GLS1 inhibitors for treating disease

The present disclosure relates to new heterocyclic compounds and compositions, and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of GLS1 activity in a human or animal subject are also provided for the treatment of diseases such as cancer.

Metabolic deregulation is a hallmark of cancer as tumors exhibit an increased demand for nutrients and macromolecules to fuel their rapid proliferation. Glutamine (Gln), the most abundant amino acid in circulation, plays an essential role in providing cancer cells with biosynthetic intermediates required to support proliferation and survival. Specifically, glutaminolysis, or the enzymatic conversion of glutamine to glutamate, provides proliferating cancer cells with a source of nitrogen for amino acid and nucleotide synthesis, and a carbon skeleton to fuel ATP and NADPH synthesis through the TCA cycle. In addition to supporting cell growth, glutamine metabolism plays a critical role in maintaining cellular redox homeostasis as glutamate can be converted into glutathione, the major intracellular antioxidant.

Glutaminolysis is regulated by mitochondrial glutaminase (GLS), the rate limiting enzyme that catalyzes the conversion of Gln to glutamate and ammonia. Mammalian cells contain 2 genes that encode glutaminase: the kidney-type (GLS1) and liver-type (GLS2) enzymes. Each has been detected in multiple tissue types, with GLS1 being widely distributed throughout the body. GLS1 is a phosphate-activated enzyme that exists in humans as two major splice variants, a long form (referred to as KGA) and a short form (GAC), which differ only in their C-terminal sequences. Both forms of GLS1 are thought to bind to the inner membrane of the mitochondrion in mammalian cells, although at least one report suggests that glutaminase may exist in the intramembrane space, dissociated from the membrane. GLS is frequently overexpressed in human tumors and has been shown to be positively regulated by oncogenes such as Myc. Consistent with the observed dependence of cancer cell lines on glutamine metabolism, pharmacological inhibition of GLS offers the potential to target Gln addicted tumors.

Thus, there is a need for glutaminase inhibitors that are specific and capable of being formulated for in vivo use.

SUMMARY

Accordingly, the inventors herein disclose new compositions and methods for inhibiting glutaminase activity.

Provided is a compound of structural Formula I

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or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^Xand R^Yis independently chosen from alkyl, cyano, H, and halo, or two R^Xgroups together with the atoms to which they are attached optionally form a cycloalkyl ring; A¹is chosen from C and N; A², A³, and A⁴are independently chosen from N, O, S, and CH, wherein at least one of A¹, A², A³, and A⁴is chosen from N, O, and S; R¹and R²are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹and R²each may be optionally substituted with one to three R^Zgroups, wherein R¹and R²together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; R³is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂, C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂, C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³may be optionally substituted with one to three R^Zgroups; each R⁴is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R⁴may be optionally substituted with one to three R^Zgroups, wherein two R⁴groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; each R^Zgroup is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂, NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂, S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; each R⁵is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R⁵groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Xgroups; and Z is a monocyclic heteroaryl, which may be optionally substituted.

Provided is a composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

Provided is a method of inhibiting GLS1 activity in a biological sample comprising contacting the biological sample with a compound of Formula I.

Provided is a method of treating a GLS1-mediated disorder in a subject in need thereof, comprising the step of administering to the subject a compound of Formula I.

Provided is a method of treating a GLS1-mediated disorder in a subject in need thereof, comprising the sequential or co-administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

Provided is a compound of any of Formula I for use in human therapy.

Provided is a compound of any of Formula I for use in treating a GLS1-mediated disease.

Provided is a use of a compound of Formula I for the manufacture of a medicament to treat a GLS1-mediated disease.

DETAILED DESCRIPTION
Abbreviations and Definitions

To facilitate understanding of the disclosure, a number of terms and abbreviations as used herein are defined below as follows:

When introducing elements of the present disclosure or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The term “and/or” when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression “A and/or B” is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression “A, B and/or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.

When ranges of values are disclosed, and the notation “from n₁. . . to n₂” or “between n₁. . . and n₂” is used, where n₁and n₂are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 μM (micromolar),” which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numerical values that it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

The term “acyl,” as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An “acetyl” group refers to a —C(O)CH₃group. An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl will comprise from 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(—CH═CH—),(—C::C—)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

The term “alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (—CH₂—). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers to an alkyl thioether (R—S—) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, the alkynyl comprises from 2 to 4 carbon atoms. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (—C:::C—, —C—C—). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.

The terms “amido” and “carbamoyl” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term “C-amido” as used herein, alone or in combination, refers to a —C(O)N(RR′) group with R and R′ as defined herein or as defined by the specifically enumerated “R” groups designated. The term “N-amido” as used herein, alone or in combination, refers to a RC(O)N(R′)— group, with R and R′ as defined herein or as defined by the specifically enumerated “R” groups designated. The term “acylamino” as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an “acylamino” group is acetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to —NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R′ may combine to form heterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term “aryl” embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent radical C₆H₄=derived from benzene. Examples include benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers to an ester of carbamic acid (—NHCOO—) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers to a —OC(O)NRR′, group—with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers to a ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H] and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt. An “O-carboxy” group refers to a RC(O)O— group, where R is as defined herein. A “C-carboxy” group refers to a —C(O)OR groups where R is as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to —CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, the cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (—CFH—), difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N. In certain embodiments, the heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each the heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur In certain embodiments, the heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, the heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to —OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

The term “imino,” as used herein, alone or in combination, refers to ═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refers to ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

The term “lower,” as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.

The term “lower heteroaryl,” as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four the members may be heteroatoms selected from the group consisting of O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refers to NRR′, wherein R and R′ are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R′ of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers to an RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to —NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer the —SO₃H group and its anion as the sulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to —S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to —S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to —S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ as defined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′ as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination, refer to a —S— group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an —SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl —C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′ as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ as defined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group with X is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X is a halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that the group is absent.

The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”

The term R or the term R′, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R′ groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R′ and Rn where n=(1, 2, 3, . . . n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as —C(O)N(R)— may be attached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this disclosure. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

GLS1 inhibitor is used herein to refer to a compound that exhibits an IC50 with respect to GLS1 activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the GLS1 enzyme assay described generally herein below. IC50 is that concentration of inhibitor that reduces the activity of an enzyme (e.g., GLS1) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against GLS1. In certain embodiments, compounds will exhibit an IC50 with respect to GLS1 of no more than about 10 μM; in further embodiments, compounds will exhibit an IC50 with respect to GLS1 of no more than about 5 μM; in yet further embodiments, compounds will exhibit an IC50 with respect to GLS1 of not more than about 1 μM; in yet further embodiments, compounds will exhibit an IC50 with respect to GLS1 of not more than about 200 nM, as measured in the GLS1 binding assay described herein.

The phrase “therapeutically effective” is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

The term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.

The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock (farm animals) such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

The compounds disclosed herein can exist as therapeutically acceptable salts. The present disclosure includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N′-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

Compounds

The present disclosure provides a compound of structural Formula I

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or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^Xand R′ is independently chosen from alkyl, cyano, H, and halo, or two R^Xgroups together with the atoms to which they are attached optionally form a cycloalkyl ring; A¹is chosen from C and N; A², A³, and A⁴are independently chosen from N, O, S, and CH, wherein at least one of A¹, A², A³, and A⁴is chosen from N, O, and S; R¹and R²are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹and R²each may be optionally substituted with one to three R^Zgroups, wherein R¹and R²together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; R³is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂, C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂, C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³may be optionally substituted with one to three R^Zgroups; each R⁴is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R⁴may be optionally substituted with one to three R^Zgroups, wherein two R⁴groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; each R^Zgroup is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂, NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂, S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; each R⁵is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R⁵groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Xgroups; and Z is a monocyclic heteroaryl, which may be optionally substituted.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has Formula II

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or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^Xand R^Yis independently chosen from alkyl, cyano, H, and halo, or two R^Xgroups together with the atoms to which they are attached optionally form a cycloalkyl ring; A¹and Z¹are independently chosen from C and N; A², A³, A⁴, Z², Z³, and Z⁴are independently chosen from N, O, S, and CH, wherein at least one of A¹, A², A³, and A⁴and at least one of Z¹, Z², Z³, and Z⁴is chosen from N, O, and S; R¹and R²are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹and R²each may be optionally substituted with one to three R^Zgroups, wherein R¹and R²together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; R³is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂, C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂, C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³may be optionally substituted with one to three R^Zgroups; each R⁴is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R⁴may be optionally substituted with one to three R^Zgroups, wherein two R⁴groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; each R^Zgroup is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂, NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂, S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; each R⁵is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R⁵groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Xgroups.

In certain embodiments A¹, A², and A³are N; and A⁴is CH.

In certain embodiments A¹is C; A²and A³are N; and A⁴is S.

In certain embodiments Z¹, Z², and Z³are N; Z⁴is CH; and R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)R⁴, and NR⁴C(O)N(R⁴)₂.

In certain embodiments Z¹, Z², and Z³are N; Z⁴is CH; and R³is chosen from C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, C(O)OR⁴.

In certain embodiments Z¹is C; Z²and Z³are N; Z⁴is S; and R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂.

In certain embodiments n is 4.

In certain embodiments each R^Xand R^Yis independently chosen from H and fluoro.

In certain embodiments one of R^Xis independently fluoro.

In certain embodiments A¹, A², and A³are N; A⁴is CH; n is 4; Z¹is C; Z²and Z³are N; Z⁴is S; and R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂.

In certain embodiments A¹is C; A²and A³are N; A⁴is S; n is 4; Z¹, Z², and Z³are N; Z⁴is CH; and R³is chosen from C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, C(O)OR⁴.

In certain embodiments A¹, A², and A³are N; A⁴is CH; n is 4; Z¹, Z², and Z³are N; Z⁴is CH; and R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has structural Formula III:

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or a salt thereof, wherein: n is chosen from 3, 4, and 5; each R^Xand R^Yis independently chosen from alkyl, cyano, H, and halo, or two R^Xgroups together with the atoms to which they are attached optionally form a cycloalkyl ring; A¹is chosen from C and N; A², A³, and A⁴, are independently chosen from N, O, S, and CH, wherein at least one of A¹, A², A³, and A⁴is chosen from N, O, and S; Z¹is C; Z², Z³and Z⁴are independently chosen from N and CH, wherein at least one of Z¹, Z², Z³, and Z⁴is N; R¹and R²are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹and R²each may be optionally substituted with one to three R^Zgroups, wherein R¹and R²together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; R³is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R⁴)₂C(O)R⁴, C(R⁴)₂C(O)N(R⁴)₂, C(R⁴)₂N(R⁴)₂, C(R⁴)₂NR⁴C(O)R⁴, C(R⁴)₂NR⁴C(O)OR⁴, C(R⁴)₂NR⁴C(O)N(R⁴)₂, C(R⁴)₂NR⁴S(O)R⁴, C(R⁴)₂NR⁴S(O)₂R⁴, N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, NR⁴C(O)N(R⁴)₂, NR⁴S(O)R⁴, NR⁴S(O)₂R⁴, C(O)N(R⁴)₂, S(O)N(R⁴)₂, S(O)₂N(R⁴)₂, C(O)R⁴, SR⁴, S(O)R⁴, and S(O)₂R⁴; wherein each R³may be optionally substituted with one to three R^Zgroups; each R⁴is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R⁴may be optionally substituted with one to three R^Zgroups, wherein two R⁴groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups; each R^Zgroup is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂, NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂, S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; each R⁵is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R⁵groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Xgroups; and R⁶is chosen from, alkyl, cyano, cycloalkyl, H, halo, haloalkyl, and heterocycloalkyl, wherein R³and R⁶groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Zgroups.

The In certain embodiments A¹is C; A²and A³are N; and A⁴is S.

In certain embodiments A¹, A², and A³are N; and A⁴is CH.

In certain embodiments n is 4.

In certain embodiments each R^Xand R^Yis independently chosen from H and fluoro.

In certain embodiments one of R^Xis independently fluoro.

In certain embodiments R¹is methyl; and R²is H.

In certain embodiments R¹is methyl; R²is H; and one of R^Xis independently fluoro.

In certain embodiments; Z²and Z³are N; Z⁴is CH; R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶is H.

In certain embodiments A¹is C; A²and A³are N; A⁴is S; n is 4; Z²and Z³are N; Z⁴is CH; R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶is H.

In certain embodiments A¹, A², and A³are N; A⁴is CH; n is 4; Z²and Z³are N; Z⁴is CH; R³is chosen from N(R⁴)₂, NR⁴C(O)R⁴, NR⁴C(O)OR⁴, and NR⁴C(O)N(R⁴)₂; and R⁶is H.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has structural Formula IV:

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or a salt thereof, wherein: R^Xis chosen from fluoro and H; R¹is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R¹may be optionally substituted with one to three R^Zgroups; each R⁴is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R⁴may be optionally substituted with one to three R^Zgroups; each R^Zgroup is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R⁵)₂, NR⁵C(O)R⁵, NR⁵C(O)OR⁵, NR⁵C(O)N(R⁵)₂, NR⁵S(O)R⁵, NR⁵S(O)₂R⁵, C(O)N(R⁵)₂, S(O)N(R⁵)₂, S(O)₂N(R⁵)₂, C(O)R⁵, C(O)OR⁵, SR⁵, S(O)R⁵, and S(O)₂R⁵; and each R⁵is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R⁵groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R^Xgroups.

In particular embodiments, R¹is methyl.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has structural Formula V:

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has structural Formula VI:

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has structural Formula VII:

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or a salt thereof, wherein: R^Xis chosen from fluoro and H; each of R^Z1and R^Z2is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, and oxo.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is chosen from structural Formula VIIa or VIIb:

In certain embodiments R^Xis chosen from fluoro and H; and each of R^Z1and R^Z2is independently chosen from alkyl, cycloalkyl, cycloalkylhaloalkyl, cycloalkyloxy, H, haloalkoxy, haloalkoxyaryl, haloalkyl, halocycloalkyloxy, heterocycloalkyl, and heterocycloalkyloxy.

In certain embodiments R^Xis chosen from fluoro and H; each of R^Z1and R^Z2is independently chosen from H,

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In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has structural Formula VIII:

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or a salt thereof, wherein: R^Xis chosen from fluoro and H; R^Z1is chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, and oxo.

In particular embodiments the compound is chosen from Examples 1-609 and Prophetic Examples 1-2 as disclosed herein.

Pharmaceutical Compositions

While it may be possible for the compounds of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject disclosure or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Compounds described herein can be administered as follows:

Oral Administration

The compounds of the present invention may be administered orally, including swallowing, so the compound enters the gastrointestinal tract, or is absorbed into the blood stream directly from the mouth, including sublingual or buccal administration.

Suitable compositions for oral administration include solid formulations such as tablets, pills, cachets, lozenges and hard or soft capsules, which can contain liquids, gels, powders, or granules.

In a tablet or capsule dosage form the amount of drug present may be from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the dosage form.

In addition, tablets or capsules may contain a disintegrant, comprising from about 0.5% to about 35% by weight, more typically from about 2% to about 25% of the dosage form. Examples of disintegrants include methyl cellulose, sodium or calcium carboxymethyl cellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropyl cellulose, starch and the like.

Suitable binders, for use in a tablet, include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropyl cellulose and the like. Suitable diluents, for use in a tablet, include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch.

Suitable surface active agents and glidants, for use in a tablet or capsule, may be present in amounts from about 0.1% to about 3% by weight, and include polysorbate 80, sodium dodecyl sulfate, talc and silicon dioxide.

Suitable lubricants, for use in a tablet or capsule, may be present in amounts from about 0.1% to about 5% by weight, and include calcium, zinc or magnesium stearate, sodium stearyl fumarate and the like.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with a liquid diluent. Dyes or pigments may be added to tablets for identification or to characterize different combinations of active compound doses.

Liquid formulations can include emulsions, solutions, syrups, elixirs and suspensions, which can be used in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or an oil. The formulation may also include one or more emulsifying agents and/or suspending agents.

Compositions for oral administration may be formulated as immediate or modified release, including delayed or sustained release, optionally with enteric coating.

In another embodiment, a pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Parenteral Administration

Compounds of the present invention may be administered directly into the blood stream, muscle, or internal organs by injection, e.g., by bolus injection or continuous infusion. Suitable means for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial, and the like. Suitable devices for parenteral administration include injectors (including needle and needle-free injectors) and infusion methods. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials.

Most parenteral formulations are aqueous solutions containing excipients, including salts, buffering, suspending, stabilizing and/or dispersing agents, antioxidants, bacteriostats, preservatives, and solutes which render the formulation isotonic with the blood of the intended recipient, and carbohydrates.

Parenteral formulations may also be prepared in a dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, such as sterile water. Solubility-enhancing agents may also be used in preparation of parenteral solutions.

Compositions for parenteral administration may be formulated as immediate or modified release, including delayed or sustained release. Compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

Topical Administration

Compounds of the present invention may be administered topically (for example to the skin, mucous membranes, ear, nose, or eye) or transdermally. Formulations for topical administration can include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches and the like. Carriers that are pharmaceutically acceptable for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol and the like. Topical administration can also be performed by, for example, electroporation, iontophoresis, phonophoresis and the like.

Typically, the active ingredient for topical administration may comprise from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w; less than 5% w/w; from 2% w/w to 5% w/w; or from 0.1% to 1% w/w of the formulation.

Compositions for topical administration may be formulated as immediate or modified release, including delayed or sustained release.

Rectal, Buccal, and Sublingual Administration

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature, and which will therefore melt in the rectum and release the drug.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

Administration by Inhalation

For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray or powder. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the disclosure may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. Preferred unit dosage formulations are those containing an effective dose, as herein recited, or an appropriate fraction thereof, of the active ingredient. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on the condition and its severity. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3^rdEd.), American Pharmaceutical Association, Washington, 1999.

Methods of Treatment

The present disclosure provides compounds and pharmaceutical compositions that inhibit glutaminase activity, particularly GLS1 activity and are thus useful in the treatment or prevention of disorders associated with GLS1. Compounds and pharmaceutical compositions of the present disclosure selectively modulate GLS1 and are thus useful in the treatment or prevention of a range of disorders associated with GLS1 and include, but are not limited to, cancer, immunological or neurological diseases associated with GLS1.

