeutic treatment or radiation treatment of the cancer.

[0149] In an embodiment, the facet of mammalian health is orthodontic tooth movement.

[0150] In an embodiment, the facet of mammalian health is bone joint disease.

[0151] In an embodiment, the facet of mammalian health is selected from osteoporosis; osteoarthritis; osteopetrosis; bone inconsistency; osteosarcoma; and cancer metastasis to the bone.

[0152] In an embodiment, the facet of mammalian health is diabetes mellitus.

[0153] In an embodiment, the facet of mammalian health is ischemia-reperfusion injury associated with ischemic and post-ischemic events in organs and tissues and in a group of patients with thrombotic stroke; myocardial infarction; angina pectoris; embolic vascular occlusions; peripheral vascular insufficiency; splanchnic artery occlusion; arterial occlusion by thrombi or embolisms, arterial occlusion by non-occlusive processes such as following low mesenteric flow or sepsis; mesenteric arterial occlusion; mesenteric vein occlusion; ischemia-reperfusion injury to the mesenteric microcirculation; ischemic acute renal failure; ischemia-reperfusion injury to the cerebral tissue; intestinal intussusception; hemodynamic shock; tissue dysfunction; organ failure; restenosis; atherosclerosis; thrombosis; platelet aggregation, ischemia-reperfusion injury following cardiac surgery; organ surgery; organ transplantation; angiography; cardiopulmonary and cerebral resuscitation.

[0154] In an embodiment, the facet of mammalian health is an inflammatory condition associated with an infection, wherein the infection is selected from a viral infection caused by human immunodeficiency virus I (HIV-1) or HIV-2, acquired immune deficiency (AIDS), West Nile encephalitis virus, coronavirus, rhinovirus, influenza virus, dengue virus, HCV, HBV, HAV, hemorrhagic fever; an otological infection; severe acute respiratory syndrome (SARS), sepsis and sinusitis.

[0155] In an embodiment, the facet of mammalian health is kidney diseases selected from diabetic nephropathy; glomerulosclerosis; nephropathies; renal impairment; scleroderma renal crisis and chronic renal failure.

[0156] In an embodiment, the facet of mammalian health is an angiogenesis related condition selected from retinal angiogenesis in a number of mammalian ocular diseases such as diabetes mellitus, retinopathy of prematury, and age-related macular degeneration, or cancer associated angiogenesis in primary or metastatic cancer, including but not limited to cancer of the prostate, brain, breast, colorectal, lung, ovarian, pancreatic, renal, cervical, melanoma, soft tissue sarcomas, lymphomas, head-and-neck, and glioblastomas.

[0157] In an embodiment, the facet of mammalian health is an inflammatory disorder selected from gastritis, gout, gouty arthritis, arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ulcers, chronic bronchitis, asthma, allergy, acute lung injury, pulmonary inflammation, airway hyper-responsiveness, vasculitis, septic shock and inflammatory skin disorders, including but not limited to psoriasis, atopic dermatitis, eczema.

[0158] In an embodiment, the facet of mammalian health is an autoimmune disorder is selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus

erythematosus, ulcerative colitis, Crohn's disease, transplant rejection, immune disorders associated with graft transplantation rejection, benign lymphocytic angiitis, lupus

erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis, and chondro calcino sis .

[0159] In an embodiment, the facet of mammalian health is an behavioral abnormality or disease.

[0160] [Therapeutic intervention in a facet of mammalian health that is mediated by a mammalian relaxin receptor 1 Qefers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, the term ameliorating, Qvith reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. Treatment of cardiovascular disease can be evidenced, for example, by reduction of blood pressure, an enhancement of vascular compliance, a reduction in clinical symptoms resulting from the cardiovascular disease, or other parameters well known in the art that are specific to the cardiovascular disease. The phrase [treating a disease ttefers to inhibiting the full

development of a disease or condition, for example, in a subject who is at risk for a disease such as cardiovascular disease.

[0161] In other embodiments, the therapeutic intervention provides an enhancement in a desirable facet of mammalian health.In certain embodiments the therapeutic intervention provides an enhancement in a desirable facet of human health. For example, the therapeutic intervention can lead to improved outcomes in organ transplantation, in improvements in female fertility such as increased success in in vitro fertilization, and the like. [0162] One skilled in the art will appreciate that suitable methods of utilizing a compound and administering it to a mammal for the treatment or prevention of disease states which would be useful in the method of the present disclosure, are available. Although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the described methods are merely exemplary and are in no way limiting.

[0163] The dose administered to a mammal, particularly, a human, in accordance with the present disclosure should be sufficient to effect the desired response. Such responses include reversal or prevention of the bad effects of the disease for which treatment is desired or to elicit the desired benefit. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the age, condition, and body weight of the mammal, as well as the source, particular type of the disease, and extent of the disease in the human. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.

[0164] Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound.

Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The present inventive method typically will involve the administration of about 0.1 to about 300 mg of one or more of the compounds described above per kg body weight of the mammal.

[0165] The therapeutically effective amount of the compound or compounds

administered can vary depending upon the desired effects and the factors noted

above. Typically, dosages will be between 0.01 mg/kg and 250 mg/kg of the subjects body weight, and more typically between about 0.05 mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, from about 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of the subjects body weight. Thus, unit dosage forms can be formulated based upon the suitable ranges recited above and the subjects body weight. The term Unit dosage formCas used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated.

[0166] Alternatively, dosages are calculated based on body surface area and from about 1 mg/m² to about 200 mg/m², such as from about 5 mg/m² to about 100 mg/m² will be administered to the subject per day. In particular embodiments, administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg/m² to about 50 mg/m², such as from about 10 mg/m² to about 40 mg/m² per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day. Thus, unit dosage forms also can be calculated using a subjects body surface area based on the suitable ranges recited above and the desired dosing schedule.

[0167] The disclosure further provides a use of a compound or salt of the disclosure in the manufacture of a medicament for therapeutic intervention in a facet of mammalian health that is mediated by a mammalian relaxin receptor 1. The medicament typically is a pharmaceutical composition as described herein.

[0168] The following examples further illustrate the disclosure but, of course, should not be construed as in any way limiting its scope.

[0169] General Methods for Chemistry. All air or moisture sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware. Anhydrous solvents such as dichloromethane, N,N-dimethylformamide (DMF), acetonitrile, methanol and triethylamine were purchased from Sigma- Aldrich (St. Louis, MO). Preparative purification was performed on a Waters semi-preparative HPLC system (Waters Corp.,

Milford, MA). The column used was a Phenomenex Luna C₁₈ (5 micron, 30 x 75 mm;

Phenomenex, Inc., Torrance, CA) at a flow rate of 45.0 mL/min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoro acetic acid). A gradient of 10% to

50% acetonitrile over 8 minutes was used during the purification. Fraction collection was triggered by UV detection at 220 nM. Analytical analysis was performed on an Agilent

LC/MS (Agilent Technologies, Santa Clara, CA). Method 1 ( ): A 7-minute gradient of 4% to 100% acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an 8-minute run time at a flow rate of 1.0 mL/min.

Method 2 (t₂): A 3-minute gradient of 4% to 100% acetonitrile (containing 0.025% trifluoro acetic acid) in water (containing 0.05% trifluoroacetic acid) was used with a 4.5- minute run time at a flow rate of 1.0 mL/min. A Phenomenex Luna C₁₈ column (3 micron, 3 x 75 mm) was used at a temperature of 50 °C. Purity determination was performed using an Agilent diode array detector for both Method 1 and Method 2. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode. 1H NMR spectra were recorded on Varian 400 MHz spectrometers (Agilent Technologies, Santa Clara, CA). Chemical shifts are reported in ppm with undeuterated solvent (DMSO-<i6 at 2.49 ppm) as internal standard for DMSO-<i6 solutions. All of the analogs tested in the biological assays have a purity of greater than 95% based on both analytical methods. High resolution mass spectrometry was recorded on Agilent 6210 Time- of-Flight (TOF) LC/MS system. Confirmation of molecular formula was accomplished using electrospray ionization in the positive mode with the Agilent Masshunter software (Version B.02).

[0170] General Protocol A. A solution of methyl or ethyl benzoate (0.191 mmol) and amine (0.383 mmol) in toluene (2.00 mL) was treated at room temperature with AlMe₃ (0.192 mL, 2.0 M in toluene, 0.384 mmol). The reaction mixture was stirred overnight at 100 °C and then quenched with 100 of water. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product.

[0171] General Protocol B. A solution of carboxylic acid (0.178 mmol) in DMF (2.00 mL) was treated at room temperature with 2-amino-N-(3-(trifluoromethyl)phenyl)benzamide (25.0 mg, 0.089 mmol) followed by EDC (17.1 mg, 0.089 mmol) and DMAP (10.9 mg, 0.089 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was purified via C₁₈ reverse phase HPLC to give the final product.

[0172] General Protocol C. A solution of 2-amino-N-(3-

(trifluoromethyl)phenyl)benzamide (50.0 mg, 0.178 mmol) in dichloromethane (2.00 mL) and TEA (0.075 mL, 0.535 mmol) was treated at room temperature with carbonyl chloride (0.357 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product.

[0173] General Protocol D. A solution of carboxylic acid (0.357 mmol) in DMF (2.00 mL) was added DIPEA (0.093 mL, 0.535 mmol) and HATU (136 mg, 0.357 mmol). The reaction mixture was stirred at room temperature for 5 min, followed by 2-amino-N-(3- (trifluoromethyl)phenyl)benzamide (50.0 mg, 0.178 mmol). The reaction mixture was stirred overnight at room temperature, filtered and purified via C₁₈ reverse phase HPLC to give the final product.

[0174] General Protocol E. A mixture of 2-bromo-N-(3- (trifluoromethyl)phenyl)benzamide (50.0 mg, 0.145 mmol, 1.0 equiv.) or N-(3- bromophenyl)-2-(cyclohexanecarboxamido)benzamide (100 mg, 0.249 mmol, 1.0 equiv.), boronic acid or pinacol ester (2.0 equiv.) and Pd(PPh₃)₄ (0.05 equiv) in DMF (1.50 mL) and 2.0 N Na₂C0₃ (0.50 mL) aqueous solution was heated in μW at 100 °C for 30 min - 1 h. The reaction was cooled to room temperature, added a small portion of Si-THIOL to get rid of Palladium. The reaction mixture was filtered and purified via C₁₈ reverse phase HPLC to give the final product.

[0175] General Protocol F. 2-Iodo-N-(3-(trif uoromethyl)phenyl)benzamide (100 mg, 0.256 mmol), amine (0.767 mmol), and CuCl (7.59 mg, 0.077 mmol) in DMF (1.00 mL) was stirred at room temperature for 15-30 min. The reaction was treated with a small portion of Si-THIOL to get rid of Palladium, filtered and purified via C₁₈ reverse phase HPLC to give the final product.

[0176] General Protocol G. A solution of thio-compound (0.255 mmol) in

dichloromethane (3.00 mL) was treated at room temperature with MCPBA (220 mg, 1.27 mmol). The reaction mixture was stirred overnight at room temperature. 10% aqueous NaHS0₃ solution was added to quench excess MCPBA and the mixture was stirred at room temperature for 15 min. The reaction mixture was worked up with dichloromethane and water. The organic layer was separated, dried, concentrated, and purified via C₁₈ reverse phase HPLC to give the final product.

[0177] General Protocol H. A tube was charged with Cul (0.1 equiv.), 1,10- phenanthroline (0.2 equiv.), Cs₂C0₃ (2.0 equiv.), iodo substrate (1.0 equiv.) and alcohol (2.0 equiv.) in toluene (2.00 mL) under N₂. The tube was sealed and the reaction mixture was stirred at 110 °C for 24 h. The resulting mixture was cooled to room temperature and treated with a small portion of Si-THIOL to get rid of copper. The mixture was concentrated, re- dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product EXAMPLE 1

[0179] This example illustrates a synthesis of Methyl 2-

(cyclohexanecarboxamido)benzoate (XJB05-077, NCGC00189490-01). A solution of methyl 2-aminobenzoate (3.00 g, 19.9 mmol) in dichloromethane (100 mL) and triethylamine (8.30 mL, 59.5 mmol) was treated at 0 °C with cyclohexanecarbonyl chloride (2.70 mL, 19.9 mmol). The reaction was stirred at 0 °C for 2 h and room temperature for additional 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-40% of EtOAc in hexanes to give 5.00 g (96%>) of the title product as a white solid. LC- MS Retention Time: ti (Method 1) = 6.453 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.65 (s, 1 H), 8.31 (dd, J=8.5, 1.1 Hz, 1 H), 7.90 (dd, J=7.9, 1.7 Hz, 1 H), 7.57 (ddd, J=8.6, 7.2, 1.7 Hz, 1 H), 6.87 - 7.29 (m, 1 H), 3.83 (s, 3 H), 2.31 (tt, J=11.3, 3.5 Hz, 1 H), 1.88 (dd, J=12.9, 2.5 Hz, 2 H), 1.73 (ddd, J=12.4, 3.3, 3.1 Hz, 2 H), 1.55 - 1.67 (m, 1 H), 1.08 - 1.47 (m, 5 H).

EXAMPLE 2

[0181] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)benzoic acid (XJB05-087, NCGC00189489-01). A solution of methyl 2-

(cyclohexanecarboxamido)benzoate (4.00 g, 15.3 mmol) in MeOH (100 mL) was treated at room temperature with 4.0 N NaOH aqueous solution (40.0 mL, 153 mmol). The reaction mixture was stirred at room temperature for 1 h. MeOH was removed by rotavapor and the mixture was cooled in ice-bath and acidified with 5.0 N HC1 until white precipitation was appeared. The white precipitation was filtered and washed with water to give 3.60 g (95%) of the title product as a white solid. LC-MS Retention Time: ti (Method 1) = 5.345 min.

EXAMPLE 3

[0183] This example illustrates a synthesis of tert-Butyl 2-(3-

(trifiuoromethyl)phenylcarbamoyl)phenylcarbamate (XJB05-088, NCGC00189488-01). A solution of 2-(fert-butoxycarbonylamino)benzoic acid (3.00 g, 12.6 mmol) and 3- (trifluoromethyl)aniline (2.36 mL, 19.0 mmol) in dichloromethane (75.0 mL) was treated at room temperature with DMAP (1.55 g, 12.6 mmol) and EDC (4.85 g, 25.3 mmol) and stirred at room temperature for 24 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of dichloromethane in hexanes followed by 10% of EtOAc in dichloromethane to give 2.20 g (46%) of the title product as a white solid. LC-MS Retention Time: ti (Method 1) = 7.042 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.64 (s, 1 H), 9.75 (s, 1 H), 8.14 (s, 1 H), 7.98 (d, J=7.6 Hz, 1 H), 7.94 (d, J=9.2 Hz, 1 H), 7.77 (dd, J=7.9, 1.5 Hz, 1 H), 7.58 (t, J=8.0 Hz, 1 H), 7.51 (ddd, J=8.5, 7.2, 1.5 Hz, 1 H), 7.45 (d, J=7.8 Hz, 1 H), 7.16 (td, J=7.6, 1.1 Hz, 1 H), 1.41 (s, 9 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.20 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C19H20F3N2O3, 381.1421; found 381.1426.

EXAMPLE 4

[0185] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N- phenylbenzamide (XJB06-001, NCGC00189487-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.326 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.54 (s, 1 H), 10.37 (s, 1 H), 8.23 (dd, J=8.2, 1.0 Hz, 1 H), 7.77 (dd, J=7.9, 1.5 Hz, 1 H), 7.63 - 7.71 (m, 2 H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.28 - 7.41 (m, 2 H), 7.19 (td, J=7.6, 1.3 Hz, 1 H), 7.07 - 7.14 (m, 1 H), 2.17 - 2.34 (m, 1 H), 1.76 - 1.88 (m, 2 H), 1.69 (ddd, J=12.5, 3.4, 3.2 Hz, 2 H), 1.59 (d, J=12.1 Hz, 1 H), 1.03 - 1.43 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C20H23N2O0, 323.1754; found 323.1758.

EXAMPLE 5

[0187] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-002, NCGC00189486-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.910 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.61 (s, 1 H), 10.27 (s, 1 H), 8.12 (s, 1 H), 8.07 (dd, J=8.4, 1.0 Hz, 1 H), 7.94 (d, J=9.2 Hz, 1 H), 7.74 (dd, J=7.7, 1.5 Hz, 1 H), 7.58 (t, J=8.0 Hz, 1 H), 7.47 - 7.54 (m, 1 H), 7.44 (dt, J=7.7, 0.8 Hz, 1 H), 7.21 (td, J=7.5, 1.2 Hz, 1 H), 2.22 - 2.35 (m, 1 H), 1.79 (dd, J=13.3, 2.3 Hz, 2 H), 1.68 (ddd, J=12.3, 3.1, 2.9 Hz, 2 H), 1.58 (ddd, J=l 1.9, 3.2, 3.0 Hz, 1 H), 1.00 - 1.40 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.30 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H22F3N2O2, 391.1628; found 391.1632.

EXAMPLE 6

[0189] This example illustrates a synthesis of N-(3-Bromophenyl)-2- (cyclohexanecarboxamido)benzamide (XJB06-005, NCGC00189485-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.904 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.47 (s, 1 H), 10.31 (s, 1 H), 8.11 (dd, J=8.4, 1.0 Hz, 1 H), 7.94 - 8.04 (m, 1 H), 7.72 (dd, J=7.8, 1.6 Hz, 1 H), 7.64 (ddd, J=6.7, 2.3, 2.2 Hz, 1 H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.24 - 7.35 (m, 2 H), 7.19 (td, J=7.6, 1.2 Hz, 1 H), 2.21 - 2.37 (m, 1 H), 1.80 (d, J=11.5 Hz, 2 H), 1.69 (dt, J=12.2, 3.2 Hz, 2 H), 1.59 (d, J=12.5 Hz, 1 H), 1.07 - 1.42 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂oH22BrN₂02, 401.0859; found 401.0859.

EXAMPLE 7

[0191] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- fhiorophenyl)benzamide (XJB06-006, NCGC00189484-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.529 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.51 (s, 1 H), 10.33 (s, 1 H), 8.12 (dd, J=8.3, 1.1 Hz, 1 H), 7.73 (dd, J=7.7, 1.5 Hz, 1 H), 7.64 (dt, J=11.7, 2.3 Hz, 1 H), 7.43 - 7.55 (m, 2 H), 7.37 (td, J=8.2, 6.7 Hz, 1 H), 7.20 (td, J=7.5, 1.2 Hz, 1 H), 6.82 - 6.98 (m, 1 H), 2.21 - 2.35 (m, 1 H), 1.81 (d, J=11.5 Hz, 2 H), 1.69 (dt, J=12.4, 3.3 Hz, 2 H), 1.59 (d, J=11.7 Hz, 1 H), 1.02 - 1.43 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -112.20 - -112.29 (m, 1 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂FN₂O₂, 341.1660; found 341.1660.

EXAMPLE 8

[0193] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- methoxyphenyl)benzamide (XJB06-007, NCGC00189483-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.344 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.47 (s, 1 H), 10.33 (s, 1 H), 8.20 (dd, J=8.4, 1.0 Hz, 1 H), 7.74 (dd, J=7.8, 1.4 Hz, 1 H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.33 (t, J=2.2 Hz, 1 H), 7.13 - 7.30 (m, 3 H), 6.69 (ddd, J=7.8, 2.5, 1.4 Hz, 1 H), 3.73 (s, 3 H), 2.26 (tt, J=11.3, 3.6 Hz, 1 H), 1.82 (dd, J=12.5, 2.7 Hz, 2 H), 1.69 (ddd, J=12.4, 3.1, 2.8 Hz, 2 H), 1.51 - 1.64 (m, 1 H), 1.02 - 1.41 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₃, 353.1860; found 353.1856. EXAMPLE 9

[0195] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-m- tolylbenzamide (XJB06-008, NCGC00189482-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.632 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.54 (s, 1 H), 10.30 (s, 1 H), 8.24 (dd, J=8.3, 1.1 Hz, 1 H), 7.76 (dd, J=7.8, 1.4 Hz, 1 H), 7.38 - 7.54 (m, 3 H), 7.10 - 7.31 (m, 2 H), 6.93 (dddd, J=7.5, 1.5, 1.1, 0.8 Hz, 1 H), 2.29 (s, 3 H), 2.19 - 2.35 (m, 1 H), 1.82 (dd, J=12.8, 2.6 Hz, 2 H), 1.69 (dt, J=12.4, 3.4 Hz, 2 H), 1.59 (d, J=12.3 Hz, 1 H), 1.04 - 1.42 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₂, 337.1911; found 337.1908.

EXAMPLE 10

[0197] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- nitrophenyl)benzamide (XJB06-009, NCGC00189481-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.392 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.76 (s, 1 H), 10.26 (s, 1 H), 8.69 (t, J=2.2 Hz, 1 H), 8.01 - 8.15 (m, 2 H), 7.95 (ddd, J=8.3, 2.3, 1.0 Hz, 1 H), 7.75 (dd, J=7.8, 1.6 Hz, 1 H), 7.64 (t, J=8.2 Hz, 1 H), 7.46 - 7.56 (m, 1 H), 7.22 (td, J=7.6, 1.2 Hz, 1 H), 2.19 - 2.35 (m, 1 H), 1.79 (dd, J=12.5, 2.5 Hz, 2 H), 1.68 (dt, J=12.3, 3.1 Hz, 2 H), 1.58 (d, J=12.5 Hz, 1 H), 1.03 - 1.43 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C20H22N3O4, 368.1605; found 368.1616. EXAMPLE 11

[0199] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(4- (trifiuoromethyl)phenyl)benzamide (XJB06-012, NCGC00189480-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.943 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.65 (s, 1 H), 10.29 (s, 1 H), 8.09 (dd, J=8.4, 1.0 Hz, 1 H), 7.91 (d, J=8.6 Hz, 2 H), 7.74 (dd, J=7.8, 1.4 Hz, 1 H), 7.71 (d, J=8.4 Hz, 2 H), 7.51 (ddd, J=8.4, 7.3, 1.6 Hz, 1 H), 7.21 (td, J=7.6, 1.2 Hz, 1 H), 2.18 - 2.35 (m, 1 H), 1.80 (dd, J=12.7, 2.9 Hz, 2 H), 1.68 (dt, J= 12.2, 3.4 Hz, 2 H), 1.59 (d, J=11.9 Hz, 1 H), 1.01 - 1.43 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -60.26 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H22F3N2O2, 391.1628; found 391.1628.

EXAMPLE 12

[0201] This example illustrates a synthesis of N-(4-Bromophenyl)-2- (cyclohexanecarboxamido)benzamide (XJB06-013, NCGC00189479-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.893 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.46 (s, 1 H), 10.41 (s, 1 H), 8.16 (dd, J=8.2, 1.0 Hz, 1 H), 7.74 (dd, J=7.8, 1.6 Hz, 1 H), 7.60 - 7.69 (m, 2 H), 7.50 - 7.56 (m, 2 H), 7.46 - 7.50 (m, 1 H), 7.19 (td, J=7.5, 1.2 Hz, 1 H), 2.18 - 2.34 (m, 1 H), 1.81 (dd, J=12.1, 3.3 Hz, 2 H), 1.69 (dt, J=12.3, 3.1 Hz, 2 H), 1.59 (d, J=11.9 Hz, 1 H), 1.06 - 1.42 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂oH₂₂BrN₂0₂, 401.0859; found 401.0858.

EXAMPLE 13

[0203] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(4- fluorophenyl)benzamide (XJB06-014, NCGC00189478-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.413 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.52 (s, 1 H), 10.41 (s, 1 H), 8.22 (dd, J=8.3, 0.9 Hz, 1 H), 7.76 (dd, J=7.8, 1.4 Hz, 1 H), 7.62 - 7.73 (m, 2 H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.10 - 7.28 (m, 3 H), 2.17 - 2.35 (m, 1 H), 1.82 (dd, J=12.9, 2.5 Hz, 2 H), 1.69 (dt, J=12.3, 3.3 Hz, 2 H), 1.53 - 1.63 (m, 1 H), 0.97 - 1.43 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO- d₆) δ ppm -118.31 - -118.38 (m, 1 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂FN₂O₂, 341.1660; found 341.1659.

EXAMPLE 14

[0205] This example illustrates a synthesis of 2-(cyclohexanecarboxamido)-N-p- tolylbenzamide (XJB06-015, NCGC00189477-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.636 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.61 (s, 1 H), 10.30 (s, 1 H), 8.26 (dd, J=8.2, 0.8 Hz, 1 H), 7.77 (dd, J=7.8, 1.4 Hz, 1 H), 7.52 - 7.59 (m, 2 H), 7.48 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.18 (dd, J=7.8, 1.2 Hz, 1 H), 7.11 - 7.17 (m, 2 H), 2.26 (s, 3 H), 2.16 - 2.36 (m, 1 H), 1.82 (dd, J=13.0, 2.1 Hz, 2 H), 1.69 (ddd, J=12.2, 3.3, 3.1 Hz, 2 H), 1.51 - 1.64 (m, 1 H), 1.02 - 1.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₂, 337.1911; found 337.1916.

EXAMPLE 15

[0207] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(4- methoxyphenyl)benzamide (XJB06-016, NCGC00189476-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.243 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.71 (s, 1 H), 10.27 (s, 1 H), 8.29 (dd, J=8.3, 0.9 Hz, 1 H), 7.78 (dd, J=7.8, 1.4 Hz, 1 H), 7.52 - 7.63 (m, 2 H), 7.48 (ddd, J=8.4, 7.3, 1.5 Hz, 1 H), 7.17 (td, J=7.5, 1.2 Hz, 1 H), 6.83 - 7.02 (m, 2 H), 3.73 (s, 3 H), 2.25 (tt, J=l 1.2, 3.4 Hz, 1 H), 1.77 - 1.93 (m, 2 H), 1.70 (ddd, J=12.3, 3.2, 2.9 Hz, 2 H), 1.52 - 1.64 (m, 1 H), 1.00 - 1.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₃, 353.1860; found 353.1857.

EXAMPLE 16

[0209] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(4- nitrophenyl)benzamide (XJB06-017, NCGC00189475-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.408 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.85 (s, 1 H), 10.17 (s, 1 H), 8.16 - 8.32 (m, 2 H), 7.85 - 8.06 (m, 3 H), 7.72 (dd, J=7.8, 1.4 Hz, 1 H), 7.43 - 7.58 (m, 1 H), 7.22 (td, J=7.5, 1.2 Hz, 1 H), 2.27 (tt, J=11.2, 3.5 Hz, 1 H), 1.72 - 1.88 (m, 2 H), 1.68 (ddd, J=9.0, 6.1 , 2.7 Hz, 2 H), 1.52 - 1.63 (m, 1 H), 0.99 - 1.45 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C20H22N3O4, 368.1605; found 368.1605.

EXAMPLE 17

[0211] This example illustrates a synthesis of N-(2-Bromophenyl)-2- (cyclohexanecarboxamido)benzamide (XJB06-027, NCGC00189474-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti

(Method 1) = 6.689 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.91 (s, 1 H), 10.26 (s, 1 H), 8.36 (dd, J=8.4, 1.0 Hz, 1 H), 7.93 (dd, J=7.8, 1.4 Hz, 1 H), 7.71 (dd, J=8.0, 1.4 Hz, 1 H), 7.49 - 7.59 (m, 2 H), 7.44 (td, J=7.6, 1.4 Hz, 1 H), 7.22 - 7.27 (m, 1 H), 7.20 (td, J=7.6, 1.2 Hz, 1 H), 2.24 (tt, J=11.3, 3.5 Hz, 1 H), 1.82 (dd, J=12.6, 2.4 Hz, 2 H), 1.69 (ddd, J=12.5, 3.2, 2.9 Hz, 2 H), 1.51 - 1.64 (m, 1 H), 1.05 - 1.45 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂oH22BrN₂02, 401.0859; found 401.0863.

EXAMPLE 18

[0213] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2- fhiorophenyl)benzamide (XJB06-028, NCGC00189473-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.305 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.85 (br. s., 1 H), 10.28 (s, 1 H), 8.34 (dd, J=8.4, 1.0 Hz, 1 H), 7.88 (dd, J=7.8, 1.4 Hz, 1 H), 7.42 - 7.64 (m, 2 H), 7.24 - 7.34 (m, 2 H), 7.13 - 7.24 (m, 2 H), 2.24 (tt, J=11.2, 3.5 Hz, 1 H), 1.76 - 1.86 (m, 2 H), 1.64 - 1.75 (m, 2 H), 1.52 - 1.64 (m, 1 H), 0.99 - 1.43 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -120.74 - - 120.85 (m, 1 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂FN₂O₂, 341.1660; found

341.1656.

EXAMPLE 19

[0215] This example illustrates a synthesis of 2-(cyclohexanecarboxamido)-N-o- tolylbenzamide (XJB06-029, NCGC00189472-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.401 min; 1H

NMR (400 MHz, DMSC /₆) δ ppm 11.00 (s, 1 H), 10.09 (s, 1 H), 8.38 (dd, J=8.4, 1.2 Hz, 1 H), 7.91 (d, J=7.8 Hz, 1 H), 7.51 (ddd, J=8.6, 7.2, 1.7 Hz, 1 H), 7.25 - 7.35 (m, 2 H), 7.10 - 7.25 (m, 3 H), 2.21 (s, 3 H), 2.16 - 2.28 (m, 1 H), 1.77 - 1.91 (m, 2 H), 1.69 (dt, J=12.4, 3.5 Hz, 2 H), 1.53 - 1.65 (m, 1 H), 0.99 - 1.44 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₂, 337.1911; found 337.1912.

EXAMPLE 20

[0217] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2- nitrophenyl)benzamide (XJB06-031, NCGC00189471-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.550 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.85 (s, 1 H), 10.44 (s, 1 H), 8.25 (dd, J=8.4, 1.2 Hz, 1 H), 8.01 (dd, J=8.2, 1.6 Hz, 1 H), 7.84 (dd, J=7.8, 1.6 Hz, 1 H), 7.67 - 7.80 (m, 2 H), 7.54 (ddd, J=8.6, 7.3, 1.6 Hz, 1 H), 7.44 (ddd, J=8.4, 6.7, 2.0 Hz, 1 H), 7.23 (td, J=7.6, 1.3 Hz, 1 H), 2.22 (tt, J=11.4, 3.5 Hz, 1 H), 1.80 (d, J=14.7 Hz, 2 H), 1.68 (ddd, J=12.3, 3.4, 3.3 Hz, 2 H), 1.59 (d, J=11.9 Hz, 1 H), 1.05 - 1.41 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂oH₂₂N₃04, 368.1605; found 368.1605.

EXAMPLE 21

[0219] This example illustrates a synthesis of 2-Amino-N-(3-

(trifiuoromethyl)phenyl)benzamide (XJB06-036, NCGC00189470-01). A solution of tert- butyl 2-(3-(trifluoromethyl)phenylcarbamoyl)phenylcarbamate (2.11 g, 5.55 mmol) in dichloro methane (15.0 mL) was treated at 0 °C with TFA (5.34 mL, 69.3 mmol). The reaction mixture was stirred at 0 °C for 1 h and room temperature for additional 2 h. The reaction mixture was concentrated and re-dissolved in dichloromethane and washed with saturated Na₂C03 aqueous solution. The organic layer was separated, dried and concentrated to give 1.45 g (99%) of the title compound as a white solid. LC-MS Retention Time:

(Method 1) = 5.590 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.24 (s, 1 H), 8.18 (t, J=2.2 Hz, 1 H), 7.95 (ddd, J=8.4, 1.2, 1.0 Hz, 1 H), 7.63 (dd, J=8.0, 1.6 Hz, 1 H), 7.54 (t, J=8.3 Hz, 1 H), 7.34 - 7.43 (m, 1 H), 7.19 (ddd, J=8.4, 7.0, 1.6 Hz, 1 H), 6.74 (dd, J=8.3, 1.3 Hz, 1 H), 6.57 (ddd, J=8.1, 7.0, 1.2 Hz, 1 H), 6.34 (br. s., 2 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.18 (s, 3 F).

EXAMPLE 22

[0221] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2-

(trifiuoromethyl)benzyl)benzamide (XJB06-038, NCGC00189469-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.797 min; ^!H NMR (400 MHz, DMSO- ₆) δ ppm 11.12 (s, 1 H), 9.29 (t, J=5.9 Hz, 1 H), 8.40 (dd, J=8.4, 1.4 Hz, 1 H), 7.82 (dd, J=7.9, 1.7 Hz, 1 H), 7.73 (dt, J=7.8, 0.8 Hz, 1 H), 7.64 (t, J=7.3 Hz, 1 H), 7.42 - 7.56 (m, 3 H), 7.09 - 7.19 (m, 1 H), 4.65 (d, J=6.1 Hz, 2 H), 2.21 (tt, J=11.2, 3.5 Hz, 1 H), 1.76 - 1.88 (m, 2 H), 1.63 - 1.73 (m, 2 H), 1.51 - 1.63 (m, 1 H), 1.03 - 1.44 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -58.97 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₄F₃N₂0₂, 405.1784; found 405.1790.

EXAMPLE 23

[0223] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(furan-2- ylmethyl)benzamide (XJB06-039, NCGC00189468-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 5.946 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.24 (s, 1 H), 9.19 (t, J=5.7 Hz, 1 H), 8.40 (dd, J=8.4, 1.4 Hz, 1 H), 7.72 (dd, J=7.8, 1.6 Hz, 1 H), 7.56 (dd, J=1.9, 0.9 Hz, 1 H), 7.45 (ddd, J=8.5, 7.1, 1.6 Hz, 1 H), 6.99 - 7.15 (m, 1 H), 6.38 (dd, J=3.2, 1.9 Hz, 1 H), 6.22 - 6.33 (m, 1 H), 4.45 (dd, J=5.6, 0.5 Hz, 2 H), 2.23 (tt, J=11.2, 3.5 Hz, 1 H), 1.79 - 1.93 (m, 2 H), 1.71 (dt, J=12.6, 3.6 Hz, 2 H), 1.54 - 1.67 (m, 1 H), 1.03 - 1.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C19H23N2O3, 327.1703; found 327.1708.

EXAMPLE 24

[0225] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2-fluoro- 5-(trifiuoromethyl)phenyl)benzamide (XJB06-040, NCGC00189467-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.825 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.51 (s, 1 H), 10.44 (s, 1 H), 8.14 (dd, J=8.3, 1.3 Hz, 1 H), 8.07 (dd, J=6.8, 2.3 Hz, 1 H), 7.81 (dd, J=7.8, 1.6 Hz, 1 H), 7.61 - 7.73 (m, 1 H), 7.46 - 7.59 (m, 2 H), 7.21 (td, J=7.6, 1.3 Hz, 1 H), 2.20 - 2.34 (m, 1 H), 1.75 - 1.88 (m, 2 H), 1.68 (ddd, J=12.8, 3.1, 2.9 Hz, 2 H), 1.52 - 1.64 (m, 1 H), 1.07 - 1.42 (m, 5 H); F NMR (376 MHz, DMSO-dg) δ ppm -60.47 (s, 3 F), -119.15 - -111.85 (m, 1 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H21F4N2O2, 409.1534; found 409.1534.

EXAMPLE 25

[0227] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3-

(trifiuoromethyl)benzyl)benzamide (XJB06-041, NCGC00189466-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.781 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.13 (s, 1 H), 9.34 (t, J=6.1 Hz, 1 H), 8.37 (dd, J=8.4, 1.4 Hz, 1 H), 7.76 (dd, J=7.9, 1.7 Hz, 1 H), 7.66 - 7.70 (m, 1 H), 7.58 - 7.66 (m, 2 H), 7.53 - 7.58 (m, 1 H), 7.47 (ddd, J=8.5, 7.2, 1.7 Hz, 1 H), 7.13 (td, J=7.6, 1.3 Hz, 1 H), 4.54 (d, J=5.9 Hz, 2 H), 2.20 (tt, J=11.2, 3.5 Hz, 1 H), 1.75 - 1.87 (m, 2 H), 1.68 (dt, J=12.3, 3.2 Hz, 2 H), 1.53 - 1.64 (m, 1 H), 1.02 - 1.42 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO- d₆) δ ppm - 61.02 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C22H24F3N2O2, 405.1784; found 405.1790.

EXAMPLE 26

[0229] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(thiophen- 2-ylmethyl)benzamide (XJB06-042, NCGC00189465-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.211 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.21 (s, 1 H), 9.22 - 9.73 (m, 1 H), 8.40 (dd, J=8.4, 1.4 Hz, 1 H), 7.70 (dd, J=8.0, 1.6 Hz, 1 H), 7.45 (ddd, J=8.5, 7.1 , 1.6 Hz, 1 H), 7.38 (dd, J=5.1, 1.2 Hz, 1 H), 7.10 (td, J=7.6, 1.3 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 6.94 (dd, J=5.1 , 3.5 Hz, 1 H), 4.61 (dd, J=5.9, 1.0 Hz, 2 H), 2.23 (tt, J=l 1.3, 3.4 Hz, 1 H), 1.80 - 1.93 (m, 2 H), 1.68 - 1.79 (m, 2 H), 1.56 - 1.68 (m, J=12.3, 3.4, 1.8, 1.8 Hz, 1 H), 1.03 - 1.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₂₃N₂O₂S, 343.1475; found 343.1485.

EXAMPLE 27

[0231] This example illustrates a synthesis of 2-(cyclohexanecarboxamido)-N-(4-

(trifiuoromethyl)benzyl)benzamide (XJB06-043, NCGC00189464-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.763 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.15 (s, 1 H), 9.36 (t, J=6.0 Hz, 1 H), 8.38 (dd, J=8.4, 1.4 Hz, 1 H), 7.78 (dd, J=7.8, 1.6 Hz, 1 H), 7.68 (d, J=8.0 Hz, 2 H), 7.50 - 7.58 (m, 2 H), 7.47 (ddd, J=8.6, 7.3, 1.6 Hz, 1 H), 7.08 - 7.20 (m, 1 H), 4.54 (d, J=5.9 Hz, 2 H), 2.20 (tt, J=11.2, 3.4 Hz, 1 H), 1.73 - 1.89 (m, 2 H), 1.68 (ddd, J=12.5, 3.4, 3.1 Hz, 2 H), 1.53 - 1.63 (m, 1 H), 1.02 - 1.43 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -60.75 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₄F₃N₂O₂, 405.1784; found 405.1789. EXAMPLE 28

[0233] This example illustrates a synthesis of 2-(Cyclopentanecarboxamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-046, NCGC00189463-01). The title compound was prepared according to general protocol B. LC-MS Retention Time: ti (Method 1) = 6.780 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.60 (s, 1 H), 10.29 (s, 1 H), 8.15 (t, J=2.2 Hz, 1 H), 8.04 (d, J=7.8 Hz, 1 H), 7.93 (d, J=8.4 Hz, 1 H), 7.73 (dd, J=7.8, 1.6 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 7.50 (ddd, J=8.5, 7.2, 1.6 Hz, 1 H), 7.44 (d, J=7.6 Hz, 1 H), 7.21 (td, J=7.6, 1.3 Hz, 1 H), 2.75 (quin, J=8.0 Hz, 1 H), 1.74 - 1.86 (m, 2 H), 1.63 - 1.74 (m, 2 H), 1.41 - 1.63 (m, 4 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.21 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C20H20F3N2O2, 377.1471; found 377.1481.

EXAMPLE 29

[0235] This example illustrates a synthesis of 2-(2-Ethylbutanamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-047, NCGC00189462-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.751 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.60 (s, 1 H), 10.25 (s, 1 H), 8.15 (t, J=2.2 Hz, 1 H), 7.98 (dd, J=8.2, 1.4 Hz, 1 H), 7.93 (ddd, J=8.2, 1.2, 1.0 Hz, 1 H), 7.72 (dd, J=7.7, 1.7 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 7.50 (ddd, J=8.4, 7.1, 1.7 Hz, 1 H), 7.38 - 7.47 (m, 1 H), 7.23 (td, J=7.6, 1.3 Hz, 1 H), 2.15 (tt, J=8.8, 5.4 Hz, 1 H), 1.30 - 1.62 (m, 4 H), 0.74 - 0.86 (m, 6 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.23 (s, 3 F); HRMS (ESI) m/z (M+H)⁴ calcd. for C20H22F3N2O2, 379.1628; found 379.1634.

EXAMPLE 30

[0237] This example illustrates a synthesis of 2-Pentanamido-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-048, NCGC00189461-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.546 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.61 (s, 1 H), 10.19 (s, 1 H), 8.17 (t, J=2.2 Hz, 1 H), 7.98 (dd, J=8.1, 1.1 Hz, 1 H), 7.92 (ddd, J=8.2, 2.0, 0.8 Hz, 1 H), 7.71 (dd, J=7.7, 1.7 Hz, 1 H), 7.57 (t, J=8.1 Hz, 1 H), 7.47 - 7.54 (m, 1 H), 7.39 - 7.47 (m, 1 H), 7.21 (td, J=7.6, 1.3 Hz, 1 H), 2.28 (t, J=7.4 Hz, 2 H), 1.43 - 1.60 (m, 2 H), 1.18 - 1.34 (m, 2 H), 0.80 (t, J=7.6 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.21 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C19H20F3N2O2, 365.1471; found 365.1476.

EXAMPLE 31

[0239] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)adamantane- 1 -carboxamide (XJB06-049, NCGC00189460-01). The title compound was prepared according to general protocol C. LC- MS Retention Time: ti (Method 1) = 7.461 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.68 (s, 1 H), 10.64 (s, 1 H), 8.34 (dd, J=8.3, 1.3 Hz, 1 H), 8.07 (t, J=2.2 Hz, 1 H), 7.95 - 8.04 (m, 1 H), 7.85 (dd, J=7.8, 1.6 Hz, 1 H), 7.61 (t, J=8.0 Hz, 1 H), 7.53 (ddd, J=8.6, 7.2, 1.7 Hz, 1 H), 7.41 - 7.50 (m, 1 H), 7.17 - 7.26 (m, 1 H), 1.90 - 2.10 (m, 3 H), 1.79 - 1.89 (m, 6 H), 1.57 - 1.75 (m, 6 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.22 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C25H26F3N2O2, 443.1941; found 443.1939.

EXAMPLE 32

[0240]

[0241] This example illustrates a synthesis of 2-Amino-N-(furan-2-ylmethyl)benzamide (XJB06-052, NCGC00165247-02). A solution of methyl 2-aminobenzoate (0.857 mL, 6.62 mmol) and furan-2-ylmethanamine (1.84 mL, 19.9 mmol) in toluene (20.0 mL) was treated at room temperature with AlMe₃ (6.62 mL, 2.0 M in toluene, 13.2 mmol). The reaction mixture was stirred at 100 °C for 5 h and then quenched with water after cooling to room temperature. The reaction mixture was concentrated in vacuo and the crude residue was purified via silica gel chromatography using a gradient of 0-80% of EtOAc in hexanes to give 1.35 g (94%) of the title compound as a white solid. LC-MS Retention Time: (Method 1) = 3.644 min.

EXAMPLE 33

[0243] This example illustrates a synthesis of 2-(Cyclobutanecarboxamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-053, NCGC00189459-01). The title compound was prepared according to general protocol B. LC-MS Retention Time: ti (Method 1) = 6.412 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.61 (s, 1 H), 10.22 (s, 1 H), 8.15 (t, J=2.2 Hz, 1 H), 8.09 (dt, J=8.1, 0.6 Hz, 1 H), 7.93 (ddd, J=8.2, 1.2, 1.0 Hz, 1 H), 7.75 (dd, J=7.8, 1.6 Hz, 1 H), 7.58 (t, J=7.8 Hz, 1 H), 7.51 (ddd, J=8.5, 7.2, 1.6 Hz, 1 H), 7.40 - 7.48 (m, 1 H), 7.21 (td, J=7.6, 1.3 Hz, 1 H), 3.15 - 3.26 (m, 1 H), 2.01 - 2.24 (m, 4 H), 1.80 - 1.97 (m, 1 H), 1.64 - 1.80 (m, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for Ci₉Hi₈F₃N₂0₂, 363.1315; found 363.1317.

EXAMPLE 34

[0245] This example illustrates a synthesis of 2-(4-Methylcyclohexanecarboxamido)-N- (3-(trifluoromethyl)phenyl)benzamide (XJB06-054, NCGC00189458-01, mixture of cis- and trans-isomers). The title compound was prepared according to general protocol B. LC-MS Retention Time: ti (Method 1) = 7.150 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.60 (s, 1 H), 10.32 (s, 0.5 H), 10.27 (s, 0.5 H), 8.09 - 8.18 (m, 1 H), 8.02 - 8.09 (m, 1 H), 7.88 - 7.97 (m, 1 H), 7.68 - 7.80 (m, 1 H), 7.54 - 7.61 (m, 1 H), 7.47 - 7.54 (m, 1 H), 7.40 - 7.47 (m, 1 H), 7.14 - 7.26 (m, 1 H), 2.13 - 2.26 (m, 1 H), 1.73 - 1.89 (m, 2 H), 1.66 (dd, J=13.4, 3.4 Hz, 1 H), 1.13 - 1.60 (m, 5 H), 0.85 - 1.01 (m, 1 H), 0.83 (d, J=6.7 Hz, 1.5 H), 0.80 (d, J=6.8 Hz, 1.5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.21 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₄F₃N₂0₂, 405.1784; found 405.1788.

EXAMPLE 35

[0247] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)benzo [d] [ 1 ,3 ] dioxo le-5 -carboxamide (XJB06- 055, NCGC00189457-01). The title compound was prepared according to general protocol B. LC-MS Retention Time: ti (Method 1) = 6.524 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.19 (s, 1 H), 10.72 (s, 1 H), 8.28 (dd, J=8.3, 1.3 Hz, 1 H), 8.08 (t, J=2.2 Hz, 1 H), 7.92 - 8.01 (m, 1 H), 7.87 (dd, J=7.8, 1.6 Hz, 1 H), 7.53 - 7.64 (m, 2 H), 7.41 - 7.49 (m, 2 H), 7.37 (d, J=1.8 Hz, 1 H), 7.27 (td, J=7.6, 1.3 Hz, 1 H), 7.05 (d, J=8.2 Hz, 1 H), 6.11 (s, 2 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂2Hi₆F₃N204, 429.1057; found 429.1055.

EXAMPLE 36

[0249] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)cyclo-heptanecarboxamide (XJB06-056, NCGC00189456-01, CID-56593317). The title compound was prepared according to general protocol B. LC-MS Retention Time: ti (Method 1) = 7.093 min; 1H NMR (400 MHz, DMSO- ά₆) δ ppm 10.58 (s, 1 H), 10.18 (s, 1 H), 8.13 (s, 1 H), 7.98 (dd, J=8.1 , 0.9 Hz, 1 H), 7.93 (d, J=8.0 Hz, 1 H), 7.71 (dd, J=7.8, 1.6 Hz, 1 H), 7.57 (t, J=7.8 Hz, 1 H), 7.49 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.39 - 7.46 (m, 1 H), 7.21 (td, J=7.6, 1.2 Hz, 1 H), 2.40 - 2.51 (m, 1 H), 1.75 - 1.88 (m, 2 H), 1.31 - 1.71 (m, 10 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.20 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C22H24F3N2O2, 405.1784; found 405.1794.

EXAMPLE 37

[0251] This example illustrates a synthesis of 2-Benzamido-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-058, NCGC00189455-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.644 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₆F₃N202, 385.1158; found 385.1163.

[0253] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide (XJB06-059, NCGC00189454- 01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 5.174 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.35 (s, 1 H), 10.74 (d, J=0.4 Hz, 1 H), 8.67 - 8.99 (m, 2 H), 8.13 - 8.22 (m, 1 H), 8.04 - 8.1 1 (m, 1 H), 7.94 - 8.02 (m, 1 H), 7.87 (dd, J=7.8, 1.6 Hz, 1 H), 7.74 - 7.81 (m, 2 H), 7.52 - 7.67 (m, 2 H), 7.44 (dt, J=7.7, 1.0 Hz, 1 H), 7.34 (td, J=7.6, 1.3 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for

386.1111; found

386.1123.

EXAMPLE 39

[0255] This example illustrates a synthesis of N-(2-((3-

(trifluoromethyl)phenyl)carbamoyl)phenyl)thiophene-2-carboxamide (XJB06-060,

NCGC00189453-01). The title compound was prepared according to general protocol C. LC- MS Retention Time: ti (Method 1) = 6.571 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.31 (s, 1 H), 10.73 (s, 1 H), 8.21 (dd, J=8.2, 1.2 Hz, 1 H), 8.10 (td, J=1.8, 0.9 Hz, 1 H), 7.99 (d, J=8.8 Hz, 1 H), 7.81 - 7.92 (m, 2 H), 7.75 (dd, J=3.8, 1.3 Hz, 1 H), 7.55 - 7.63 (m, 2 H), 7.43 - 7.49 (m, 1 H), 7.29 (td, J=7.6, 1.2 Hz, 1 H), 7.22 (dd, J=5.0, 3.8 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.16 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₁₄F₃N₂O₂S, 391.0723; found 391.0731.

[0257] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)furan-2-carboxamide (XJB06-061 ,

NCGC00189452-01). The title compound was prepared according to general protocol C. LC-

MS Retention Time: ti (Method 1) = 6.221 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.42 (s, 1 H), 10.77 (s, 1 H), 8.41 (dd, J=8.4, 1.4 Hz, 1 H), 8.04 - 8.15 (m, 1 H), 7.98 - 8.04 (m, 1 H), 7.96 (dd, J=1.9, 0.9 Hz, 1 H), 7.91 (dd, J=8.0, 1.6 Hz, 1 H), 7.52 - 7.65 (m, 2 H), 7.44 - 7.50 (m, 1 H), 7.28 (td, J=7.6, 1.2 Hz, 1 H), 7.24 (dd, J=3.5, 0.8 Hz, 1 H), 6.69 (dd, J=3.5, 1.8 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.15 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C19H14F3N2O3, 375.0951; found 375.0957.

EXAMPLE 41

[0259] This example illustrates a synthesis of N-(2-((3-

(Trifiuoromethyl)phenyl)carbamoyl)phenyl)nicotinamide (XJB06-062, NCGC00189451-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 5.342 min; 1H NMR (400 MHz, DMSO-d₆) δ ppm 1 1.27 (s, 1 H), 10.74 (s, 1 H), 8.95 - 9.12 (m, 1 H), 8.67 - 8.91 (m, 1 H), 8.19 - 8.29 (m, 1 H), 8.17 (dd, J=8.3, 1.3 Hz, 1 H), 8.10 (t, J=2.1 Hz, 1 H), 7.92 - 8.02 (m, 1 H), 7.86 (dd, J=7.8, 1.6 Hz, 1 H), 7.52 - 7.69 (m, 3 H), 7.38 - 7.48 (m, 1 H), 7.33 (td, J=7.6, 1.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.20 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for CzoH^^Oz, 386.1111; found 386.1116.

EXAMPLE 42

[0261] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)isoxazole-5-carboxamide (XJB06-063,

NCGC00189450-01). The title compound was prepared according to general protocol C. LC- MS Retention Time: ti (Method 1) = 6.043 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.63 (s, 1 H), 10.79 (s, 1 H), 8.80 (d, J=2.0 Hz, 1 H), 8.23 (dd, J=8.4, 1.2 Hz, 1 H), 8.08 - 8.15 (m, 1 H), 7.99 (dd, J=8.3, 1.5 Hz, 1 H), 7.91 (dd, J=7.8, 1.6 Hz, 1 H), 7.56 - 7.68 (m, 2 H), 7.44 - 7.51 (m, 1 H), 7.36 (td, J=7.6, 1.4 Hz, 1 H), 7.19 (d, J=2.0 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C18H13F3N3O3, 376.0904; found 376.0910.

EXAMPLE 43

[0263] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2-((furan- 2-ylmethyl)carbamoyl)phenyl)benzamide (XJB06-065, NCGC00189449-01). A solution of methyl 2-(cyclohexanecarboxamido)benzoate (50.0 mg, 0.191 mmol) and 2-amino-N-(furan- 2-ylmethyl)benzamide (41.4 mg, 0.191 mmol) in toluene (2.00 mL) was treated at room temperature with AlMe3 (0.192 mL, 2.0 M in toluene, 0.384 mmol). The reaction mixture was stirred at 100 °C for overnight and then quenched with 100 of water. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the title compound as a white solid. LC-MS Retention Time: ti (Method 1) = 6.799 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 12.07 (s, 1 H), 10.69 (s, 1 H), 9.29 (t, J=5.8 Hz, 1 H), 8.41 (dd, J=8.3, 1.3 Hz, 1 H), 8.22 (dd, J=8.3, 1.3 Hz, 1 H), 7.80 (dd, J=8.0, 1.6 Hz, 1 H), 7.73 (dd, J=7.8, 1.6 Hz, 1 H), 7.45 - 7.64 (m, 3 H), 7.13 - 7.29 (m, J=7.9, 7.7, 7.7, 1.3 Hz, 2 H), 6.36 (dd, J=3.2, 1.9 Hz, 1 H), 6.22 - 6.33 (m, 1 H), 4.45 (d, J=5.5 Hz, 2 H), 2.18 - 2.36 (m, 1 H), 1.76 - 1.91 (m, 2 H), 1.64 - 1.76 (m, 2 H), 1.50 - 1.64 (m, 1 H), 1.05 - 1.44 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C26H28N3O4, 446.2074; found 446.2080.

EXAMPLE 44

[0265] This example illustrates a synthesis of Methyl 2-(furan-2-carboxamido)benzoate (XJB06-066, NCGC00026064-02). A solution of methyl 2-aminobenzoate (1.71 mL, 13.2 mmol) in dichloro methane (50.0 mL) and TEA (5.53 mL, 39.7 mmol) was treated at room temperature with furan-2-carbonyl chloride (2.62 mL, 26.5 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with methanol, concentrated, and purified via silica gel chromatography using a gradient of 0-40% of EtOAc in hexanes to give 3.00 g (92%) of the title compound as a white solid. LC-MS Retention Time: ti (Method 1) = 6.516 min.

[0267] This example illustrates a synthesis of N-(2-((2-((Furan-2- ylmethyl)carbamoyl)phenyl)carbamoyl)phenyl)furan-2-carboxamide (XJB06-067,

NCGC00052938-02). A solution of 2-(furan-2-carboxamido)benzoate (50.0 mg, 0.204 mmol) and 2-amino-N-(furan-2-ylmethyl)benzamide (44.1 mg, 0.204 mmol) in toluene (2.00 mL) was treated at room temperature with AlMe3 (0.204 mL, 2.0 M in toluene, 0.408 mmol). The reaction mixture was stirred at 100 °C for overnight and then quenched with 100 of water. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via Ci8 reverse phase HPLC to give the title compound as a white solid. LC-MS Retention Time: ti (Method 1) = 6.103 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 12.33 (s, 1 H), 11.87 (s, 1 H), 9.32 (t, J=5.3 Hz, 1 H), 8.53 (dd, J=8.4, 1.4 Hz, 1 H), 8.45 (dd, J=8.3, 1.3 Hz, 1 H), 7.97 (dd, J=1.8, 1.0 Hz, 1 H), 7.86 (dd, J=8.0, 1.6 Hz, 1 H), 7.83 (dd, J=8.0, 1.6 Hz, 1 H), 7.55 - 7.67 (m, 2 H), 7.53 (dd, J=2.0, 1.0 Hz, 1 H), 7.27 - 7.35 (m, 1 H), 7.18 - 7.27 (m, 2 H), 6.70 (dd, J=3.5, 1.8 Hz, 1 H), 6.35 (dd, J=3.2, 1.9 Hz, 1 H), 6.28 (dd, J=3.1, 1.0 Hz, 1 H), 4.44 (d, J=5.5 Hz, 2 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂4H2oN₃0₅, 430.1397; found 430.1406.