Neurological Disorders

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of neurological diseases.

The most common neurotransmitter is glutamate, derived from the enzymatic conversion of glutamine via glutaminase. High levels of glutamate have been shown to be neurotoxic. Following traumatic insult to neuronal cells, there occurs a rise in neurotransmitter release, particularly glutamate. Accordingly, inhibition of glutaminase has been hypothesized as a means of treatment following an ischemic insult, such as stroke.

Huntington's disease is a progressive, fatal neurological condition. In genetic mouse models of Huntington's disease, it was observed that the early manifestation of the disease correlated with dysregulated glutamate release (Raymond et al., Neuroscience, 2011). In HIV-associated dementia, HIV infected macrophages exhibit upregulated glutaminase activity and increased glutamate release, leading to neuronal damage (Huang et al., J. Neurosci., 2011). Similarly, in another neurological disease, the activated microglia in Rett Syndrome release glutamate causing neuronal damage. The release of excess glutamate has been associated with the up-regulation of glutaminase (Maezawa et al., J. Neurosci, 2010). In mice bred to have reduced glutaminase levels, sensitivity to psychotic-stimulating drugs, such as amphetamines, was dramatically reduced, thus suggesting that glutaminase inhibition may be beneficial in the treatment of schizophrenia (Gaisler-Salomon et al., Neuropsychopharmacology, 2009). Bipolar disorder is a devastating illness that is marked by recurrent episodes of mania and depression. This disease is treated with mood stabilizers such as lithium and valproate; however, chronic use of these drugs appear to increase the abundance of glutamate receptors (Nanavati et al., J. Neurochem., 2011), which may lead to a decrease in the drug's effectiveness over time. Thus, an alternative treatment may be to reduce the amount of glutamate by inhibiting glutaminase. This may or may not be in conjunction with the mood stabilizers. Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), is an approved therapeutic in the treatment of Alzheimer's disease. Currently, research is being conducted looking at memantine as a means of treating vascular dementia and Parkinson's disease (Oliverares et al., Curr. Alzheimer Res., 2011). Since memantine has been shown to partially block the NMDA glutamate receptor also, it is not unreasonable to speculate that decreasing glutamate levels by inhibiting glutaminase could also treat Alzheimer's disease, vascular dementia and Parkinson's disease. Alzheimer's disease, bipolar disorder, HIV-associated dementia, Huntington's disease, ischemic insult, Parkinson's disease, schizophrenia, stroke, traumatic insult and vascular dementia are but a few of the neurological diseases that have been correlated to increased levels of glutamate. Thus, inhibiting glutaminase with a compound described herein can reduce or prevent neurological diseases. Therefore, in certain embodiments, the compounds may be used for the treatment or prevention of neurological diseases.

Immunological Disorders

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of immunological diseases.

Activation of T lymphocytes induces cell growth, proliferation, and cytokine production, thereby placing energetic and biosynthetic demands on the cell. Glutamine serves as an amine group donor for nucleotide synthesis, and glutamate, the first component in glutamine metabolism, plays a direct role in amino acid and glutathione synthesis, as well as being able to enter the Krebs cycle for energy production (Carr et al., J. Immunol., 2010). Mitogen-induced T cell proliferation and cytokine production require high levels of glutamine metabolism, thus inhibiting glutaminase may serve as a means of immune modulation. In multiple sclerosis, an inflammatory autoimmune disease, the activated microglia exhibit up-regulated glutaminase and release increased levels of extracellular glutamate. Glutamine levels are lowered by sepsis, injury, burns, surgery and endurance exercise (Calder et al., Amino Acids, 1999). These situations put the individual at risk of immunosuppression. In fact, in general, glutaminase gene expression and enzyme activity are both increased during T cell activity. Patients given glutamine following bone marrow transplantation resulted in a lower level of infection and reduced graft v. host disease (Crowther, Proc. Nutr. Soc., 2009). T cell proliferation and activation is involved in many immunological diseases, such as inflammatory bowel disease, Crohn's disease, sepsis, psoriasis, arthritis (including rheumatoid arthritis), multiple sclerosis, graft v. host disease, infections, lupus and diabetes. In an embodiment of the invention, the compounds described herein can be used to treat or prevent immunological diseases.

Cancer

In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in the treatment or prevention of cancer.

In addition to serving as the basic building blocks of protein synthesis, amino acids have been shown to contribute to many processes critical for growing and dividing cells, and this is particularly true for cancer cells. Nearly all definitions of cancer include reference to dysregulated proliferation. Numerous studies on glutamine metabolism in cancer indicate that many tumors are avid glutamine consumers (Souba, Ann. Surg., 1993; Collins et al., J. Cell. Physiol., 1998; Medina, J. Nutr., 2001; Shanware et al., J. Mol. Med., 2011). An embodiment of the invention is the use of the compounds described herein for the treatment of cancer.

In some embodiments, the compounds of the present disclosure may be used to prevent or treat cancer, wherein the cancer is one or a variant of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS-Related Cancers (Kaposi Sarcoma and Lymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepithelioma, Pineal Parenchymal Tumors of Intermediate Differentiation, Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System (such as Atypical Teratoid/Rhabdoid Tumor, Embryonal Tumors and Lymphoma), Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome), Duct, Bile (Extrahepatic), Ductal Carcinoma In Situ (DCIS), Embryonal Tumors (Central Nervous System), Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (like Intraocular Melanoma, Retinoblastoma), Fibrous Histiocytoma of Bone (including Malignant and Osteosarcoma) Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal, Ovarian), Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi Sarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell), Lymphoma (AIDS-Related, Burkitt, Cutaneous T-Cell (Mycosis Fungoides and Sézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), Macroglobulinemia, Waldenström, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor, and Low Malignant Potential Tumor), Pancreatic Cancer (including Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (like Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue, Uterine), Sézary Syndrome, Skin Cancer (such as Melanoma, Merkel Cell Carcinoma, Nonmelanoma), Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach (Gastric) Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma (Cutaneous, Mycosis Fungoides and Sézary Syndrome), Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Unknown Primary, Unusual Cancers of Childhood, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Waldenström Macroglobulinemia or Wilms Tumor.

In certain embodiments, the cancer to be treated is one specific to T-cells such as T-cell lymphomia and lymphoblastic T-cell leukemia.

In some embodiments, methods described herein are used to treat a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, wherein the condition is cancer which has developed resistance to chemotherapeutic drugs and/or ionizing radiation.

Combinations and Combination Therapy

The compounds of the present invention can be used, alone or in combination with other pharmaceutically active compounds, to treat conditions such as those previously described hereinabove. The compound(s) of the present invention and other pharmaceutically active compound(s) can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. Accordingly, in one embodiment, the present invention comprises methods for treating a condition by administering to the subject a therapeutically-effective amount of one or more compounds of the present invention and one or more additional pharmaceutically active compounds.

In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of the present invention, one or more additional pharmaceutically active compounds, and a pharmaceutically acceptable carrier.

In another embodiment, the one or more additional pharmaceutically active compounds is selected from the group consisting of anti-cancer drugs, anti-proliferative drugs, and anti-inflammatory drugs.

GLS1 inhibitor compositions described herein are also optionally used in combination with other therapeutic reagents that are selected for their therapeutic value for the condition to be treated. In general, the compounds described herein and, in embodiments where combination therapy is employed, other agents do not have to be administered in the same pharmaceutical composition and, because of different physical and chemical characteristics, are optionally administered by different routes. The initial administration is generally made according to established protocols and then, based upon the observed effects, the dosage, modes of administration and times of administration subsequently modified. In certain instances, it is appropriate to administer a GLS1 inhibitor compound, as described herein, in combination with another therapeutic agent. By way of example only, the therapeutic effectiveness of a GLS1 inhibitor is enhanced by administration of another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is either simply additive of the two therapeutic agents or the patient experiences an enhanced (i.e., synergistic) benefit. Alternatively, if a compound disclosed herein has a side effect, it may be appropriate to administer an agent to reduce the side effect; or the therapeutic effectiveness of a compound described herein may be enhanced by administration of an adjuvant.

Therapeutically effective dosages vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are documented methodologies. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. In any case, the multiple therapeutic agents (one of which is a GLS1 inhibitor as described herein) may be administered in any order, or simultaneously. If simultaneously, the multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills).

In some embodiments, one of the therapeutic agents is given in multiple doses, or both are given as multiple doses. If not simultaneous, the timing between the multiple doses optionally varies from more than zero weeks to less than twelve weeks.

In addition, the combination methods, compositions and formulations are not to be limited to the use of only two agents, the use of multiple therapeutic combinations are also envisioned. It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is optionally modified in accordance with a variety of factors. These factors include the disorder from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed varies widely, in some embodiments, and therefore deviates from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapy disclosed herein are optionally a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy are optionally also administered sequentially, with either agent being administered by a regimen calling for two-step administration. The two-step administration regimen optionally calls for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time between the multiple administration steps ranges from a few minutes to several hours, depending upon the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent.

In another embodiment, a GLS1 inhibitor is optionally used in combination with procedures that provide additional benefit to the patient. A GLS1 inhibitor and any additional therapies are optionally administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a GLS1 inhibitor varies in some embodiments. Thus, for example, a GLS1 inhibitor is used as a prophylactic and is administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. A GLS1 inhibitor and compositions are optionally administered to a subject during or as soon as possible after the onset of the symptoms. While embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that in some embodiments of the invention various alternatives to the embodiments described herein are employed in practicing the invention.

A GLS1 inhibitor can be used in combination with anti-cancer drugs, including but not limited to the following classes: alkylating agents, anti-metabolites, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, angiogenesis inhibitors and tyrosine kinase inhibitors.

For use in cancer and neoplastic diseases a GLS1 inhibitor may be optimally used together with one or more of the following non-limiting examples of anti-cancer agents: (1) alkylating agents, including but not limited to cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN) and cyclophosphamide (ENDOXAN); (2) anti-metabolites, including but not limited to mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (ARA-C), gemcitabine (GEMZAR), fluorouracil (CARAC), leucovorin (FUSILEV) and methotrexate (RHEUMATREX); (3) plant alkaloids and terpenoids, including but not limited to vincristine (ONCOVIN), vinblastine and paclitaxel (TAXOL); (4) topoisomerase inhibitors, including but not limited to irinotecan (CAMPTOSAR), topotecan (HYCAMTIN) and etoposide (EPOSIN); (5) cytotoxic antibiotics, including but not limited to actinomycin D (COSMEGEN), doxorubicin (ADRIAMYCIN), bleomycin (BLENOXANE) and mitomycin (MITOSOL); (6) angiogenesis inhibitors, including but not limited to sunitinib (SUTENT) and bevacizumab (AVASTIN); and (7) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB) and axitinib (INLYTA).

Where a subject is suffering from or at risk of suffering from an inflammatory condition, a GLS1 inhibitor compound described herein is optionally used together with one or more agents or methods for treating an inflammatory condition in any combination. Therapeutic agents/treatments for treating an autoimmune and/or inflammatory condition include, but are not limited to any of the following examples: (1) corticosteroids, including but not limited to cortisone, dexamethasone, and methylprednisolone; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON), flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium (VOLTAREN), diclofenac potassium (CATAFLAM), etodolac (LODINE), indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL), tolmetin (TOLECTIN), meclofenamate (MECLOMEN), mefenamic acid (PONSTEL), nabumetone (RELAFEN) and piroxicam (FELDENE); (3) immunosuppressants, including but not limited to methotrexate (RHEUMATREX), leflunomide (ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE), tacrolimus and cyclophosphamide (CYTOXAN); (4) CD20 blockers, including but not limited to rituximab (RITUXAN); (5) Tumor Necrosis Factor (TNF) blockers, including but not limited to etanercept (ENBREL), infliximab (REMICADE) and adalimumab (HUMIRA); (6) interleukin-1 receptor antagonists, including but not limited to anakinra (KINERET); (7) interleukin-6 inhibitors, including but not limited to tocilizumab (ACTEMRA); (8) interleukin-17 inhibitors, including but not limited to AIN457; (9) Janus kinase inhibitors, including but not limited to tasocitinib; and (10) syk inhibitors, including but not limited to fostamatinib.

Compound Synthesis

Compounds of the present invention can be prepared using methods illustrated in general synthetic schemes and experimental procedures detailed below. General synthetic schemes and experimental procedures are presented for purposes of illustration and are not intended to be limiting. Starting materials used to prepare compounds of the present invention are commercially available or can be prepared using routine methods known in the art.

List of Abbreviations

Ac₂O=acetic anhydride; AcCl=acetyl chloride; AcOH=acetic acid; AIBN=azobisisobutyronitrile; aq.=aqueous; BAST=bis(2-methoxyethyl)aminosulfur trifluoride; Bu₃SnH=tributyltin hydride; CD₃OD=deuterated methanol; CDCl₃=deuterated chloroform; CDI=1,1′-Carbonyldiimidazole; DAST=(diethylamino)sulfur trifluoride; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DCM=dichloromethane; DEAD=diethyl azodicarboxylate; DIBAL-H=di-iso-butyl aluminium hydride; DIEA=DIPEA═N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine; DMF═N,N-dimethylformamide; DMSO-d₆=deuterated dimethyl sulfoxide; DMSO=dimethyl sulfoxide; DPPA=diphenylphosphoryl azide; EDC·HCl=EDCI·HCl=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et₂O=diethyl ether; EtOAc=ethyl acetate; EtOH=ethanol; h=hour; HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium; HMDS=hexamethyldisilazane; HOBT=1-hydroxybenzotriazole; i-PrOH=isopropanol; LAH=lithium aluminumhydride; LDA=lithium diisopropyl amide; LiHMDS=Lithium bis(trimethylsilyl)amide; MeCN=acetonitrile; MeOH=methanol; MP-carbonate resin=macroporous triethylammonium methylpolystyrene carbonate resin; MsCl=mesyl chloride; MTBE=methyl tertiary butyl ether; n-BuLi=n-butyllithium; NaHMDS=Sodium bis(trimethylsilyl)amide; NaOMe=sodium methoxide; NaOtBu=sodium t-butoxide; NBS═N-bromosuccinimide; NCS═N-chlorosuccinimide; NMP═N-Methyl-2-pyrrolidone; Pd(Ph₃)₄=tetrakis(triphenylphosphine)palladium(0); Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0); PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium(II) dichloride; PG=protecting group; prep-HPLC=preparative high-performance liquid chromatography; PMBCl=para-methoxybenzyl chloride; PyBop=(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr=pyridine; RT=room temperature; RuPhos=2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl; sat.=saturated; ss=saturated solution; t-BuOH=tert-butanol; T3P=Propylphosphonic Anhydride; TEA=Et₃N=triethylamine; TFA=trifluoroacetic acid; TFAA=trifluoroacetic anhydride; THF=tetrahydrofuran; Tol=toluene; TsCl=tosyl chloride; Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; X-Phos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

General Methods for Preparing Compounds

The following schemes can be used to practice the present invention. Additional structural groups, including but not limited to those defined elsewhere in the specification and not shown in the compounds described in the schemes can be incorporated to give various compounds disclosed herein, or intermediate compounds which can, after further manipulations using techniques known to those skilled in the art, be converted to compounds of the present invention. For example in certain embodiments the A-ring in the structures described in the schemes—wherein A is a heteroaromatic ring—can be substituted with various groups as defined herein.

One route for preparation of compounds of the present invention is described in Scheme 1. A substituted functionalized halo-heteroaromatic amine is reacted with a suitable acyl chloride in the presence of a base such as DIEA or TEA in a solvent such as DMF, DCM or NMP. The resulting carboxamide can be further functionalized, for example by Sonogashira cross-coupling reaction with a suitably functionalized hydroxy alkyne (Tetrahedron Lett. 16: 4467-4470). Typically the above transformation is performed in the presence of a suitable Pd catalyst such as PdCl₂(PPh₃)₂or Pd(PPh₃)₄, a copper co-catalyst, typically a halide salt of copper (I), such as CuI or CuBr, and a base such as DIEA or TEA. The transformation can typically be run at RT or with mild heating in a variety of solvents, including DMF, toluene and EtOAc. Further functional group manipulations include hydrogenation of the resulting heteroaromatic alkyne derivative in the presence of a suitable Pd catalyst (such as Pd/C or Pd(OH₂)) in a solvent such as EtOH, and conversion of the hydroxyl moiety into an azide, for example by treatment with DPPA and a base such as TEA heating in a solvent such as toluene, according to the procedure published in Bose et al., Tetrahedron Lett. 1977, 18, 1977-1980. Alternatively, the hydroxyl group could be converted into the corresponding mesylate or tosylate and then displaced with NaN₃in a suitable polar solvent such as DMF. The obtained azide derivative can then be progressed to the corresponding triazole-4-carboxylic ester by copper-mediated azide-alkyne cycloaddition with a suitable alkyl propiolate in the presence of a base (e.g. TEA or DIEA), and a copper (I) salt such as CuI, or a copper (II) salt such as CuSO₄in the presence of a reducing agent such as sodium ascorbate, in a solvent such as THF, DMSO, tBuOH or H₂O (H. C. Kolb, M. G. Finn and K. B. Sharpless, Angewandte Chemie International Edition, 2001, 40 (11): 2004-2021). Finally, the desired amide in the 4-position of the triazole ring can be installed by direct displacement of the carboxylic ester with a suitable amine heating in a polar solvent such as DMF or MeOH. Alternatively, the same transformation could be achieved with a two-step sequence involving the base-mediated hydrolysis of the carboxylic ester followed by coupling of the resulting carboxylic acid with amine, using standard coupling reagents such as HATU, PyBOP or EDCI·HCl, in the presence of a suitable base such as TEA or DIEA, in a polar solvent such as DMF.

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Another route for the preparation of compounds of the present invention is described in Scheme 2. A suitably functionalized alkyne hydrazide could be converted in the corresponding 1,3,4-thiadiazole 2-carboxylate derivative by acylation with ethyl chlorooxoacetate followed by heating in a solvent such as toluene in the presence of P₂S₅. The resulting alkyne thiadiazole could be further functionalized by Sonogashira cross-coupling with a suitably substituted heteroaryl chloride, in similar conditions to those described in Scheme 1 for such transformation. The resulting heteroaromatic alkyne can then be reduced by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C or Pd(OH₂)) in a solvent such as EtOH. Finally, functional group manipulations similar to those described for Scheme 1 could be employed to progress the 2-carboxy ester thiadiazoles into the desired 2-carboxylic amides derivatives.

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A further route of preparation of the compounds described in this invention is depicted in Scheme 3. A suitably functionalized alkyl nitrile bearing a protected hydroxyl moiety can be converted to a 5-alkyl-2-amino thiadiazole by heating in the presence of TFA and hydrazinecarbothioamide. Suitable protecting groups for the hydroxyl moiety can be chosen amongst substituted ethers (e.g. benzyl ether, 3,4-dimethoxy-benzylether, t-butyl ether, t-butyldimethylsilyl ether), esters or other suitable functional groups known to those skilled in the art (see also: P. G. M. Wutz, T. W. Greene, “Greene's protective Groups in Organic Synthesis”, Fourth Edition, John Wiley & Sons). The obtained thiadiazole can then be progressed to the corresponding 2-carboxamide derivative by acylation with a suitable acyl chloride in the presence of a base such as TEA or DIEA in a solvent such as DCM. Removal of the hydroxyl protecting group with techniques known to those skilled in the art (for example: reductive removal of a benzyl ether group; see also P. G. M. Wutz, T. W. Greene in reference cited above) can then enable the conversion of the liberated hydroxyl moiety into an azide group, with conditions similar to those described in Scheme 1, i.e. treatment with DPPA heating in the presence of a base such as TEA, or conversion to the corresponding mesylate or tosylate followed by displacement with NaN₃in a polar solvent like DMF. The obtained azide can then be progressed to the corresponding triazole by copper-mediated azide-alkyne cycloaddition in the presence of a suitable alkylpropriolate in the presence of a base such as DIEA, and a copper compound like CuI, or CuSO₄in the presence of sodium ascorbate, similarly to the conditions described for Scheme 1 and 2. Finally, the triazole-2-carboxy ester derivatives can be converted to the corresponding triazole-2-carboxy amides, employing procedures and conditions similar to those described in detail for Scheme 1.

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An additional synthetic route to prepare compounds of this invention is described in Scheme 4.

A suitably functionalized alkyl hydrazide bearing a protected hydroxyl moiety can be converted to a 5-alkyl-2-amino thiadiazole by heating in a solvent such as toluene in the presence of P₂S₅, similarly to the transformation described in Scheme 2. Suitable protecting groups for the hydroxyl moiety can be chosen amongst substituted ethers and others suitable functional groups known to those skilled in the art, as detailed in G. M. Wutz, T. W. Greene, “Greene's protective Groups in Organic Synthesis”, Fourth Edition, John Wiley & Sons, and can be removed following the transformations and procedures reported therein. Following removal of the selected protecting group, the hydroxyl moiety can then be converted into an azide group employing the transformations described in Schemes 1 and 3. The obtained functionalized amide can then be progressed to the desired triazole derivatives by employing a copper-mediated azide-alkyne cycloaddition in the presence of a suitable alkylpropriolate to obtain the 2-carboxy ester triazoles, followed by functional group manipulation to install the 2-carboxy amide, as already described in detail for Schemes 1-3.

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An additional synthetic route for the compounds described in this invention is described in Scheme 5. A suitable hydroxy alkyne can be progressed into the corresponding azide by a two-step sequence involving mesylation or tosylation with the required sulfonyl chloride in the presence of a base such as TEA or DIEA in a solvent like DCM, followed by displacement with an inorganic azide such as NaN₃in a polar solvent like DMF. Copper-mediated azide-alkyne cycloaddition in the presence of a suitable alkyl propiolate can then afford the N-alkyne-2-carboxyester triazole derivatives, in conditions similar to those already detailed for Schemes 1-4. The 2-carboxyester triazole derivatives can in turn be progressed to the corresponding 2-carboxyamides, employing similar transformations and conditions to those described for Schemes 1-4. A further copper-mediated azide-alkyne cycloaddion step employing a suitably functionalized azide and in analogous conditions to those detailed in Schemes 1-4 can then afford the desired bis-triazolo derivatives.

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Non-limiting examples include the following compounds and pharmaceutically acceptable salts thereof.

Example 1: N-(pyridin-3-ylmethyl)-1-[4-(5-{2-[3-(trifluoromethoxy)phenyl]acetamido}-1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 4

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Step 1: 4-cyanobutyl Benzoate

To a solution of benzoic acid (0.543 g, 4.44 mmol) in DMF (5 mL) was added K₂CO₃(1.02 g, 7.41 mmol) and the mixture was stirred at RT for 10 minutes. 5-Bromopentanenitrile (0.60 g, 3.7 mmol) was added dropwise and the reaction was heated in a sealed vial at 85° C. for 2.5 h, then at 60° C. for 17 h. The mixture was concentrated under reduced pressure, diluted with water (75 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give the title compound as a clear oil (765 mg, 3.58 mmol, 97%). MS (ES⁺) C₁₂H₁₃NO₂requires: 203.1, found: 204 [M+H]⁺.

Step 2: 4-(5-amino-1,3,4-thiadiazol-2-yl)butyl Benzoate

To a solution of 4-cyanobutyl benzoate (760 mg, 3.74 mmol) in TFA (10 mL) was added hydrazinecarbothioamide (409 mg, 4.49 mmol) and the resulting mixture was stirred at 85° C. for 3 h. The reaction mixture was allowed to cool to RT and the volatiles were removed under reduced pressure. The residue was dissolved in DCM/MeOH (5 mL, 1/1 v/v), MP-carbonate resin (6 g, 6.06 mmol/g) was added, and the mixture was stirred for 3 h at RT. The mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (822 mg, 2.96 mmol, 79%). MS (ES⁺) C₁₃H₁₅N₃O₂S requires: 277.1, found: 278 [M+H]⁺.

Step 3: 4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl Benzoate

To a solution of 4-(5-amino-1,3,4-thiadiazol-2-yl)butyl benzoate (571 mg, 2.06 mmol) in DMF (15 mL) were added 2-(3-(trifluoromethoxy)phenyl)acetic acid (544 mg, 2.47 mmol), HOBT (378 mg, 2.47 mmol), DIEA (0.45 mL, 2.6 mmol), and EDC·HCl (474 mg, 2.47 mmol) and the resulting mixture was stirred at RT for 18 h. The reaction was slowly poured onto ice water (250 mL) and stirred for 1 h. The mixture was filtered and the white solid was washed with water, saturated NaHCO₃, water, and hexanes to give the title compound as a white solid (530 mg, 1.10 mmol, 54%). MS (ES⁺) C₂₂H₂₀F₃N₃O₄S requires: 479.1, found: 480 [M+H]⁺.

Step 4: N-(5-(4-hydroxybutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

To a solution of 4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl benzoate (527 mg, 1.10 mmol) in THF (7 mL) and water (7 mL) was added LiOH (2 M aq., 5.50 mL, 11.0 mmol) and the resulting mixture was stirred at RT for 5 h. The volatiles were removed under reduced pressure. The residue was partitioned between DCM (200 mL) and H₂O (200 mL), and the layers were separated. The aqueous phase was extracted with DCM (3×100 mL) and the organic layers were combined, washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give the title compound as an off white solid (300 mg, 0.799 mmol, 73%). MS (ES⁺) C₁₅H₁₆F₃N₃O₃S requires: 375.1, found: 376 [M+H]⁺.

Steps 5 to 8

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Step 5: N-(5-(4-azidobutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

To a solution of N-(5-(4-hydroxybutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (297 mg, 0.790 mmol) and DBU (0.179 mL, 1.19 mmol) in THF (5 mL) was added DPPA (0.26 mL, 1.2 mmol) dropwise and the resulting mixture was stirred at 60° C. for 3 h. The volatiles were removed under reduced pressure and the residue was purified via SiO₂gel chromatography (0-100% EtOAc in hexanes) to give the title compound as a white solid (217 mg, 0.542 mmol, 69%). MS (ES⁺) C₁₅H₁₅F₃N₆O₂S requires: 400.1, found: 401 [M+H]⁺.

Step 6: ethyl 1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of N-(5-(4-azidobutyl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (214 mg, 0.534 mmol) in DCM (5 mL) were added DIEA (9.3 μl, 0.053 mmol), AcOH (3.06 μl, 0.053 mmol), ethyl propiolate (0.065 mL, 0.641 mmol), and copper(I) iodide (5.1 mg, 0.027 mmol) and the resulting mixture was stirred at RT for 16 h. The reaction was concentrated under reduced pressure, the residue was taken up in MeOH, and the product was precipitated by addition of saturated aq. NH₄Cl. The precipitate was washed with water, hexanes, and dried under reduced pressure to give the title compound as a white solid (217 mg, 0.430 mmol, 81%). MS (ES⁺) C₂₀H₂₁F₃N₆O₄S requires: 498.1, found: 499 [M+H]⁺.

Step 7: 1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

To a suspension of ethyl 1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (211 mg, 0.423 mmol) in THF/H₂O (10 mL, 1/1 v/v) was added LiOH (2 M aq., 1.06 mL, 2.12 mmol) and the resulting mixture was stirred at RT for 16 h. The volatiles were removed under reduced pressure, the aqueous phase was brought to pH 2 by the addition of 1N aq. HCl, and the resulting solid product was collected by filtration and dried under reduced pressure to give the title compound as a white solid (193 mg, 0.411 mmol, 97%). MS (ES⁺) C₁₈H₁₇F₃N₆O₄S requires: 470.1, found: 471 [M+H]⁺.

Step 8: N-(pyridin-3-ylmethyl)-1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (10 mg, 0.021 mmol) in DMSO (0.1 mL) were added DIEA (8.17 μl, 0.0470 mmol), pyridin-3-ylmethanamine (2.3 mg, 0.021 mmol), and HATU (12.1 mg, 0.032 mmol). The resulting mixture was stirred at RT for 16 h and diluted with water. The resulting precipitate was filtered, washed with water, and dried under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as a white solid (3.3 mg, 5.9 μmol, 28%). MS (ES⁺) C₂₄H₂₃F₃N₈O₃S requires: 560.2, found: 561 [M+H]⁺. ¹H NMR (DMSO-d₆) δ: 12.70 (br s, 1H), 9.25 (m, 1H), 8.79-8.56 (m, 3H), 8.09 (d, J=7.9 Hz, 1H), 7.67 (m, 1H), 7.47 (m, 1H), 7.38-7.31 (m, 2H), 7.28 (d, J=8.7 Hz, 1H), 4.54 (d, J=6.0 Hz, 2H), 4.45 (t, J=7.0 Hz, 2H), 3.89 (s, 2H), 3.00 (t, J=7.4 Hz, 2H), 1.94-1.87 (m, 2H), 1.68-1.59 (m, 2H).

Example 2: N-Methyl-1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Prepared as described for Example 1. MS (ES⁺) C₁₉H₂₀F₃N₇O₃S requires: 483.1, found: 484 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ: 12.69 (s, 1H), 8.54 (s, 1H), 8.44 (q, J=4.5 Hz, 1H), 7.47 (m, 1H), 7.38-7.32 (m, 2H), 7.28 (d, J=8.7 Hz, 1H), 4.48-4.40 (m, 2H), 3.89 (s, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.75 (d, J=4.9 Hz, 3H), 1.95-1.86 (m, 2H), 1.69-1.58 (m, 2H).

Example 3: 1-(4-(5-(2-(3-(Trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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To a suspension of N-(2,4-dimethoxybenzyl)-1-(4-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxamide (prepared as described for Example 1; 14 mg, 0.023 mmol) in DCM (1 mL) was added TFA (0.106 mL, 1.375 mmol) and the resulting mixture was stirred at RT for 7 h. The reaction was concentrated under reduced pressure and the residue was triturated with aq. NaHCO₃(10/1 v/v water/saturated aq. NaHCO₃). The resulting solid was filtered and washed with water to give the title compound as an off white solid (7.4 mg, 0.016 mmol, 69%). MS (ES⁺) C₁₈H₁₈F₃N₇O₃S requires: 469.1, found: 470 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ: 8.53 (s, 1H), 7.83 (s, 1H), 7.49 (m, 1H), 7.38-7.32 (m, 2H), 7.27 (d, J=8.7 Hz, 1H), 4.44 (t, J=6.8 Hz, 2H), 3.88 (s, 2H), 3.00 (t, J=7.4 Hz, 2H), 1.95-1.86 (m, 2H), 1.69-1.60 (m, 2H).

Example 4: N-Benzyl-1-(5-(5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)pentyl)-1H-1,2,3-triazole-4-carboxamide

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Prepared as Example 1, using 5-cyanopentyl benzoate instead of 4-cyanobutyl benzoate. MS (ES⁺) C₂₅H₂₇N₇O₂S requires: 489.2, found: 490 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ: 8.08 (s, 1H), 7.49 (br s, 1H), 7.42-7.37 (m, 2H), 7.37-7.27 (m, 8H), 4.68-4.59 (m, 2H), 4.37 (t, J=7.0 Hz, 2H), 3.98 (s, 2H), 3.02 (t, J=7.4 Hz, 2H), 1.97 (m, 2H), 1.85 (m, 2H), 1.44 (m, 2H).

Example 5: N-Benzyl-1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 5

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Step 1: N-(6-chloropyridazin-3-yl)-2-phenylacetamide

To a mixture of 6-chloropyridazin-3-amine (4.0 g, 31 mmol) and DIEA (6.5 mL, 37 mmol) in NMP (40 mL) at 0° C. was added 2-phenylacetyl chloride (4.49 mL, 34.0 mmol) dropwise. The reaction was stirred at 0° C. for 30 minutes, allowed to warm to RT over 19 h, and poured onto ice water (500 mL). The resulting precipitate was filtered, washed with water and Et₂O (3×20 mL), and dried under reduced pressure to give the title compound as an off-white solid (3.4 g, 13 mmol, 42%). MS (ES⁺) C₁₂H₁₀ClN₃O requires: 247.1, found: 248 [M+H]⁺.

Step 2: N-(6-(4-hydroxybut-1-yn-1-yl)pyridazin-3-yl)-2-phenylacetamide

To a solution of N-(6-chloropyridazin-3-yl)-2-phenylacetamide in DMF (4 mL) were added TEA (2.0 mL, 14 mmol) and but-3-yn-1-ol (0.306 mL, 4.04 mmol), and the mixture was degassed with a stream of N₂for 5 minutes. Copper(I) iodide (0.038 g, 0.20 mmol) and PdCl₂(PPh₃)₂(0.071 g, 0.101 mmol) were added and the mixture was heated in a sealed vial at 85° C. 16 h. The mixture was cooled to RT, the volatiles were removed under reduced pressure, and the residue was purified via silica gel chromatography (0-5% MeOH in DCM) to give the title compound as a yellow solid (238 mg, 0.846 mmol, 42%). MS (ES⁺) C₁₆H₁₅N₃O₂requires: 281.1, found: 282 [M+H]⁺.

Step 3: N-(6-(4-hydroxybutyl)pyridazin-3-yl)-2-phenylacetamide

To a flask containing Pd(OH)₂(20% wt on carbon, 353 mg, 0.252 mmol) under N₂was added EtOH (10 mL) followed by N-(6-(4-hydroxybut-1-yn-1-yl)pyridazin-3-yl)-2-phenylacetamide (236 mg, 0.839 mmol). The flask was evacuated, filled with H₂, and the mixture stirred at RT under a hydrogen atmosphere for 3.5 h. The flask was evacuated and filled with N₂. The suspension was filtered through a pad of Celite®, rinsed with MeOH and DCM, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (210 mg, 0.735 mmol, 88%). MS (ES⁺) C₁₆H₁₉N₃O₂requires: 285.2, found: 286 [M+H]⁺.

Step 4: N-(6-(4-azidobutyl)pyridazin-3-yl)-2-phenylacetamide

Prepared as described for Example 1, step 5. MS (ES⁺) C₁₆H₁₈N₆O requires: 310.1, found: 311[M+H]⁺.

Steps 5 to 7

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Prepared as described for Example 1, steps 5-to 7;

Step 5: ethyl 1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

MS (ES⁺) C₂₁H₂₄N₆O₃requires: 408.2, found: 409 [M+H]⁺.

Step 6: 1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

MS (ES⁺) C₁₉H₂₀N₆O₃requires: 380.2, found: 381 [M+H]⁺.

Step 7: N-benzyl-1-(4-(6-(2-phenylacetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

MS (ES⁺) C₂₆H₂₇N₇O₂requires: 469.2, found: 470 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ: 11.23 (br s, 1H), 9.02 (d, J=5.3 Hz, 1H), 8.57 (s, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.37-7.28 (m, 8H), 7.27-7.18 (m, 2H), 4.49-4.40 (m, 4H), 3.76 (s, 2H), 2.88 (t, J=7.6 Hz, 2H), 1.94-1.83 (m, 2H), 1.69-1.59 (m, 2H).

Example 6: N-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

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Steps 1 to 3

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Step 1: Ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate

To a solution of pent-4-ynehydrazide (560 mg, 5.00 mmol) and TEA (530 mg, 5.25 mmol) in DCM/THF (25 mL/5 mL) at 0° C. was slowly added ethyl 2-chloro-2-oxoacetate (717 mg, 5.25 mmol). The resulting mixture was stirred for 30 minutes while warming to RT, then concentrated under reduced pressure. The residue was triturated with EtOAc (20 mL), filtered, and the filtrate was concentrated under reduced pressure to give the title compound. MS (ES⁺) C₉H₁₂N₂O₄, requires: 212.08, found: 213 [M+H]⁺.

Step 2: Ethyl 5-(but-3-yn-1-yl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate (1.0 g, 5.0 mmol) in toluene (50 mL) heated at 70° C. was added P₂S₅(1.11 g, 5.0 mmol) portionwise, and the resulting mixture was stirred for 30 minutes at 70° C. The mixture was cooled to RT, filtered, and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (20% EtOAc in hexanes) to give the title compound as a yellow solid (532 mg, 50%). MS (ES⁺) C₉H₁₀N₂O₂S, requires: 210.05, found: 211[M+H]⁺. ¹H NMR (500 MHz, CDCl3) δ 4.54 (m, 2H), 3.44 (t, J=6.9 Hz, 2H), 2.75 (td, J=7.0, 2.7 Hz, 2H), 2.13 (t, J=2.6 Hz, 1H), 1.49 (m, 3H).