EXAMPLE 46

[0269] This example illustrates a synthesis of 2-(3-(Trifluoromethyl)benzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-070, NCGC00189448-01). The title compound was prepared according to general protocol D. LC-MS Retention Time: ti (Method 1) = 7.060 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.28 (s, 1 H), 10.72 (s, 1 H), 8.13 - 8.32 (m, 3 H), 8.11 (dd, J=8.2, 1.2 Hz, 1 H), 7.88 - 8.00 (m, 2 H), 7.84 (dd, J=7.8, 1.6 Hz, 1 H), 7.78 (t, J=7.7 Hz, 1 H), 7.49 - 7.66 (m, 2 H), 7.39 - 7.45 (m, 1 H), 7.33 (td, J=7.6, 1.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.32 (s, 6 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂2Hi₅F₆N₂02, 453.1032; found 453.1033. EXAMPLE 47

[0271] This example illustrates a synthesis of 2-Acetamido-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-071, NCGCOO 189447-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 5.593 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.64 (s, 1 H), 10.18 (br. s., 1 H), 8.18 (t, J=2.2 Hz, 1 H), 7.97 - 8.04 (m, 1 H), 7.92 (dt, J=8.0, 1.2 Hz, 1 H), 7.71 (dd, J=7.7, 1.7 Hz, 1 H), 7.57 (t, J=8.0 Hz, 1 H), 7.50 (ddd, J=8.4, 7.1, 1.7 Hz, 1 H), 7.41 - 7.47 (m, 1 H), 7.21 (td, J=7.6, 1.3 Hz, 1 H), 2.02 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO- d₆) δ ppm -61.18 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C16H14F3N2O2, 323.1002; found 323.1010.

EXAMPLE 48

[0273] This example illustrates a synthesis of 2-Acetamido-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-072, NCGCOO 189446-01). The title compound was prepared according to general protocol D. LC-MS Retention Time: ti (Method 1) = 7.415 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.25 (s, 1 H), 10.71 (s, 1 H), 8.39 - 8.57 (m, 2 H), 8.35 (s, 1 H), 8.19 (s, 1 H), 7.92 - 8.00 (m, 1 H), 7.84 - 7.92 (m, 1 H), 7.81 (dd, J=7.7, 1.7 Hz, 1 H), 7.58 - 7.68 (m, 1 H), 7.53 (t, J=7.9 Hz, 1 H), 7.22 - 7.47 (m, 2 H); ¹⁹F NMR (376 MHz, DMSO- g) δ ppm -61.42 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H14F9N2O2, 521.0906; found 521.0905.

EXAMPLE 49

[0275] This example illustrates a synthesis of 2-(2-Phenylacetamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-074, NCGC00189445-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.443 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.61 (s, 1 H), 10.30 (s, 1 H), 8.17 (t, J=2.1 Hz, 1 H), 8.00 - 8.07 (m, 1 H), 7.83 - 7.91 (m, 1 H), 7.71 (dd, J=7.8, 1.6 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 7.50 (ddd, J=8.5, 7.2, 1.6 Hz, 1 H), 7.41 - 7.47 (m, 1 H), 7.1 1 - 7.34 (m, 6 H), 3.66 (s, 2 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.15 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₂, 399.1315; found 399.1312.

EXAMPLE 50

[0277] This example illustrates a synthesis of 2-(Cyclopropanecarboxamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB06-081, NCGCOO 189444-01). The title compound was prepared according to general protocol B. LC-MS Retention Time: ti (Method 1) = 6.131 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.61 (s, 1 H), 10.46 (s, 1 H), 8.17 (s, 1 H), 7.95 - 8.08 (m, 1 H), 7.91 (dd, J=7.9, 1.3 Hz, 1 H), 7.71 (dd, J=7.9, 1.5 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 7.46 - 7.53 (m, 1 H), 7.40 - 7.46 (m, 1 H), 7.20 (tt, J=7.6, 0.8 Hz, 1 H), 1.61 - 1.81 (m, 1 H), 0.65 - 0.79 (m, 4 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for Ci₈Hi₆F₃N202, 349.1158; found 349.1160.

EXAMPLE 51

[0279] This example illustrates a synthesis of N-(3-(fert-Butyl)phenyl)-2- (cyclohexanecarboxamido)benzamide (XJB07-026, NCGC00238733-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.324 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C24H31N2O2, 379.2380; found 379.2387.

EXAMPLE 52

[0281] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2,3- dihydro-lH-inden-5-yl)benzamide (XJB07-028, NCGC00238732-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.053 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.62 (s, 1 H), 10.27 (s, 1 H), 8.26 (d, J=8.2 Hz, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.55 (s, 1 H), 7.42 - 7.51 (m, 1 H), 7.31 - 7.41 (m, 1 H), 7.08 - 7.23 (m, 2 H), 2.74 - 2.90 (m, 4 H), 2.17 - 2.32 (m, 1 H), 1.92 - 2.08 (m, J=7.8, 7.5, 7.4, 7.4 Hz, 2 H), 1.76 - 1.89 (m, 2 H), 1.63 - 1.76 (m, 2 H), 1.52 - 1.63 (m, 1 H), 1.05 - 1.46 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H27N2O2, 363.2067; found 363.2075.

EXAMPLE 53

[0283] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(lH-indol- 5-yl)benzamide (XJB07-031, NCGC00238734-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 5.982 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.04 (br. s., 1 H), 10.87 (s, 1 H), 10.26 (s, 1 H), 8.34 (d, J=8.4 Hz, 1 H), 7.65 - 8.00 (m, 2 H), 7.44 - 7.53 (m, 1 H), 7.24 - 7.41 (m, 3 H), 7.16 (t, J=7.6 Hz, 1 H), 6.31 - 6.45 (m, 1 H), 2.17 - 2.31 (m, 1 H), 1.77 - 1.92 (m, 2 H), 1.68 (ddd, J=12.5, 3.4, 3.2 Hz, 2 H), 1.51 - 1.62 (m, 1 H), 1.01 - 1.44 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C22H24N3O2, 362.1863; found 362.1867.

EXAMPLE 54

[0285] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- iodophenyl)benzamide (XJB07-032, NCGC00238735-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.076 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.39 (s, 1 H), 10.32 (s, 1 H), 8.05 - 8.20 (m, 2 H), 7.68 - 7.76 (m, 1 H), 7.66 (ddd, J=8.2, 1.1, 0.9 Hz, 1 H), 7.39 - 7.55 (m, 2 H), 7.06 - 7.27 (m, 2 H), 2.11 - 2.33 (m, 1 H), 1.79 (dd, J=12.7, 2.2 Hz, 2 H), 1.63 - 1.73 (m, 2 H), 1.49 - 1.63 (m, 1 H), 1.05 - 1.44 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C20H22IN2O2, 449.0720; found 449.0720.

EXAMPLE 55

[0287] This example illustrates a synthesis of N-(3-Chlorophenyl)-2- (cyclohexanecarboxamido)benzamide (XJB07-033, NCGC00238736-01, CID-56593336). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.898 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.48 (s, 1 H), 10.31 (s, 1 H), 8.11 (d, J=7.8 Hz, 1 H), 7.85 (t, J=2.0 Hz, 1 H), 7.71 (dd, J=7.7, 1.3 Hz, 1 H), 7.59 (dd, J=8.0, 1.8 Hz, 1 H), 7.43 - 7.54 (m, 1 H), 7.35 (t, J=8.1 Hz, 1 H), 7.06 - 7.24 (m, 2 H), 2.26 (tt J=11.3, 3.6 Hz, 1 H), 1.79 (d, J=14.1 Hz, 2 H), 1.68 (ddd, J=12.7, 3.0, 2.7 Hz, 2 H), 1.52 - 1.62 (m, 1 H), 1.03 - 1.41 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C20H22CI 2O2, 357.1364; found 357.1366.

EXAMPLE 56

[0289] This example illustrates a synthesis of N-([ 1 , 1 '-Biphenyl]-3-yl)-2- (cyclohexanecarboxamido)benzamide (XJB07-034, NCGC00238737-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti

(Method 1) = 7.181 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.49 (s, 1 H), 10.44 (s, 1 H), 8.19 (ddd, J=8.2, 0.8, 0.6 Hz, 1 H), 7.96 (t, J=2.0 Hz, 1 H), 7.78 (dd, J=7.8, 1.6 Hz, 1 H), 7.70 (dt, J=7.6, 1.9 Hz, 1 H), 7.56 - 7.66 (m, 2 H), 7.31 - 7.55 (m, 6 H), 7.15 - 7.23 (m, 1 H), 2.19 - 2.32 (m, 1 H), 1.76 - 1.87 (m, 2 H), 1.62 - 1.74 (m, 2 H), 1.52 - 1.62 (m, 1 H), 1.04 - 1.45 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C26H27N2O2, 399.2067; found 399.2071.

EXAMPLE 57

[0291] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- ethynylphenyl)benzamide (XJB07-035, NCGC00238738-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.586 min; ^!H NMR (400 MHz, DMSO- ₆) δ ppm 10.42 (s, 1 H), 10.38 (s, 1 H), 8.15 (d, J=8.2 Hz, 1 H), 7.84 (s, 1 H), 7.71 - 7.78 (m, 1 H), 7.62 - 7.71 (m, 1 H), 7.44 - 7.53 (m, 1 H), 7.34 (t, J=8.0 Hz, 1 H), 7.14 - 7.24 (m, 2 H), 4.17 (s, 1 H), 2.08 - 2.35 (m, 1 H), 1.74 - 1.89 (m, 2 H), 1.62 - 1.74 (m, 2 H), 1.53 - 1.62 (m, 1 H), 1.00 - 1.43 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C22H23N2O2, 347.1754; found 347.1757.

EXAMPLE 58

[0293] This example illustrates a synthesis of N-(4-(tert-Butyl)phenyl)-2- (cyclohexanecarboxamido)benzamide (XJB07-037, NCGC00238739-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.389 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.63 (s, 1 H), 10.33 (s, 1 H), 8.26 (d, J=8.2 Hz, 1 H), 7.76 (dt, J=7.9, 1.0 Hz, 1 H), 7.52 - 7.61 (m, 2 H), 7.43 - 7.52 (m, 1 H), 7.29 - 7.42 (m, 2 H), 7.17 (tt, J=7.6, 1.0 Hz, 1 H), 2.16 - 2.29 (m, 1 H), 1.77 - 1.89 (m, 2 H), 1.64 - 1.77 (m, 2 H), 1.49 - 1.64 (m, 1 H), 1.25 (s, 9 H), 1.01 - 1.44 (m, 5 H);

HRMS (ESI) m/z (M+H)⁺ calcd. for C24H31N2O2, 379.2380; found 379.2391.

EXAMPLE 59

[0295] This example illustrates a synthesis of N-(Benzo[d][l,3]dioxol-5-yl)-2- (cyclohexanecarboxamido)benzamide (XJB07-039, NCGC00238740-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.279 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.57 (s, 1 H), 10.28 (s, 1 H), 8.23 (d, J=8.6 Hz, 1 H), 7.73 (dd, J=7.9, 1.7 Hz, 1 H), 7.44 - 7.62 (m, 1 H), 7.26 - 7.35 (m, 1 H), 7.13 - 7.21 (m, 1 H), 7.08 (dd, J=8.4, 2.0 Hz, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 5.98 (s, 2 H), 2.25 (tt, J=11.3, 3.6 Hz, 1 H), 1.75 - 1.90 (m, 2 H), 1.64 - 1.75 (m, 2 H), 1.50 - 1.64 (m, 1 H), 1.01 - 1.43 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H23N2O4, 367.1652; found 367.1657. EXAMPLE 60

[0297] This example illustrates a synthesis of 2-(3-Nitrobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-047, NCGC00238741-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.687 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.32 (s, 1 H), 10.73 (s, 1 H), 8.68 (t, J=2.1 Hz, 1 H), 8.36 - 8.48 (m, 1 H), 8.29 (dt, J=7.8, 1.5 Hz, 1 H), 8.12 (s, 1 H), 7.99 - 8.10 (m, 1 H), 7.95 (d, J=8.2 Hz, 1 H), 7.76 - 7.88 (m, 2 H), 7.58 - 7.66 (m, J=7.6, 7.6, 1.2, 0.8 Hz, 1 H), 7.50 - 7.58 (m, 1 H), 7.38 - 7.45 (m, 1 H), 7.29 - 7.38 (m, 1 H); ¹⁹F NMR (376 MHz, DMSO- d₆) δ ppm -61.34 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H15F3N3O4, 430.1009; found 430.1012.

EXAMPLE 61

[0299] This example illustrates a synthesis of 2-(3-Cyanobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-048, NCGC00238743-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.508 min; 1H NMR (400 MHz, DMSO-< ₆) δ ppm 11.16 (s, 1 H), 10.71 (s, 1 H), 8.27 (t, J=1.8 Hz, 1 H), 8.15 (dt, J=7.9, 1.6 Hz, 1 H), 8.01 - 8.12 (m, 3 H), 7.88 - 7.96 (m, 1 H), 7.79 - 7.87 (m, 1 H), 7.73 (t, J=7.8 Hz, 1 H), 7.51 - 7.65 (m, 2 H), 7.42 (d, J=7.6 Hz, 1 H), 7.32 (td, J=7.7, 0.8 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.33 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₅F₃N₃0₂, 410.1111; found 410.1120.

EXAMPLE 62

[0301] This example illustrates a synthesis of 2-Bromo-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB07-050, NCGC00238742-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.641 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅BrF₃N₂0₂, 463.0264; found 463.0264.

EXAMPLE 63

[0303] This example illustrates a synthesis of 2-(4-Chlorobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-051, NCGC00238744-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 7.132 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.26 (s, 1 H), 10.72 (s, 1 H), 8.21 (d, J=8.2 Hz, 1 H), 8.06 (s, 1 H), 7.96 (d, J=8.4 Hz, 1 H), 7.82 - 7.93 (m, 3 H), 7.52 - 7.66 (m, 4 H), 7.44 (d, J=7.8 Hz, 1 H), 7.30 (t, J=7.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅ClF₃N₂0₂, 419.0769; found 419.0775. EXAMPLE 64

[0305] This example illustrates a synthesis of 2-(4-Methylbenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-052, NCGC00238745-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.967 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.31 (s, 1 H), 10.73 (s, 1 H), 8.33 (d, J=8.4 Hz,

1 H), 8.08 (s, 1 H), 7.98 (d, J=8.4 Hz, 1 H), 7.88 (dd, J=7.6, 1.6 Hz, 1 H), 7.78 (d, J=8.2 Hz,

2 H), 7.53 - 7.64 (m, 2 H), 7.45 (ddd, J=7.7, 1.8, 0.9 Hz, 1 H), 7.33 (d, J=8.6 Hz, 2 H), 7.27 (td, J=7.6, 1.2 Hz, 1 H), 2.34 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₂, 399.1315; found 399.1321.

EXAMPLE 65

[0307] This example illustrates a synthesis of 2-(4-(Trifluoromethyl)benzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-054, NCGC00238746-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 7.128 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.33 (d, J=0.4 Hz, 1 H), 10.73 (s, 1 H), 8.19 (d, J=8.2 Hz, 1 H), 8.01 - 8.11 (m, 3 H), 7.97 (d, J=8.4 Hz, 1 H), 7.90 (d, J=8.6 Hz, 2 H), 7.82 - 7.88 (m, 1 H), 7.51 - 7.64 (m, 2 H), 7.40 - 7.45 (m, 1 H), 7.32 (t, J=7.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO- g) δ ppm -61.30 (s, 3 F), -61.45 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₅F₆N₂0₂, 453.1032; found 453.1034.

EXAMPLE 66

[0309] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)-[l, -biphenyl]-3-carboxamide (XJB07-055, NCGC00238747-01). The title compound was prepared according to general protocol C. LC- MS Retention Time: ti (Method 1) = 7.398 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.40 (s, 1 H), 10.76 (s, 1 H), 8.25 - 8.35 (m, 1 H), 8.10 - 8.22 (m, 2 H), 7.99 (d, J=8.2 Hz, 1 H), 7.81 - 7.94 (m, 3 H), 7.67 - 7.75 (m, 2 H), 7.54 - 7.66 (m, 3 H), 7.43 - 7.51 (m, 3 H), 7.37 - 7.43 (m, 1 H), 7.32 (td, J=7.6, 1.3 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C27H20F3N2O2, 461.1471; found 461.1478.

EXAMPLE 67

[0311] This example illustrates a synthesis of 2-(3-Methylbenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-056, NCGC00238759-02). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.975 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.27 (s, 1 H), 10.75 (s, 1 H), 8.30 (dd, J=8.3, 1.3 Hz, 1 H), 8.14 (s, 1 H), 7.98 (d, J=8.4 Hz, 1 H), 7.88 (dd, J=7.8, 1.6 Hz, 1 H), 7.71 (t, J=1.7 Hz, 1 H), 7.64 - 7.69 (m, 1 H), 7.54 - 7.64 (m, 2 H), 7.43 - 7.48 (m, 1 H), 7.37 - 7.43 (m, 2 H), 7.30 (td, J=7.6, 1.3 Hz, 1 H), 2.36 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.31 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₂, 399.1315; found

399.1323.

[0313] This example illustrates a synthesis of 2-(4-Methoxybenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-057, NCGC00238760-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.679 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.31 (s, 1 H), 10.75 (s, 1 H), 8.36 (dd, J=8.3, 1.3 Hz, 1 H), 8.08 (t, J=2.2 Hz, 1 H), 8.01 (ddd, J=8.2, 1.2, 1.0 Hz, 1 H), 7.78 - 7.92 (m, 3 H), 7.54 - 7.64 (m, 2 H), 7.42 - 7.49 (m, 1 H), 7.27 (td, J=7.6, 1.2 Hz, 1 H), 7.00 - 7.12 (m, 2 H), 3.81 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.25 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₃, 415.1264; found 415.1272.

EXAMPLE 69

[0315] This example illustrates a synthesis of 2-Methyl-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB07-058, NCGC00238761-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.769 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.74 (s, 1 H), 10.70 (s, 1 H), 8.08 - 8.19 (m, 2 H), 7.95 (dt, J=8.2, 1.2 Hz, 1 H), 7.79 (dd, J=7.8, 1.8 Hz, 1 H), 7.48 - 7.65 (m, 3 H), 7.33 - 7.47 (m, 2 H), 7.22 - 7.33 (m, 3 H), 2.37 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.30 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂2Hi₈F₃N202, 399.1315; found 399.1324.

EXAMPLE 70

[0317] This example illustrates a synthesis of 2-(Trifluoromethyl)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB07-059, NCGC00238762-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.708 min; 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.83 (s, 1 H), 10.71 (s, 1 H), 8.13 (s, 1 H), 8.00 (d, J=8.2 Hz, 1 H), 7.94 (d, J=8.2 Hz, 1 H), 7.64 - 7.87 (m, 5 H), 7.49 - 7.63 (m, 2 H), 7.42 (dt, J=7.8, 1.0 Hz, 1 H), 7.33 (td, J=7.6, 1.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -57.86 (s, 3 F), -61.31 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₅F₆N₂0₂, 453.1032; found 453.1027.

EXAMPLE 71

[0319] This example illustrates a synthesis of 2-(3-Methoxybenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-060, NCGC00238763-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.778 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.33 (s, 1 H), 10.75 (s, 1 H), 8.32 (dd, J=8.3, 1.3 Hz, 1 H), 8.14 (t, J=2.1 Hz, 1 H), 7.98 (dt, J=8.1, 1.2 Hz, 1 H), 7.89 (dd, J=7.9, 1.7 Hz, 1 H), 7.52 - 7.66 (m, 2 H), 7.39 - 7.52 (m, 4 H), 7.30 (td, J=7.6, 1.4 Hz, 1 H), 7.13 - 7.25 (m, 1 H), 3.80 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.31 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N203, 415.1264; found 415.1270.

EXAMPLE 72

[0321] This example illustrates a synthesis of 2-(3-Chlorobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-062, NCGC00238764-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 7.105 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.20 (s, 1 H), 10.73 (s, 1 H), 8.15 (dd, J=8.2, 1.4 Hz, 1 H), 8.13 (t, J=2.1 Hz, 1 H), 7.92 - 7.99 (m, 1 H), 7.90 (t, J=2.0 Hz, 1 H), 7.76 - 7.89 (m, 2 H), 7.64 - 7.69 (m, 1 H), 7.53 - 7.64 (m, 3 H), 7.40 - 7.47 (m, 1 H), 7.33 (td, J=7.6, 1.2 Hz, 1 H); ^iyF NMR (376 MHz, DMSO- ₆) δ ppm -61.30 (s, 3 F); HRMS (ESI) m/z (M+H) calcd. for C₂iHi₅ClF₃N₂0₂, 419.0769; found 419.0772.

EXAMPLE 73

[0323] This example illustrates a synthesis of 2-Methoxy-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB07-063 , NCGC00238748-01 ). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.734 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.54 (s, 1 H), 10.84 (s, 1 H), 8.52 - 8.63 (m, 1 H), 8.32 (t, J=2.2 Hz, 1 H), 7.94 - 8.06 (m, 2 H), 7.79 (dd, J=7.7, 1.7 Hz, 1 H), 7.51 - 7.68 (m, 3 H), 7.43 - 7.51 (m, 1 H), 7.24 - 7.30 (m, 1 H), 7.17 - 7.23 (m, 1 H), 6.99 - 7.13 (m, 1 H), 3.97 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.40 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N203, 415.1264; found 415.1266.

EXAMPLE 74

[0325] This example illustrates a synthesis of N-(2-((3-

(Trifiuoromethyl)phenyl)carbamoyl)phenyl)- 1 -naphthamide (XJB07-064, NCGC00238749- 01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.952 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.94 (s, 1 H), 10.74 (s, 1 H), 8.26 - 8.32 (m, 1 H), 8.16 (t, J=2.2 Hz, 1 H), 8.02 - 8.1 1 (m, 2 H), 7.91 - 8.01 (m, 2 H), 7.81 (dd, J=3.2, 1.5 Hz, 1 H), 7.79 (dd, J=3.9, 1.6 Hz, 1 H), 7.44 - 7.67 (m, 5 H), 7.38 - 7.43 (m, 1 H), 7.34 (td, J=7.6, 1.3 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm - 61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂5Hi₈F₃N₂0₂, 435.1315; found 435.1318

EXAMPLE 75

[0327] This example illustrates a synthesis of 2-(3-Bromobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-065, NCGC00238750-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 7.174 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.19 (s, 1 H), 10.73 (s, 1 H), 8.09 - 8.24 (m, 2 H), 8.04 (t, J=1.8 Hz, 1 H), 7.96 (dt, J=8.2, 1.2 Hz, 1 H), 7.82 - 7.91 (m, 2 H), 7.79 (ddd, J=8.0, 2.1, 1.1 Hz, 1 H), 7.54 - 7.65 (m, 2 H), 7.50 (t, J=7.8 Hz, 1 H), 7.44 (dt, J=7.8, 0.9 Hz, 1 H), 7.32 (td, J=7.6, 1.3 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.29 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅BrF₃N₂0₂, 463.0264; found 463.0271.

EXAMPLE 76

[0329] This example illustrates a synthesis of 2-(4-Cyanobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-066, NCGC00238751-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.522 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.32 (s, 1 H), 10.74 (s, 1 H), 8.18 (dd, J=8.2, 1.2 Hz, 1 H), 8.08 (t, J=2.2 Hz, 1 H), 8.00 - 8.06 (m, 4 H), 7.94 - 7.99 (m, 1 H), 7.87 (dd, J=7.8, 1.6 Hz, 1 H), 7.54 - 7.66 (m, 2 H), 7.40 - 7.50 (m, 1 H), 7.34 (td, J=7.6, 1.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.27 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂2Hi₅F₃N302, 410.1111; found 410.1119.

EXAMPLE 77

[0331] This example illustrates a synthesis of 2-(4-Nitrobenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-067, NCGC00238752-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.711 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.36 (s, 1 H), 10.75 (s, 1 H), 8.33 - 8.41 (m, 2 H), 8.16 (dd, J=8.2, 1.2 Hz, 1 H), 8.05 - 8.14 (m, 3 H), 7.93 - 8.01 (m, 1 H), 7.83 - 7.92 (m, 1 H), 7.63 (ddd, J=8.4, 7.3, 1.6 Hz, 1 H), 7.58 (t, J=8.0 Hz, 1 H), 7.45 (dt, J=7.8, 0.9 Hz, 1 H), 7.35 (td, J=7.6, 1.2 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.27 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅F₃N₃0₄, 430.1009; found 430.1008.

EXAMPLE 78

[0333] This example illustrates a synthesis of N-(2-((3-

(Trifiuoromethyl)phenyl)carbamoyl)phenyl)-2-naphthamide (XJB07-069, NCGC00238753- 01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 7.197 min; HRMS (ESI) m/z (M+H)⁺ calcd. for CzsHigFsNzOz, 435.1315; found 435.1314.

EXAMPLE 79

[0335] This example illustrates a synthesis of 2-(4-Bromobenzamido)-N-(3-

(trifiuoromethyl)phenyl)benzamide (XJB07-073, NCGC00238754-01). A solution of 2- amino-N-(3-(trifluoromethyl)phenyl)benzamide (50.0 mg, 0.178 mmol) in dichloromethane

(2.00 mL) and TEA (0.075 mL, 0.535 mmol) was treated at room temperature with 4- bromobenzoyl bromide (70.6 mg, 0.268 mmol). The reaction mixture was stirred at room temperature for overnight. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention

Time: ti (Method 1) = 7.158 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.28 (s, 1 H),

10.74 (s, 1 H), 8.23 (dd, J=8.2, 1.2 Hz, 1 H), 8.08 (t, J=2.2 Hz, 1 H), 7.92 - 8.02 (m, 1 H),

7.87 (dd, J=7.8, 1.8 Hz, 1 H), 7.79 - 7.85 (m, 2 H), 7.72 - 7.78 (m, 2 H), 7.55 - 7.64 (m, 2 H), 7.42 - 7.50 (m, 1 H), 7.27 - 7.36 (m, 1 H); ^iyF NMR (376 MHz, DMSO-dg) δ ppm -61.26 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅BrF₃N202, 463.0264; found 463.0268.

PLE 80

[0337] This example illustrates a synthesis of 2-(3-(Methylsulfonyl)benzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-075, NCGC00238755-01). The title compound was prepared according to general protocol D. LC-MS Retention Time: ti (Method 1) = 6.025 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.30 (s, 1 H), 10.74 (s, 1 H), 8.42 (t, J=1.9 Hz, 1 H), 8.20 (ddd, J=7.9, 1.5, 1.4 Hz, 1 H), 8.08 - 8.17 (m, 3 H), 7.97 (d, J=8.2 Hz, 1 H), 7.77 - 7.89 (m, 2 H), 7.62 (ddd, J=8.4, 7.2, 1.6 Hz, 1 H), 7.57 (t, J=8.0 Hz, 1 H), 7.44 (dd, J=6.8, 1.2 Hz, 1 H), 7.35 (td, J=7.6, 1.2 Hz, 1 H), 3.25 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₄S, 463.0934; found 463.0939.

EXAMPLE 81

[0339] This example illustrates a synthesis of 2-(4-Acetylbenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-076, NCGC00238756-01). The title compound was prepared according to general protocol D. LC-MS Retention Time: ti (Method 1) = 6.474 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.38 (s, 1 H), 10.76 (s, 1 H), 8.21 - 8.30 (m, 1 H), 8.04 - 8.12 (m, 3 H), 7.94 - 8.03 (m, 3 H), 7.89 (dd, J=7.8, 1.6 Hz, 1 H), 7.54 - 7.68 (m, 2 H), 7.41 - 7.52 (m, 1 H), 7.33 (td, J=7.6, 1.2 Hz, 1 H), 2.62 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.26 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for CzsHigFsNzOs, 427.1264; found 427.1267.