Step 3: 5-(but-3-ynyl)-N-(2-methoxyethyl)-1,3,4-thiadiazole-2-carboxamide

A mixture of ethyl 5-(but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate (300 mg, 1.43 mmol) and 2-methoxyethanamine (2 mL) was heated at 80° C. in a sealed tube for 2 h. The mixture was then cooled to RT, diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give the title compound as a yellow solid (310 mg, 91%). MS (ES⁺) C₁₀H₁₃N₃O₂S requires: 239, found: 240[M+H]⁺.

Step 4: N-(6-iodopyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

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A mixture of 6-iodopyridazin-3-amine hydrogen iodide salt (1.05 g, 3.00 mmol), 2-(3-(trifluoromethoxy)phenyl)acetic acid (792 mg, 3.6 mmol), propylphosphonic anhydride (2.86 g, 4.5 mmol, 50% wt in EtOAc), and DIPEA (1.16 g, 9 mmol) in DMF (10 mL) was stirred at RT for 16 h. The mixture was then poured onto H₂O (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (30% EtOAc in hexanes) to give the title compound as a white solid (1.1 g, 87%). MS (ES⁺) C₁₃H₉F₃IN₃O₂requires: 423, found: 424 [M+H]⁺.

Steps 5 to 6

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Step 6: N-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

To a flask containing 10% Pd—C (10 mg) under N₂was added THF (1 mL) followed by N-(2-methoxyethyl)-5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxamide (30 mg, 0.056 mmol). The flask was evacuated and filled with H₂, and the mixture stirred at 30° C. under a H₂atmosphere for 3 h. The flask was evacuated and filled with N₂, the suspension was filtered through a pad of Celite®, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to afford the title compound as a white solid (25 mg, 78%). MS (ES⁺) C₂₃H₂₅F₃N₆O₄S requires: 538, found: 539[M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 9.11 (t, J=5.4 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 7.57 (d, J=9.1 Hz, 1H), 7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.26 (d, J=7.8 Hz, 1H), 3.85 (s, 2H), 3.51-3.39 (m, 4H), 3.25 (s, 3H), 3.18 (t, J=6.1 Hz, 2H), 2.90 (t, J=6.8 Hz, 2H), 1.83-1.71 (m, 4H).

Example 7: N-(2-methoxyethyl)-5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

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Steps 1 to 6

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Step 1: 5-(benzyloxy)pentanoic Acid

To a solution of tetrahydro-2H-pyran-2-one (5.0 g, 50 mmol) in toluene (50 mL) were added KOH (15.8 g, 28.2 mmol) and benzylbromide (17.8 mL, 150 mmol), and the mixture was stirred at 125° C. for 16 h. The solution was cooled to RT and diluted with ice/H₂O (70 mL). The organic layer was separated and the aqueous layer was washed with MTBE (3×30 mL). The aqueous layer was then cooled to 0° C. and the pH was adjusted to 3-4 by the addition of concentrated aq. HCl (15 mL) and 6N aq. HCl (8 mL). The mixture was extracted with EtOAc (4×50 mL) and the combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give 5-(benzyloxy)pentanoic acid as a light yellow oil (10 g, 96%). MS (ES⁺) C₁₂H₁₆O₃requires: 208, found: 209[M+H]⁺.

Step 2: methyl 5-(benzyloxy)pentanoate

To a solution of 5-(benzyloxy)pentanoic acid (1.0 g, 4.8 mmol) in MeOH (40 mL) at 0° C. was slowly added SOCl₂(0.39 mL, 5.3 mmol) and the mixture was stirred at RT for 1 h. The mixture was then treated with saturated aq. NaHCO₃(5 mL), the volatiles were removed under reduced pressure, and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄), and concentrated under reduced pressure to afford methyl 5-(benzyloxy) pentanoate as a light yellow oil (1.0 g, 94%). MS (ES⁺) C₁₃H₁₈O₃requires: 222, found: 223[M+H]⁺.

Step 3: 5-(benzyloxy)pentanehydrazide

A mixture of methyl 5-(benzyloxy)pentanoate (1.0 g, 4.5 mmol) and NH₂NH₂(35% wt. solution in H₂O, 1.3 mL, 14 mmol) in MeOH (15 mL) was heated at reflux in a pressure safe vial for 18 h. The mixture was cooled to RT and the volatiles were removed under reduced pressure. The residue was taken up in toluene (2×5 mL) and concentrated again. The resulting solid was triturated with hexanes (2×5 mL) and filtered to give 5-(benzyloxy)pentanehydrazide as a white solid (840 mg, 84%). MS (ES⁺) C₁₂H₁₈N₂O₂requires: 222, found: 223[M+H]⁺.

Step 4: ethyl 2-(2-(5-(benzyloxy)pentanoyl)hydrazinyl)-2-oxoacetate

To a solution of 5-(benzyloxy)pentanehydrazide (500 mg, 2.25 mmol) and TEA (0.627 mL, 4.50 mmol) in DCM (5.0 mL) at 0° C. was added ethyl 2-chloro-2-oxoacetate (0.448 mL, 4.00 mmol), and the resulting mixture was stirred at RT for 30 minutes. The volatiles were removed under reduced pressure to give the title compound as a white solid (800 mg, 100%). MS (ES⁺) C₁₆H₂₂N₂O₅requires: 322, found: 323 [M+H]⁺.

Step 5: ethyl 5-(4-(benzyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl 2-(2-(5-(benzyloxy)pentanoyl)hydrazinyl)-2-oxoacetate (400 mg, 2.30 mmol) in toluene (5 mL) at 60° C. was added P₂O₅(500 mg, 2.3 mmol). The reaction mixture was stirred at 60° C. for 15 minutes, cooled to RT, and partitioned between saturated aq. NaHCO₃(30 mL) and EtOAc (50 mL). The organic layer was collected, washed with brine (5 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (5% to 20% EtOAc in hexanes) to give the title compound as a yellow oil (1.3 g, 48%). MS (ES⁺) C₁₆H₂₀N₂O₃S requires: 320, found: 321 [M+H]⁺.

Step 6: ethyl 5-(4-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 5-(4-(benzyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate (1.0 g, 3.1 mmol) in DCM (30 mL) was added anhydrous FeCl₃(2.0 g, 13 mmol) portionwise. The reaction mixture was stirred at RT for 25 minutes, a further aliquot of anhydrous FeCl₃(1.0 g, 6.3 mmol) was added, and the mixture was stirred for an additional 10 minutes. The mixture was then treated with saturated aq. NH₄Cl (10 mL), the layers were separated, and the aqueous phase was extracted with DCM/MeOH=10/1 v/v (3×50 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 2% MeOH in DCM) to give the title compound as a brown oil (730 mg, 100%). MS (ES⁺) C₉H₁₄N₂O₃S requires: 230, found: 231 [M+H]⁺.

Steps 7 to 10

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Step 7: 5-(4-(Methylsulfonyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 5-(4-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate (2.30 g, 10.0 mmol; prepared as described for Example 6, step 3) and Et₃N (3.0 g, 30 mmol) in DCM (25 mL) at 0° C. was added MsCl (1.2 mL, 15.0 mmol) in DCM (5 mL) dropwise. The reaction mixture was stirred at 0° C. for 10 minutes, then at RT for 20 minutes. The mixture was then diluted with H₂O (50 mL) and extracted with DCM (100 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the title compound as an oil (3.0 g, 97%). MS (ES⁺) C₁₀H₁₆N₂O₅S₂requires: 308, found: 309 [M+H]⁺.

Step 8: Ethyl 5-(4-azidobutyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 5-(4-(methylsulfonyloxy)butyl)-1,3,4-thiadiazole-2-carboxylate (3.0 g, 9.7 mmol) in DMF (15 mL) was added NaN₃(1.26 g, 19.4 mmol) and the reaction mixture was stirred at 80° C. for 2 h. The mixture was then cooled to RT, poured onto ice water (100 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give the title compound as an oil (2.45 g, 96%). MS (ES⁺) C₉H₁₃N₅O₂S requires: 255, found: 256 [M+H]⁺.

Step 9: Ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 5-(4-azidobutyl)-1,3,4-thiadiazole-2-carboxylate (2.45 g, 9.60 mmol) in t-BuOH (15 mL) and H₂O (15 mL) were added CuSO₄·0.5H₂O (490 mg, 2.65 mmol) and L-(+)-ascorbic acid (980 mg, 5.57 mmol). The reaction mixture was stirred at RT for 3 h, diluted with water (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give the title compound as a light yellow solid (2.2 g, 5.8 mmol, 60%). MS (ES⁺) C₁₆H₂₃N₅O₄S requires: 381, found: 382 [M+H]⁺.

Step 10: 1-(4-(5-(Ethoxycarbonyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

To a solution of ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate (3.2 g, 5.8 mmol) in DCM (10 mL) was added TFA (5.0 mL). The reaction mixture was stirred at RT for 16 h then concentrated under reduced pressure. CH₃CN (10 mL) was added resulting in the formation of a precipitate, which was filtered off to give the title compound as a light yellow solid (1.30 g, 70%). MS (ES⁺) C₁₂H₁₅N₅O₄S requires: 325, found: 326 [M+H]⁺.

Steps 11 to 12

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Step 11: Ethyl 5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate

To a solution of 1-(4-(5-(ethoxycarbonyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.0 g, 3.1 mmol) and (3-(trifluoromethyl)phenyl)methanamine (592 mg, 3.38 mmol) in DMF (6.0 mL) were added HATU (1.75 g, 4.61 mmol) and DIEA (990 mg, 7.70 mmol). The reaction mixture was stirred at RT for 2 h then diluted with H₂O (20 mL). The solid was collected by filtration to give the title compound as a light yellow solid (1.35 g, 91%). MS (ES⁺) C₂₀H₂₁F₃N₆O₃S requires: 482, found: 483 [M+H]⁺.

Step 12: N-(2-Methoxyethyl)-5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

To a suspension of ethyl 5-(4-(4-(3-(trifluoromethyl)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1,3,4-thiadiazole-2-carboxylate (96 mg, 0.20 mmol) in MeOH (1.0 mL) was added 2-methoxyethanamine (0.05 mL, 0.7 mmol) and the reaction mixture was heated in a sealed tube at 80° C. for 2 h. The mixture was cooled to RT, the solid was filtered off and washed with MeOH (5.0 mL) to give the title compound as a white solid (82 mg, 77%). MS (ES⁺) C₂₁H₂₄F₃N₇O₃S requires: 511, found: 512 [M+H]⁺; ¹H NMR (400 MHz, DMSO) δ 9.22 (t, J=6.1 Hz, 1H), 9.13 (t, J=5.2 Hz, 1H), 8.63 (s, 1H), 7.46 (m, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 4.61-4.35 (m, 4H), 3.54-3.41 (m, 4H), 3.25 (s, 3H), 2.01-1.87 (m, 2H), 1.79-1.65 (m, 2H).

Example 8: Tert-butyl 4-((4-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate

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Steps 1 to 5

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Step 1: Hex-5-ynyl 4-methylbenzenesulfonate

To a solution of hex-5-yn-1-ol (1 g, 10 mmol) in DCM (20 ml) were added TEA (1.24 g, 12.2 mmol) and 4-methylbenzene-1-sulfonyl chloride (1.9 g, 10 mmol). The resulting mixture was stirred at RT for 1 h and concentrated under reduced pressure to give the title compound as yellow oil (2.5 g, 97%). MS (ES⁺) C₁₃H₁₆O₃S required: 252, found: 253 [M+H]⁺.

Step 2: 6-Azidohex-1-yne

To a solution of hex-5-ynyl 4-methylbenzenesulfonate (1.0 g, 3.9 mmol) in DMF (10 mL) and water (10 mL) was added NaN₃(525 mg, 7.90 mmol). The resulting mixture was stirred at 80° C. for 12 h, then cooled to RT and partitioned between Et₂O (20 mL) and water (20 mL). The organic layer was collected, washed with water (30 mL), brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure at 0° C. to give the title compound as a yellow oil (460 mg, 94%). MS (ES⁺) C₆H₉N₃requires: 123, found: 124 [M+H]⁺.

Step 3: Methyl 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of 6-azidohex-1-yne (488 mg, 3.90 mmol) in ^tBuOH (10 mL) and water (10 mL) were added methyl propiolate (499 mg, 5.90 mmol), CuSO₄·0.5H₂O (100 mg, 0.400 mmol) and sodium ascorbate (200 mg, 1.00 mmol). The resulting mixture was stirred at RT for 1 h, then partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was collected, washed with water (30 mL), sat. NH₄Cl (3×30 mL), brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the title compound as yellow solid (500 mg, 61%). MS (ES⁺) C₁₀H₁₃N₃O₂requires: 207, found: 208 [M+H]⁺.

Step 4: 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylic Acid

To a solution of methyl 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylate (500 mg, 2.40 mmol) in MeOH (10 mL) and water (10 mL) was added LiOH·H₂O (250 mg, 6.00 mmol) and the resulting mixture was stirred at RT for 2 h. The reaction was partitioned between EtOAc (20 mL) and water (20 mL), the organic layer was collected, washed with water (30 mL), brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the title compound as yellow solid (450 mg, 96%). MS (ES⁺) C₉H₁₁N₃O₂requires: 193, found: 194 [M+H]⁺.

Step 5: 1-(Hex-5-ynyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(hex-5-ynyl)-1H-1,2,3-triazole-4-carboxylic acid (235 mg, 1.22 mmol) in DCM (15 mL) were added 3-(trifluoromethoxy)phenyl)methanamine (255 mg, 1.34 mmol), HATU (695 mg, 1.83 mmol), and DIEA (472 mg, 3.66 mmol), and the resulting mixture was stirred at RT for 12 h. The mixture was partitioned between DCM (20 mL) and water (20 mL), the organic layer was collected, washed with water (3×30 mL), brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0 to 20% MeOH in DCM) to give the title compound as yellow solid (300 mg, 67%). MS (ES⁺) C₁₇H₁₇F₃N₄O₂requires: 366, found: 367 [M+H]⁺.

Steps 6 to 7

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Step 6: Tert-butyl 4-(azidomethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 4.6 mmol) in DCM (20 mL) at 0° C., were added TEA (0.67 g, 6.9 mmol) and methylsulfonyl chloride (0.57 g, 5.0 mmol). The mixture was stirred at 0° C. for 0.5 h, then diluted with water (20 mL). The organic layer was collected and concentrated under reduced pressure. The residue was immediately taken up in DMF (10 mL) and NaN₃(330 mg, 5.0 mmol) was added. The mixture was stirred at 80° C. for 2 h, cooled to RT, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduce pressure to afford the title compound as a colorless oil (0.9 g, 80%). ¹H NMR (500 MHz, CDCl₃) δ 4.15-4.11 (m, 2H), 3.20-3.18 (d, J=6 Hz, 2H), 2.72-2.66 (m, 2H), 1.74-1.70 (m, 3H), 1.46 (s, 9H), 1.18-1.14 (m, 2H).

Step 7: Tert-butyl 4-((4-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of 1-(hex-5-ynyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.14 mmol) in ^tBuOH (1.5 ml) and water (1.5 ml) were added CuSO₄(10 mg, 0.06 mmol), sodium ascorbate (20 mg) and tert-butyl 4-(azidomethyl)piperidine-1-carboxylate (49 mg, 0.21 mmol) and the mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as a white solid (25 mg, 30%). ¹H NMR (500 MHz, CDCl₃) δ 8.07 (s, 1H), 7.55 (m, 1H), 7.39-7.20 (m, 3H), (bd, J=8.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 4.45 (t, J=6.8 Hz, 2H), 4.19 (d, J=7.2 Hz, 2H), 4.13-4.08 (m, 2H), 2.78-2.75 (t, J=7.6 Hz, 2H), 2.70-2.64 (m, 2H), 2.08-1.98 (m, 3H), 1.80-1.76 (m, 1H), 1.60-1.55 (m, 2H), 1.45 (s, 9H), 1.28-1.15 (m, 3H). MS (ES⁺) C₂₈H₃₇F₃N₈O₄requires: 606, found: 607 [M+H]⁺.

Example 9: 1-(4-(4-(Methylsulfonamidomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 5

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Step 1: 4-Hydroxybutyl Benzoate

To a solution of butane-1,4-diol (7.44 ml, 84.0 mmol) and DIEA (4.70 ml, 27.0 mmol) in MeCN (180 ml) at 0° C. was added dropwise a solution of benzoyl chloride (3.13 ml, 27.0 mmol) in MeCN (10 ml), at such a rate to keep the reaction mixture between 0-5° C. The mixture was stirred for an additional 15 minutes at 0° C., then warmed to RT, stirred for 16 h, and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (20% EtOAC in hexanes) to give the title compound as a colorless oil (4.82 g, 92%). MS (ES⁺) C₁₁H₁₄O₃requires: 194, found: 195 [M+H]⁺.

Step 2: 4-(Methylsulfonyloxy)butyl Benzoate

To a solution of 4-hydroxybutyl benzoate (5.0 g, 18 mmol) and TEA (3.7 g, 36.8 mmol) in DCM (20 ml) was added dropwise MsCl (2.5 g, 22 mmol) as a solution in DCM (10 ml). The mixture was stirred at RT for 30 minutes, diluted with water (30 ml), and extracted with DCM (50 ml). The organic layer was concentrated under reduced pressure to afford 4-(methylsulfonyloxy)butyl benzoate as a colorless oil (5.2 g, 98%). MS (ES⁺) C₁₂H₁₆O₅S requires: 273, found: 274 [M+H]⁺.

Step 3: 4-Azidobutyl Benzoate

To a solution of 4-(methylsulfonyloxy)butyl benzoate (3.0 g, 11.0 mmol) in DMF (15 ml) was added NaN₃(1.35 g, 22.1 mmol) and the mixture was stirred at 80° C. for 16 h. The mixture was then cooled to RT, diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was concentrated under reduced pressure to afford 4-azidobutyl benzoate as a yellow oil (3 g, 98%). MS (ES⁺) C₁₁H₁₃N₃O₂requires: 219, found: 220 [M+H]⁺.

Step 4: Tert-butyl 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of 4-azidobutyl benzoate (5.0 g, 23 mmol) in ^tBuOH/H₂O (20 ml, 1/1 v/v), tert-butyl propiolate (2.90 g, 22.8 mmol) and L-(+)-Ascorbic acid (1.0 g, 5.7 mmol) was added CuSO₄·0.5H₂O (2.0 g, 13 mmol). The mixture was stirred at RT for 16 h and concentrated under reduced pressure. The residue was taken up in water (50 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was collected by filtration to afford the title compound as a white solid (6.5 g, 83%). MS (ES⁺) C₁₈H₂₃N₃O₄requires: 345.2, found: 346 [M+H]⁺.

Step 5: 1-(4-(Benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of tert-butyl 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate (5.0 g, 15 mmol) in TFA/DCM (40 ml, 1/1 v/v) was stirred at RT for 3 h and then concentrated under reduced pressure. The residue was taken up in water (30 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was collected by filtration and crystallized from MeCN/H₂O to afford the title compound as a white solid (3.8 g, 90%). MS (ES⁺) C₁₄H₁₅N₃O₄requires: 289.1, found: 290 [M+H]⁺.

Steps 6 to 9

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Step 6: 4-(4-(3-(Trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl Benzoate

A mixture of 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.0 g, 3.5 mmol), (3-(trifluoromethoxy)phenyl)methanamine (0.66 g, 3.5 mmol), HATU (1.9 g, 5.0 mmol) and DIPEA (1.30 g, 10.5 mmol) in DMF (10 ml) was stirred at RT for 16 h. The residue was taken up in water (100 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was filtered to give the title compound as a white solid (1.0 g, 62%). MS (ES⁺) C₂₂H₂₁F₃N₄O₄requires: 462.2, found: 463 [M+H]⁺.

Step 7: 1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl benzoate (1.0 g, 2.2 mmol) and LiOH·H₂O (0.27 g, 6.6 mmol) in THF/H₂O (10 ml, 1/1 v/v) was stirred at RT for 16 h. The reaction mixture was then partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was collected and concentrated under reduced pressure to give the title compound as a white solid (600 mg, 77%). MS (ES⁺) C₁₅H₁₇F₃N₄O₃requires: 358.1, found: 359 [M+H]⁺.

Step 8: 1-(4-azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (600 mg, 1.68 mmol) and TEA (340 mg, 3.36 mmol) in DCM (5 ml) was added dropwise a solution of MsCl (240 mg, 2.10 mmol) in DCM (5 ml). The mixture was stirred at RT for 30 minutes, then diluted with water (10 ml) and extracted with DCM (20 ml). The organic layer was concentrated under reduced pressure. The residue was taken up in DMF (3 ml), NaN₃(110 mg, 1.68 mmol) was added and the mixture was stirred at 80° C. for 1 h, then cooled to RT. The residue was taken up in water (20 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was collected by filtration to give the title compound as a white solid (600 mg, 93%). MS (ES⁺) C₁₅H₁₆F₃N₇O₂requires: 383.1, found: 384 [M+H]⁺.

Step 9: Tert-butyl (1-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-4-yl)methylcarbamate

A mixture of 1-(4-Azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (100 mg, 0.26 mmol), tert-butyl prop-2-ynylcarbamate (40 mg, 0.26 mmol), L-(+)-ascorbic acid (40 mg, 0.23 mmol) and CuSO₄·0.5H₂O (20 mg, 0.12 mmol) in ^tBuOH/H₂O (3 ml, 1/1 v/v) was stirred at RT for 16 h and concentrated under reduced pressure. The residue was taken up in water (10 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was collected by filtration to give the title compound as a white solid (100 mg, 71%). MS (ES⁺) C₂₃H₂₉F₃N₈O₄requires: 538.2, found: 539 [M+H]⁺.

Steps 10 to 11

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Step 10: 1-(4-(4-(Aminomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A solution of tert-butyl (1-(4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazol-4-yl)methylcarbamate (100 mg, 0.19 mmol) in TFA/DCM (3 ml, 1/1 v/v) was stirred at RT for 3 h and concentrated under reduced pressure. The residue was taken up in water (100 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was collected by filtration to give the title compound as a white solid (70 mg, 86%). MS (ES⁺) C₁₈H₂₁F₃N₈O₂requires: 438.2, found: 439 [M+H]⁺.

Step 11: 1-(4-(4-(methylsulfonamidomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (70 mg, 0.16 mmol) in DCM (3 ml) were added TEA (48 mg, 0.48 mmol) and methanesulfonyl chloride (36.7 mg, 0.32 mmol). The mixture was stirred at RT for 3 h and concentrated under reduced pressure. The residue was taken up in water (10 ml) and the mixture was stirred for 15 minutes at RT. The resulting solid was collected by filtration to give the title compound as a white solid (37 mg, 45%). MS (ES⁺) C₁₉H₂₃F₃N₈O₄S requires: 516, found: 517 [M+H]⁺. ¹H NMR (500 MHz, DMSO) δ 9.21 (t, J=8.0, 1H), 8.60 (s, 1H), 8.01 (s, 1H), 7.51-7.40 (m, 2H), 7.35-7.20 (m, 3H), 4.50-4.32 (m, 6H), 4.10 (d, J=7.5, 2H), 2.88 (s, 3H), 1.78-1.73 (m, 4H).

Example 157: N-methyl-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 3

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Step 1: tert-butyl 1-(but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 4-azidobut-1-yne (20 g, 0.21 mol), t-butyl propiolate (26.5 g, 0.21 mol), L-(+)-ascorbic acid (8.0 g, 46 mmol), and CuSO₄(4.0 g, 25 mmol) in 1:1 v:v t-BuOH/H₂O (400 ml) was stirred at RT for 16 h, then concentrated under reduced pressure. Water (200 ml) was added, and the mixture was extracted with EtOAc (3×300 mL). The combined organic layers were concentrated under reduced pressure to afford a yellow solid. The solid was washed with petroleum ether to give the title compound as a white solid (25 g, 54%). MS (ES⁺) C₁₁H₁₅N₃O₂requires: 221, found: 222 [M+H]⁺.

Step 2: tert-butyl 1-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl 1-(but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate (15 g, 68 mmol), 6-iodopyridazin-3-amine (15 g, 68 mmol), Pd(PPh₃)₂Cl₂(4.8 g, 6.8 mmol), CuI (1.3 g, 6.8 mmol), and TEA (34.2 g, 339 mmol) in 300 mL of anhydrous THF was stirred at 60° C. under N₂for 16 h, then allowed cool to RT. DCM/MeOH (500 mL of a 10:1 v:v mixture) was added, the mixture was filtered and the filtrate concentrated under reduced pressure to give a yellow oil. The oil was purified by SiO₂gel chromatography (0% to 9% MeOH in DCM) to give the title compound as a yellow solid (18.0 g, 84%). MS (ES⁺) C₁₅H₁₈N₆O₂requires: 314, found: 315 [M+H]⁺.

Step 3: tert-butyl 1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl 1-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1H-1,2,3-triazole-4-carboxylate (3.5 g, 11 mmol), Raney Ni (300 mg) and MeOH (250 ml) was evacuated and refilled with hydrogen, then stirred under an atmosphere of H₂at 1 atm for 16 h. The mixture was filtered, and the filtrate concentrated under reduced pressure to give a yellow solid. The solid was purified by SiO₂gel chromatography (0% to 9% MeOH in DCM) to give the title compound as a yellow solid (3.17 g, 89%). MS (ES⁺) C₁₅H₂₂N₆O₂requires: 318, found: 319 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 6.15 (s, 2H), 4.52-4.37 (m, 2H), 2.69 (t, J=7.6 Hz, 2H), 1.96-1.79 (m, 2H), 1.65-1.42 (m, 11H).

Steps 4 to 6

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Step 4: tert-butyl 1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of tert-butyl 1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (80 mg, 0.25 mmol), pyridine (0.101 mL, 1.25 mmol) and 2-(3-(trifluoromethoxy)phenyl)acetic acid (83 mg, 0.37 mmol) was added T3P® (50 wt. %, 795 mg, 1.25 mmol) and the resulting mixture was stirred at 80° C. for 1 h and then RT for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (0% to 15% MeOH in DCM with 1% NH₄OH) to give the title compound as an orange solid (136 mg, 78% yield). MS (ES⁺) C₂₄H₂₇F₃N₆O₄requires: 520, found: 521 [M+H]⁺.

Step 5: 1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of tert-butyl 1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (134 mg, 0.257 mmol), TFA (0.992 mL, 12.9 mmol) and DCM (1 mL) was stirred at RT for 1 h, then concentrated under reduced pressure, azeotroping with toluene, to give the title compound as a waxy residue (120 mg, 100%). MS (ES⁺) C₂₀H₁₉F₃N₆O₄requires: 464, found: 465 [M+H]⁺.

Step 6: N-methyl-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of 1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, 0.258 mmol), methylamine in THF (2.0 M, 0.258 mL, 0.517 mmol) and BOP (149 mg, 0.336 mmol) in DMF (1.0 mL) was added DIEA (0.135 mL, 0.775 mmol) and the resulting mixture was stirred at RT for 1 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 20 min; Column: C18) to give the title compound as an off-white solid (35 mg, 28% yield). MS (ES⁺) C₂₁H₂₂F₃N₇O₃requires: 477, found: 478 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.55 (s, 1H), 8.47-8.41 (m, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.40-7.34 (m, 2H), 7.29-7.24 (m, 1H), 4.44 (t, J=7.0 Hz, 2H), 3.85 (s, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.75 (d, J=4.7 Hz, 3H), 1.92-1.84 (m, 2H), 1.69-1.59 (m, 2H).

Example 192: N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1-3

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Step 1: 2-methyl-4-(3-(trifluoromethoxy)phenyl)pyridine

A mixture of 4-bromo-2-methylpyridine (1.2 g, 7.0 mmol), (3-(trifluoromethoxy)phenyl)boronic acid (1.87 g, 9.07 mmol) and PdCl₂(dppf)-CH₂Cl₂(0.285 g, 0.349 mmol) in DME (23 mL) was degassed by bubbling through N₂for 5 min. Aq. K₂CO₃(2.0 M, 10.5 mL, 20.9 mmol) was added and the mixture was degassed by bubbling through N₂for an additional 5 min. The mixture was stirred at 70° C. for 12 h, then diluted with EtOAc (25 mL) and water (25 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×25 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 100% EtOAc with 20% MeOH in hexanes) to give the title compound as a yellow liquid (1.6 g, 91% yield). MS (ES⁺) C₁₃H₁₀F₃NO requires: 253, found: 254 [M+H]⁺.

Step 2: methyl 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate

To a solution of 2-methyl-4-(3-(trifluoromethoxy)phenyl)pyridine (1.6 g, 6.3 mmol) in THF (12.6 ml) at −78° C. was added LDA in THF (2.0 M, 9.48 ml, 19.0 mmol) and the resulting mixture was stirred at −78° C. for 30 min. Dimethyl carbonate (0.639 ml, 7.58 mmol) was then added and the mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat. aq. NH₄Cl (10 mL) at −78° C. and diluted with water (10 mL). The mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 100% EtOAc with 20% MeOH in hexanes) to give the title compound as a brown liquid (1.8 g, 92% yield). MS (ES⁺) C₁₅H₁₂F₃NO₃requires: 311, found: 312 [M+H]⁺.

Step 3: lithium 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate

To a solution of methyl 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (1.8 g, 5.8 mmol) in THF (23 mL) and MeOH (5.8 ml) at RT was added aq. LiOH (2.0 M, 3.1 ml, 6.2 mmol) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure (bath <35° C.) and lyophilized to give the title compound as a light orange solid (1.75 g, 100% yield). MS (ES⁺) C₁₄H₁₀F₃NO₃requires: 297, found: 298 [M+H]⁺.

Steps 4 to 6

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Step 4: 1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of tert-butyl 1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (265 mg, 0.832 mmol), TFA (1.0 mL, 13 mmol) and DCM (2.1 mL) was stirred at RT for 1 h, then concentrated under reduced pressure, azeotroping with toluene, to give the title compound as a waxy residue that was immediately used in the next step.

Step 5: 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a suspension of 1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (0.832 mmol), methylamine hydrochloride (97 mg, 1.4 mmol) and DIEA (0.499 mL, 2.86 mmol) in DMF (4.8 ml) was added HATU (471 mg, 1.24 mmol) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by SiO₂gel chromatography (0% to 30% MeOH in DCM with 1% NH₄OH) to give the title compound as a pale yellow solid (66 mg, 29% yield). MS (ES⁺) C₁₂H₁₇N₇O requires: 275, found: 276 [M+H]⁺.

Step 6: N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of lithium 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (702 mg, 2.26 mmol) and 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (500 mg, 1.82 mmol) in DMF (6.0 ml) at 0° C. was added T3P® in DMF (50 wt. %, 462 mg, 7.26 mmol) dropwise and the resulting mixture was allowed to warm to RT over 30 min and then stirred for 2 h. The brown mixture was adsorbed onto Celite® and purified by SiO₂gel chromatography (0% to 15% MeOH in DCM with 0.5% NH₄OH) to give a tan solid. The solid was then triturated with EtOAc (10 mL) to give the title compound as a light tan solid (361 mg, 34%). MS (ES⁺) C₂₆H₂₅F₃N₈O₄requires: 554, found: 555 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 11.31 (s, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.55 (d, J=1.2 Hz, 1H), 8.47-8.37 (m, 1H), 8.22 (d, J=9.1 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.81 (d, J=10.5 Hz, 2H), 7.72-7.64 (m, 2H), 7.56 (d, J=9.2 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 4.45 (t, J=7.0 Hz, 2H), 4.08 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.76 (d, J=4.4 Hz, 3H), 1.96-1.84 (m, 2H), 1.72-1.59 (m, 2H).

Example 211: 1-(2-fluoro-4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 4

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Step 1: 6-iodo-N,N-bis(4-methoxybenzyl)pyridazin-3-amine

To a solution of 6-iodopyridazin-3-amine (1.00 g, 4.52 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.543 g, 13.6 mmol) portionwise. The mixture was stirred for 20 min at RT and then cooled to 0° C. 1-(chloromethyl)-4-methoxybenzene (1.56 g, 9.95 mmol) was then added, then the mixture was stirred at RT for 30 min, quenched with MeOH, concentrated under reduced pressure, diluted with EtOAc, and washed with sat. aq. NaCl. The organic layer was concentrated under reduced pressure, and the residue was purified by SiO₂gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound as a yellow liquid (1.41 g, 68% yield). MS (ES⁺) C₂₀H₂₀IN₃O₂requires: 461, found: 462 [M+H]⁺.

Step 2: diethyl 2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)malonate

A mixture of copper(I) iodide (0.178 g, 0.932 mmol), picolinic acid (0.230 g, 1.86 mmol), Cs₂CO₃(9.11 g, 28.0 mmol), 6-iodo-N,N-bis(4-methoxybenzyl)pyridazin-3-amine (4.30 g, 9.32 mmol) and diethyl malonate (2.99 g, 18.6 mmol) in 1,4-dioxane (40 mL) was evacuated and backfilled with nitrogen three times. The mixture was heated to 85° C. and stirred for 1 h. The mixture was then treated with SiO₂gel (20 g), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 75% EtOAc in hexanes) to give the title compound as a brown liquid (3.3 g, 72% yield). MS (ES⁺) C₂₇H₃₁N₃O₆requires: 493, found: 494 [M+H]⁺.

Step 3: diethyl 2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)malonate

A mixture of K₂CO₃(428 mg, 3.10 mmol), diethyl 2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)malonate (1.67 g, 3.38 mmol), and tert-butyl 1-(2-fluoro-3-iodopropyl)-1H-1,2,3-triazole-4-carboxylate (1.00 g, 2.82 mmol) in DMF (10 mL) was stirred at RT for 16 h. The mixture was diluted with water and washed with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound (1.01 g, 50% yield). MS (ES⁺) C₃₇H₄₅FN₆O₈requires: 720, found: 721 [M+H]⁺.

Step 4: 1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of diethyl 2-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)malonate (0.900 g, 1.25 mmol), THF (36 mL), MeOH (12 mL), and water (6 mL) was treated with lithium hydroxide (0.150 g, 6.24 mmol) and stirred at 45° C. for 16 h. The mixture was concentrated under reduced pressure and then 1:1 v:v MeOH/water (20 mL) was added. The pH was adjusted carefully to 4-5 using 1 M aq. HCl, and the mixture was heated up to 90° C. and stirred for 2 h, then concentrated under reduced pressure and treated with 15% MeOH in DCM. The mixture was shaken vigorously, filtered through a Celite®, concentrated under reduced pressure, and dried to give the title compound, which was used without further purification in the following step. MS (ES⁺) C₂₇H₂₉FN₆O₄requires: 520, found: 521 [M+H]⁺.

Steps 5 to 7

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Step 5: 1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylic acid (0.36 g, 0.69 mmol) in DMF (0.2 ml) were added HATU (0.315 g, 0.828 mmol), (4-(trifluoromethyl)pyridin-2-yl)methanamine (0.158 g, 0.897 mmol) and DIEA (0.482 ml, 2.76 mmol) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water and precipitate was isolated by filtration to give the title compound as a solid, which was used in the following step without further purification. MS (ES⁺) C₃₄H₃₄F₄N₈O₃requires: 678, found: 679 [M+H]⁺.

Step 6: 1-(4-(6-aminopyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To 1-(4-(6-(bis(4-methoxybenzyl)amino)pyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (0.47 g, 0.69 mmol) at 0° C. was added sulfuric acid (0.736 ml, 13.8 mmol). The mixture was diluted with sat. aq. NaHCO₃and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give the title compound, which was used in the following step without further purification. MS (ES⁺) C₁₈H₁₈F₄N₈O requires: 438, found: 439 [M+H]⁺.