EXAMPLE 82

[0341] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- isopropylphenyl)benzamide (XJB07-080, NCGC00238757-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.166 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.52 (s, 1 H), 10.30 (s, 1 H), 8.21 (dd, J=8.4, 1.4 Hz, 1 H), 7.77 (dd, J=7.8, 1.6 Hz, 1 H), 7.44 07.58 (m, 3 H), 7.26 (t, J=7.8 Hz, 1 H), 7.19 (td, J=7.6, 1.2 Hz, 1 H), 7.00 (dt, J=7.7, 1.5 Hz, 1 H), 2.86 (quin, J=6.8 Hz, 1 H), 2.20 02.36 (m, 1 H), 1.76 01.90 (m, 2 H), 1.65 01.76 (m, 2 H), 1.55 01.65 (m, 1 H), 1.20 (d, J=4.0 Hz, 6 H), 1.08 01.44 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H29N2O2, 365.2239; found 365.2239.

EXAMPLE 83

[0343] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-((5- methylfuran-2-yl)methyl)benzamide (XJB07-081, NCGC00238758-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.284 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.26 (s, 1 H), 9.16 (t, J=5.5 Hz, 1 H), 8.40 (dd, J=8.4, 1.2 Hz, 1 H), 7.72 (dd, J=7.8, 1.6 Hz, 1 H), 7.42 07.48 (m, 1 H), 7.10 (ddd, J=8.0, 7.2, 1.2 Hz, 1 H), 6.15 (d, J=2.9 Hz, 1 H), 5.96 Q5.00 (m, 1 H), 4.39 (d, J=5.7 Hz, 2 H), 2.21 (d, J=0.8 Hz, 3 H), 2.18 02.28 (m, 1 H), 1.78 01.94 (m, 2 H), 1.66 01.78 (m, 2 H), 1.55 01.66 (m, 1 H), 1.07 01.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂oH2₅N₂03, 341.1860; found 341.1869. XAMPLE 84

[0345] This example illustrates a synthesis of 2-(3-Methylbenzamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB07-093, NCGC00238759-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.938 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.26 (s, 1 H), 10.74 (s, 1 H), 8.29 (dd, J=8.3, 0.9 Hz, 1 H), 8.13 (s, 1 H), 7.94 - 7.99 (m, 1 H), 7.87 (ddd, J=7.8, 1.1 , 0.9 Hz, 1 H), 7.70 (s, 1 H), 7.63 - 7.69 (m, 1 H), 7.54 - 7.63 (m, 2 H), 7.36 - 7.49 (m, 3 H), 7.20 - 7.32 (m, 1 H), 2.35 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.31 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₂, 399.1315; found 399.1319.

EXAMPLE 85

[0347] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)-[ 1 , 1 Bbiphenyl]-3-carboxamide (XJB07-094, NCGC00238747-02). The title compound was prepared according to general protocol C. LC- MS Retention Time: ti (Method 1) = 7.389 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.39 (s, 1 H), 10.75 (s, 1 H), 8.28 (dt, J=8.3, 0.7 Hz, 1 H), 8.13 C8.19 (m, 2 H), 7.97 ES.01 (m, 1 H), 7.82 07.92 (m, 3 H), 7.67 07.79 (m, 2 H), 7.53 07.66 (m, 3 H), 7.36 07.53 (m, 4 H), 7.31 (tt, J=7.7, 0.7 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.29 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C27H20F3N2O2, 461.1471; found 461.1476.

EXAMPLE 86

[0349] This example illustrates a synthesis of 2-Bromo-N-(3-

(trifluoromethyl)phenyl)benzamide (XJB09-014). A solution of 3-(trifluoromethyl)aniline (0.850 mL, 6.83 mmol) in dichloromethane (15.0 mL) and triethylamine (2.86 mL, 20.5 mmol) was treated at 0 °C with 2-bromobenzoyl chloride (0.893 mL, 6.83 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with Na₂C0₃ solution. The organic layer was separated, dried, and concentrated to give 2.30 g (98%) of the title compound as a white foam which was used directly for the next reaction without further purification.

EXAMPLE 87

[0351] This example illustrates a synthesis of N-(3-(Trifluoromethyl)phenyl)-[l,l 0 biphenyl]-2-carboxamide (XJB09-016, NCGC00244471-01). The title compound was prepared according to general protocol E. LC-MS Retention Time: ti (Method 1) = 6.365 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.54 (s, 1 H), 7.97 (t, J=2.1 Hz, 1 H), 7.64□ 7.73 (m, 1 H), 7.55 07.64 (m, 2 H), 7.44 07.54 (m, 3 H), 7.32 07.44 (m, 5 H), 7.25 07.32 (m, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.34 (s, 3 F); HRMS (ESI) m/z (M+H) calcd. for C₂oHi₅F₃NO, 342.1100; found 342.1110. LE 88

[0353] This example illustrates a synthesis of 2 B(Benzyloxy)-N-(3- (trifiuoromethyl)phenyl)-[l,l 0biphenyl]-2-carboxamide (XJB09-019, NCGC00244472-01). The title compound was prepared according to general protocol E. LC-MS Retention Time: ti (Method 1) = 6.997 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂7H₂iF₃N0₂, 448.1519; found 448.1524.

EXAMPLE 89

[0355] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(30 (trifiuoromethyl)-[l,l Bbiphenyl]-3-yl)benzamide (XJB09-023, NCGC00244469-01). A mixture ofN-(3-bromophenyl)-2-(cyclohexanecarboxamido)benzamide (50.0 mg, 0.125 mmol), 3-(trifluoromethyl)phenylboronic acid (35.5 mg, 0.187 mmol) and Pd(PPh₃)₄ (7.2 mg, 6.23 μιηοΐ) in DMF (1.50 mL) and 2.0 N Na₂C0₃ (0.50 mL) aqueous solution was heated in μW at 100 °C for 30 min. The reaction was cooled to room temperature, added a small portion of Si-THIOL to get rid of Palladium. The mixture was filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 7.438 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.50 (br. s., 1 H), 10.49 (s, 1 H), 8.14 C8.24 (m, 1 H), 8.01 C8.08 (m, 1 H), 7.94 [3.01 (m, 1 H), 7.91 (s, 1 H), 7.78 07.84 (m, 2 H), 7.70 □7.77 (m, 2 H), 7.41 07.56 (m, 3 H), 7.22 (td, J=7.6, 1.3 Hz, 1 H), 2.21 02.35 (m, 1 H), 1.83 (d, J=15.8 Hz, 2 H), 1.64 [1.74 (m, 2 H), 1.52 01.63 (m, 1 H), 1.08 01.46 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.11 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₆F₃N₂0₂, 467.1941; found 467.1943.

EXAMPLE 90

[0357] This example illustrates a synthesis of 2-Iodo-N-(3-

(trifluoromethyl)phenyl)benzamide (XJB09-026). A solution of 3-(trifluoromethyl)aniline (0.467 mL, 3.75 mmol) in dichloromethane (15.0 mL) and triethylamine (1.57 mL, 11.3 mmol) was treated at 0 °C with 2-iodobenzoyl chloride (1.00 g, 3.75 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with Na₂C0₃ solution. The organic layer was separated, dried, and concentrated to give 1.40 g (95%) of the title compound as a white foam which was used directly for the next reaction without further purification.

EXAMPLE 91

[0359] This example illustrates a synthesis of 2-(Benzylamino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-027, NCGC00244464-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 7.001 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₈F₃N0₂, 371.1366; found 371.1374. MPLE 92

[0361] This example illustrates a synthesis of 2-((2-Methoxybenzyl)amino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-028, NCGC00244511-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 6.914 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.36 (s, 1 H), 8.18 (t, J=2.1 Hz, 1 H), 7.87□ 8.01 (m, 1 H), 7.65 07.80 (m, 2 H), 7.49 07.61 (m, 1 H), 7.38 07.45 (m, 1 H), 7.16 07.31 (m, 3 H), 6.95 07.03 (m, 1 H), 6.83 05.90 (m, 1 H), 6.57 05.67 (m, 2 H), 4.35 (d, J=5.9 Hz, 2 H), 3.81 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.25 (s, 3 F). XAMPLE 93

[0363] This example illustrates a synthesis of 2-(Phenylamino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-029, NCGC00244510-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 6.999 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.59 (s, 1 H), 8.99 (s, 1 H), 8.18 (t, J=2.2 Hz, 1 H), 7.89 07.99 (m, 1 H), 7.76 (dd, J=7.8, 1.6 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 7.34□ 7.47 (m, 2 H), 7.20 07.33 (m, 3 H), 7.11 07.20 (m, 2 H), 6.82 D7.02 (m, 2 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.26 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for

C₂oHi₆F₃N₂0, 357.1209; found 357.1216. XAMPLE 94

[0365] This example illustrates a synthesis of 2-((2-Methoxyphenyl)amino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-030, NCGC00244488-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 6.918 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.59 (s, 1 H), 9.02 (s, 1 H), 8.13 (t, J=2.2 Hz, 1 H), 7.94 C8.03 (m, 1 H), 7.78 (dd, J=7.8, 1.6 Hz, 1 H), 7.53 07.65 (m, 1 H), 7.42 07.49 (m, 1 H), 7.35 07.42 (m, 1 H), 7.24 07.34 (m, 2 H), 7.01 D7.08 (m, 1 H), 6.82 07.01 (m, 3 H), 3.82 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.23 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₈F₃N₂0₂, 387.1315; found 387.1322. AMPLE 95

[0367] This example illustrates a synthesis of 2-(Phenethylamino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-031, NCGC00244489-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 7.119 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.32 (s, 1 H), 8.16 (t, J=2.2 Hz, 1 H), 7.85 - 7.98 (m, 1 H), 7.70 (dd, J=7.9, 1.7 Hz, 1 H), 7.56 (t, J=8.0 Hz, 1 H), 7.47 (t, J=5.5 Hz, 1 H), 7.39 - 7.44 (m, 1 H), 7.35 (ddd, J=8.5, 7.0, 1.6 Hz, 1 H), 7.23 - 7.31 (m, 4 H), 7.12 - 7.22 (m, 1 H), 6.76 - 6.87 (m, 1 H), 6.64 (ddd, J=7.9, 7.0, 1.1 Hz, 1 H), 3.33 - 3.46 (m, 2 H), 2.87 (t, J=7.3 Hz, 2 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.25 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₀F₃N₂O, 385.1522; found 385.1533. AMPLE 96

[0369] This example illustrates a synthesis of 2-((2-Methoxyethyl)amino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-032, NCGC00244512-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 6.254 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.33 (s, 1 H), 8.14 (t, J=2.2 Hz, 1 H), 7.88□ 8.05 (m, 1 H), 7.70 (dd, J=7.8, 1.6 Hz, 1 H), 7.54 07.63 (m, 1 H), 7.44 07.52 (m, 1 H), 7.37 □7.44 (m, 1 H), 7.34 (ddd, J=8.6, 7.0, 1.7 Hz, 1 H), 6.72 05.84 (m, 1 H), 6.65 (ddd, J=8.0, 7.1, 1.2 Hz, 1 H), 3.53 (t, J=5.5 Hz, 2 H), 3.28 (s, 3 H), 3.24 03.33 (m, 2 H); ¹⁹F NMR (376 MHz, DMSO- g) δ ppm -61.23 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for Ci₇Hi₈F₃N202, 339.1315; found 339.1326.

EXAMPLE 97

[0371] This example illustrates a synthesis of 2-((Cyclohexylmethyl)amino)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-033, NCGC00244473-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 7.597 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.31 (s, 1 H), 8.11 (t, J=2.2 Hz, 1 H), 7.92□ 8.00 (m, 1 H), 7.70 (dd, J=8.0, 1.6 Hz, 1 H), 7.49 07.61 (m, 2 H), 7.39 07.45 (m, 1 H), 7.32 (ddd, J=8.6, 7.0, 1.6 Hz, 1 H), 6.69 05.76 (m, 1 H), 6.61 (ddd, J=8.0, 7.1, 1.2 Hz, 1 H), 2.92 D3.06 (m, 2 H), 1.72 01.83 (m, 2 H), 1.65 01.72 (m, 2 H), 1.49 01.65 (m, 2 H), 1.04 Dl.30 (m, 3 H), 0.88 01.05 (m, 2 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.21 (s, 3 F);

HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂4F₃N₂0, 377.1835; found 377.1843. XAMPLE 98

[0372]

[0373] This example illustrates a synthesis of N-(3-(Trifluoromethyl)phenyl)-2-((3- (trifiuoromethyl)phenyl)amino)benzamide (XJB09-034, NCGC00244513-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 7.252 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅F₆N₂0, 425.1083; found

425.1092.

EXAMPLE 99

[0375] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- (methylthio)phenyl)benzamide (XJB09-035, NCGC00244465-02). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.687 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.44 (s, 1 H), 10.37 (s, 1 H), 8.18 (d, J=8.2 Hz, 1 H), 7.75 (dd, J=7.8, 1.6 Hz, 1 H), 7.63 (t, J=2.1 Hz, 1 H), 7.44 - 7.55 (m, 2 H), 7.29 (t, J=7.9 Hz, 1 H), 7.20 (td, J=7.6, 1.3 Hz, 1 H), 7.01 (ddd, J=7.8, 2.0, 1.0 Hz, 1 H), 2.46 (s, 3 H), 2.19 - 2.35 (m, 1 H), 1.76 - 1.90 (m, 2 H), 1.65 - 1.76 (m, 2 H), 1.52 - 1.65 (m, 1 H), 1.03 - 1.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₂S, 369.1631; found

369.1625. E 100

[0377] This example illustrates a synthesis of 2-((3-(Trifluoromethyl)benzyl)amino)-N- (3-(trifluoromethyl)phenyl)benzamide (XJB09-037, NCGC00244514-01). The title compound was prepared according to general protocol F. LC-MS Retention Time: ti (Method 1) = 7.370 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₇F₆N₂0, 439.1240; found

439.1247. AMPLE 101

[0379] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- (piperidin-l-yl)phenyl)benzamide (XJB09-040, NCGC00244515-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 4.605 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C25H32N3O2, 406.2489; found 406.2501. MPLE 102

[0381] This example illustrates a synthesis of 2-Chloro-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-047, NCGC00244490-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.765 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.83 (s, 1 H), 10.70 (s, 1 H), 8.01 C8.22 (m, 2 H), 7.89 C8.00 (m, 1 H), 7.69 07.85 (m, 1 H), 7.38 07.67 (m, 7 H), 7.33 (td, J=7.6, 1.4 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for

419.0769; found 419.0769. XAMPLE 103

[0383] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- ((trifiuoromethyl)thio)phenyl)benzamide (XJB09-048, NCGC00244491-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.349 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₂S, 423.1349; found 423.1360. AMPLE 104

[0385] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- (thiophen-2-yl)phenyl)benzamide (XJB09-050, NCGC00244466-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.234 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.46 (br. s., 1 H), 10.45 (br. s., 1 H), 8.1 1□ 8.25 (m, 1 H), 7.92 C8.02 (m, 1 H), 7.75 07.83 (m, 1 H), 7.62 07.71 (m, 1 H), 7.55 (dd, J=5.1, 1.2 Hz, 1 H), 7.48 07.54 (m, 1 H), 7.34 07.48 (m, 3 H), 7.17 07.26 (m, 1 H), 7.14 (dd, J=5.0, 3.6 Hz, 1 H), 2.19 02.31 (m, 1 H), 1.78 01.89 (m, 2 H), 1.65 01.76 (m, 2 H), 1.53 01.64 (m, 1 H), 1.08 01.47 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for

C₂₄H₂₅N₂0₂S, 405.1631; found 405.1637. PLE 105

[0387] This example illustrates a synthesis of 2-(Trifluoromethoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-052, NCGC00244470-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.983 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.97 (s, 1 H), 10.74 (s, 1 H), 8.09 - 8.26 (m, 2 H), 7.91 - 8.03 (m, 1 H), 7.83 (dd, J=7.8, 1.6 Hz, 1 H), 7.77 (dd, J=7.6, 2.0 Hz, 1 H), 7.39 - 7.70 (m, 6 H), 7.33 (td, J=7.6, 1.3 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -56.63 (s, 3 F), -61.33 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C2₂Hi₅F₆N₂03, 468.0981; found 468.0982. MPLE 106

[0389] This example illustrates a synthesis of 2-Ethoxy-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-053, NCGC00244467-01, compound 99). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.998 min; 1H NMR (400 MHz, DMSO-d₆) δ 1 1.33 (s, 1 H), 10.82 (s, 1 H), 8.51 (dd, J=8.4, 1.2 Hz, 1 H), 8.28 (t, J=2.1 Hz, 1 H), 7.89 - 8.07 (m, 2 H), 7.80 (dd, J=7.8, 1.6 Hz, 1 H), 7.55 - 7.65 (m, 2 H), 7.38 - 7.55 (m, 2 H), 7.27 (td, J=7.6, 1.3 Hz, 1 H), 7.19 (dd, J=8.4, 1.0 Hz, 1 H), 7.01 - 7.12 (m, 1 H), 4.30 (q, J=6.9 Hz, 2 H), 1.30 (t, J=6.9 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.40 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃, 429.1421; found 429.1425. MPLE 107

[0391] This example illustrates a synthesis of 2-Nitro-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-055, NCGC00244468-01). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.695 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅F₃N30₄, 430.1009; found 430.1009. MPLE 108

[0393] This example illustrates a synthesis of 2,6-Dimethoxy-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-056, NCGC00244474-01 , CID-56593296). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.400 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.68 (s, 1 H), 10.62 (s, 1 H), 8.43 (d, J=8.2 Hz, 1 H), 8.08 (s, 1 H), 7.93 (d, J=8.4 Hz, 1 H), 7.85 (dd, J=7.7, 1.1 Hz, 1 H), 7.52 - 7.64 (m, 2 H), 7.45 (d, J=7.6 Hz, 1 H), 7.34 (t, J=8.4 Hz, 1 H), 7.27 (td, J=7.6, 1.1 Hz, 1 H), 6.71 (d, J=8.4 Hz, 2 H), 3.69 (s, 6 H); ¹⁹F NMR (376 MHz, DMSO- g) δ ppm -61.29 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H20F3N2O4, 445.1370; found 445.1380.

EXAMPLE 109

[0395] This example illustrates a synthesis of Methyl 2-(2-methoxybenzamido)benzoate (XJB09-051). A solution of 2-aminobenzoate (2.57 mL, 19.9 mmol) in dichloro methane (50.0 mL) and TEA (8.30 mL, 59.5 mmol) was treated at 0 °C with 2-methoxybenzoyl chloride (2.67 mL, 19.9 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 5.50 g (97%) of the title product as a white solid. LC-MS Retention Time: t2 (Method 2) = 3.761 min; m/z (M+H)⁺ 286.0. PLE 110

[0397] This example illustrates a synthesis of 2-Methoxy-N-(2-((3- ((trifiuoromethyl)thio)phenyl)carbamoyl)phenyl)benzamide (XJB09-058, NCGC00244475- 01, compound 158). The title compound was prepared according to general protocol A. LC- MS Retention Time: ti (Method 1) = 7.128 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.53 (s, 1 H), 10.79 (s, 1 H), 8.56 (dd, J=8.4, 1.2 Hz, 1 H), 8.22 - 8.39 (m, 1 H), 8.02 (dd, J=7.8, 1.8 Hz, 1 H), 7.91 (ddd, J=8.2, 2.2, 1.2 Hz, 1 H), 7.78 (dd, J=7.8, 1.6 Hz, 1 H), 7.50 - 7.64 (m, 3 H), 7.43 - 7.49 (m, 1 H), 7.26 (td, J=7.5, 1.2 Hz, 1 H), 7.20 (dd, J=8.5, 1.1 Hz, 1 H),

7.09 (ddd, J=7.9, 7.2, 1.2 Hz, 1 H), 3.97 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm - 41.91 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂03S, 447.0985; found

447.0984. PLE 111

[0399] This example illustrates a synthesis of 2-Methoxy-N-(2-((3- (methylthio)phenyl)carbamoyl)phenyl)benzamide (XJB09-059, NCGC00244476-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.575 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.55 (s, 1 H), 10.54 (s, 1 H), 8.56 (dd, J=8.4, 1.2 Hz, 1 H), 8.02 (dd, J=7.8, 1.8 Hz, 1 H), 7.67 - 7.86 (m, 2 H), 7.46 - 7.65 (m, 3 H), 7.30 (t, J=7.9 Hz, 1 H), 7.24 (td, J=7.6, 1.3 Hz, 1 H), 7.19 (dd, J=8.5, 1.1 Hz, 1 H), 7.05 - 7.12 (m, 1 H), 7.01 (ddd, J=7.8, 2.0, 1.0 Hz, 1 H), 3.98 (s, 3 H), 2.46 (s, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂iN₂0₃S, 393.1267; found 393.1268. LE 112

[0401] This example illustrates a synthesis of 2-Methoxy-N-(2-((3-(piperidin-l- yl)phenyl)carbamoyl)phenyl)benzamide (XJB09-061, NCGC00244492-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti

(Method 1) = 4.511 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.56 (br. s., 1 H), 10.43 (br. s., 1 H), 8.56 (dd, J=8.4, 1.2 Hz, 1 H), 8.01 (dd, J=7.8, 1.8 Hz, 1 H), 7.62 - 7.80 (m, 1 H), 7.50 - 7.61 (m, 4 H), 7.15 - 7.31 (m, 4 H), 7.09 (ddd, J=7.9, 7.2, 1.2 Hz, 1 H), 3.98 (s, 3 H), 3.10 - 3.33 (m, 4 H), 1.60 - 1.78 (m, 4 H), 1.50 - 1.61 (m, 2 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₆H₂₈N₃O₃, 430.2125; found 430.2135. PLE 113

[0403] This example illustrates a synthesis of 2-(2-Methoxybenzamido)-N-methyl-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-062, NCGC00244493-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.442 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.65 (d, J=0.8 Hz, 1 H), 8.21 (dt, J=8.4, 0.6 Hz,

1 H), 8.03 (dd, J=7.8, 1.8 Hz, 1 H), 7.54 - 7.66 (m, 2 H), 7.37 - 7.54 (m, 3 H), 7.20 - 7.33 (m,

2 H), 7.13 (ddd, J=7.9, 7.2, 1.0 Hz, 1 H), 7.04 - 7.11 (m, 1 H), 6.86 - 6.96 (m, 1 H), 4.02 (s, 3 H), 3.44 (s, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃, 429.1241; found 429.1418. MPLE 114

[0405] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- ((trifiuoromethyl)sulfonyl)phenyl)benzamide (XJB09-067, NCGC00244477-01). The title compound was prepared according to general protocol G. LC-MS Retention Time: ti (Method 1) = 6.964 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.83 (s, 1 H), 10.16 (s, 1 H), 8.57 (t, J=1.6 Hz, 1 H), 8.26 (ddd, J=5.7, 3.7, 2.2 Hz, 1 H), 7.93 (dd, J=8.3, 1.3 Hz, 1 H), 7.76 - 7.86 (m, 2 H), 7.72 (dd, J=7.8, 1.6 Hz, 1 H), 7.52 (ddd, J=8.5, 7.2, 1.6 Hz, 1 H), 7.23 (td, J=7.6, 1.2 Hz, 1 H), 2.16 - 2.36 (m, 1 H), 1.73 - 1.87 (m, 2 H), 1.62 - 1.73 (m, 2 H), 1.50 - 1.62 (m, 1 H), 0.82 - 1.46 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -78.42 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₁H₂₂F₃N₂O₄S, 455.1247; found 455.1253. AMPLE 115

[0407] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(3- (methylsulfonyl)phenyl)benzamide (XJB09-068, NCGC00244478-01). The title compound was prepared according to general protocol G. LC-MS Retention Time: ti (Method 1) = 5.745 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.69 (s, 1 H), 10.34 (s, 1 H), 8.30 - 8.40 (m, 1 H), 8.11 (dd, J=8.3, 1.3 Hz, 1 H), 8.00 (dt, J=7.2, 2.1 Hz, 1 H), 7.76 (dd, J=7.8, 1.6 Hz, 1 H), 7.59 - 7.71 (m, 2 H), 7.52 (ddd, J=8.5, 7.1, 1.6 Hz, 1 H), 7.22 (td, J=7.6, 1.3 Hz, 1 H), 3.20 (s, 3 H), 2.20 - 2.37 (m, 1 H), 1.75 - 1.91 (m, 2 H), 1.65 - 1.75 (m, 2 H), 1.52 - 1.64 (m, 1 H), 0.95 - 1.45 (m, 5 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iH₂₅N₂0₄S, 401.1530; found 401.1524. E 116

[0409] This example illustrates a synthesis of 2-Methoxy-N-(2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-069, NCGC00244479-01, compound 159). The title compound was prepared according to general protocol G. LC-MS Retention Time: ti (Method 1) = 6.810 min; 1H NMR (400 MHz, DMSO- d₆) δ ppm 11.58 (s, 1 H), 1 1.09 (s, 1 H), 8.82 (t, J=2.1 Hz, 1 H), 8.58 (dd, J=8.5, 1.3 Hz, 1 H), 8.23 (dt, J=7.0, 2.2 Hz, 1 H), 8.02 (dd, J=7.7, 1.9 Hz, 1 H), 7.76 - 7.99 (m, 3 H), 7.51 - 7.63 (m, 2 H), 7.27 (td, J=7.5, 1.2 Hz, 1 H), 7.22 (dd, J=8.4, 1.2 Hz, 1 H), 7.09 (ddd, J=7.9, 7.2, 1.2 Hz, 1 H), 3.99 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -78.39 (s, 3 F);

HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N₂0₅S, 479.0883; found 479.0886. LE 117

[0411] This example illustrates a synthesis of 2-Methoxy-N-(2-((3- (methylsulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-070, NCGC00244501-01). The title compound was prepared according to general protocol G. LC-MS Retention Time: ti (Method 1) = 5.590 min; 1H NMR (400 MHz, DMSO-d₆) δ ppm 1 1.60 (s, 1 H), 10.90 (s, 1 H), 8.47 - 8.71 (m, 2 H), 7.93 - 8.16 (m, 2 H), 7.81 (dd, J=7.8, 1.6 Hz, 1 H), 7.62 - 7.72 (m, 2 H), 7.47 - 7.62 (m, 2 H), 7.26 (td, J=7.6, 1.3 Hz, 1 H), 7.21 (dd, J=8.5, 1.1 Hz, 1 H), 7.09 (ddd, J=7.9, 7.2, 1.0 Hz, 1 H), 4.00 (s, 3 H), 3.20 (s, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂iN₂0₅S, 425.1166; found 425.1169.

EXAMPLE 118

[0413] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(4'- (trifiuoromethyl)-[l,r-biphenyl]-3-yl)benzamide (XJB09-073, NCGC00244494-01). The title compound was prepared according to general protocol E. LC-MS Retention Time: ti (Method 1) = 7.588 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.51 (d, J=0.4 Hz, 1 H), 10.48 (d, J=0.4 Hz, 1 H), 8.20 (dd, J=8.4, 1.2 Hz, 1 H), 7.99 - 8.09 (m, 1 H), 7.85 (s, 4 H), 7.75 - 7.82 (m, 2 H), 7.46 - 7.59 (m, 3 H), 7.22 (td, J=7.6, 1.3 Hz, 1 H), 2.18 - 2.35 (m, 1 H), 1.77 - 1.89 (m, 2 H), 1.64 - 1.75 (m, 2 H), 1.51 - 1.64 (m, 1 H), 1.08 - 1.45 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -60.89 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C27H26F3N2O2, 467.1941; found 467.1942.