Step 7: 1-(2-fluoro-4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(6-aminopyridazin-3-yl)-2-fluorobutyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (20 mg, 0.046 mmol) in DMF (0.2 ml) were added 2-(pyridin-2-yl)acetic acid hydrochloride (10 mg, 0.059 mmol), HATU (23 mg, 0.059 mmol) and DIEA (0.029 ml, 0.16 mmol). The resulting mixture was stirred at RT for 20 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with sat. aq. NaCl, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting bright yellow residue was purified by SiO₂gel chromatography (3% to 5% MeOH in DCM) to give the title compound as an orange solid (12 mg, 47% yield). MS (ES⁺) C₂₅H₂₃F₄N₉O₂requires: 557, found: 558 [M+H]⁺. ¹H NMR (MeOH-d₄) δ 8.80 (d, J=5.4 Hz, 1H), 8.76 (d, J=5.3 Hz, 1H), 8.76 (dt, J=1.8, 8.5 Hz, 1H), 8.41 (s, 1H), 8.37 (d, J=9.4 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.90 (m, 1H), 7.67 (s, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 5.01 (m, 1H), 4.78 (s, 2H), 4.77 (m, 2H), 3.14 (m, 2H), 2.18 (m, 2H).

Example 259: 1-(2-fluoro-4-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 6

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Step 1: (R)-1-azido-3-(benzyloxy)propan-2-ol

To a solution of (R)-2-((benzyloxy)methyl)oxirane (2.42 ml, 15.9 mmol) and NH₄Cl (1.7 g, 32 mmol) in MeOH (39.5 ml) and water (5.9 ml) was added NaN₃(5.2 g, 79 mmol) and the resulting mixture was stirred at RT for 16 h. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (60 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over MgSO₄, filtered, and concentrated under reduced pressure to give the title compound as a colorless oil (3.01 g, 91% yield). MS (ES⁺) C₁₀H₁₃N₃O₂requires: 207, found: 208 [M+H]⁺.

Step 2: (R)-tert-butyl 1-(3-(benzyloxy)-2-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-1-azido-3-(benzyloxy)propan-2-ol (3.01 g, 14.5 mmol), tert-butyl propiolate (2.33 ml, 17.4 mmol), DIEA (0.253 ml, 1.45 mmol), and AcOH (0.083 ml, 1.4 mmol) in DCM (58.1 ml) was added copper(I) iodide (0.138 g, 0.726 mmol) and the resulting mixture was stirred at RT for 16 h. Silica gel (10 g) was added to the stirring mixture and the resulting suspension was filtered and washed with DCM (20 mL) and EtOAc (20 mL). The filtrate was concentrated under reduced pressure to give the crude title compound as an orange oil, which was used without further purification (3.95 g, 82% yield). MS (ES⁺) C₁₇H₂₃N₃O₄requires: 333, found: 334 [M+H]⁺.

Step 3: (S)-tert-butyl 1-(3-(benzyloxy)-2-fluoropropyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-tert-butyl 1-(3-(benzyloxy)-2-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate (3.95 g, 11.8 mmol) and pyridine (1.909 ml, 23.70 mmol) in DCM (23.7 ml) at 0° C. was added DAST (3.13 ml, 23.7 mmol). The resulting mixture was stirred at RT for 2.5 h, then filtered through a plug of silica gel, rinsing with DCM (50 mL). The filtrate was concentrated under reduced pressure and the residue was adsorbed onto Celite® and purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the title compound as a tan solid (1.78 g, 45% yield). MS (ES⁺) C₁₇H₂₂FN₃O₃requires: 335, found: 336 [M+H]⁺.

Step 4: (S)-tert-butyl 1-(2-fluoro-3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate

A reaction vessel was charged with (S)-tert-butyl 1-(3-(benzyloxy)-2-fluoropropyl)-1H-1,2,3-triazole-4-carboxylate (1.78 g, 5.31 mmol) and EtOAc (53.1 ml) under an atmosphere of N₂. The solution was degassed by bubbling through N₂for 10 min and then with N₂still flowing, palladium hydroxide on carbon (0.746 g, 1.06 mmol) was added. The resulting suspension was purged with H₂for 2 min then stirred under an atmosphere of H₂at 1 atm for 12 h. The reaction mixture was purged with N₂, filtered through a Celite® and concentrated under reduced pressure to give the crude title compound as a pale yellow solid (1.32 g, 101% yield). MS (ES⁺) C₁₀H₁₆FN₃O₃requires: 245, found: 246 [M+H]⁺.

Step 5: (S)-tert-butyl 1-(2-fluoro-3-(tosyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (S)-tert-butyl 1-(2-fluoro-3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxylate (1.32 g, 5.38 mmol) and DMAP (0.986 g, 8.07 mmol) in DCM (26.9 ml) was added 4-toluenesulfonyl chloride (1.23 g, 6.46 mmol) while maintaining the temperature at RT by a water bath, and the resulting mixture was stirred at RT for 1.5 h. The mixture was diluted with EtOAc (100 mL) and washed with sat. aq. NH₄Cl (2×40 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure to give crude title compound, which was used without further purification (1.80 g, 84% yield). MS (ES⁺) C₁₇H₂₂FN₃O₅S requires: 399, found: 400 [M+H]⁺.

Step 6: (S)-tert-butyl 1-(2-fluoro-3-iodopropyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (S)-tert-butyl 1-(2-fluoro-3-(tosyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (2.12 g, 5.31 mmol) in acetone (26.5 ml) was added NaI (0.796 g, 5.31 mmol) and the resulting mixture was stirred at 80° C. for 3 h, then at RT for 16 h. Additional NaI (2 eq., 1.6 g) was added and the mixture as stirred at 90° C. for 2 h. The reaction was allowed to cool to RT, diluted with 50:50 v:v EtOAc/Hexanes (150 mL) and washed with water (2×50 mL) and sat. aq. NaCl (50 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the title compound as a white solid (1.71 g, 91% yield). MS (ES⁺) C₁₀H₁₅FIN₃O₂requires: 355, found: 356 [M+H]⁺.

Steps 7 to 9

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Step 7: diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate

To a suspension of Cs₂CO₃(90.8 g, 279 mmol) in DMSO (200 ml) were added 2-fluoro-4-(trifluoromethyl)pyridine (25 g, 150 mmol) and diethyl malonate (46 ml, 300 mmol). The resulting mixture was stirred at 80° C. for 21 h. The resulting bright yellow reaction mixture was allowed to cool to RT, the solution was decanted and the solids were filtered and washed with DCM (using a total of 300-400 mL). The combined organic layers were washed with water (2×400 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a bright yellow liquid (32.3 g, 70% yield). MS (ES⁺) C₁₃H₁₄F₃NO₄requires: 305, found 306 [M+H]⁺.

Step 8: methyl 2-(4-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate (11.9 g, 39.0 mmol) in MeOH (100 ml) were added sodium methoxide in MeOH (25 wt. %, 10.0 ml, 43.7 mmol) and the resulting mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and poured onto a slurry of ice. The mixture was neutralized with aq. HCl (1 M, 45 mL, 45 mmol), extracted with EtOAc (200 mL), and the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a crude dark-yellow liquid. The residue was purified by SiO₂gel chromatography (10% to 20% EtOAc in hexanes) to give the title compound as a pale yellow liquid (5.66 g, 66% yield). MS(ES⁺) C₉H₈F₃NO₂requires: 219, found 220 [M+H]⁺.

Step 9: 2-(4-(trifluoromethyl)pyridin-2-yl)acetamide

To a solution of methyl 2-(4-(trifluoromethyl)pyridin-2-yl)acetate (6.04 g, 27.6 mmol) in MeOH (10 ml) was added ammonia (7 M in MeOH, 40 ml, 280 mmol). The reaction mixture was stirred at RT for 21 h, then concentrated under reduced pressure. The residue was taken up in hexanes/EtOAc and filtered. The collected solids were dried to give a crop of product as a white powder and the remaining filtrate was concentrated under reduced pressure to give another crop of product as a pale-yellow solid. The combined product was used without further purification (5.40 g, 96% yield). MS(ES⁺) C₈H₇F₃N₂O requires: 204, found 205 [M+H]⁺.

Steps 10 to 13

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Step 10: (R)-di-tert-butyl 2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-iodopyridazin-3-yl)malonate

A mixture of K₂CO₃(257 mg, 1.86 mmol), di-tert-butyl 2-(6-iodopyridazin-3-yl)malonate (781 mg, 1.86 mmol), and (S)-tert-butyl 1-(2-fluoro-3-iodopropyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.69 mmol) was evacuated and backfilled with N₂, and then DMF (5.6 mL) was added. The mixture was evacuated and backfilled with N₂three times, then stirred for 24 h at RT and another 24 h at 33° C. The mixture was diluted with 1:1 v:v EtOAc/hexanes (30 mL) and washed twice with water (30 mL then 15 mL). The combined aqueous layers were extracted with 1:1 v:v EtOAc/hexanes (15 mL). The combined organic layers were concentrated under reduced pressure to give crude title compound as a foamy solid, which was used without further purification. MS (ES⁺) C₂₅H₃₅FIN₅O₆requires: 647, found: 648 [M+H]⁺.

Step 11: (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

To a solution of (R)-di-tert-butyl 2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-iodopyridazin-3-yl)malonate (1.09 g, 1.69 mmol) in DCM (14.1 ml) was added TFA (14.1 ml), and the mixture was stirred at 40° C. for 1 h. The mixture was concentrated under reduced pressure to give an oily mixture, which was treated with THF (10 mL) and then concentrated under reduced pressure to give the crude title compound as a solid, which was used in the following step without further purification. MS (ES⁺) C₁₁H₁₁FIN₅O₂requires: 391, found: 392 [M+H]⁺.

Step 12: ((R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (661 mg, 1.69 mmol) and HATU (861 mg, 2.26 mmol) in DMF (8.4 mL) was treated with DIEA (1.475 mL, 8.468 mmol). The mixture was stirred for 20 min and then methylamine in THF (2.0 M, 1.689 mL, 3.378 mmol) was added. The reaction was vigorously stirred for 40 min (precipitate forms over time), diluted with water (5 mL), and then concentrated under reduced pressure to give a solid, which was triturated in water. Precipitate was isolated by filtration, washed with water then EtOAc, and dried to give the crude title compound, which was used in the following step without further purification (380 mg, 56% yield). MS (ES⁺) C₁₂H₁₄FIN₆O requires: 404, found: 405 [M+H]⁺.

Step 13: (R)-1-(2-fluoro-4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of Pd(PPh₃)₄(11.4 mg, 9.90 μmol), Xantphos (11.4 mg, 0.020 mmol), Cs₂CO₃(64.5 mg, 0.198 mmol), 2-(4-(trifluoromethyl)pyridin-2-yl)acetamide (20 mg, 0.099 mmol), and (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (40 mg, 0.099 mmol) in 1,4-dioxane (1 mL) was evacuated and back-filled with N₂three times. The mixture was stirred at 75° C. for 2.5 h. The reaction mixture was directly loaded onto silica gel and purified by SiO₂gel chromatography (0% to 25% DCM in MeOH) to give impure title compound as a brown solid. Further purification by reverse phase preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 12 min; Column: C18) gave the title compound as an off-white solid (27 mg, 57% yield). MS (ES⁺) C₂₀H₂₀F₄N₈O₂requires: 480, found: 481 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.38 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 8.51 (s, 1H), 8.46 (q, J=4.6, Hz, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.81 (s, 1H), 7.67 (d, J=4.6 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 5.03 (m, 1H), 4.77 (m, 2H), 4.17 (s, 2H), 3.05 (m, 2H), 2.75 (d, J=5.7 Hz, 3H), 2.08 (m, 2H). The title compound (1 mg/mL, 10 μL per injection) was analyzed on a Shimadzu Prominence HPLC system with a Lux Cellulose 4 column (4.6×150 millimeter, 5 micrometer, 1 mL/min) using a mobile phase of water:acetonitrile (40:60), and showed an ee of >98%.

Example 272: (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 2-bromo-4-(3,3-difluorocyclobutoxy)pyridine

To a solution of 2-bromo-4-fluoropyridine (5.0 g, 28 mmol) in DMF (100 ml) were added 3,3-difluorocyclobutanol (3.07 g, 28.4 mmol) and Cs₂CO₃(18.5 g, 56.8 mmol) and the resulting mixture was stirred at 60° C. for 2 h. The volatiles were removed under reduced pressure. DCM was added and the suspension was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 30% EtOAc in hexanes) to give the title compound as a pale yellow liquid (2.7 g, 36% yield). MS (ES⁺) C₉H₈ClF₂NO requires: 263, found: 264 [M+H]⁺.

Step 2: tert-butyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate

A degassed solution of 2-bromo-4-(3,3-difluorocyclobutoxy)pyridine (2.7 g, 10 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 40.9 ml, 20.4 mmol), Pd₂(dba)₃(0.468 g, 0.511 mmol) and X-Phos (0.244 g, 0.511 mmol) in THF (30 ml) was stirred at 65° C. for 1 h. The mixture was concentrated under reduced pressure, and sat. aq. NH₄Cl (30 mL) was added. The aqueous phase was extracted with EtOAc (3×20 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 60% EtOAc in hexanes) to give the title compound as a pale yellow liquid (2.5 g, 82% yield). MS (ES⁺) C₁₅H₁₉F₂NO₃requires: 299, found: 244 [M−(t−Bu)+2H]⁺.

Step 3: methyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate

To a solution of tert-butyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate (2.5 g, 8.4 mmol) in MeOH (50 ml) were added dropwise acetyl chloride (5.9 ml, 84 mmol) and the resulting mixture was stirred at 60° C. for 4 h then concentrated under reduced pressure. The reaction mixture was partitioned between EtOAc (100 mL) and sat. aq. NaHCO₃(100 mL). The aqueous layer was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure to give the title compound as a yellow liquid, which was used without further purification (2.1 g, 98% yield). MS (ES⁺) C₁₂H₁₃F₂NO₃requires: 257, found: 258 [M+H]⁺.

Step 4: 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide

A mixture of methyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate (2.1 g, 8.2 mmol) and ammonia in MeOH (7 M, 23.3 ml, 163 mmol) was stirred at 80° C. for 16 h in a pressure vessel, allowed to cool to RT, then concentrated under reduced pressure. The residue was triturated with Et₂O to give the title compound as a pale yellow solid (1.9 g, 96% yield). MS (ES⁺) C₁₁H₁₂F₂N₂O₂requires: 242, found: 243 [M+H]⁺.

Step 5: (R)-di-tert-butyl 2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)malonate

A degassed solution of 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide (1.12 g, 4.63 mmol), (R)-di-tert-butyl 2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-iodopyridazin-3-yl)malonate (3.0 g, 4.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.65 g, 0.93 mmol), Xantphos (1.072 g, 1.853 mmol) and Cs₂CO₃(3.02 g, 9.27 mmol) in 1,4-dioxane (30 ml) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by SiO₂gel chromatography (0% to 4% MeOH in DCM) to give the title compound as a yellow solid (1.21 g, 34% yield). MS (ES⁺) C₃₆H₄₆F₃N₇O₈requires: 761, found: 762 [M+H]⁺.

Step 6: (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylic acid

A solution of (R)-di-tert-butyl 2-(3-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-2-fluoropropyl)-2-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)malonate (1.15 g, 1.51 mmol) in TFA (5 ml) and 1,2-dichloroethane (5 ml) was stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was diluted with ACN (20 ml) and TEA (1 ml) was added. The resulting precipitate was isolated by filtration and washed with ACN to give the title compound as a pale yellow solid (455 mg, 60% yield). MS (ES⁺) C₂₂H₂₂F₃N₇O₄requires: 505, found: 506 [M+H]⁺.

Step 7: (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylic acid (410 mg, 0.811 mmol) in DMF (4 ml) were added HATU (339 mg, 0.892 mmol), DIEA (0.425 ml, 2.433 mmol) and methylamine in THF (2.0 M, 0.608 ml, 1.22 mmol) and the resulting mixture was stirred at 20° C. for 0.5 h then concentrated under reduced pressure. Water was added and resulting precipitate was isolated by filtration to give the title compound as a yellow solid (395 mg, 94% yield). MS (ES⁺) C₂₃H₂₅F₃N₈O₃requires: 518, found: 519 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.29 (s, 1H), 8.52 (s, 1H), 8.47 (m, 1H), 8.36 (m, 1H), 8.22 (d, J=9.1 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 5.03 (m, 1H), 4.90-4.70 (m, 3H), 3.94 (s, 2H), 3.28-3.22 (m, 2H), 3.08-2.98 (m, 2H), 2.79-2.70 (m, 5H), 2.20-1.95 (m, 2H).

Example 255: (R)-1-(2-fluoro-4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide

A sealed tube was charged with methyl 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (1.0 g, 3.2 mmol) and ammonia in MeOH (7 M, 11 ml, 77 mmol). The solution was sealed and heated at 80° C. for 24 h, then allowed to cool to RT and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 15% MeOH in DCM with 1% NH₄OH) to give the title compound as an off-white solid (0.92 g, 97% yield). MS (ES⁺) C₁₄H₁₁F₃N₂O₂requires: 296, found: 297 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 8.57 (d, J=5.2 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.63 (dd, J=5.3, 1.8 Hz, 1H), 7.56-7.46 (m, 2H), 6.98 (s, 1H), 3.66 (s, 2H).

Step 2: (R)-1-(2-fluoro-4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A vial was charged with 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide (0.366 g, 1.24 mmol), (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (0.50 g, 1.2 mmol), Cs₂CO₃(0.806 g, 2.47 mmol), Pd(PPh₃)₄(0.143 g, 0.124 mmol), Xantphos (0.143 g, 0.247 mmol), and 1,4-dioxane (12.4 mL). The mixture was degassed by bubbling N₂through the suspension for 5 min. The mixture was heated at 80° C. for 8 h, then allowed to cool to RT, adsorbed onto Celite® and purified by SiO₂gel chromatography (0% to 15% MeOH in DCM with 0.5% NH₄OH) to give a yellow solid (550 mg). The solid was triturated with 2:1 v:v EtOAc/Hexanes (2×10 mL) to give the title compound as an off-white solid (379 mg, 51% yield). MS (ES⁺) C₂₆H₂₄F₄N₈O₃requires: 572, found: 573 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 11.33 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.52 (s, 1H), 8.46 (m, 1H), 8.23 (d, J=9.2 Hz, 1H), 7.86 (dd, J=7.7, 1.5 Hz, 1H), 7.83-7.78 (m, 2H), 7.70-7.66 (m, 2H), 7.61 (d, J=9.2 Hz, 1H), 7.50 (m, 1H), 5.03 (dddd, J=49.4, 11.4, 7.4, 3.3 Hz, 1H), 4.86-4.67 (m, 2H), 4.08 (s, 2H), 3.09-2.96 (m, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.21-1.93 (m, 2H). The title compound (1 mg/mL, 10 μL per injection) was analyzed on a Shimadzu Prominence HPLC system with a Lux Cellulose 4 column (4.6×150 millimeter, 5 micrometer, 1 mL/min) using a mobile phase of water:acetonitrile (20:80), and showed an ee of >98%.

Example 270: (R)-1-(2-fluoro-4-(6-(2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 5

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Step 1: methyl 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetate

A mixture of 1-bromo-3-(trifluoromethoxy)benzene (2.6 g, 11 mmol), methyl 2-(1H-imidazol-4-yl)acetate (1.5 g, 11 mmol), copper(I) iodide (205 mg, 1.08 mmol), picolinic acid (133 mg, 1.08 mmol), and Cs₂CO₃(10.5 g, 32.4 mmol) in DMSO (50 ml) under Ar was stirred at 120° C. for 16 h. The mixture was treated with water (100 ml), filtered, and the residue was washed with EtOAc. The filtrate layers were separated, and the aqueous layer was extracted with EtOAc (3×100 mL). The combined EtOAc layers were washed with sat. aq. NaCl (100 ml), concentrated under reduced pressure and the residue purified by SiO₂gel chromatography (25% to 75% EtOAc in petroleum ether) to give the title compound as a light brown solid (980 mg, 25%). MS (ES⁺) C₁₃H₁₁F₃N₂O₃requires: 300, found: 301 [M+H]⁺.

Step 2: 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetic Acid

A mixture of methyl 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetate (980 mg, 3.27 mmol) and HCl in 1,4-dioxane (4.0 M, 10 ml, 40 mmol) was stirred at 75° C. for 16 h. The mixture was concentrated under reduced pressure to give the title compound as a light yellow solid (900 mg, 90%). MS (ES⁺) C₁₂H₉F₃N₂O₃requires: 286, found: 287 [M+H]⁺.

Step 3: 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamide

To a solution of 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetic acid (100 mg, 0.349 mmol) in DMF (1.7 ml) were added TEA (0.146 mL, 1.05 mmol) and HATU (133 mg, 0.349 mmol) and the resulting mixture was stirred at RT for 1 h. Aq. NH₄OH (1 M, 0.110 mL, 1.1 mmol) was added and the mixture was stirred at RT for 12 h, then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as a yellow liquid (48 mg, 34%). MS (ES⁺) C₁₂H₁₀F₃N₃O₂requires: 285, found: 286 [M+H]⁺.

Step 4: (R)-1-(2-fluoro-4-(6-(2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A solution of (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.12 mmol), 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamide 2,2,2-trifluoroacetate (49 mg, 0.12 mmol), Cs₂CO₃(141 mg, 0.433 mmol) and Xantphos (14 mg, 0.025 mmol) in 1,4-dioxane (1.24 ml) was degassed by bubbling N₂through for 1 min, then Pd(Ph₃)₄(14 mg, 0.012 mmol) was added and the mixture was further degassed for 1 min. The reaction mixture was then stirred at 70° C. for 12 h. The mixture was cooled to RT, diluted with MeOH (2 mL), filtered through Celite® and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (3% to 15% MeOH in DCM) to give a pale yellow solid. The residue was recrystallized from hot MeOH (1 mL), and solid was isolated by filtration, washed with MeOH (0.2 mL) and Et₂O (3×0.2 mL) and dried to give the title compound as a white solid (20 mg, 29%). MS (ES⁺) C₂₄H₂₃F₄N₉O₃requires: 561, found: 562 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.16 (s, 1H), 8.52 (s, 1H), 8.47 (m, 1H), 8.34 (s, 1H), 8.25 (d, J=9.2 Hz, 1H), 7.77 (s, 1H), 7.74-7.71 (m, 2H), 7.68-7.59 (m, 2H), 7.35 (d, J=8.6 Hz, 1H), 5.02 (m, 1H), 4.86-4.65 (m, 2H), 3.76 (s, 2H), 3.14-2.98 (m, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.14 (m, 1H), 2.00 (m, 1H).

Example 268: (R)-1-(2-fluoro-4-(6-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: diethyl 2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)malonate

To a suspension of NaH (60% in mineral oil, 1.39 g, 34.7 mmol) in DMF (116 mL) at 0° C. was added diethyl malonate (5.3 ml, 35 mmol) dropwise and the mixture was allowed to warm to RT and stirred for 15 min. 2,6-dichloro-4-(trifluoromethyl)pyridine (2.50 g, 11.6 mmol) was added slowly and then the mixture was stirred at 70° C. for 18 h. The mixture was allowed to cool to RT, quenched with water and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound as a colorless liquid (2.0 g, 52%). MS (ES⁺) C₁₂H₁₁ClF₃NO₄requires: 339, found: 340 [M+H]⁺.

Step 2: diethyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)malonate

To a solution of diethyl 2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)malonate (2.0 g, 5.9 mmol) and ferric acetylacetonate (208 mg, 0.589 mmol) in THF (24 mL) and NMP (5.9 mL) at 0° C. was added MeMgBr in diethyl ether (3.0 M, 5.9 mL, 18 mmol) dropwise and the resulting mixture was stirred at 0° C. for 5 min, then allowed to warm to RT and stirred for 30 min. Additional MeMgBr in diethyl ether (3.0 M, 29.5 mL total, 90 mmol total) was added in aliquots of 3.0 equivalents each. The mixture was cooled to 0° C. and slowly quenched with 1 M aq. HCl (100 mL), and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (4×50 mL) and sat. aq. NaCl (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 20% EtOAc in hexanes) to give the title compound as a yellow liquid (1.46 g, 78% yield). MS (ES⁺) C₁₄H₁₆F₃NO₄requires: 319, found: 320 [M+H]⁺.

Step 3: methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of diethyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)malonate (1.46 g, 4.57 mmol) in MeOH (45.7 mL) at 0° C. was added sodium methoxide (741 mg, 13.7 mmol) and the resulting mixture was stirred at RT for 12 h. The mixture was then stirred at 45° C. for 6 h, then allowed to cool to RT and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and EtOAc (40 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with sat. aq. K₂CO₃(2×10 mL) and sat. aq. NaCl (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a colorless liquid. MS (ES⁺) C₁₀H₁₀F₃NO₂requires: 233, found: 234 [M+H]⁺.

Step 4: 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamide

A vial was charged with methyl 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetate (813 mg, 3.49 mmol) and ammonia in MeOH (7 M, 10.0 ml, 69.7 mmol). The vial was sealed and the reaction mixture was stirred at RT for 72 h, then concentrated under reduced pressure to give the title compound as an off-white solid (748 mg, 98%). MS (ES⁺) C₉H₉F₃N₂O requires: 218, found: 219 [M+H]⁺.

Step 5: (R)-1-(2-fluoro-4-(6-(2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A suspension of (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (500 mg, 1.24 mmol), 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)acetamide (297 mg, 1.36 mmol) and Cs₂CO₃(1.01 g, 3.09 mmol) in 1,4-dioxane (12.4 mL) was degassed by bubbling through N₂for 1 min. Xantphos (143 mg, 0.247 mmol) and Pd(Ph₃)₄(143 mg, 0.124 mmol) were added and the mixture was degassed by bubbling through N₂for an additional 1 min. The reaction mixture was heated to 70° C. and stirred for 3 h. The mixture was cooled to RT, diluted with 1:1 v:v MeOH/DCM (4 mL), filtered through Celite®, washing with 1:1 v:v MeOH/DCM (4×3 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 6% MeOH in DCM) to give an off-white solid. The solid was triturated with MeOH (2 mL), collected by vacuum filtration and washed with cold MeOH (3×0.5 mL), then taken up in mixture of ACN/water (1:1), sonicated and lyophilized to give the title compound as a white solid (277 mg, 44%). MS (ES⁺) C₂₁H₂₂F₄N₈O₂requires: 494, found: 495 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.36 (s, 1H), 8.52 (s, 1H), 8.47 (m, 1H), 8.21 (d, J=9.1 Hz, 1H), 7.63-7.58 (m, 2H), 7.55 (s, 1H), 5.02 (m, 1H), 4.85-4.69 (m, 2H), 4.10 (s, 2H), 3.11-2.96 (m, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.56 (s, 3H), 2.14 (m, 1H), 2.00 (m, 1H).

Example 251: 1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

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Step 1: 2-chloro-4-cyclobutoxypyridine

To a solution of cyclobutanol (0.327 ml, 4.18 mmol) in DMF (19.01 ml) at 0° C. was added sodium hydride (60% in mineral oil, 0.198 g, 4.94 mmol) and the resulting mixture was stirred at RT for 5 min. 2-chloro-4-fluoropyridine (0.343 ml, 3.80 mmol) was then added dropwise and the resulting mixture was allowed to warm to RT, then diluted with sat. aq. NaHCO₃(5 mL) and water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO₄and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound as a colorless liquid (570 mg, 82%). MS (ES⁺) C₉H₁₀ClNO requires: 183, found: 184 [M+H]⁺.

Step 2: tert-butyl 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetate 2,2,2-trifluoroacetate

A degassed solution of 2-chloro-4-cyclobutoxypyridine (200 mg, 1.09 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 5.45 ml, 2.72 mmol), Pd₂(dba)₃(100 mg, 0.109 mmol) and X-Phos (26 mg, 0.054 mmol) in THF (3 ml) was stirred at 65° C. for 2 h then concentrated under reduced pressure. Water (10 mL) was added, the mixture was extracted with EtOAc (3×5 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the title compound as a white solid (187 mg, 46% yield). MS (ES⁺) C₁₅H₂₁NO₃requires: 263, found: 264 [M+H]⁺.

Step 3: 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide 2,2,2-trifluoroacetate

A solution of tert-butyl 2-(4-cyclobutoxypyridin-2-yl)acetate 2,2,2-trifluoroacetate (185 mg, 0.490 mmol) in TFA (3 ml) and DCM (3 ml) was stirred at RT for 2 h, then concentrated under reduced pressure. The residue was taken up in MeOH (3 ml) and treated with thionyl chloride (0.082 ml, 1.1 mmol), and the resulting mixture was stirred at 60° C. for 1 h. The mixture was concentrated under reduced pressure, and to the residue was added ammonia in MeOH (7 M, 3.0 ml, 21 mmol). The reaction mixture was heated in a pressure tube at 80° C. for 16 h, then allowed to cool to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 12 min; Column: C18) to give the title compound as a colorless liquid (102 mg, 85% yield). MS (ES⁺) C₁₁H₁₄N₂O₂requires: 206, found: 207 [M+H]⁺.

Step 4: 1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

A degassed suspension of 1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (60 mg, 0.15 mmol), 2-(4-cyclobutoxypyridin-2-yl)acetamide 2,2,2-trifluoroacetate (52.3 mg, 0.163 mmol), Pd(PPh₃)₄(17 mg, 0.015 mmol), Xantphos (17 mg, 0.030 mmol) and Cs₂CO₃(145 mg, 0.445 mmol) in 1,4-dioxane (2 ml) was stirred at 90° C. for 16 h, then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as a white solid (34 mg, 38% yield). MS (ES⁺) C₂₃H₂₇FN₈O₃requires: 482, found: 483 [M+H]⁺. ¹H NMR (MeOH-d₄) δ 8.58 (d, J=7.0 Hz, 1H), 8.39-8.33 (m, 2H), 7.65 (d, J=9.2 Hz, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.36 (dd, J=7.0 Hz, 2.7 Hz, 1H), 5.13-4.68 (m, 6H), 3.19-3.08 (m, 2H), 2.92 (s, 3H), 2.64-2.56 (m, 2H), 2.33-1.77 (m, 6H).

Example 245: 1-(4-(6-(2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 3-bromo-5-(3,3-difluorocyclobutoxy)pyridine 2,2,2-trifluoroacetate

To a solution of 5-bromopyridin-3-ol (174 mg, 1.00 mmol) in THF (5 ml) were added diisopropyl azodicarboxylate (0.389 ml, 2.00 mmol), triphenylphosphine (525 mg, 2.00 mmol) and 3,3-difluorocyclobutanol (130 mg, 1.20 mmol). The mixture was stirred at 80° C. for 2 h, then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as a yellow liquid (105 mg, 28%). MS (ES⁺) C₉H₈BrF₂NO requires: 263, found: 264 [M+H]⁺.

Step 2: tert-butyl 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetate 2,2,2-trifluoroacetate

A degassed solution of 3-bromo-5-(3,3-difluorocyclobutoxy)pyridine 2,2,2-trifluoroacetate (100 mg, 0.264 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 2.12 ml, 1.06 mmol), Pd₂(dba)₃(12 mg, 0.013 mmol) and X-Phos (6.3 mg, 0.013 mmol) in THF (2 ml) was stirred at 70° C. for 1 h, then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give title compound as a white solid (76 mg, 69%). MS (ES⁺) C₁₅H₁₉F₂NO₃requires: 299, found: 300 [M+H]⁺.

Step 3: 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetic Acid

A solution of tert-butyl 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetate 2,2,2-trifluoroacetate (75 mg, 0.18 mmol) in TFA (1 ml) and DCM (1 ml) was stirred at 20° C. for 2 h, then concentrated under reduced pressure. The residue was freeze dried to give the title compound as a white solid (65 mg, 100% yield). MS (ES⁺) C₁₁H₁₁F₂NO₃requires: 243, found: 244 [M+H]⁺.

Step 4: 1-(4-(6-(2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

To a solution of 2-(5-(3,3-difluorocyclobutoxy)pyridin-3-yl)acetic acid (17.5 mg, 0.072 mmol) in DMF (0.5 ml) were added HATU (18.7 mg, 0.049 mmol), DIEA (8.6 μl, 0.049 mmol) and 1-(4-(6-aminopyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate (20 mg, 0.049 mmol) and the resulting mixture was stirred at 20° C. for 3 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as a white solid (11 mg, 35%). MS (ES⁺) C₂₃H₂₅F₃N₈O₃requires: 518, found: 519 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.35 (s, 1H), 8.51 (s, 1H), 8.48 (d, J=4.7 Hz, 1H), 8.22-8.18 (m, 3H), 7.61 (d, J=9.3 Hz, 1H), 7.40 (m, 1H), 5.02 (m, 1H), 4.89-4.69 (m, 3H), 3.84 (s, 2H), 3.28-3.18 (m, 2H), 3.07-2.99 (m, 2H), 2.78-2.68 (m, 5H), 2.20-1.93 (m, 2H).

Example 262: 1-(2-Fluoro-4-(6-(2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 2,2,2-trifluoroethanol (0.72 ml, 9.8 mmol) in DMF (38 ml) was added NaH (60% in mineral oil, 0.39 g, 9.8 mmol) and the resulting mixture was stirred at RT for 5 min. 2-Chloro-4-fluoropyridine (0.68 ml, 7.6 mmol) was added and the reaction was stirred for 18 h. Additional NaH (60% in mineral oil, 0.39 g, 9.8 mmol) and 2,2,2-trifluoroethanol (0.72 ml, 9.8 mmol) were added. After 1 h, the reaction mixture was diluted with sat. aq. NaHCO₃(10 mL) and water (30 mL) and extracted with DCM (3×20 mL). The solution was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 100% EtOAc with 20% MeOH in hexanes) to give the title compound as a colorless liquid (1.1 g, 72%). MS (ES⁺) C₇H₅ClF₃NO requires: 211, found: 212 [M+H]⁺.

Step 2: Ethyl 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetate

Preparation of (2-ethoxy-2-oxoethyl)zinc(II) bromide reagent: To a suspension of Zn (1.2 g, 18 mmol) in THF (4.5 ml) was added chlorotrimethylsilane (0.11 ml, 0.89 mmol) and the resulting mixture was stirred at RT for 15 min. Ethyl 2-bromoacetate (0.99 ml, 8.9 mmol) in THF (13 ml) was added and the resulting mixture was stirred at 30° C. for 30 min. The light green mixture was taken up in a syringe and filtered using a 0.45 uM syringe filter (PTFE) to provide (2-ethoxy-2-oxoethyl)zinc(II) bromide as a ˜0.5 M solution in THF.

Reaction: A solution of 2-chloro-4-(2,2,2-trifluoroethoxy)pyridine (200 mg, 0.94 mmol), X-Phos (33 mg, 0.05 mmol) and Pd₂(dba)₃(21 mg, 0.024 mmol) in THF (6.3 mL) was degassed by bubbling through N₂for 5 min. (2-Ethoxy-2-oxoethyl)zinc(II) bromide in THF (˜0.5 M, 5.6 mL, 2.8 mmol) was added and the mixture was degassed by bubbling through N₂for 10 min. The mixture was stirred for 1 h, then diluted with EtOAc (5 mL) and treated with sat. aq. NH₄Cl (5 mL). Layers were separated, the aqueous phase was extracted with EtOAc (3×5 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 30% MeOH in DCM) to give the title compound as a colorless liquid (249 mg, 99%). MS (ES⁺) C₁₁H₁₂F₃NO₃requires: 263, found: 264 [M+H]⁺.

Step 3: 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamide

To ethyl 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetate (249 mg, 0.94 mmol) was added ammonia in MeOH (7 M, 2.0 mL, 14 mmol) and the resulting mixture was stirred at 65° C. for 18 h, then allowed to cool to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 12 min; Column: C18) to give the title compound as a white powder (192 mg, 58%). MS (ES⁺) C₉H₉F₃N₂O₂requires: 234.0, found: 256.2 [M+Na]⁺.