EXAMPLE 119

[0415] This example illustrates a synthesis of Methyl 3-

(cyclohexanecarboxamido)benzoate (XJB09-080). A solution of methyl 3-aminobenzoate (0.903 mL, 6.62 mmol) in dichloromethane (10.0 mL) and triethylamine (2.77 mL, 19.9 mmol) was treated at 0 °C with cyclohexanecarbonyl chloride (0.970 g, 6.62 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0- 50% of EtOAc in hexanes to give 1.61 g (94%>) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.676 min; m/z (M+H)⁺ 276.1. EXAMPLE 120

[0417] This example illustrates a synthesis of 3-(Cyclohexanecarboxamido)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB09-097, NCGC00244495-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.516 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.53 (s, 1 H), 10.00 (s, 1 H), 8.21 (t, J=2.1 Hz, 1 H), 8.14 (t, J=2.0 Hz, 1 H), 8.03 (ddd, J=8.2, 1.2, 1.0 Hz, 1 H), 7.81 (ddd, J=8.1 , 2.2, 1.1 Hz, 1 H), 7.55 - 7.64 (m, 2 H), 7.37 - 7.49 (m, 2 H), 2.24 - 2.41 (m, 1 H), 1.69 - 1.92 (m, 4 H), 1.57 - 1.69 (m, 1 H), 1.08 - 1.50 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.29 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H22F3N2O2, 391.1628; found 391.1637.

EXAMPLE 121

[0419] This example illustrates a synthesis of Ethyl 3-

(cyclohexanecarboxamido)benzoate (XJB09-079). A solution of ethyl 3-aminobenzoate (1.00 g, 6.05 mmol) in dichloromethane (10.0 mL) and triethylamine (2.53 mL, 18.2 mmol) was treated at 0 °C with 2-methoxybenzoyl chloride (0.814 mL, 6.05 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 1.11 g (61%) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.664 min; m/z (M+H)⁺ 300.1.

EXAMPLE 122

[0421] 2-Methoxy-N-(3-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB09-098, NCGC00244496-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.471 min; 1H NMR (400 MHz, DMSO- d₆) δ ppm 10.58 (s, 1 H), 10.30 (s, 1 H), 8.27 - 8.35 (m, 1 H), 8.23 (t, J=2.1 Hz, 1 H), 8.04 (dt, J=8.2, 1.1 Hz, 1 H), 7.88 - 7.99 (m, 1 H), 7.67 (ddd, J=8.0, 1.4, 1.2 Hz, 1 H), 7.63 (dd, J=7.6, 1.8 Hz, 1 H), 7.56 - 7.62 (m, 1 H), 7.47 - 7.56 (m, 2 H), 7.41 - 7.47 (m, 1 H), 7.14 - 7.23 (m, 1 H), 7.06 (td, J=7.4, 1.0 Hz, 1 H), 3.90 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂2Hi₈F₃N₂0₃, 415.1264; found

415.1275.

EXAMPLE 123

[0423] This example illustrates a synthesis of Ethyl 4-(2-methoxybenzamido)benzoate (XJB09-077). A solution of ethyl 3-aminobenzoate (1.00 g, 6.05 mmol) in dichloromethane (10.0 mL) and triethylamine (2.53 mL, 18.2 mmol) was treated at 0 °C with 2- methoxybenzoyl chloride (0.814 mL, 6.05 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 1.77 g (98%>) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.683 min; m/z (M+H) 300.1.

EXAMPLE 124

[0425] This example illustrates a synthesis of 2-Methoxy-N-(4-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-001 , NCGC00244497-01 ). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.452 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.43 (s, 1 H), 10.39 (s, 1 H), 8.24 (t, J=2.2 Hz, 1 H), 8.02 - 8.10 (m, 1 H), 7.95 - 8.02 (m, 2 H), 7.80 - 7.94 (m, 2 H), 7.63 (dd, J=7.6, 1.8 Hz, 1 H), 7.55 - 7.62 (m, 1 H), 7.47 - 7.55 (m, 1 H), 7.43 (ddd, J=7.8, 1.9, 0.9 Hz, 1 H), 7.19 (dd, J=8.5, 1.1 Hz, 1 H), 7.07 (td, J=7.5, 1.1 Hz, 1 H), 3.90 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.27 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₈F₃N203, 415.1264; found 415.1269. EXAMPLE 125

[0427] This example illustrates a synthesis of Ethyl 4-

(cyclohexanecarboxamido)benzoate (XJB09-078). A solution of ethyl 4-aminobenzoate (1.00 g, 6.05 mmol) in dichloromethane (10.0 mL) and triethylamine (2.53 mL, 18.2 mmol) was treated at 0 °C with cyclohexanecarbonyl chloride (0.888 g, 6.05 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 1.58 g (95%>) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.687 min; m/z (M+H)⁺ 276.1.

EXAMPLE 126

[0429] This example illustrates a synthesis of 4-(Cyclohexanecarboxamido)-N-(3-

(trifiuoromethyl)phenyl)benzamide (XJB10-015, NCGC00244480-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.473 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.37 (s, 1 H), 10.09 (s, 1 H), 8.23 (t, J=2.1 Hz,

1 H), 8.03 (dd, J=8.4, 1.0 Hz, 1 H), 7.85 - 7.97 (m, 2 H), 7.68 - 7.79 (m, 2 H), 7.52 - 7.64 (m,

1 H), 7.36 - 7.47 (m, 1 H), 2.27 - 2.43 (m, 1 H), 1.69 - 1.94 (m, 4 H), 1.58 - 1.69 (m, 1 H), 1.10 - 1.51 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO- ₆) δ ppm -61.28 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H22F3N2O2, 391.1628; found 391.1631. MPLE 127

[0430]

[0431] This example illustrates a synthesis of 2-(2-(Dimethylamino)ethoxy)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJBlO-024, NCGC00244498-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.204 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.49 (s, 1 H), 8.11 - 8.39 (m, 1 H), 7.76 - 7.99 (m, 1 H), 7.48 - 7.68 (m, 3 H), 7.39 - 7.47 (m, 1 H), 7.23 (dd, J=8.4, 0.8 Hz, 1 H), 7.13 (td, J=7.5, 1.0 Hz, 1 H), 4.41 (dd, J=5.5, 4.5 Hz, 2 H), 3.41 - 3.57 (m, 2 H), 2.80 (s, 6 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C18H20F3N2O2, 353.1471; found 353.1474.

EXAMPLE 128

[0433] This example illustrates a synthesis of Methyl 2-(2-methoxy-N- methylbenzamido)benzoate (XJB 10-022). A solution of methyl 2-(2- methoxybenzamido)benzoate (1.16 g, 4.07 mmol) in DMF (10.0 mL) and was treated at 0 °C with NaH (0.813 g, 60%, 20.3 mmol). The reaction mixture was warmed to room temperature and stirred at room temperature for 1 h. Then a solution of Mel (1.27 mL, 20.3 mmol) in DMF (4.00 mL) was added drop wise. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was carefully quenched with water and extracted with EtOAc. The organic layer was separated, dried, concentrated to give the final product which was used directly in the next reaction. LC-MS Retention Time: t₂ (Method 2) = 3.293 min; m/z (M+H) 300.1. PLE 129

[0435] This example illustrates a synthesis of 2-Methoxy-N-methyl-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-025 , NCGC00244499-01 ). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.046 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃, 429.1421;

found 429.1438. PLE 130

[0437] This example illustrates a synthesis of 2-Methoxy-N-methyl-N-(2-(methyl(3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-026, NCGC00244500-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 5.994 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₂F₃N₂O₃, 443.1577;

found 443.1579. AMPLE 131

[0439] This example illustrates a synthesis of 2-Iodo-N-(2-((3-

(trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-027, NCGC00244482-01 ). The title compound was prepared according to general protocol C. LC-MS Retention Time: ti (Method 1) = 6.879 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₅F₃IN₂0₂, 511.0125; found 511.0122. 132

[0441] This example illustrates a synthesis of 2-(2-(Dimethylamino)ethoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-028, NCGC00244483-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.705 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.1 1 (s, 1 H), 10.84 (s, 1 H), 8.41 (dd, J=8.5, 1.3 Hz, 1 H), 8.07 - 8.20 (m, 1 H), 7.96 (dd, J=8.0, 1.2 Hz, 1 H), 7.87 (dd, J=7.7, 1.9 Hz, 1 H), 7.84 (dd, J=7.8, 1.8 Hz, 1 H), 7.57 - 7.65 (m, 2 H), 7.52 - 7.57 (m, 1 H), 7.45 - 7.52 (m, 1 H), 7.24 - 7.33 (m, 2 H), 7.13 (td, J=7.5, 1.0 Hz, 1 H), 4.55 (t, J=5.1 Hz, 2 H), 3.49 - 3.74 (m, 2 H), 2.78 (s, 6 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₅F₃N303, 472.1843; found 472.1851. 133

[0443] This example illustrates a synthesis of 2-(2-Methoxyethoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-029, NCGC00244484-01 ). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 6.625 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1H NMR (400 MHz, DMSO-de) δ ppm 11.22 (s, 1 H), 10.80 (s, 1 H), 8.44 (dd, J=8.3, 1.3 Hz, 1 H), 8.21 (t, J=2.2 Hz, 1 H), 7.93 - 7.99 (m, 1 H), 7.91 (dd, J=7.8, 1.8 Hz, 1 H), 7.80 (dd, J=7.7, 1.7 Hz, 1 H), 7.55 - 7.64 (m, 2 H), 7.48 - 7.55 (m, 1 H), 7.42 - 7.48 (m, 1 H), 7.27 (td, J=7.6, 1.3 Hz, 1 H), 7.23 (dd, J=8.5, 1.1 Hz, 1 H), 7.03 - 7.13 (m, 1 H), 4.26 - 4.37 (m, 2 H), 3.61 - 3.72 (m, 2 H), 3.11 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.36 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C24H22F3N2O4, 459.1526; found 459.1527. MPLE 134

[0445] This example illustrates a synthesis of 2-(2-Methoxyethoxy)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB10-030, NCGC00244485-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 6.644 min; 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.45 (s, 1 H), 8.08 - 8.29 (m, 1 H), 7.93 (d, J=8.2 Hz, 1 H), 7.83 (dt, J=7.7, 1.8 Hz, 1 H), 7.57 - 7.66 (m, 1 H), 7.49 - 7.57 (m, 1 H), 7.40 - 7.49 (m, 1 H), 7.20 - 7.28 (m, 1 H), 7.05 - 7.18 (m, 1 H), 4.31 (td, J=4.5, 1.9 Hz, 2 H), 3.70 - 3.83 (m, 2 H), 3.29 (s, 3 H); ¹⁹F NMR (376 MHz, DMSO- ₆) δ ppm -61.26 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₇H₁₇F₃NO₃, 340.1155; found 340.1162. 135

[0447] This example illustrates a synthesis of tert-Butyl 4-(2-(2-((3- (trifluoromethyl)phenyl)carbamoyl)phenoxy)ethyl)piperazine- 1 -carboxylate (XJB 10-031 , NCGC00244486-01). The title compound was prepared according to general protocol H. LC- MS Retention Time: ti (Method 1) = 4.945 min; HRMS (ESI) m/z (M+H)⁺ calcd. for

C25H31F3N3O4, 494.2261; found 494.2270. PLE 136

[0449] This example illustrates a synthesis of 2-Isopropoxy-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB10-036, NCGC00244516-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 7.126 min; HRMS (ESI) m/z (M+H)⁺ calcd. For C₂₄H₂₂F₃N₂O₃, 443.1577; found 443.1599. E 137

[0451] This example illustrates a synthesis of 2-Phenoxy-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB10-037, NCGC00244517-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 7.314 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.45 (s, 1 H), 10.73 (s, 1 H), 8.41 - 8.58 (m, 1 H), 8.11 (t, J=2.1 Hz, 1 H), 7.97 (dd, J=7.8, 2.0 Hz, 1 H), 7.85 (ddd, J=8.3, 2.2, 1.3 Hz, 1 H), 7.80 (dd, J=7.8, 1.6 Hz, 1 H), 7.42 - 7.65 (m, 4 H), 7.21 - 7.37 (m, 4 H), 7.15 (tt, J=7.4, 1.2 Hz, 1 H), 7.01 - 7.12 (m, 2 H), 6.84 (dd, J=8.2, 1.2 Hz, 1 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -61.27 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for

C₂₇H₂₀F₃N₂O₃, 477.1421; found 477.1425. 8

[0453] This example illustrates a synthesis of 2-(2-(Piperidin-l-yl)ethoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-038, NCGC00244518-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.945 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₈H₂₉F₃N₃O₃, 512.2156;

found 512.2172.

[0455] This example illustrates a synthesis of 2-(2-Morpholinoethoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB10-039, NCGC00244519-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.752 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₇F₃N₃O₄, 514.1948;

found 514.1972. PLE 140

[0457] This example illustrates a synthesis of 2-(2-(Piperidin-l-yl)ethoxy)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJB 10-040, NCGC00244519-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.527 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.57 (s, 1 H), 8.23 (br. s., 1 H), 7.89 (d, J=8.8 Hz, 1 H), 7.49 - 7.66 (m, 3 H), 7.45 (d, J=8.0 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 7.13 (t, J=7.4 Hz, 1 H), 4.24 - 4.54 (m, 2 H), 3.40 - 3.61 (m, 4 H), 2.84 - 3.05 (m, 2 H), 1.44 - 1.80 (m, 5 H), 1.21 - 1.35 (m, 1 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₇H₂₇F₃N₃O₄, 514.1948; found 514.1972. LE 141

[0459] This example illustrates a synthesis of 2-(2-Morpholinoethoxy)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJBlO-041, NCGC00244502-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.280 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₀H₂₂F₃N₂O₃, 395.1577; found 395.1585. AMPLE 142

[0461] This example illustrates a synthesis of 2-(Cyclohexanecarboxamido)-N-(2'- (trifiuoromethyl)-[l,r-biphenyl]-3-yl)benzamide (XJB10-042, NCGC00244503-01). The title compound was prepared according to general protocol E. LC-MS Retention Time: ti (Method 1) = 7.417 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.46 (s, 1 H), 10.40 (s, 1 H), 8.15 (dd, J=8.3, 1.3 Hz, 1 H), 7.83 (dt, J=7.7, 0.8 Hz, 1 H), 7.66 - 7.79 (m, 4 H), 7.57 - 7.65 (m, 1 H), 7.45 - 7.57 (m, 1 H), 7.33 - 7.45 (m, 2 H), 7.20 (td, J=7.6, 1.3 Hz, 1 H), 7.05 (dd, J=7.6, 1.0 Hz, 1 H), 2.18 - 2.36 (m, 1 H), 1.73 - 1.88 (m, 2 H), 1.63 - 1.74 (m, 2 H), 1.50 - 1.63 (m, 1 H), 0.99 - 1.42 (m, 5 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -55.34 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C27H26F3N2O2, 467.1941; found 467.1931. EXAMPLE 143

[0463] This example illustrates a synthesis of 2-(2-(Piperazin-l-yl)ethoxy)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJBlO-043, NCGC00244504-01). A solution of tert- butyl 4-(2-(2-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)ethyl)piperazine-l-carboxylate (0.099 g, 0.200 mmol) in dichloromethane (2.00 mL) was treated at 0 °C with TFA (1.00 mL). The reaction mixture was stirred at 0 °C for 1 h. The mixture was concentrated, re- dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 3.872 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C20H23F3N3O2, 394.1737; found 394.1745.

EXAMPLE 144

[0465] This example illustrates a synthesis of 2-Methoxy-N-(2-((3-(thiophen-2- yl)phenyl)carbamoyl)phenyl)benzamide (XJB10-044, NCGC00244505-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.455 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₁N₂O₃S, 429.1267; found 429.1285. EXAMPLE 145

[0467] This example illustrates a synthesis of 2-(3-(Dimethylamino)propoxy)-N-(3- (trifiuoromethyl)phenyl)benzamide (XJBlO-045, NCGC00244506-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.371 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.27 - 10.74 (m, 1 H), 8.25 (s, 1 H), 7.92 (d, J=7.4 Hz, 1 H), 7.55 - 7.65 (m, 2 H), 7.48 - 7.54 (m, 1 H), 7.44 (d, J=7.8 Hz, 1 H), 7.17 (d, J=8.4 Hz, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 4.16 (t, J=5.5 Hz, 2 H), 3.04 - 3.21 (m, 2 H), 2.68 (s, 6 H), 1.97 - 2.18 (m, 2 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₁₉H₂₂F₃N₂O₂, 367.1628; found 367.1628. 6

[0469] This example illustrates a synthesis of 2-(3-(Dimethylamino)propoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB 10-046, NCGC00244507-01 ). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.868 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₆H₂₇F₃N₃O₃, 486.1999;

found 486.2002.

[0471] This example illustrates a synthesis of tert-Butyl 4-(2-(2-((2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)carbamoyl)phenoxy)ethyl)piperazine-l- carboxylate (XJB 10-047, NCGC00244481-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 5.211 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₃₂H₃₆F₃N₄0₅, 613.2632; found 613.2642. MPLE 148

[0473] This example illustrates a synthesis of N-(2-((3-

(Trifluoromethyl)phenyl)carbamoyl)phenyl)- 1 H-benzo [d] imidazo le-7-carboxamide (XJB 10- 049, NCGC00244508-01). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 4.777 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂2Hi₆F₃N₄02, 425.1220; found 425.1227.

[0475] This example illustrates a synthesis of 2-(2-(Piperazin-l-yl)ethoxy)-N-(2-((3- (trifiuoromethyl)phenyl)carbamoyl)phenyl)benzamide (XJB10-050, NCGC00244509-01). A solution of tert-butyl 4-(2-(2-(2-(3-

(trifluoromethyl)phenylcarbamoyl)phenylcarbamoyl)phenoxy)ethyl)piperazine-l-carboxylate (50.0 mg, 0.082 mmol) in dichloromethane (2.00 mL) was treated at 0 °C with TFA (1.00 mL). The reaction mixture was stirred at 0 °C for 1 h. The mixture was concentrated, re- dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 4.303 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C27H28F3N4O3, 513.2108; found 513.2128.

EXAMPLE 150

[0477] This example illustrates a synthesis of Methyl 2-(2-ethoxybenzamido)benzoate (XJB11-036). A solution of ethyl methyl 2-aminobenzoate (1.29 mL, 9.92 mmol) in dichloromethane (25.0 mL) and triethylamine (4.15 mL, 29.8 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (1.83 g, 9.92 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 2.70 g (9 /o) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.908 min; m/z (M+H)⁺ 300.1. EXAMPLE 151

[0479] This example illustrates a synthesis of 2-Ethoxy-N-(2-(pyridin-2- ylcarbamoyl)phenyl)benzamide (XJBl 1-037, NCGC00250128-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 5.072 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.30 (s, 1 H), 11.01 (s, 1 H), 8.46 (d, J=8.2 Hz, 1 H), 8.37 (dd, J=5.1, 2.3 Hz, 1 H), 8.13 (d, J=8.2 Hz, 1 H), 7.92 (dd, J=7.6, 2.2 Hz, 1 H), 7.82 - 7.89 (m, 1 H), 7.79 (dd, J=7.8, 2.0 Hz, 1 H), 7.44 - 7.61 (m, 2 H), 7.13 - 7.25 (m, 3 H), 7.02 - 7.10 (m, 1 H), 4.28 (q, J=6.9 Hz, 2 H), 1.29 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H20N3O3, 362.1499; found 362.1505.

EXAMPLE 152

[0481] This example illustrates a synthesis of 2-Ethoxy-N-(2-(pyridin-4- ylcarbamoyl)phenyl)benzamide (XJBl 1-039, NCGC00250119-02). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 4.341 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.01 (s, 1 H), 10.65 (s, 1 H), 8.17 - 8.36 (m, 3 H), 7.72 (dd, J=7.8, 2.0 Hz, 1 H), 7.57 (dd, J=7.6, 1.8 Hz, 1 H), 7.51 (dd, J=4.9, 1.8 Hz, 2 H), 7.38 (td, J=7.9, 1.8 Hz, 1 H), 7.31 (ddd, J=8.5, 7.1, 2.0 Hz, 1 H), 7.03 - 7.10 (m, 1 H), 6.99 (d, J=8.6 Hz, 1 H), 6.68 - 6.91 (m, 1 H), 4.09 (q, J=6.8 Hz, 2 H), 1.1 1 (t, J=6.8 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H20N3O3, 362.1499; found 362.1499. MPLE 153

[0483] This example illustrates a synthesis of N-(3-(fert-Butyl)phenyl)-2-(2- ethoxybenzamido)benzamide (XJBl 1-040, NCGC00250129-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.379 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₆H₂₉N₂O₃, 417.2173; found 417.2175. PLE 154

[0485] This example illustrates a synthesis of 2-Ethoxy-N-(2-(pyridin-4- ylcarbamoyl)phenyl)benzamide (XJBl 1-041, NCGC00250107-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.305 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₃S, 461.1141; found 461.1146. LE 155

[0487] This example illustrates a synthesis of 2-Ethoxy-N-(2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJB 11 -043 ,

NCGC00250130-01, compound 174). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.963 min; HRMS (ESI) m/z (M+H)⁺ calcd. for

493.1040; found 493.1044.

EXAMPLE 156

[0489] This example illustrates a synthesis of 2-Ethoxy-N-(2-(pyridin-3- ylcarbamoyl)phenyl)benzamide (XJBl 1-047, NCGC00250104-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 4.330 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.32 (s, 1 H), 10.71 (s, 1 H), 8.89 (d, J=2.3 Hz, 1 H), 8.51 (d, J=8.2 Hz, 1 H), 8.31 (dd, J=4.7, 1.6 Hz, 1 H), 8.13 (ddd, J=8.7, 2.4, 1.4 Hz, 1 H), 7.92 (dd, J=7.8, 2.0 Hz, 1 H), 7.80 (dd, J=7.8, 2.0 Hz, 1 H), 7.54 - 7.63 (m, 1 H), 7.51 (td, J=7.8, 2.0 Hz, 1 H), 7.39 (dd, J=8.2, 4.7 Hz, 1 H), 7.22 - 7.32 (m, 1 H), 7.18 (d, J=8.2 Hz, 1 H), 7.06 (t, J=7.4 Hz, 1 H), 4.27 (q, J=7.0 Hz, 2 H), 1.29 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H20N3O3, 362.1499; found 362.1507. XAMPLE 157

[0491] This example illustrates a synthesis of 2-Ethoxy-N-(2-((5-iodopyridin-3- yl)carbamoyl)phenyl)benzamide (XJBl 1-048, NCGC00250103-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.305 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.31 (s, 1 H), 10.78 (s, 1 H), 8.85 (d, J=2.3 Hz, 1 H), 8.63 (t, J=2.3 Hz, 1 H), 8.54 (d, J=2.3 Hz, 1 H), 8.49 (d, J=8.2 Hz, 1 H), 7.93 (dd, J=7.8, 2.0 Hz, 1 H), 7.80 (dd, J=7.8, 2.0 Hz, 1 H), 7.59 (td, J=7.9, 1.8 Hz, 1 H), 7.52 (ddd, J=8.6, 7.0, 2.0 Hz, 1 H), 7.23 - 7.31 (m, 1 H), 7.20 (d, J=8.2 Hz, 1 H), 7.07 (t, J=7.4 Hz, 1 H), 4.31 (q, J=6.8 Hz, 2 H), 1.33 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C21H19IN3O3, 488.0466; found 488.0475.

EXAMPLE 158

[0493] This example illustrates a synthesis of Methyl 4-(2-ethoxybenzamido)nicotinate (XJBl 1-044). A solution of 4-aminonicotinate (500 mg, 3.29 mmol) in dichloromethane (25.0 mL) and triethylamine (1.37 mL, 9.86 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (607 mg, 3.29 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 924 mg (94%) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.045 min; m/z (M+H)⁺ 301.1.

EXAMPLE 159

[0495] This example illustrates a synthesis of 4-(2-Ethoxybenzamido)-N-(3- ((trifiuoromethyl)sulfonyl)phenyl)nicotinamide (XJB11-049, NCGC00250117-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 5.507 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.71 (s, 1 H), 1 1.25 (s, 1 H), 9.00 (s, 1 H), 8.77 (t, J=2.2 Hz, 1 H), 8.65 - 8.71 (m, 1 H), 8.54 - 8.64 (m, 1 H), 8.15 - 8.26 (m, 1 H), 7.96 (dd, J=7.8, 2.3 Hz, 1 H), 7.78 - 7.93 (m, 2 H), 7.56 (ddd, J=8.6, 7.0, 2.0 Hz, 1 H), 7.24 (d, J=8.6 Hz, 1 H), 7.09 (t, J=7.4 Hz, 1 H), 4.35 (q, J=6.9 Hz, 2 H), 1.29 (t, J=6.8 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -78.37 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₉F₃N₃0₅S, 494.0992; found 494.1004.

EXAMPLE 160

[0497] This example illustrates a synthesis of Methyl 2-(2-ethoxybenzamido)nicotinate (XJB11-045). A solution of 4-aminonicotinate (500 mg, 3.29 mmol) in dichloromethane (25.0 mL) and triethylamine (1.37 mL, 9.86 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (607 mg, 3.29 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtO Ac in hexanes to give 840 mg (85%) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 2.975 min; m/z (M+H)⁺ 301.1. LE 161

[0499] This example illustrates a synthesis of 2-(2-Ethoxybenzamido)-N-(3- ((trifluoromethyl)sulfonyl)phenyl)nicotinamide (XJB11-050, NCGC00250118-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti

(Method 1) = 5.472 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.98 (s, 1 H), 10.81 (s, 1 H), 8.47 - 8.66 (m, 2 H), 8.05 - 8.24 (m, 2 H), 7.75 - 7.87 (m, 2 H), 7.72 (dd, J=7.8, 2.0 Hz, 1 H), 7.51 (ddd, J=8.5, 7.1, 2.0 Hz, 1 H), 7.39 (dd, J=7.6, 4.9 Hz, 1 H), 7.20 (d, J=8.2 Hz, 1 H), 7.00 (t, J=7.4 Hz, 1 H), 4.27 (q, J=7.0 Hz, 2 H), 1.42 (t, J=7.0 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -78.44 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi9F₃N₃0₅S, 494.0992; found 494.1004. XAMPLE 162

[0501] This example illustrates a synthesis of 2-Ethoxy-N-(2-((3- iodophenyl)carbamoyl)phenyl)benzamide (XJB11-053, NCGC00250105-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti

(Method 1) = 7.114 min; 1H NMR (400 MHz, DMSC /₆) δ ppm 1 1.31 (s, 1 H), 10.59 (s, 1

H), 8.50 (d, J=8.2 Hz, 1 H), 8.27 (t, J=2.0 Hz, 1 H), 7.94 (dd, J=7.8, 2.0 Hz, 1 H), 7.75 (dd,

J=7.6, 1.8 Hz, 1 H), 7.69 (dd, J=8.2, 2.3 Hz, 1 H), 7.41 - 7.60 (m, 3 H), 7.10 - 7.29 (m, 3 H), 7.00 - 7.11 (m, 1 H), 4.31 (q, J=7.0 Hz, 2 H), 1.33 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₀IN₂O₃, 487.0513; found 487.0514.

EXAMPLE 163

[0503] This example illustrates a synthesis of Methyl 2-(2-iodobenzamido)benzoate (XJB11-035). A solution of methyl 2-aminobenzoate (1.29 mL, 9.92 mmol) in

dichloromethane (25.0 mL) and triethylamine (4.15 mL, 29.8 mmol) was treated at 0 °C with 2-iodobenzoyl chloride (2.64 g, 9.92 mmol).²² The reaction mixture was stirred at 0 °C for 2 hours and at room temperature for another 2 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified via silica gel chromatography using a gradient of 0- 50% of EtOAc in hexanes to give 3.40 g (90%>) of the title compound as a white solid. LC- MS Retention Time: ti (Method 1) = 6.308 min; t₂ (Method 2) = 3.744 min; 1H NMR (400

MHz, DMSO-dg) δ ppm 10.97 (s, 1 H), 8.33 (d, J=8.2 Hz, 1 H), 7.87 - 8.01 (m, 2 H), 7.63 - 7.73 (m, 1 H), 7.46 - 7.62 (m, 2 H), 7.13 - 7.33 (m, 2 H), 3.82 (s, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for Ci₅Hi₃IN0₃, 381.9935; found 381.9943. PLE 164

[0505] This example illustrates a synthesis of 2-Iodo-N-(2-(3-

(trifiuoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide (XJB11-054, NCGC00250120- 01). A solution of methyl 2-(2-iodobenzamido)benzoate (500 mg, 1.31 mmol) in toluene (15.0 mL) was treated at room temperature with 3-(trifluoromethylsulfonyl)aniline (443 mg, 1.97 mmol) followed by trimethylaluminum (1.31 mL, 2.0 M in toluene, 2.62 mmol). The reaction mixture was stirred at 100 °C overnight. After cooling, the reaction mixture was concentrated in vacuo; and the crude residue was purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 677 mg (90%) of the title compound as a white solid. LC-MS Retention Time: ti (Method 1) = 6.816 min; t₂ (Method 2) = 3.857 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.96 (s, 1 H), 10.69 (s, 1 H), 8.57 (s, 1 H), 8.17 - 8.36 (m, 1 H), 8.02 (d, J=7.8 Hz, 1 H), 7.91 (d, J=7.8 Hz, 1 H), 7.70 - 7.86 (m, 3 H), 7.61 (t, J=7.4 Hz, 1 H), 7.41 - 7.56 (m, 2 H), 7.34 (t, J=7.6 Hz, 1 H), 7.11 - 7.27 (m, 1 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -78.38 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for

C₂iHi₅F3lN₂0₄S, 574.9744; found 574.9752.

EXAMPLE 165

[0507] This example illustrates a synthesis of Methyl 3-(2- ethoxybenzamido)isonicotinate (XJB11-046). A solution of methyl 3-aminoisonicotinate (200 mg, 1.31 mmol) in dichloromethane (25.0 mL) and triethylamine (0.550 mL, 3.94 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (243 mg, 1.31 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 45 mg (11%>) of the title product as a white solid which was used directly in the next reaction without further purification. LE 166

[0509] This example illustrates a synthesis of 3-(2-Ethoxybenzamido)-N-(3- ((trifiuoromethyl)sulfonyl)phenyl)isonicotinamide (XJB11-055, NCGC00250121-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 5.766 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂Hi₉F₃N₃0₅S, 494.0992; found 494.1000.

EXAMPLE 167

[0511] This example illustrates a synthesis of Methyl 3-(2-ethoxybenzamido)picolinate (XJB11-056). A solution of methyl 3-aminopicolinate (500 mg, 3.29 mmol) in

dichloro methane (25.0 mL) and triethylamine (1.37 mL, 9.86 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (607 mg, 3.29 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtO Ac in hexanes to give 741 mg (75%>) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.519 min; m/z (M+H) LE 168

[0513] This example illustrates a synthesis of 2-(2-Ethoxybenzamido)-N-(3- ((trifiuoromethyl)sulfonyl)phenyl)nicotinamide (XJB11-058, NCGC00250122-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.402 min; HRMS (ESI) m/z (M+Na)⁺ calcd. for C₂2Hi₈F₃N3Na0₅S, 516.0811; found 516.0837.

EXAMPLE 169

[0515] This example illustrates a synthesis of Methyl 2-(2-ethoxybenzamido)thiophene- 3-carboxylate (XJB 11-057). A solution of 2-aminothiophene-3-carboxylate (500 mg, 3.18 mmol) in dichloromethane (25.0 mL) and triethylamine (1.33 mL, 9.54 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (587 mg, 3.18 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 798 mg (82%) of the title product as a white solid which was used directly in the next reaction without further purification. LE 170

[0517] This example illustrates a synthesis of 2-(2-Ethoxybenzamido)-N-(3- ((trifiuoromethyl)sulfonyl)phenyl)thiophene-3-carboxamide (XJBl 1-059, NCGC00250123- 01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 7.341 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂iHi₈F3N₂0₅S2, 499.0604; found 499.0608.

EXAMPLE 171

[0519] This example illustrates a synthesis of Methyl 2-(2- ethoxyphenylsulfonamido)benzoate (XJBl 1-060). A solution of methyl 2-aminobenzoate (206 mg, 1.359 mmol) in dichloromethane (5.00 mL) and triethylamine (0.568 mL, 4.08 mmol) was treated at 0 °C with 2-ethoxybenzene-l-sulfonyl chloride (300 mg, 1.359 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0- 100% of EtOAc in hexanes to give 274 mg (60%) of the title product as a white solid which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.698 min; m/z (M+H)⁺ 336.1. LE 172

[0521] This example illustrates a synthesis of 2-(2-Ethoxyphenylsulfonamido)-N-(3- ((trifiuoromethyl)sulfonyl)phenyl)benzamide (XJB11-062, NCGC00250124-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.631 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₂H₂₀F₃N₂O₆S₂, 529.0709; found 529.0716. MPLE 173

[0523] This example illustrates a synthesis of N-(2-amino-5-(trifluoromethyl)phenyl)-2- (2-ethoxybenzamido)benzamide (XJB11-063, NCGC00250125-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.408 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.43 (s, 1 H), 9.89 (s, 1 H), 8.48 (d, J=7.8 Hz, 1 H), 7.88 (dd, J=7.8, 2.0 Hz, 2 H), 7.53 - 7.61 (m, 1 H), 7.49 (td, J=7.8, 2.0 Hz, 1 H), 7.42 (d, J=7.8 Hz, 1 H), 7.24 (t, J=7.6 Hz, 1 H), 7.14 (d, J=8.2 Hz, 1 H), 6.98 - 7.08 (m, 2 H), 6.85 (dd, J=8.6, 2.3 Hz, 1 H), 5.46 (s, 2 H), 4.20 (q, J=6.9 Hz, 2 H), 1.26 (t, J=6.8 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -60.99 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H21F3N3O3, 444.1530; found 444.1536. EXAMPLE 174

[0525] This example illustrates a synthesis of Ethyl 3-(2-ethoxybenzamido)propanoate (XJB11-061). A solution of ethyl 3-aminopropanoate, HC1 salt (300 mg, 1.95 mmol) in dichloromethane (25.0 mL) and triethylamine (0.817 mL, 5.86 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (361 mg, 1.95 mmol). The reaction mixture was stirred at 0 °C for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtO Ac in hexanes to give 478 mg (92%) of the title product as a colorless oil which was used directly in the next reaction without further purification. LC-MS Retention Time: t₂ (Method 2) = 3.346 min; m/z (M+H)⁺ 266.1.

EXAMPLE 175

[0527] This example illustrates a synthesis of 2-Ethoxy-N-(3-oxo-3-((3- ((trifiuoromethyl)sulfonyl)phenyl)amino)propyl)benzamide (XJB11-064, NCGC00250126- 01, CID-56593338). The title compound was prepared according to general protocol A. LC- MS Retention Time: ti (Method 1) = 5.985 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.62 (s, 1 H), 8.62 (s, 1 H), 8.39 (t, J=5.9 Hz, 1 H), 7.93 - 8.07 (m, 1 H), 7.82 (dd, J=7.8, 2.0 Hz, 1 H), 7.78 (d, J=5.5 Hz, 2 H), 7.38 - 7.48 (m, 1 H), 7.08 (d, J=8.6 Hz, 1 H), 6.96 - 7.04 (m, 1 H), 4.09 (q, J=6.8 Hz, 2 H), 3.61 (q, J=6.0 Hz, 2 H), 2.68 (t, J=6.3 Hz, 2 H), 1.29 (t, J=7.0 Hz, 3 H); ^iyF NMR (376 MHz, DMSO- ₆) δ ppm -78.46 (s, 3 F); HRMS (ESI) m/z (M+H) calcd. for C19H20F3N2O5S, 445.1040; found 445.1042.

[0529] This example illustrates a synthesis of Mixture of 6-(2-ethoxyphenyl)-10- (trifluoromethyl)benzo[4,5]imidazo[ 1 ,2-c]quinazoline and 6-(2-ethoxyphenyl)-9- (trifiuoromethyl)benzo[4,5]imidazo[l,2-c]quinazoline (XJBl 1-067-2, NCGC00250127-01). A solution of N-(2-amino-5-(trifluoromethyl)phenyl)-2-(2-ethoxybenzamido)benzamide (30.0 mg, 0.068 mmol) in glacial acetic acid (1.00 mL) was heated at 70 °C for 16 h. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final products as a mixture. 77

[0531] This example illustrates a synthesis of 2-Propoxy-N-(2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJBl 1-068,

NCGC00250109-01, compound 179). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 7.147 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₂F₃N₂0₅S, 507.1196; found 507.1219. MPLE 178

[0533] This example illustrates a synthesis of 2-Ethoxy-N-(2-(6-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)phenyl)benzamide (XJB11-069, NCGC00250108-01). A solution of N-(2-amino-5-(trifluoromethyl)phenyl)-2-(2-ethoxybenzamido)benzamide (30.0 mg, 0.068 mmol) in glacial acetic acid (1.00 mL) was stirred at room temperature for 24 h. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final products. LC-MS Retention Time: ti (Method 1) = 6.588 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₁₉F₃N₃O₂, 426.1424; found 426.1437.

[0535] This example illustrates a synthesis of 2-Butoxy-N-(2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJB 11 -070,

NCGC00250110-01, compound 180). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 7.325 min; t₂ (Method 2) = 3.971 min; 1H NMR (400 MHz, DMSO- d₆) δ ppm 11.25 (s, 1 H), 11.09 (s, 1 H), 8.69 (s, 1 H), 8.53 (d, J=8.6 Hz, 1 H), 8.24 (ddd, J=7.2, 2.2, 2.0 Hz, 1 H), 7.91 (dd, J=7.8, 2.0 Hz, 1 H), 7.77 - 7.89 (m, 3 H), 7.60 (td, J=7.8, 1.6 Hz, 1 H), 7.43 - 7.56 (m, 1 H), 7.28 (td, J=7.5, 1.0 Hz, 1 H),

7.20 (d, J=8.6 Hz, 1 H), 7.00 - 7.11 (m, 1 H), 4.18 (t, J=6.8 Hz, 2 H), 1.54 - 1.75 (m, 2 H),

1.21 (sxt, J=7.4 Hz, 2 H), 0.69 (t, J=7.4 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm - 78.42 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₅H₂₄F₃N₂0₅S, 521.1353; found

521.1359. 80

[0537] This example illustrates a synthesis of 2-(2,2,2-Trifluoroethoxy)-N-(2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJB 11-071,

NCGC00250111-01, compound 177). The title compound was prepared according to general protocol H. LC-MS Retention Time: ti (Method 1) = 6.804 min; 1H NMR (400 MHz, DMSO- d₆) δ ppm 11.07 (s, 1 H), 1 1.03 (s, 1 H), 8.61 (t, J=2.2 Hz, 1 H), 8.41 (d, J=8.2 Hz, 1 H), 8.19 - 8.33 (m, 1 H), 7.70 - 7.94 (m, 4 H), 7.58 - 7.67 (m, 1 H), 7.47 - 7.58 (m, 1 H), 7.35 (d, J=8.6 Hz, 1 H), 7.26 - 7.33 (m, 1 H), 7.17 (t, J=7.4 Hz, 1 H), 4.92 (q, J=9.0 Hz, 2 H); ¹⁹F NMR (376 MHz, DMSO-dg) δ ppm -72.45 (s, 3 F), -78.46 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃Hi₇F₆N₂0₅S, 547.0757; found 547.0762. 181

[0539] This example illustrates a synthesis of 2-(Ethylthio)-N-(2-((3- ((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl)benzamide (XJB 11 -072,

NCGC00250106-01, CID-56593341). A tube was charged with Cul (3.3 mg, 0.017 mmol), 1,10-phenanthroline (6.3 mg, 0.035 mmol), (56.7 mg, 0.174 mmol), 2-iodo-N-(2-(3- (trifiuoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide (50.0 mg, 0.087 mmol) and ethanethiol (10.8 mg, 0.174 mmol) in toluene (1.50 mL) under N₂. The tube was sealed and the reaction mixture was stirred at 110 °C for 24 h. The resulting mixture was cooled to room temperature and treated with a small portion of Si-THIOL to get rid of copper. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: (Method 1) = 6.910 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 10.95 (s, 1 H), 10.73 (s, 1 H), 8.55 (s, 1 H), 8.28 (dt, J=6.7, 2.0 Hz, 1 H), 8.10 (d, J=7.8 Hz, 1 H), 7.74 - 7.91 (m, 3 H), 7.57 - 7.66 (m, 1 H), 7.51 - 7.57 (m, 1 H), 7.39 - 7.48 (m, 2 H), 7.31 (td, J=7.6, 1.2 Hz, 1 H), 7.24 (ddd, J=7.4, 4.9, 3.7 Hz, 1 H), 2.90 (q, J=7.3 Hz, 2 H), 1.13 (t, J=7.2 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -78.40 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀F₃N₂O₄S₂, 509.0811; found 509.0814.

EXAMPLE 182

[0541] This example illustrates a synthesis of Methyl 2-(2- isopropoxybenzamido)benzoate (XJB12-040). A solution of methyl 2-aminobenzoate (0.245 mL, 1.89 mmol) in dichloromethane (8.00 mL) and triethylamine (0.53 mL, 3.78 mmol) was treated at 0 °C with 2-isopropoxybenzoyl chloride (250 mg, 1.26 mmol). The reaction mixture was stirred at 0 °C for 2 hours and then at room temperature for another 2 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified via silica gel chromatography using a gradient of 0-50% of EtOAc in hexanes to give 320 mg (81%) of the title compound as a colorless oil. LC-MS Retention Time: ti (Method 1) = 6.576 min; t₂

(Method 2) = 3.825 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 1 1.59 (s, 1 H), 8.63 (d, J=8.6 Hz, 1 H), 7.98 (dd, J=7.8, 1.6 Hz, 1 H), 7.83 (dd, J=7.8, 2.0 Hz, 1 H), 7.64 (ddd, J=8.5, 7.1, 1.6 Hz, 1 H), 7.45 - 7.56 (m, 1 H), 7.13 - 7.27 (m, 2 H), 6.94 - 7.09 (m, 1 H), 4.82 (dq, J=6.3, 6.0 Hz, 1 H), 3.85 (s, 3 H), 1.35 (d, J=5.9 Hz, 6 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C18H20NO4, 314.1387; found 314.1399. 183

[0543] This exam le illustrates a synthesis of 2-Isopropoxy-N-(2-(3- (trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide (XJB11-073, NCGC00250135- 01, compound 178). A μW tube was charged with copper (I) iodide (3.3 mg, 0.017 mmol), 1,10-phenanthroline (6.3 mg, 0.035 mmol), cesium carbonate (56.7 mg, 0.174 mmol), 2-iodo- N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide (50.0 mg, 0.087 mmol), propan-2-ol (10.5 mg, 0.174 mmol), and dry toluene (1.50 mL). The tube was sealed, and the reaction mixture was stirred at 110 °C for overnight. The resulting suspension was cooled to room temperature and treated with Si-Thio. The reaction mixture was filtered and concentrated in vacuo to give an orange oil that was taken up in 1.5 mL of DMSO and purified via C₁₈ reverse phase HPLC to give 1.7 mg (4%) of the title compound as a white solid. LC-MS Retention Time: ti (Method 1) = 6.974 min; t₂ (Method 2) = 3.881 min; 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.08 (br. s., 1 H), 1 1.07 (s, 1 H), 8.73 (s, 1 H), 8.46 (d, J=8.2 Hz, 1 H), 8.18 (dt, J=7.4, 2.0 Hz, 1 H), 7.89 (dd, J=7.8, 1.6 Hz, 1 H), 7.77 - 7.87 (m, 3 H), 7.57 - 7.63 (m, 1 H), 7.49 (ddd, J=8.7, 7.1, 1.8 Hz, 1 H), 7.28 (td, J=7.5, 1.0 Hz, 1 H), 7.19 (d, J=8.2 Hz, 1 H), 7.03 (t, J=7.6 Hz, 1 H), 4.79 (m, 1 H), 1.31 (d, 6 H); ¹⁹F NMR (376 MHz, DMSO-dg) d ppm -78.36 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂4H22F₃N₂0₅S, 507.1196; found 507.1221.

[0544] Or a solution of methyl 2-(2-isopropoxybenzamido)benzoate (110 mg, 0.351 mmol) in toluene (4.00 mL) was treated with 3-(trifluoromethylsulfonyl)aniline (119 mg, 0.527 mmol) at room temperature, followed by trimethylaluminum (0.503 mL, 2.0 M in toluene, 1.06 mmol). The reaction mixture was stirred at 100 °C for overnight. After cooling, the reaction mixture was concentrated in vacuo; and the crude residue was purified via silica gel chromatography using a gradient of 0-80% of EtOAc in hexanes to give 130 mg (73%) of the title compound as a white solid. E 184

[0546] This example illustrates a synthesis of (E)-2-Ethoxy-N-(2-((3-(prop-l-en-l- yl)phenyl)carbamoyl)phenyl)benzamide (XJB11-074, NCGC00250131-01). A mixture of 2- ethoxy-N-(2-(3-iodophenylcarbamoyl)phenyl)benzamide (50.0 mg, 0.103 mmol), (E)-prop- 1-enylboronic acid (13.3 mg, 0.154 mmol) and Pd(PPh₃)₄ (5.9 mg, 5.14 μιηοΐ) in DMF (1.50 mL) and 2.0 N Na₂C0₃ (0.500 mL) aqueous solution was heated in μW at 100 °C for 30 min. The reaction was cooled to room temperature, added a small portion of Si-THIOL to get rid of Palladium. The mixture was filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 7.093 min; 1H NMR (400 MHz, DMSO- e) δ ppm 11.35 (s, 1 H), 10.48 (s, 1 H), 8.51 (d, J=8.2 Hz, 1 H), 7.93 (dd, J=7.8, 2.0 Hz, 1 H), 7.70 - 7.82 (m, 2 H), 7.42 - 7.63 (m, 3 H), 7.21 - 7.33 (m, 2 H), 7.18 (d, J=8.6 Hz, 1 H), 7.12 (d, J=7.8 Hz, 1 H), 7.06 (t, J=7.4 Hz, 1 H), 6.33 - 6.46 (m, 1 H), 6.16 - 6.32 (m, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 1.84 (dd, J=6.7, 1.6 Hz, 3 H), 1.30 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂5H2₅N₂0₃, 401.1860; found 401.1859. PLE 185

[0548] This example illustrates a synthesis of (Z)-2-Ethoxy-N-(2-((3-(prop-l-en-l- yl)phenyl)carbamoyl)phenyl)benzamide (XJBl 1-075, NCGC00250132-01). A mixture of 2- ethoxy-N-(2-(3-iodophenylcarbamoyl)phenyl)benzamide (50.0 mg, 0.103 mmol), (Z)-prop- 1-enylboronic acid (13.3 mg, 0.154 mmol) and Pd(PPh₃)₄ (5.9 mg, 5.14 μιηοΐ) in DMF (1.50 mL) and 2.0 N Na₂C0₃ (0.500 mL) aqueous solution was heated in μW at 100 °C for 30 min. The reaction was cooled to room temperature, added a small portion of Si-THIOL to get rid of Palladium. The mixture was filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 7.100 min; 1H NMR (400 MHz, DMSO- g) δ ppm 11.33 (s, 1 H), 10.52 (s, 1 H), 8.50 (d, J=8.2 Hz, 1 H), 7.93 (dd, J=7.8, 2.0 Hz, 1 H), 7.71 - 7.80 (m, 2 H), 7.59 - 7.64 (m, 1 H), 7.53 - 7.59 (m, 1 H), 7.51 (ddd, J=8.5, 7.1, 2.0 Hz, 1 H), 7.32 (t, J=7.8 Hz, 1 H), 7.25 (t, J=7.8 Hz, 1 H), 7.18 (d, J=8.6 Hz, 1 H), 7.00 - 7.10 (m, 2 H), 6.39 (dd, J=11.7, 2.3 Hz, 1 H), 5.60 - 5.92 (m, 1 H), 4.27 (q, J=6.9 Hz, 2 H), 1.86 (dd, J=7.4, 2.0 Hz, 3 H), 1.30 (t, J=6.8 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂5H2₅N₂0₃, 401.1860; found 401.1862. MPLE 186

[0550] This example illustrates a synthesis of N-(3-Cyanophenyl)-2-(2- ethoxybenzamido)benzamide (XJBl 1-080, NCGC00250133-01). The title compound was prepared according to general protocol A. LC-MS Retention Time: ti (Method 1) = 6.342 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.28 (s, 1 H), 10.83 (s, 1 H), 8.49 (d, J=7.8 Hz, 1 H), 8.22 (t, J=1.6 Hz, 1 H), 7.95 - 8.04 (m, 1 H), 7.93 (dd, J=7.8, 2.0 Hz, 1 H), 7.78 (dd, J=7.8, 2.0 Hz, 1 H), 7.54 - 7.63 (m, 3 H), 7.51 (ddd, J=8.5, 7.1 , 2.0 Hz, 1 H), 7.23 - 7.33 (m, 1 H), 7.19 (d, J=8.2 Hz, 1 H), 7.00 - 7.13 (m, 1 H), 4.29 (q, J=7.0 Hz, 2 H), 1.30 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₀N₃O₃, 386.1499; found 386.1515. EXAMPLE 187

[0552] This example illustrates a synthesis of Methyl 2-amino-3-(2- ethoxybenzamido)benzoate (XJB 11-082). A solution of 2, 3-diaminobenzoate (100 mg, 0.602 mmol) in dichloro methane (5.00 mL) and TEA (0.252 mL, 1.81 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (11 1 mg, 0.602 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated in vacuo and the crude material was used directly in the next reaction.

EXAMPLE 188

[0554] This example illustrates a synthesis of Methyl 2-(2-ethoxyphenyl)-lH- benzo[d]imidazole-4-carboxylate (XJB 11-083). A solution of methyl crude 2-amino-3-(2- ethoxybenzamido)benzoate (189 mg, 0.602 mmol) in glacial acetic acid (3.00 mL) was heated at 70 °C for 24 h. The reaction mixture was concentrated in vacuo; and the crude residue was purified via silica gel chromatography using a gradient of 0-20% of MeOH in dichloromethane to give 165 mg (92%) of the title compound as a white solid. LC-MS Retention Time: t₂ (Method 2) = 3.088 min; m/z (M+H)⁺ 297.1. PLE 189

[0556] This example illustrates a synthesis of 2-(2-Ethoxyphenyl)-N-(3- ((trifluoromethyl)sulfonyl)phenyl)-lH-benzo[d]imidazole-4-carboxamide (XJBl 1-086, NCGC00250115-01). The title compound was prepared according to general protocol A. LC- MS Retention Time: ti (Method 1) = 6.265 min; HRMS (ESI) m/z (M+H)⁺ calcd. for

C₂₃H₁₉F₃N₃O₄S, 490.1043; found 490.1049.

EXAMPLE 190

[0557]

[0558] This example illustrates a synthesis of tert-Butyl (2-formylphenyl)carbamate (XJBl 1-088). A solution of tert-butyl 2-(hydroxymethyl)phenylcarbamate (0.370 g, 1.66 mmol) and Dess-Martin Periodinane (0.914 g, 2.15 mmol) in dichloromethane (15.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was concentrated and the crude residue was purified via silica gel chromatography using 10% of EtOAc in hexanes to give 300 mg (82%) of the title compound as a colorless oil. XAMPLE 191

[0560] This example illustrates a synthesis of tert-Butyl (2-(((3-

((trifluoromethyl)sulfonyl)phenyl)amino)methyl)phenyl)carbamate (XJB 11-090). A mixture of tert-butyl 2-formylphenylcarbamate (80.0 mg, 0.362 mmol) and 3- (trifluoromethylsulfonyl)aniline (122 mg, 0.542 mmol) in MeOH (2.00 ml) was treated with ΤΪ(0'ΡΓ)₄ (0.212 mL, 0.723 mmol). The reaction was stirred at room temperature for 6 h, then treated with NaBH₄ (20.5 mg, 0.542 mmol) and stirred overnight at room temperature. The reaction mixture was poured into 2N NH₄OH aqueous solution, the resulting inorganic precipitate was filtered off, and the filtrate was extracted with EtOAc. The organic layer was separated, dried and concentrated to give the final product as a colorless oil which was used directly in the next reaction. LC-MS Retention Time: t₂ (Method 2) = 3.869 min; m/z (M+H)⁺ 431.1. XAMPLE 192

[0562] This example illustrates a synthesis of N-(2-Aminobenzyl)-3- ((trifluoromethyl)sulfonyl)aniline (XJB11-091). A solution of tert-butyl 2-((3- (trifluoromethylsulfonyl)phenylamino)methyl)phenylcarbamate (0.156 g, 0.362 mmol) in dichloro methane (2.00 mL) was treated at 0 °C with TFA (2.00 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the final product which was used directly in the next reaction. LE 193

[0564] This example illustrates a synthesis of 2-Ethoxy-N-(2-(((3- ((trifluoromethyl)sulfonyl)phenyl)amino)methyl)phenyl)benzamide (XJB 11 -097,

NCGC00250112-01). A solution of N-(2-aminobenzyl)-3-(trifluoromethylsulfonyl)aniline (0.060 g, 0.181 mmol) in dichloromethane (2.00 mL) and TEA (0.075 mL, 0.535 mmol) was treated at 0 °C with 2-ethoxybenzoyl chloride (0.033 g, 0.181 mmol). The reaction mixture was stirred overnight at room temperature for 2 h. The mixture was concentrated, re- dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 6.813 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₃H₂₂F₃N₂O₄S, 479.1247; found 479.1249.

EXAMPLE 194

[0566] This example illustrates a synthesis of 7-Amino-2-(3-

(trifluoromethyl)phenyl)isoindolin-l-one (XJB 11-098). A mixture of 7-aminoisoindolin-l- one (80.0 mg, 0.540 mmol), l-iodo-3-(trifluoromethyl)benzene (176 mg, 0.648 mmol), (15,2iS)-M^-dimethylcyclohexane ,2-diaimne (0.017 mL, 0.108 mmol), Cul (5.1 mg, 0.027 mmol) and K₂CO₃ (149 mg, 1.08 mmol) in toluene (3.00 mL) was stirred overnight at 110 °C. The reaction mixture was concentrated and the crude residue was purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 39.0 mg (25%) of the title compound as a white solid. LC-MS Retention Time: t₂ (Method 2) = 3.736 min; m/z (M+H)⁺ 293.1.

EXAMPLE 195

[0568] This example illustrates a synthesis of 2-Ethoxy-N-(3-oxo-2-(3- (trifiuoromethyl)phenyl)isoindolin-4-yl)benzamide (XJB12-002, NCGC00250113-01). A solution of 7-amino-2-(3-(trifluoromethyl)phenyl)isoindolin-l-one (18.0 mg, 0.062 mmol) in dichloromethane (1.00 mL) and TEA (0.026 mL, 0.185 mmol) was treated at 0 °C with 2- ethoxybenzoyl chloride (17.1 mg, 0.092 mmol). The reaction mixture was stirred overnight at room temperature for 2 h. The mixture was concentrated, re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 7.538 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 12.04 (s, 1 H), 8.98 (d, J=8.2 Hz, 1 H), 8.76 (s, 1 H), 8.35 (dd, J=8.2, 2.7 Hz, 1 H), 8.27 (dd, J=7.8, 2.0 Hz, 1 H), 7.93 - 8.05 (m, 2 H), 7.79 - 7.92 (m, 2 H), 7.65 (d, J=7.8 Hz, 1 H), 7.57 (d, J=8.2 Hz, 1 H), 7.35 - 7.50 (m, 1 H), 5.41 (s, 2 H), 4.72 (q, J=6.8 Hz, 2 H), 1.68 - 1.82 (t, J=7.2 Hz, 3 H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm -61.34 (s, 3 F); HRMS (ESI) m/z (M+H)⁺ calcd. for C₂₄H₂₀F₃N₂O₃, 441.1421; found 441.1429. PLE 196

[0570] This example illustrates a synthesis of N-(3-(lH-tetrazol-5-yl)phenyl)-2-(2- ethoxybenzamido)benzamide (XJB12-006, NCGC00250114-01). A solution of N-(3- cyanophenyl)-2-(2-ethoxybenzamido)benzamide (0.066 g, 0.171 mmol) in water (1.00 mL) was treated at room temperature with ZnBr₂ (0.058 g, 0.257 mmol) and NaN₃ (0.033 g, 0.513 mmol). The pH value of the solution was adjusted to ~ 7 by several drops of 1 N NaOH aqueous solution. The reaction mixture was heated at 120 °C for 60 hours. Another aliquot of reagents was added and the mixture was heated at 120 °C for an additional 24 h. The reaction mixture filtered and purified via C₁₈ reverse phase HPLC to give two products

NCGC00250114-01 and NCGC00250134-01. LC-MS Retention Time: ti (Method 1) = 5.547 min; 1H NMR (400 MHz, DMSO- ₆) δ ppm 11.36 (s, 1 H), 10.77 (s, 1 H), 8.61 (t, J=2.0 Hz, 1 H), 8.52 (d, J=8.2 Hz, 1 H), 7.93 (dd, J=7.8, 2.0 Hz, 1 H), 7.85 - 7.91 (m, 1 H), 7.81 (dd, J=7.8, 1.6 Hz, 1 H), 7.74 (d, J=7.8 Hz, 1 H), 7.53 - 7.63 (m, 2 H), 7.50 (ddd, J=8.6, 7.0, 2.0 Hz, 1 H), 7.23 - 7.31 (m, 1 H), 7.18 (d, J=8.2 Hz, 1 H), 7.01 - 7.10 (m, 1 H), 4.30 (q, J=7.0 Hz, 2 H), 1.28 (t, J=7.0 Hz, 3 H); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H21N6O3, 429.1670; found 429.1673. PLE 197

[0572] This example illustrates a synthesis of N-(3-Carbamimidoylphenyl)-2-(2- ethoxybenzamido)benzamide (XJB12-008, NCGC00250116-01). A suspension of ammonium chloride (267 mg, 5.00 mmol) in benzene (5.00 mL) at 5 °C, was slowly added a trimethylaluminum (2.0 M in toluene, 2.50 mL, 5.00 mmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and was stirred for 1-2 hours until gas evolution has ceased. The solution was ready to use. 0.394 mL of above in situ solution was added to another solution of N-(3-cyanophenyl)-2-(2- ethoxybenzamido)benzamide (50.0 mg, 0.130 mmol) in toluene (1.00 mL) at room

temperature. The reaction mixture was heated under argon at 80 °C for 4 h. The reaction mixture was filtered through a pad of celite and concentrated as a yellow oil. The crude material was re-dissolved in 2.00 mL of DMSO, filtered and purified via C₁₈ reverse phase HPLC to give the final product. LC-MS Retention Time: ti (Method 1) = 4.349 min; 1H NMR

(400 MHz, DMSO- g) δ ppm 11.36 (s, 1 H), 10.78 (s, 1 H), 8.58 - 8.64 (m, 1 H), 8.52 (d, J=8.2 Hz, 1 H), 7.93 (dd, J=7.6, 2.2 Hz, 1 H), 7.87 (dd, J=8.2, 2.7 Hz, 1 H), 7.81 (dd, J=7.8, 2.0 Hz, 1 H), 7.74 (d, J=7.4 Hz, 1 H), 7.53 - 7.62 (m, 2 H), 7.50 (ddd, J=8.6, 7.0, 2.0 Hz, 1 H), 7.24 - 7.32 (m, 1 H), 7.18 (d, J=8.2 Hz, 1 H), 7.06 (t, J=7.6 Hz, 1 H), 4.30 (q, J=7.0 Hz, 2 H), 1.28 (t, J=6.8 Hz, 3 H) (3 N-H protons didnffi show up); HRMS (ESI) m/z (M+H)⁺ calcd. for C23H23N4O3, 403.1765; found 403.1766.

[0574] This example illustrates a synthesis of 3-(4-(lH-Tetrazol-5-yl)phenyl)-2-(2- ethoxyphenyl)quinazolin-4(3H)-one (XJB12-010, NCGC00250134-01). The title compound was prepared as a by-product of synthesizing N-(3-(lH-tetrazol-5-yl)phenyl)-2-(2- ethoxybenzamido)benzamide (XJB12-006, NCGC00250114-01). LC-MS Retention Time: ti (Method 1) = 5.100 min; HRMS (ESI) m/z (M+H)⁺ calcd. for C23H19N6O2, 411.1564; found 411.1569.

EXAMPLE 199

[0575] This example demonstrates activation of the RXFPl receptor resulting in stimulation of cAMP production by several embodiments of the disclosure in the RXFPl cAMP assay in HE K293 -RXFPl cells

[0576] The RXFPl receptor couples to the Gs protein, and activation of the receptor results in stimulation of cAMP production. To screen for agonists of the receptor, RXFPl was stably expressed in human embryonic kidney cells (HE K293 -RXFPl), which have previously been show to constitute a functional cell-based model for RXFPl -cAMP signaling pathway.¹⁶'¹⁷ Cyclic AMP levels were detected using the HTRF cAMP assay kit.¹⁸ This assay uses a europium cryptate labeled anti-cAMP antibody (K-a-cAMP) and d2 dye labeled cAMP (cAMP-d2) as a tracer in a time-resolved fluorescence energy transfer (TR-FRET) detection system. The TR-FRET between the K-a-cAMP and cAMP-d2 is disrupted by cAMP in the cell lysates, thus allowing TR-FRET detection in a homogenous format that is suitable for HTS. The assay was carried out in the presence of a phosphodiesterase 4 (PDE4) inhibitor, Ro 20-1724, to amplify cAMP signal. The primary screen was carried out in 1536- well format, however, because of a more robust signal to background ratio, all subsequent follow-up experiments were carried out in 384-well format.

[0577] For the primary screen, HEK293-RXFP1 cells were seeded at 2,000 cells/well in 3 μίΛνεΙΙ media with a MultiDrop Combi dispenser (Thermo Scientific, Logan, UT), and allowed to attach overnight at 37 °C, 5% C0₂. Next, 1 uL/well of 400 μΜ Ro 20-1724 in PBS was added, followed by addition of 23 nL/well of compound solution in DMSO with a pintool transfer (Kalypsys, San Diego, CA). The cells were allowed to be stimulated with the compounds for 30 minutes at 37 °C, 5% C0₂, after which, 1 μΙ,ΛνεΙΙ of each HTRF detection reagent was dispensed with a BioRAPTR FRD dispenser. The detection reagents were diluted before addition as follows: K-a-cAMP antibody at 1 :20 and cAMP-d2 at 1 : 18 in HTRF lysis buffer (supplied by the assay kit). The plates were incubated for 30 minute at room temperature, and then the signal was read on a ViewLux plate reader (PerkinElmer, Waltham, MA).

[0578] The assay was run according to the following protocol:

[0579] The results are set forth in Tables 1-7, wherein AC₅₀ (μΜ) indicates the potency of the compound in micromolar, or more specifically the concentration at which the compound activates the functional activity of the receptor by its half-maximal amount. Max Response indicates what the maximal amount of functional activity induced by the compound is, as a percentage of the maximal receptor activation induced by high concentrations of forskolin.

inactive N/A

ı55

Table 2



160 RXFP1 Max

AC₅₀ (μΜ) Response

Table 4

RXFP1 Max # COR₃ ΑΟ₅₀(μΜ) Response

ı66 Table 5

RXFP1 Max AC₅₀ (μΜ) Response

121 f^_N^^\ 59.3 63%

H

122 inactive N/A

123 inactive N/A

2⁴ . ^v. N inactive N/A

125 inactive N/A

 Table 6

171

153 inactive N/A

154 inactive N/A

Table 7

RXFP1 Max

AC₅₀ (μΜ) Response

ı74 EXAMPLE 200

[0580] This example illustrates the activation of VEGF expression in THP1 cells by several embodiments of the disclosure.

[0581] THP1 cells (human acute monocytic leukemia cell line) were used to analyze the stimulation of VEGF gene expression after treatment with relaxin or compounds. The VEGF stimulation in these cultured endometrial cells is a well-established property of relaxin.¹⁹ This effect is most probably responsible for the observed angiogenic and neovascularization properties of relaxin in various settings.²⁰ 400,000 THP1 cells (0.4 mL at l x lO⁶ cells/mL) in test media (RPMI-1640 without phenol red, 0.5% FBS, lx Pen/Strep, 0.05 mM of 2- mercaptoethanol) were seeded in each well on a 24-well plate. After 24 hours incubation at 37 °C, 5% C0₂, relaxin or compounds were added for 2 hours. The cells were harvested and R A was extracted by the Trizol (Invitrogen, Carlsbad, CA) method according to manufacturers instructions. cDNA was synthesized by using Verso cDNA kit (Thermo Scientific, Waltham, MA) according to manufacturers protocol. Quantitative real time RT- PCR for VEGF and GAPDH gene expression was done using a Roche LightCycler 480 (Roche Diagnostics, Indianapolis, IN) with the appropriate set of primers and probes spanning different exons. The relative fold change in VEGF mRNA level was calculated by the comparative C_t (2^ϋΔΔ^α) method using GAPDH expression for normalization of RNA.

[0582] The results are set forth in Table 8 as relative VEGF gene expression relative to control.

Table 8

Compound Relative VEGF gene expression (control = 1.0)

Relaxin 2.5

158 1.2

177 1.3

179 1.5

180 1.6

99 1.9

174 2.3

178 2.8

159 1.4 [0583] As is apparent from the results set forth, all of the compounds with the possible exception of compound 158 exhibited a significant upregulation of VEGF expression.

Compound 178 exhibited a greater upregulation of VEGF expression than did relaxin.

EXAMPLE 201

[0584] It was previously shown that relaxin increases cell impedance in RXFP1 transfected cells. Cell-substrate impedance was measured using a Roche DP RTCA xCELLigence Analyzer (Roche Diagnostics, Indianapolis, IN) on E-Plates. Real Time Cell Analyzer (RTCA) allows for continuous time-resolved measurement of cellular index without additional labeling. Cell number, cellular adherence to the plate, and intracellular

interactions all contribute to the total cellular impedance. The effect of the compound treatment is only measured within the first hour, changes in cellular density are unlikely to contribute to the overall effect, and therefore cellular impedance is most likely caused by intercellular interactions, or signaling.

[0585] Cell Index (CI) was calculated by subtracting impedance at the beginning of experiment Zo from impedance at each individual time point Z_t, divided by 15Ω [CI_t=( Z₀- Zt)/15 Ω]. Delta Cellular Indices were calculated as the change of impedance at a given time t, from the time of compound addition (CI_comp0und)

Impedance at each time point was then normalized to the average of quadruplicate CI of cells treated with vehicle (VI, V2, V3, and V4), to calculate normalized delta Cell Index NACI= (CL- CIcompound)/Average[ACIvi, ΔΟν₂, ΔΟν₃, ΔΟν₄]. Maximal relaxin activity was assigned a value of 100% and all other values adjusted proportionally.

[0586] The cell line stably transfected with RXFP 1 receptor HEK293-RXFP 1 was used for cell impedance assay to confirm relaxin-like properties of the compounds. To equilibrate the plates, 100 μΕ of test media (DMEM, 1% FBS, 1 x Pen/Strep) was added to each well of E-Plate (Roche Diagnostics, Indianapolis, IN) and the plate was incubated at room

temperature for 30 minutes at which point baseline impedance was measures. Then 20,000 HEK293-RXFP1 cell or HEK293 cells (parental control cell line) were added per well in a volume of 100 test media and allowed to sediment at room temperature for 30 minutes. The plate was placed into xCELLigence RTCA DP Instrument in the C0₂ incubator overnight to allow the cells to attach. Relaxin (10 ng/mL), vehicle, or compounds at different concentrations (250, 500, and 750 nM) were added to the wells and the cellular impedance was measured every 10-30 seconds for 1 hour. The protocol was as follows:

[0587] The results are set forth in Figure 8.

EXAMPLE 202

[0588] This Example illustrates the cyclic AMP assay in THP-1 cells. THP-1 cells were propagated in RPMI-1640 supplemented with 20% FBS, 0.05 mM β-mercaptoethanol, 100

U/mL penicillin and 100 μg/mL streptomycin at 37 C in 5% C0₂. Before assaying for cAMP response, cells were serum starved in RPMI-1640 supplemented with 0.05 mM β- mercaptoethanol, 100 U/mL penicillin and 100 μg/mL streptomycin at 37 C in 5% C0₂ for

16 firs. For 384-well format assays, cells were seeded as 30,000 cells/well in 30 μΕΛνεΙΙ media with a MultiDrop Combi dispenser (Thermo Scientific, Waltham, MA). Subsequently,

2 μΕ/well of 1.6 mM Ro 20-1724 and 160 uM forskolin in PBS+ (DPBS, 1 mM CaCl₂, 0.5 mM MgCl₂, 0.05% BSA, 0.005% Tween 20) was dispensed using a BioRAPTR FRD dispenser (Beckman Coulter, Brea, CA). Immediately after, 0.25 μΕΛνεΙΙ of compound solutions in DMSO was dispensed with CyBi-well dispenser (CyBio, Jena, Germany). The cells were allowed to be stimulated with compounds for 30 min at 37 C in 5% C0₂, after which, 8 μίΛνεΙΙ of each HTRF cAMP HiRange kit (CisBio, Bedford, MA) detection reagent was dispensed with a BioRAPTR FRD dispenser. The detection reagents were diluted as such: K-a-cAMP antibody at 1 :20 and cAMP-d2 at 1 : 18 in HTRF lysis buffer (supplied by the assay kit). The plates were incubated for 30 min at room temperature before the signal was read on an Envision plate reader (PerkinElmer, Waltham, MA). The EC50 values for selected embodiments are set forth in Table 9.

Table 9

EXAMPLE 203

[0589] This example demonstrates the RXFP2 cAMP assay in HEK293 -RXFP2 cells. HEK293 cells stably transfected with RXFP2, the cognate receptor for another relaxin family peptide, insulin-like 3, (HEK293-RXFP2) was used to test compound specificity towards the RXFP1 receptor. For this assay, cells were seeded at 8,000 cells/well in 30 μΕ/well of media with a MultiDrop Combi dispenser (Thermo Scientific), and allowed to attach overnight at 37 °C, 5% C0₂. Next, 2 μΕ/well of 1.6 mM Ro 20-1724 solution in PBS+ (DPBS, 1 mM CaCl₂, 0.5 mM MgCl₂, 0.05% BSA, 0.005% Tween 20) were dispensed using a BioRAPTR FRD dispenser (Beckman Coulter, Brea, CA), followed addition of 0.25 μΕΛνεΙΙ of compound solution in DMSO with CyBi-well dispenser (CyBio, Jena, Germany). The cells were allowed to be stimulated with the compounds for 30 minutes at 37 °C, 5%> C0₂, after which, 8 μΕΛνεΙΙ of each HTRF detection reagent (diluted according to assay kit directions in HTRF lysis buffer) was dispensed with a BioRAPTR FRD dispenser. The plates were incubated for 30 minute at 37 °C, and then the signal was read on a ViewLux plate reader (PerkinElmer, Waltham, MA). The protocol was as follows: Sequence Parameter Value Description

1 Cells 30 μΐ. 8,000 cells/well

2 Time 16-24 h Incubate at 37 °C and 5% C0₂

3 Reagent 2 μΐ. 1600 μΜ Ro 20-1724 in PBS

4 Reagent 2.5 μΐ. Compounds in DMSO, forskolin as control

5 Time 30 min Incubate at 37 °C and 5% C0₂

6 Reagent 8 μΐ. cAMP-d2 diluted 1 : 18 in lysis buffer

7 Reagent 8 μΐ. K-a-cAMP diluted 1 :20 in lysis buffer

8 Time 30 min Room temperature incubation

EXAMPLE 204

[0590] This example demonstrates the Vlb cAMP assay in HEK293-Vlb cells. HEK293 stably trans fected with a nonrelated G protein coupled receptor, vasopressin receptor lb (HEK293-Vlb), were used as an additional counter screen to eliminate compounds that increase cAMP HTRF signal through non-RXFPl dependent mechanisms. For this assay, cells were seeded at 8,000 cells/well in 30 μΕΛνεΙΙ media with a MultiDrop Combi dispenser (Thermo Scientific, Logan, UT), and allowed to attach overnight at 37 °C, 5% C0₂. Next, 2 μΕ/well of 1.6 mM Ro 20-1724 solution in PBS+ (DPBS, 1 mM CaCl₂, 0.5 mM MgCl₂, 0.05% BSA, 0.005% Tween 20) was dispensed using a BioRAPTR FRD dispenser (Beckman Coulter, Brea, CA), followed by additional of 0.25 μΕΛνεΙΙ of compound solution in DMSO with CyBi-well dispenser (CyBio, Jena, Germany). The cells were allowed to be stimulated with the compounds for 30 minutes at 37 °C, 5% C0₂, after which, 8 μΕΛνεΙΙ of each HTRF detection reagent (diluted according to assay kit directions in HTRF lysis buffer) was dispensed with a BioRAPTR FRD dispenser. The plates were incubated for 30 minute at room temperature, and then the signal was read on a ViewLux plate reader (PerkinElmer,

Waltham, MA). The protocol was as follows:

Sequence Parameter Value Description

1 Cells 30 μΕ 8,000 cells/well

2 Time 16-24 h Incubate at 37 °C and 5% C0₂

3 Reagent 2 μΕ 1,600 μΜ Ro 20-1724 in PBS

4 Reagent 2.5 μΕ Compounds in DMSO, forskolin as control

5 Time 30 min Incubate at 37 °C and 5% C0₂

6 Reagent 8 μΕ cAMP-d2 diluted 1 : 18 in lysis buffer

7 Reagent 8 μΕ K-a-cAMP diluted 1 :20 in lysis buffer

8 Time 30 min Room temperature incubation

9 Detector TR-FRET EnVision plate reader EXAMPLE 205

[0591] This example demonstrates the ATP Cytotoxicity assay in HEK293-RXFP1 cells. This follow-up assay was conducted to measure the effect of compounds on cell viability by measuring ATP levels (ATPLite™). ATPLite™ is an Adenosine Triphosphate (ATP) monitoring system based on firefly (Photinus pyralis) luciferase. The level of ATP in a metabolically active cell is a general marker for its viability. ATP levels are often reduced during necrosis or apoptosis. In this assay, the luciferase enzyme catalyzes the conversion of the added substrate D-luciferin to oxyluciferin and light with ATP. Thus, the emitted light is proportional to the ATP concentration. To evaluate the cytotoxic properties of the compounds, HEK293-RXFP1 cells were incubated with compounds for 72 hours in growth media (DMEM 10% FBS, lx Pen/Strep, 0.5 mg/mL of G418) in 384-well format. After compound incubation, the levels of ATP in each well were measured with the addition of the ATPLite assay reagent. The protocol was as follows:

EXAMPLE 206

[0592] This example illustrates the activity of several embodiments of the disclosure in the RXFPl assay (Example 199), the RXFP2 assay (Example 203), the Vlb assay (Example 204), and the ATP toxicity (Example 202), as well as the PBS solubility and the mouse liver microsome (MLM) stability. The results are set forth in Table 10. Table 10

RXFP1 AC₅₀ RXFP2 AC₅₀ V1b AC₅₀ ATP Tox. EC₅₀ PBS Solubility MLM Stability

Entry Internal ID

(μΜ, Max. Resp.) (μΜ, Max. Resp.) (μΜ, Max. Resp.) (μΜ, Max. Resp.) (μΜ) (t,/₂ In mln.)

37 99 0.297 (95%) 9.40 (47%) inactive³ inactive³ 1.7 N/A

61 158 0.297 (99%) 3.34 (54%) inactive³ 3.74 (-31%) 2.9 N/A

62 159 0.188 (99%) inactive³ inactive³ 29.7 (-76%) 6.3 N/A

63 174 0.188 (99%) 7.47 (38%) inactive³ 18.8 (-73%) < 1.1 1732

65 177 0.067 (97%) inactive³ inactive³ 29.7 (-78%) 3.3 100

66

178

ML290 0.094 (98%) inactive³ inactive³ 9.4 (-85%) 7.0 122

67 179 0.052 (98%) inactive³ inactive³ 9.4 (-83%) 17.0 133

68 180 0.047 (98%) inactive³ inactive³ 59.3 (-53%) 5.3 178

Maximum response less than 30%.

EXAMPLE 207

[0593] Referring to Figure 9, 1-3ECL are extracellular loops of transmembrane domains of RXFPl . This example demonstrates the ability of compound to activate human but not mouse relaxin receptor transfected in HEK293 cells as measured by cAMP accumulation. The compound was inactive against related to RXFPl mouse relaxin family receptor 2, RXFP2. The chimeric mouse/human RXFPl receptors were activated by compounds only if they contained the region encoded by human exon 17 plus two humanized codons from exon 18. The 3 Eend of mouse and human exon 17 encodes the 3 ^rd ECL. There are 4 amino acid differences between human and mouse 3EXL. Two mouse site-specific mutants were tested, one where iso leucine 646 and leucine 647 were substituted by two valines specific for human sequence (M10), and the other one where aspartic acid (position 659) and serine (660) were substituted by glycine and threonine (Ml 1). Both did not respond to the compound stimulation.

[0594] Example 208 provides a method for synthesizing radiolabeled precusors.

n = 1-6 n = 1 -6

[0595] Example 209 provides a method for preparing tritium ³H labeled analogs of the Relaxin Receptor 1 modulators disclosed herein.

[0596] Example 210 provides a method for preparing fluorine-18 (¹⁸F) labeled analogs of the Relaxin Receptor 1 modulators disclosed herein.

EXAMPLE 211

[0597] Synthesiso of tert-Butyl (2-((3-((trifluoromethyl)thio)phenyl)carbamoyl) phenyl)carbamate. A mixture of 2-((fert-butoxycarbonyl)amino)benzoic acid (2.50 g, 10.5 mmol) and 3-((trifluoromethyl)thio)aniline (2.44 g, 12.6 mmol) in DMF (40.0 mL) was treated at room temperature with HATU (4.01 g, 10.5 mmol) and DIPEA (5.52 mL, 31.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was separated, dried and concentrated as a brown oil. The crude material was purified on silica gel with a gradient of 0-100% EtOAc in hexanes to give 3.20 g (yield 74%) of the title product as a white solid.

EXAMPLE 212

[0598] Synthesis of tert-Butyl (2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl) phenyl)carbamate. A solution of tert-butyl (2-((3-((trifluoromethyl)thio)phenyl)carbamoyl) phenyl)carbamate (400 mg, 0.970 mmol) in mixed solvents of DCM (2.00 mL), acetonitrile (2.00 mL) and water (4.00 mL) was treated at room temperature with sodium periodate (622 mg, 2.91 mmol). To this suspension was added RuCl₃ (0.2 mg, 0.970 μιηοΐ). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and re- disolved in water and DCM. The organic layer was separated, dried and concentrated to give a grey powder which was used directly in the next reaction without further purification.

EXAMPLE 213

[0599] Synthesis of 2-Amino-N-(3-((trifluoromethyl)sulfonyl)phenyl)benzamide. A solution of crude tert-butyl (2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl)phenyl) carbamate (0.430 g, 0.970 mmol) in DCM (10.0 mL) was treated with TFA (5.00 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified using ISCO on reverse phase column to give the desired product as a TFA salt.

EXAMPLE 214

[0600] Synthesis of Ethyl 2-(but-3-en-l-yloxy)benzoate. A solution of ethyl 2- hydroxybenzoate (0.442 mL, 3.01 mmol) and 4-bromobut-l-ene (1.22 g, 9.03 mmol) in DMF (30.0 mL) was treated at room temperature with K₂C0₃ (4.16 g, 30.1 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated to give a yellow oil which was used directly in the next reaction without further purification.

EXAMPLE 215

[0601] Synthesis of 2-(But-3-en-l-yloxy)benzoic acid. A solution of ethyl 2-(but-3-en-l- yloxy)benzoate (0.66 g, 3.01 mmol) in MeOH (15.0 mL) and water (15.0 mL) was treated at room temperature with LiOH (0.72 g, 30.1 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0 °C and acidified with 1 N HC1 until pH = 1. The reaction mixture was extracted with DCM and the organic layer was separated, dried and concentrated to give a colorless oil. The crude product was purified on silica gel with a gradient of 5-20% MeOH in DCM to give a colorless oil.

EXAMPLE 216

[0602] Synthesis of 2-(Allyloxy)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)carbamoyl )phenyl)benzamide. A solution of 2-amino-N-(3-((trifluoromethyl)sulfonyl)phenyl) benzamide, TFA salt (30.5 mg, 0.067 mmol) in DMF (2.00 mL) was treated at room temperature with 2-(allyloxy)benzoic acid (23.7 mg, 0.13 mmol), HATU (25.3 mg, 0.067 mmol) and DIPEA (0.058 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 days. The crude mixture was purified on ISCO under reverse phase column to give the title product as a grey solid.

EXAMPLE 217

[0603] Synthesis of 2-(But-3-en-l-yloxy)-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl) carbamoyl)phenyl)benzamide. A solution of 2-amino-N-(3-((trifluoromethyl)sulfonyl) phenyl)benzamide, TFA salt (10.0 mg, 0.022 mmol) in DMF (2.00 mL) was treated at room temperature with 2-(but-3-en-l-yloxy)benzoic acid (8.4 mg, 0.044 mmol), HATU (8.3 mg, 0.022 mmol) and DIPEA (0.019 mL, 0.109 mmol). The reaction mixture was stirred at room temperature for 2 days. The crude mixture was purified on ISCO under reverse phase column to give the title product as a grey solid. EXAMPLE 218

[0604] Synthesis of 2-Butoxy-N-(2-((3-((trifluoromethyl)sulfonyl)phenyl)

carbamoyl)phenyl)benzamide. A solution of 2-(but-3-en-l-yloxy)-N-(2-((3-((trifluoromethyl) sulfonyl)phenyl)carbamoyl)phenyl)benzamide (1.8 mg, 3.47 μηιοΐ) in a mixed solvents of THF (0.60 mL) and water (0.20 mL) was treated at 0 °C with ruthenium (III) chloride (1.0 mg, 4.8 μιηοΐ). NaBH₄ (2.0 mg, 15.2 μmol) was added slowly into the mixture. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered through a pad of celite and purified using reverse phase column to give the desired product as a white powder. In the scaled up reaction, ruthenium (III) chloride can be catalytic and NaBH₄ will be 2 equivalents.

EXAMPLE 219

[0605] Identification of a human RXFP1 region responsible for activation by compound 178 (Figure 11). Human RXFP1 (hRXFPl) is fully activated (100%) after treatment with relaxin or compound 178. Mouse RXFP1 (mRXFPl) does not respond to compound 178 (marked as 0%) at 66 μΜ. The RXFP1 contains the extracellular, 7 transmembrane, and intracellular (ICD) domains. Using chimeric mouse-human receptors (m/hRXFPl) the region responsible for RXFP1 activation by compound 178 was mapped to the part containing extracellular loop 3 (ECL3) of 7 transmembrane domain. Alignment of hRXFPl and mRXFPl shows two pairs of diverse amino acids within ECL3. The N- terminal IL to VV substitution in mRXFPl (mRXFPl-MlO) did not change mouse receptor response, whereas C-terminal GT to DS substitution in hRXFPl (hRXFPl -Ml 1) abolished its compound 178 dependent activation. The mRXFPl -Ml 1 mutant was partially active and the mouse receptor with humanized ECL3 (mRXFPl -M10/M1 1) was fully active after stimulation with compound 178. The cAMP response to compound 178 (66 μΜ) in cells transfected with a specific construct was normalized to the response of the same cells to relaxin (15nM). The results represent the average of 3 independent experiments ± s.e.m. repeated in quadruplicates. ** P<0.01 vs hRXFPl by Students t-test.

EXAMPLE 220

[0606] Pharmacokinetics of compound 178 (NCGC00250135). The pharmacokinectics of compound 178 (NCGC00250135) were determined in male C57/B16 mice after a single intravenous (IV) administration of 3 mg/kg and oral (PO) administration of 30 mg/kg of compound 178. The data is present in TABLE 11.

[0607] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0608] The use of the terms HCand HnCand IheCand similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms Bomprising, DtLaving, DShcluding, Cand

BontainingCare to be construed as open-ended terms (i.e., meaning [including, but not limited to, [J unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., Huch as provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0609] Embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is

encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S):

1. A compound of the formula

wherein A is 1 ,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or -CH₂CH₂-, wherein the 1 ,2-phenylenyl, 1,2-heteroarylenyl, and 1,2-heterocyclyl are optionally substituted with one or more substituents selected from halo, CF₃, alkyl, alkyloxy,haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and S0₂CF₃,

Ri is -NHCOR₃, R₄, -NHR₅, or -OR₆,

R₂ is alkyl, cycloalkyl, heteroarylalkyl, or phenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, trihalo C1-C10 alkyl, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, aryl, haloalkylaryl, heterocyclylalkyl, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂, -CN, and -S0₂CF₃,

R₃ is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, aryl, heteroaryl, arylalkyl, or phenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, Ci-Ciohaloalkyl, Ci- Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂,-CN, and -S0₂CF₃,

and R₇ is C1-C10 alkyl or C1-C10 haloalkyl,

with the provisos that:

(ii) when R₃ is phenyl, and A is 1 ,2-phenylenyl, then R₂ is not halophenyl, methoxyphenyl, 2,6-dimethylphenyl, or 2,4,6-trimethylphenyl; and (iii) when R₃ is phenyl substituted with alkyl, and A is 1 ,2-phenylenyl, then R₂ is not methoxyphenyl;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1, wherein R₂ is phenyl substituted with a substituent selected from the group consisting of -S0₂CF₃, -SCF₃, and -CF₃.

3. The compound or salt of claim 1 or 2, wherein A is 1 ,2-phenylene optionally substituted with one or more substituents independently selected from hydrogen, halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

4. The compound or salt of claim 3, wherein Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from the group consisting of -CF₃, Ci-Cio alkyl, Ci-Cio alkyloxy, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, alkyloxyalkyloxy,

dimethylaminoalkyloxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

5. The compound or salt of claim 3 or 4, wherein R₃ is

2-(Ci-Cio)alkyloxyphenyl.

6. The compound or salt of any one of claims 1-5, wherein R₂ is phenyl substituted with a substituent selected from -CF₃, Ci-Cio alkyl, Ci-Cio alkyloxy, , Ci- Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

7. The compound or salt of any one of claims 3-6, wherein the compound is selected from the group consisting of:

8. The compound or salt of claim 3, wherein Ri is R₄, wherein R₄ Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

9. The compound or salt of claim 3, wherein Ri is -NHR₅, wherein R5 is aryl optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl.

10. The compound or salt of claim 3, wherein Ri is -OR₅, wherein 5 is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl.

11. The compound or salt of claim 1 or 2, wherein A is 1 ,2-heteroarylenyl optionally substituted with one or more subsitutents independently selected from halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

13. The compound or salt of claim 11 or 12, wherein Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from -CF₃, C1-C10 alkyl, C1-C10 alkyloxy,Ci- C10 haloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

14. The compound or salt of any one of claims 11-13, wherein R₃ is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

15. The compound or salt of any one of claims 11-14, wherein the compound is selected from the group consisting of:

16. The compound or salt of claim 1 or 2, wherein A is -CH₂CH₂-

17. The compound or salt of claim 16, wherein Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from -CF₃ C1-C10 alkyl, C1-C10 alkyloxy, C1-C10 haloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

18. The compound or salt of claiml7, wherein R₃ is 2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkoxyphenyl.

19. The compound or salt of any one of claims 16-18, wherein the compound is:

20. A pharmaceutical composition comprising a compound or salt according to any of claims 1-19, and a pharmaceutically acceptable carrier.

21. A method for therapeutic intervention in a facet of mammalian health that is mediated by a mammalian relaxin receptor 1, the method comprising administering to a mammal in need thereof an effective amount of a compound of the formula (I):

wherein A is 1 ,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, and -CH₂CH₂-, wherein the 1 ,2-phenylenyl, 1,2-heteroarylenyl, or 1,2-heterocyclyl, each of which are optionally substituted with one or more substituents independently selected from halo, CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and S0₂CF₃,

Ri is selected from -NHCOR₃, R₄, -NHR₅, and -ORe,

R₂ is selected from alkyl, cycloalkyl, heteroarylalkyl, and phenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, C1-C10 haloalkyl, Ci-Ciohaloalkoxy, aryl, haloalkylaryl, heterocyclylalkyl, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂, -CN, and -S0₂CF₃,

R₃ is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl,

tricycloalkyl, aryl, heteroaryl, arylalkyl, and phenyl, which are optionally substituted with one or more substituents independently selected from halo, CF₃, C1-C10 alkyl, C₂-Cio alkenyl, C1-C10 alkyloxy, C1-C10 haloalkyl, Ci-Ciohaloalkoxy, - SR₇, -SOR₇, -S0₂R₇, -SCF₃, -N0₂,-CN, and -S0₂CF₃,

R₄ is phenyl optionally substituted with alkyloxy, haloalkoxy, arylalkyl, or

arylalkyloxy,

R₅ is selected from hydrogen, alkyl, alkylaryl, aryl, alkylcycloalkyl, and

cycloalkylalkyl which are optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl,

and R₇ is C1-C10 alkyl, C1-C10 haloalkyl, or haloalkoxy,

or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein R₂ is phenyl substituted with a substituent selected from -S0₂CF₃, -SCF₃, and -CF₃.

23. The method of claim 21 or 22, wherein A is 1 ,2-phenylene optionally substituted with one or more substituents independently selected from hydrogen, halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

24. The method of claim 23, wherein Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent independently selected from -CF₃, Ci-Cio alkyl, Ci-Cio alkyloxy, Ci-Ciohalo alkyl, Ci-Ciohaloalkoxy„ alkyloxyalkyloxy, dimethylammoalkyloxy, - SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

25. The method of claim 23 or 24, wherein R₃ is 2-(Ci-Cio)alkyloxyphenyl.

26. The method of any one of claims 21-25, wherein R₂ is phenyl substituted with a substituent selected from Ci-Cio alkyl, Ci-Cio alkyloxy, Ci-Cio haloalkyl, Ci- Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

27. The method of any one of claims 23-26, wherein the compound is selected from the group consisting of:

28. Themethod of claim 23, wherein Ri is R4, wherein R₄ is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

29. The method of claim 23, wherein Ri is -NHR₅, wherein R5 is aryl optionally substituted with one or more substituents independently selected from alkyloxy and trifluoromethyl.

30. The method of claim 23, wherein Ri is -OR₆, wherein R^ is alkyl optionally substituted with alkylamino, dialkylamino, alkyloxy, and heteroaryl

31. The method of claim 21 or 22, wherein A is 1 ,2-heteroarylenyl optionally substituted with one or more subsitutents independently selected from halo, -CF₃, alkyl, alkyloxy, haloalkyl, haloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

33. The method of claim 31 or 32, wherein Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from -CF₃, C1-C10 alkyl, C1-C10 alkyloxy, trihalo C1-C10 alkyl, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

34. The method of any one of claims 31-33, wherein R3 is

2-(Ci-Cio)alkyloxyphenyl or 2-(Ci-Cio)haloalkyloxyphenyl.

35. The method of any one of claims 31-34, wherein the compound is selected from the group consisting of:

36. The method of claim 1 or 2, wherein A is -CH₂CH₂-

37. The method of claim 36, wherein Ri is -NHCOR₃, wherein R₃ is phenyl substituted with a substituent selected from -CF₃, C1-C10 alkyl, C1-C10 alkyloxy, Ci- Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, -S0₂R₇, -SCF₃, and -S0₂CF₃.

38. The method of claim 37, wherein R₃ is 2-(Ci-Cio)alkyloxyphenyl or

2-(C 1 -C 1 o)haloalkyloxyphenyl.

39. The method of any one of claims 36-38, wherein the compound is:

40. The method of any one of claims 21-39, wherein the facet of mammalian health is cardiovascular disease.

41. The method of claim 40, wherein the cardiovascular disease is selected from myocardial ischemia-reperfusion injury, cardiac fibrosis, acute congestive heart failure, cerebrovascular disease and stroke, post-infarction heart, cardiac anaphylaxis, cerebral ischemia (stroke), intestinal ischemia-reperfusion injury, systemic and pulmonary

hypertension, vascular inflammation, hypertension, high blood pressure; left ventricular hypertrophy (LVH); vasodilation; renal hypertension; diuresis; nephritis; natriuresis;

scleroderma renal crisis; angina pectoris (stable and unstable); myocardial infarction; heart attack; coronary artery disease; coronary heart disease; cardiac arrhythmias; atrial fibrillation; portal hypertension; raised intraocular pressure; vascular restenosis; chronic hypertension; valvular disease; myocardial ischemia; acute pulmonary edema; acute coronary syndrome; hypertensive retinopathy; hypertensive pregnancy sickness; Raynaud's phenomenon; erectile dysfunction, glaucoma, and preeclampsia.

42. The method of any one of claims 21-39, wherein the facet of mammalian health is dyspnea associated with acute heart failure in a mammal, wherein the mammal has dyspnea associated with acute heart failure and is in a hypertensive or normotensive state at the onset of said administering.

43. The method of any one of claims 21-39, wherein the facet of mammalian health is acute decompensated heart failure, wherein the method is effective to reduce in- hospital worsening of said acute decompensated heart failure in the mammal.

44. The method of claim 43, wherein said in-hospital worsening of said acute decompensated heart failure comprises one or more of worsening dyspnea, need for additional therapy to treat said heart failure, need for mechanical support of breathing, and need for mechanical support of blood pressure.

45. The method of claim 43, further comprising a reduction in the risk of death or rehospitalization of the mammal.

46 The method of any one of claims 21-39, wherein the facet of mammalian health is fibrotic disease.

47. The method of claim 46, wherein the fibrotic disease is selected from pulmonary fibrosis, renal tubulo interstitial fibrosis, mesangial proliferative nephritis, hepatic fibrosis (cirrhosis) alcohol and non-alcohol related (including viral infection such as HAV, HBV and HCV); fibromatosis; granulomatous lung disease; glomerulonephritis, myocardial scarring following infarction; endometrial fibrosis and endometriosis, polycystic kidney disease, scleroderma and systemic sclerosis, keloids, arthritis, autoimmune disorder, inflammatory condition associated with infection, skeletal muscle injuries, conditions involving tissue remodeling following inflammation or ischemia-reperfusion injury and is selected from the group consisting of endomyocardial and cardiac fibrosis; mediastinal fibrosis; retroperitoneal fibrosis; fibrosis of the spleen; fibrosis of the pancreas; wound healing whether by injury or surgical procedures, diabetes related wound fibrosis.

48. The method of any one of claims 21-39, wherein the facet of mammalian health is respiratory disease selected from asthma, bronchial disease, lung diseases, chronic obstructive pulmonary disease (COPD), Acute Respiratory Distress Syndrome (ARDS), severe acute respiratory syndrome (SARS), Fibrosis related Asthma, and cystic fibrosis.

49. The method of any one of claims 21-39, wherein the facet of mammalian health is skin disease selected from dermal repair, wound healing; burns, erythemas, lesions, wound healing following surgical procedures; skin or tissue lesions including lesions induced by Psoriasis, Lupus and Kaposhi Sarcoma; Scleroderma, and collagenous diseases of the skin and skin tumors.

50. The method of any one of claims 21-39, wherein the facet of mammalian health is female reproduction.

51. The method of claim 50, wherein the facet of female reproduction is selected from in vitro fertilization, abnormal implantation, pre-term birth and induction of labor, mammary functions and lactation disorders;, plasma osmolarity during pregnancy, uterine fibroids, abnormal endometrial angiogenesis; placental development defects; cervical ripening (softening); nipple development and disfunction; pregnancy related remodeling of the uterine tissue; endometriosis; preeclampsia; estrogenic and non-estrogenic related hormonal disorders; pre-term labor; post term labor; and labor complications.

52. The method of any one of claims 21-39, wherein the facet of mammalian health is male reproduction.

53. The method of claim 52, wherein the facet of male reproduction is selected from sperm function and fertilization.

54. The method of any one of claims 21-39, wherein the facet of mammalian health is surgical transplantation of a liver.

55. The method of any one of claims 21-39, wherein the facet of mammalian health is a cancer selected from colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, pancreatic cancer, ovarian cancer, kidney cancer, testicular cancer, bone cancer, osteosarcoma, liver cancer, melanoma, glioma, sarcoma, leukemia, or lymphoma, and wherein the cancer is invasive or metastatic.

56. The method of any one of claims 21-39, wherein the facet of mammalian health is enhancement of drug delivery in the treatment of a solid cancer, in combination with a chemotherapeutic treatment or radiation treatment of the cancer.

57. The method of any one of claims 21-39, wherein the facet of mammalian health is orthodontic tooth movement.

58. The method of any one of claims 21-39, wherein the facet of mammalian health is bone joint disease.

59. The method of any one of claims 21-39, wherein the facet of mammalian health is selected from osteoporosis; osteoarthritis; osteopetrosis; bone inconsistency;

osteosarcoma; and cancer metastasis to the bone.

60. The method of any one of claims 21-39, wherein the facet of mammalian health is diabetes mellitus.

61. The method of any one of claims 21-39, wherein the facet of mammalian health is ischemia-reperfusion injury associated with ischemic and post-ischemic events in organs and tissues and in a group of patients with thrombotic stroke; myocardial infarction; angina pectoris; embolic vascular occlusions; peripheral vascular insufficiency; splanchnic artery occlusion; arterial occlusion by thrombi or embolisms, arterial occlusion by non- occlusive processes such as following low mesenteric flow or sepsis; mesenteric arterial occlusion; mesenteric vein occlusion; ischemia-reperfusion injury to the mesenteric microcirculation; ischemic acute renal failure; ischemia-reperfusion injury to the cerebral tissue; intestinal intussusception; hemodynamic shock; tissue dysfunction; organ failure; restenosis; atherosclerosis; thrombosis; platelet aggregation, ischemia-reperfusion injury following cardiac surgery; organ surgery; organ transplantation; angiography;

cardiopulmonary and cerebral resuscitation.

62. The method of any one of claims 21-39, wherein the facet of mammalian health is an inflammatory condition associated with an infection, wherein the infection is selected from a viral infection caused by human immunodeficiency virus I (HIV-1) or HIV-2, acquired immune deficiency (AIDS), West Nile encephalitis virus, coronavirus, rhinovirus, influenza virus, dengue virus, HCV, HBV, HAV, hemorrhagic fever; an otological infection; severe acute respiratory syndrome (SARS), sepsis and sinusitis.

63. The method of any one of claims 21-39, wherein the facet of mammalian health is kidney diseases selected from diabetic nephropathy; glomerulosclerosis;

nephropathies; renal impairment; scleroderma renal crisis and chronic renal failure.

64. The method of any one of claims 21-39, wherein the facet of mammalian health is an angiogenesis related condition selected from retinal angiogenesis in a number of human ocular diseases such as diabetes mellitus, retinopathy of prematury, and age-related macular degeneration, or cancer associated angiogenesis in primary or metastatic cancer, including but not limited to cancer of the prostate, brain, breast, colorectal, lung, ovarian, pancreatic, renal, cervical, melanoma, soft tissue sarcomas, lymphomas, head-and-neck, and glioblastomas.

65. The method of any one of claims 21-39, wherein the facet of mammalian health is an inflammatory disorder selected from of gastritis, gout, gouty arthritis, arthritis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ulcers, chronic bronchitis, asthma, allergy, acute lung injury, pulmonary inflammation, airway hyper-responsiveness, vasculitis, septic shock and inflammatory skin disorders, including but not limited to psoriasis, atopic dermatitis, eczema.

66. The method of any one of claims 21-39, wherein the facet of mammalian health is an autoimmune disorder is selected from f multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, transplant rejection, immune disorders associated with graft transplantation rejection, benign

lymphocytic angiitis, lupus erythematosus, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, insulin dependent diabetes mellitis, Good pasture's syndrome, myasthenia gravis, pemphigus, sympathetic ophthalmia, autoimmune uveitis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulceratis colitis, Sjogren's syndrome, rheumatic disease, polymyositis, scleroderma, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, collagen diseases, chronic polyarthritis, psoriasis arthropathica, ankylosing spondylitis, juvenile rheumatoid arthritis, periarthritis humeroscapularis, panarteriitis nodosa, progressive systemic scleroderma, arthritis uratica, dermatomyositis, muscular rheumatism, myositis, myogelosis, and chondrocalcinosis.

67. The method of any one of claims 21-39, wherein the facet of mammalian health is an behavioral abnormality or disease.

68. The method of any one of claims 21-67, wherein the facet of mammalian health is a facet of human health.

69. The method of any one of claims 21-68, wherein the mammalian relaxin receptor 1 is a human relaxin receptor 1.

70. The method of any one of claims 21-69, wherein the mammal is a human.

71. A com ound or pharmaceutically acceptable salt thereof, having the formula

where

is a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, each of which A ring is optionally fused to a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, to form a bicylic ring system; and the A ring and 3 - to 8--membered carbocyclic or heterocyclic ring to which A is optionally fused are each substituted with R₁₀; m, n, o, and p are integers independently chosen from 0, 1, and 2 and each

W ⁿ , W ⁰ , and W P , is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, Ci-C₂alkyl, and Ci-C₂alkoxy;

X and Y are independently chosen from O and S;

Rs and R9 are independently chosen from hydrogen and Ci-C₄alkyl;

R₂₀ is NO2, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Ciocarbyhdryl or Ci-Ciohaloalkyl;

A compound or salt of Claim 71, wherein

is a group of formula

each of which is substituted with R 10·

73. A compound or salt of Claim 71 or 72, wherein m, n, o, and p are all 0 and X and Y are both O. 4. A compound or salt thereof of Claim 71 , having the formula

R20 is NO2, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Cioalkyl or Ci-Ciohaloalkyl;

R30 is hydrogen or R₃₀ is Ci-Csalkoxy or Ci-Csalkylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci- C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

75. A compound or salt of Claim 74, wherein R₂o is Ci-Cehaloalkyl, -S(Ci- C₆haloalkyl), or -S0₂(Ci-C₆haloalkyl).

76. A compound or salt therof of Claim 74, wherein Rio, R21, and R31 are each 0 substituents.

77. A compound or salt thereof of claim 74, wherein Rio, R21, and R₃i are each 0 substituents; R20 is CF₃, SCF₃, or S02CF_3i and R₃o is C2-C₆alkoxy or C2-C₆alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and -CF₃.

A compound or salt thereof of any one of Claims 74 to 77, wherein R20 A compound or pharmaceutically acceptable salt thereof, having the formula

Rio and R31 are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy; and

R₂ is (phenyl)Co-C₂alkyl- or (5- or 6-membered heteroaryl)Co-C₂alkyl, each of which is substituted with 0 or 1 or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-Cealkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C3-C₇Cycloalkyl)Co-C₂alkyl, 5- and 6-membered heterocycloalkyl, thienyl, phenyl, phenyl substituted with CF₃, mono- and di-Ci-Cealkylamino, Ci-Cealkylthio, Ci-Cealkylsulfonyl Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy, -SR₇, -SOR₇, and -SO₂R₇, where R₇ is Ci-Ciocarbhydryl or Ci-Ciohaloalkyl; or

R₂ is dihydroindenyl, benzo[<i][l,3]dioxolyl, or indolyl, each of which is substituted with 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- or di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci- C₂haloalkoxy.

80. A compound or salt thereof of Claim 79, wherein Rio and R31 are both 0 substituents.

81. A compound or salt thereof of Claim 79 or 80, wherein

R₂ is phenyl substituted with one or two substituents independently chosen from hydroxyl, halogen, nitro, SCF₃, SC>₂CF₃, Ci-Cealkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 5- and 6- membered heterocycloalkyl, thienyl, phenyl, phenyl substituted with CF₃, mono- and di-Ci- Cealkylamino, Ci-Cealkylthio, Ci-Cealkylsulfonyl Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci- C₂haloalkoxy.

82. A compound or salt thereof of Claim 79 or 80, wherein R₂ is phenyl substituted in the meta position with CF₃, SCF₃, or S0₂CF₃.

83. A compound or salt thereof of Claim 79 or 80, wherein

84. A compound or pharmaceutically acceptable salt thereof, having the formula

Rio and R₂i are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₃ is cyclohexyl; or

R₃ is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, S0₂CF₃, Ci-Cealkyl, C₂-C₆alkenyl, C₂- C6alkynyl, phenyl mono- and di-Ci-Cealkylamino, Ci-C6alkylthio, Ci-C6alkylsulfonyl Ci- C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

85. A compound or salt of Claim 84, wherein R₁₀ and R₂i are both 0 substituents and R₃ is phenyl substituted with one meta-position substituent.

86. A compound or salt of Claim 84 or 85, wherein Rio and R₂i are both 0 substituents and R₂o is CF₃, SCF₃, or S0₂CF₃.

87. A compound or salt of Claim 84, wherein R₂o is CF₃; and R₃ is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SO₂CF₃, Ci-Cealkyl, C₂-C₆alkenyl, C₂- C₆alkynyl, phenyl mono- and di-Ci-Cealkylamino, Ci-C₆alkylthio, Ci-Cealkylsulfonyl Ci- C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

88. A compound or salt of Claim 84, wherein R₂o is SO₂CF₃; and

R3 is phenyl substituted with one or more substituents independently chosen from hydroxyl, halogen, nitro, cyano, amino, SCF₃, SO₂CF₃, Ci-Cealkyl, C₂-Cealkenyl, C₂- Cealkynyl, phenyl mono- and di-Ci-Cealkylamino, Ci-Cealkylthio, Ci-Cealkylsulfonyl Ci- C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy. 9. A compound or salt thereof of Claim 71, wherein

is a group of formula

each of which is substituted with R₁₀.

90. A compound or salt of Claim 89, wherein R₁₀, R₂₁, and R31 are each 0 substituents.

91. A compound or salt of Claim 89 or 90, wherein each of m, n, o, and p are 0 and X and Y are both O.

92. A compound or salt of any one of Claims 89 to 91, wherein

R₂₀ is NO₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Cioalkyl or Ci-Ciohaloalkyl; and R30 is hydrogen or R₃₀ is Ci-Csalkoxy or Ci-Csalkylthio- each or which is substituted with 0 to 3 substituents independently chosen from hydroxyl, halogen, nitro, cyano, Ci- C₄alkyl, Ci-C₄alkoxy, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy.

93. A compound or salt of Claim 92, wherein R₂o is Ci-Cehaloalkyl, -S(Ci- C₆haloalkyl), or -S0₂(Ci-C₆haloalkyl).

94. A compound or salt thereof of Claim 93, wherein R₁₀, R₂₁, and R31 are each 0 substituents; R₂₀ is CF₃, SCF₃, or S0₂CF_3i and R₃o is C₂-C₆alkoxy or C₂-C₆alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and -CF₃.

95. A compound or salt thereof of any one of Claims 89 to 94, wherein R₂₀ is S0₂CF₃.

96. A compound or pharmaceutically acceptable salt thereof, having the formula

m

, n, o, and p are integers independently chosen from 0, 1, and 2 and each of n , ⁰ , and P , is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, Ci-C₂alkyl, and Ci-C₂alkoxy;

X and Y are independently chosen from O and S;

Rs and R9 are independently chosen from hydrogen and Ci-C₄alkyl; Rio, R21 , and R31 are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R20 is N0₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Ciocarbyhdryl or Ci-Ciohaloalkyl;

97. A compound or salt of Claim 96, wherein m, n, o, and p are all 0 and X and Y are both O.

98. A compound or salt thereof of Claim 97, having the formula

99. A compound or salt thereof of Claim 97, having the formula

Rio, R₂₁, and R31 are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy;

R₂₀ is NO₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Cioalkyl or Ci-Ciohaloalkyl;

100. A compound or salt of Claim 98 or 99, wherein R₂o is Ci-Cehaloalkyl, -S(Ci- C₆haloalkyl), or -S0₂(Ci-C₆haloalkyl).

101. A compound or salt therof of any one of Claims 98 to 100, wherein R₂₁, and R31 are both 0 substituents.

102. A compound or salt thereof of any one of Claims 98 to 100, wherein R₂₁ and R₃i are both 0 substituents; R₂₀ is CF₃, SCF₃, or S0₂CF_3i and R₃o is C₂-C₆alkoxy or C₂- C₆alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and -CF₃.

103. A compound or salt thereof of any one of Claims 98 to 102, wherein R₂₀ is S0₂CF₃..

A compound or pharmaceutically acceptable salt thereof, having the formula

membered carbocyclic ring and a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, each of which A ring is optionally fused to a 3- to 8-membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, to form a bicylic ring system; the A ring and 3 - to 8--membered carbocyclic or heterocyclic ring to which A is optionally fused are each substituted with R₁₀;

the B ring and 3 - to 8— membered carbocyclic or heterocyclic ring to which B is optionally fused are each substituted with R₃i;

the C ring and 3 - to 8— membered carbocyclic or heterocyclic ring to which C is optionally fused are each substituted with R₂i; m, n, o, and p are integers independently chosen from 0, 1, and 2 and each of

, n , ⁰ , and P , is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, Ci-C₂alkyl, and Ci-C₂alkoxy;

X and Y are independently chosen from O and S;

Rs and R9 are independently chosen from hydrogen and Ci-C₄alkyl;

Rio, R₂₁, and R₃i are each 0 to 3 substitutents independently chosen from hydroxyl, halogen, nitro, cyano, amino, Ci-C₄alkyl, Ci-C₄alkoxy, mono- and di-(Ci-C₂alkyl)amino-, Ci-C₂haloalkyl, and Ci-C₂haloalkoxy; R₂₀ is NO₂, CN, Ci-Ciohaloalkyl, Ci-Ciohaloalkoxy, -SR₇, -SOR₇, or -S0₂R₇, where R₇ is Ci-Ciocarbyhdryl or Ci-Ciohaloalkyl;

105. A compound or salt of Claim 104, wherein

where

each independently chosen from phenyl and a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, each of which A ring is optionally fused to a 5 - to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, to form a bicylic ring system;

the A ring and 5 - to 6--membered carbocyclic or heterocyclic ring to which A is optionally fused are each substituted with Ri₀;

the B ring and 5 - to 6— membered carbocyclic or heterocyclic ring to which B is optionally fused are each substituted with R₃₁; and

the C ring and 5 - to 6— membered carbocyclic or heterocyclic ring to which C is optionally fused are each substituted with R₂i .

is substituted with R₁₀.

107. A compound or salt of any one of Claims 104 to 106, wherein m, n, o, and p are all 0, X and Y are both O; and Rs and Rgare both hydrogen. compound or salt of any one of Claims 104 to 107, wherein

is cyclohexyl, pyridyl, or phenyl, each of which is substituted with R₃₀ and optionally substituted with R₃i. pound or salt of any one of Claims 104 to 108 wherein

is a pyridyl, phenyl, or indolyl, each of which is substituted with R₂o and optionally substituted with R₂i.

110. A compound or salt of any one of Claims 104 to 109, wherein R₂o is Ci- Cehaloalkyl, -S(Ci-C₆haloalkyl), or -S0₂(Ci-C₆haloalkyl).

111. A compound or salt therof of Claim 110 wherein Rio, R₂₁, and R₃i are each 0 substituents.

112. A compound or salt thereof of any one of Claims 104 to 110, wherein Rio, R₂i, and R₃i are each 0 substituents; R₂o is CF₃, SCF₃, or S0₂CF_3i and R₃o is C₂-C6alkoxy or C₂- C₆alkylthio-, each of which is substituted with 0 to 2 substituents independently chosen from halogen and -CF₃.

113. A mpound or salt of Claim 71 , wherein

wherein

is phenyl or a 5-to 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, each of which A ring is optionally fused to a 5- to 6-membered carbocyclic ring or a 5-to 6—membered heterocyclic ring containing 1 to 3 heteroatoms independently chosen from N, O, and S, to form a bicylic ring system; and the A ring and 5- to 6-membered carbocyclic or heterocyclic ring to which A is optionally fused are each substituted with R₁₀.