Step 4: 1-(2-fluoro-4-(6-(2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A solution of 1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (23 mg, 0.057 mmol), 2-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetamide 2,2,2-trifluoroacetate (30 mg, 0.086 mmol), Cs₂CO₃(75 mg, 0.23 mmol) and Xantphos (13 mg, 0.023 mmol) in 1,4-dioxane (0.57 mL) was degassed by bubbling through N₂for 10 min. Pd(PPh₃)₄(13 mg, 0.011 mmol) was added and the resulting solution was degassed by bubbling through N₂for 10 min. The mixture was stirred at 70° C. for 18 h, then allowed to cool to RT, filtered through Celite®, and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as an off-white solid (13.1 mg, 36%). MS (ES⁺) C₂₁H₂₂F₄N₈O₃requires: 510, found: 511 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.45 (s, 1H), 8.66 (d, J=7.25 Hz, 1H), 8.52 (s, 1H), 8.48 (q, J=3.86 Hz, 1H) 8.19 (d, J=9.65 Hz, 1H), 7.63 (d, J=9.21 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J=5.25 Hz, 1H), 5.07 (q, J=9.88 Hz, 2H), 4.87-4.67 (m, 2H), 4.14, (2, 2H), 3.09-2.98 (m, 2H), 2.76 (d, J=4.58 Hz, 3H), 2.22-2.06 (m, 1H), 2.06-1.95 (m, 1H), 1.21-1.13 (m, 1H).

Example 253: 1-(2-fluoro-4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamide

A vial was charged with methyl 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate (100 mg, 0.425 mmol) and ammonia in MeOH (7 M, 607 μl, 4.25 mmol). The vial was sealed and heated at 60° C. for 12 h, then allowed to cool to RT and concentrated under reduced pressure to give the title compound as a pale yellow liquid (94 mg, 100%). MS (ES⁺) C₁₂H₁₆N₂O₂requires: 220, found: 221 [M+H]⁺.

Step 2: 1-(2-fluoro-4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide trifluoroacetate

A solution of 1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (29 mg, 0.073 mmol), 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamide (16 mg, 0.073 mmol), Cs₂CO₃(83 mg, 0.25 mmol) and Xantphos (17 mg, 0.029 mmol) in 1,4-dioxane (726 μl) was degassed by bubbling through N₂for 1 min, then Pd(Ph₃)₄(17 mg, 0.015 mmol) was added and the mixture was degassed by bubbling through N₂for 1 min. The reaction mixture was stirred at 70° C. for 3 d. The mixture was allowed to cool to RT, filtered through Celite® and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as an off-white solid (5.3 mg, 12%). MS (ES⁺) C₂₄H₂₉FN₈O₃requires: 496, found: 497 [M+H]⁺. ¹H NMR (500 MHz, MeOH-d₄) δ 8.72 (d, J=6.1 Hz, 1H), 8.36-8.30 (m, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.88 (dd, J=6.1, 1.9 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 4.99 (m, 1H), 4.83-4.68 (m, 2H), 4.13-4.03 (m, 2H), 3.65-3.55 (m, 2H), 3.22-3.07 (m, 3H), 2.93 (s, 2H), 2.66 (s, 3H), 2.25-2.01 (m, 3H), 1.91-1.86 (m, 3H).

Example 258: N-methyl-1-(4-(6-(2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: methyl 2-(4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)acetate

A suspension of methyl 2-(4-bromopyridin-2-yl)acetate (300 mg, 1.30 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (347 mg, 1.57 mmol) and K₂CO₃(541 mg, 3.91 mmol) in 1,4-dioxane (5.9 mL) and water (0.6 mL) was degassed by bubbling through N₂for 1 min. PdCl₂(dppf)-CH₂Cl₂(53 mg, 0.065 mmol) was added and the mixture was degassed by bubbling through N₂for 1 min. The mixture was stirred at 90° C. for 2 h, then allowed to cool to RT, filtered through Celite® and partitioned between water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with sat. aq. NaCl (3 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the title compound as a pale yellow liquid (318 mg, 99%). MS (ES⁺) C₁₁H₁₀F₃NO₂requires: 245, found: 246 [M+H]⁺.

Step 2: methyl 2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate

A reaction vessel was charged with methyl 2-(4-(3,3,3-trifluoroprop-1-en-2-yl)pyridin-2-yl)acetate (100 mg, 0.408 mmol), 10% Pd/C (43 mg, 0.041 mmol) and EtOAc (4.1 ml) under an atmosphere of N₂. The suspension was degassed by bubbling through N₂for 1 min, and purged with H₂for 1 min. The reaction mixture was stirred under an atmosphere of H₂at 1 atm for 4 h. The reaction mixture was purged with N₂, filtered through Celite® and concentrated under reduced pressure to give the title compound as a pale yellow liquid (98 mg, 97%). MS (ES⁺) C₁₁H₁₂F₃NO₂requires: 247, found: 248 [M+H]⁺.

Step 3: lithium 2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate

To a solution of methyl 2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate (24 mg, 0.097 mmol) in THF (0.69 mL), MeOH (0.14 mL) and water (0.14 mL) was added LiOH (5.8 mg, 0.24 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was filtered, washing with MeOH, and the filtrate was concentrated under reduced pressure and dried by lyophilization to give the title compound as a white solid (23 mg, 100%). MS (ES⁺) C₁₀H₁₀F₃NO₂requires: 233, found: 234 [M+H]⁺.

Step 4: N-methyl-1-(4-(6-(2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (18 mg, 0.065 mmol) and lithium 2-(4-(1,1,1-trifluoropropan-2-yl)pyridin-2-yl)acetate (13 mg, 0.054 mmol) in DMF (0.54 mL) at 0° C. were added TEA (0.023 mL, 0.16 mmol) and T3P® (50 wt. % in EtOAc, 0.048 mL, 0.082 mmol) and the resulting mixture was stirred at 0° C. for 1 h. The mixture was allowed to warm to RT and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 16 min; Column: C18) to give the title compound as a pale yellow solid (3.4 mg, 10%). MS (ES⁺) C₂₂H₂₅F₃N₈O₂requires: 490, found: 491 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄) δ 8.70 (d, J=5.7 Hz, 1H), 8.43 (d, J=9.2 Hz, 1H), 8.32 (s, 1H), 7.82 (m, 1H), 7.72 (m, 1H), 7.69 (d, J=9.2 Hz, 1H), 4.50 (t, J=6.9 Hz, 2H), 3.92 (m, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.92 (s, 3H), 2.04-1.94 (m, 2H), 1.82-1.73 (m, 2H), 1.60-1.57 (m, 3H).

Example 267: (R)-1-(4-(6-(2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: N-methoxy-N,2-dimethylisonicotinamide

A mixture of 2-methylisonicotinic acid (4.0 g, 29 mmol), HATU (16.5 g, 1.14 mol) and DIEA (15.0 g, 116 mmol) in DMF (30 ml) was stirred at RT for 30 min, then N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35 mmol) was added. The mixture was stirred at RT for 16 h, then diluted with water (100 ml) and extracted with 10:1 v:v DCM/MeOH (3×200 ml). The combined organic layers were washed with sat. aq. NaCl (3×200 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a brown oil (4.0 g, 76%) MS (ES⁺) C₉H₁₂N₂O₂requires: 180, found: 181 [M+H]⁺.

Step 2: cyclopropyl(2-methylpyridin-4-yl)methanone

To a solution of N-methoxy-N,2-dimethylisonicotinamide (3.8 g, 21 mmol) in THF (100 mL) at 0° C. was slowly added cyclopropylmagnesium bromide in THF (0.5 M, 63 mmol). The mixture was stirred at 0° C. for 2 h, then treated with sat. aq. NH₄Cl (20 mL), and the mixture was extracted with DCM (3×300 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by SiO₂gel chromatography (0% to 7% MeOH in DCM) to give the title compound as a yellow oil (2.3 g, 67%). MS (ES⁺) C₁₀H₁₁NO requires: 161, found: 162 [M+H]⁺.

Step 3: 4-(cyclopropyldifluoromethyl)-2-methylpyridine

A mixture of cyclopropyl(2-methylpyridin-4-yl)methanone (1.0 g, 6.2 mmol) and BAST (5.5 g, 25 mmol) was stirred at 60° C. for 8 h then added to ice water (30 mL). The resulting mixture was extracted with DCM (3×50 mL), and the combined organic layers were concentrated under reduced pressure to a black oil. The oil was purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to give the title compound as a black oil (150 mg, 13%). MS (ES⁺) C₁₀H₁₁F₂N requires: 183, found: 184 [M+H]⁺.

Step 4: methyl 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetate

To a solution of 4-(cyclopropyldifluoromethyl)-2-methylpyridine (100 mg, 0.55 mmol) in THF (10 mL) at −78° C. was slowly added LDA in THF (2.0 M, 2.75 mmol). The mixture was stirred at −78° C. for 30 min. Dimethyl carbonate (59 mg, 0.66 mmol) was added. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with water at −78° C., allowed to warm to RT, and extracted with EtOAc (3×50 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the crude title compound as a yellow oil (130 mg, 100%). MS (ES⁺) C₁₂H₁₃F₂NO₂requires: 241, found: 242 [M+H]⁺.

Step 5: 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamide

A mixture of methyl 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetate (130 mg, 0.55 mmol) and ammonia in MeOH (7 M, 6 mL) was stirred at 60° C. for 16 h then concentrated under reduced pressure. The residue was purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to give the title compound as a yellow oil (33 mg, 27%). MS (ES⁺) C₁₁H₁₂F₂N₂O requires: 226, found: 227 [M+H]⁺.

Step 6: (R)-1-(4-(6-(2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of Pd(PPh₃)₄(9.3 mg, 8.0 μmol), Xantphos (9.3 mg, 0.016 mmol), Cs₂CO₃(52 mg, 0.16 mmol), 2-(4-(cyclopropyldifluoromethyl)pyridin-2-yl)acetamide (20 mg, 0.088 mmol), and (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (32 mg, 0.080 mmol) in 1,4-dioxane (0.27 mL) was evacuated and back-filled with N₂three times. The mixture was stirred at 55° C. for 12 h, then concentrated under reduced pressure, and the residue was partitioned between Et₂O (4 mL) and 1:1 v:v sat. aq. NH₄Cl/water (4 mL). The mixture was vortexed and precipitate was isolated by filtration, rinsing with Et₂O and water, and purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 12 min; Column: C18) to give the title compound (3.2 mg, 8% yield) as a off-white solid. MS (ES⁺) C₂₃H₂₅F₃N₈O₂requires: 502, found: 503 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.36 (s, 1H), 8.66 (d, J=5.2 Hz, 1H), 8.51 (s, 1H), 8.47 (q, J=4.6, Hz, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.60 (m, 2H), 7.47 (d, J=5.3 Hz, 1H), 5.03 (m, 1H), 4.76 (m, 2H), 4.09 (s, 2H), 3.03 (m, 2H), 2.76 (d, J=5.7 Hz, 3H), 2.06 (m, 2H), 1.71 (m, 1H), 0.72 (m, 4H).

Example 227: N-methyl-1-(4-(6-(2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: methyl 2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate

A degassed suspension of methyl 2-(2-oxopiperazin-1-yl)acetate hydrochloride (104 mg, 0.498 mmol), 1-bromo-3-(trifluoromethoxy)benzene (120 mg, 0.498 mmol), Pd(OAc)₂(11 mg, 0.050 mmol), Xantphos (14 mg, 0.025 mmol) and Cs₂CO₃(487 mg, 1.50 mmol) in 1,4-dioxane (3 ml) was stirred at 100° C. for 3 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as a colorless liquid (66 mg, 50%). MS (ES⁺) C₁₄H₁₅F₃N₂O₄requires: 332, found: 333 [M+H]⁺.

Step 2: 2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetic Acid

To a solution of methyl 2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate (60 mg, 0.18 mmol) in THF (1 ml) and water (1 ml) was added LiOH (13 mg, 0.54 mmol) and the resulting mixture was stirred at RT for 1 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 12 min; Column: C18) to give the title compound as a white solid (45 mg, 78%). MS (ES⁺) C₁₃H₁₃F₃N₂O₄requires: 318, found: 319 [M+H]⁺.

Step 3: N-methyl-1-(4-(6-(2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

A solution of 2-(2-oxo-4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetic acid (16 mg, 0.051 mmol), 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate (20 mg, 0.051 mmol), T3P® (50 wt. % in EtOAc, 163 mg, 0.257 mmol) and pyridine (0.021 ml, 0.26 mmol) in DMF (0.5 ml) was stirred at 80° C. for 0.5 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 20 min; Column: C18) to give the title compound as a white solid (5 mg, 14%). MS (ES⁺) C₂₅H₂₈F₃N₉O₄requires: 575, found: 576 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.23 (s, 1H), 8.55 (s, 1H), 8.43 (m, 1H), 8.20 (m, 1H), 7.57 (d, J=9.1 Hz, 1H), 7.34 (m, 1H), 6.98-6.95 (m, 1H), 6.89 (s, 1H), 6.74 (d, J=8.1 Hz, 1H), 4.45 (t, J=6.9 Hz, 2H), 4.34 (s, 2H), 3.92 (s, 2H), 3.61-3.55 (m, 4H), 2.90 (t, J=7.9 Hz, 2H), 2.76 (d, J=4.7 Hz, 3H), 1.93-1.87 (m, 2H), 1.68-1.62 (m, 2H).

Example 228: N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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A degassed suspension of ethyl 2-(piperazin-1-yl)acetate (86 mg, 0.50 mmol), 1-bromo-3-(trifluoromethoxy)benzene (120 mg, 0.499 mmol), Pd(OAc)₂(11 mg, 0.050 mmol), Xantphos (14 mg, 0.025 mmol) and Cs₂CO₃(488 mg, 1.50 mmol) in 1,4-dioxane (3 ml) was stirred at 100° C. for 3 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as a colorless liquid (108 mg, 65%). MS (ES⁺) C₁₅H₁₉F₃N₂O₃requires: 332, found: 333 [M+H]⁺.

Step 2: 2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetic acid 2,2,2-trifluoroacetate

To a solution of ethyl 2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetate (100 mg, 0.301 mmol) in THF (1 ml) and water (1 ml) were added LiOH (14.4 mg, 0.602 mmol) and the resulting mixture was stirred at RT for 1 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the title compound as a white solid (89 mg, 71%). MS (ES⁺) C₁₃H₁₅F₃N₂O₃requires: 304, found: 305 [M+H]⁺.

Step 3: N-methyl-1-(4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

To a solution of 2-(4-(3-(trifluoromethoxy)phenyl)piperazin-1-yl)acetic acid (21 mg, 0.051 mmol) in DMF (0.5 ml) were added HATU (21 mg, 0.057 mmol), 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate (20 mg, 0.051 mmol) and DIEA (0.045 ml, 0.257 mmol), and the resulting mixture was stirred at RT for 6 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the title compound as a white solid (18 mg, 52%). MS (ES⁺) C₂₅H₃₀F₃N₉O₃requires: 561, found: 562 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.59 (s, 1H), 8.42 (m, 1H), 8.21 (m, 1H), 7.64 (d, J=9.1 Hz, 1H), 7.37 (appar t, J=8.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.95 (s, 1H), 6.80 (m, 1H), 4.45 (t, J=7.0 Hz, 2H), 4.35-4.34 (m, br, 2H), 3.99-3.78 (m, 2H), 3.69-3.62 (m, 2H), (3.34-3.21 (m, 4H), 2.91 (t, J=7.6 Hz, 2H), 2.75 (d, J=4.7 Hz, 3H), 1.93-1.87 (m, 2H), 1.68-1.62 (m, 2H).

Example 233: 1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 2-chloro-4-cyclobutoxypyridine

To a suspension of NaH (60% in mineral oil, 0.395 g, 9.88 mmol) in DMF (38.0 ml) at 0° C. was added cyclobutanol (0.655 ml, 8.36 mmol) and the resulting mixture was stirred at 0° C. for 15 min. 2-chloro-4-fluoropyridine (0.687 ml, 7.60 mmol) was then added at 0° C. and the mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with EtOAc (20 mL), sat. aq. NaHCO₃(20 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound as a colorless liquid (1.3 g, 93% yield). MS (ES⁺) C₉H₁₀ClNO requires: 183, found: 184 [M+H]⁺.

Step 2: tert-butyl 2-(4-cyclobutoxypyridin-2-yl)acetate

A vial was charged with 2-chloro-4-cyclobutoxypyridine (0.50 g, 2.7 mmol), Pd₂(dba)₃(0.125 g, 0.136 mmol), and X-Phos (0.065 g, 0.14 mmol). (2-(Tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 12 ml, 6.0 mmol) was then added and the resulting mixture degassed by bubbling through N₂for 5 min. The mixture was heated at 40° C. for 1 h, then adsorbed onto silica gel and purified by SiO₂gel chromatography (0% to 10% MeOH in DCM with 1% NH₄OH) to give the title compound as a yellow oil (354 mg, 49%). MS (ES⁺) C₁₅H₂₁NO₃requires: 263, found: 264 [M+H]⁺.

Step 3: 2-(4-cyclobutoxypyridin-2-yl)acetic Acid Hydrochloride

HCl in 1,4-dioxane (4.0 M, 0.665 mL, 2.66 mmol) was added to tert-butyl 2-(4-cyclobutoxypyridin-2-yl)acetate (70 mg, 0.27 mmol) at 0° C. The resulting yellow solution was stirred at RT for 2 h. The solution was concentrated under reduced pressure, azeotroping with heptanes, to give the title compound as a light yellow solid (62 mg, 96%). MS (ES⁺) C₁₁H₁₃NO₃requires: 207, found: 208 [M+H]⁺.

Step 4: 1-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a suspension of 2-(4-cyclobutoxypyridin-2-yl)acetic acid hydrochloride (62 mg, 0.25 mmol), HATU (97 mg, 0.25 mmol), and 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate (76 mg, 0.20 mmol) in DMF (0.98 mL) was added 4-methylmorpholine (0.108 mL, 0.979 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was diluted with MeOH and purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-90%; 16 min; Column: C18) to give the title compound as a yellow solid (23 mg, 23% yield). MS (ES⁺) C₂₃H₂₈N₈O₃requires: 464, found: 465 [M+H]⁺; ¹H NMR (500 MHz, MeOH-d₄) δ 8.58 (d, J=6.9 Hz, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.31 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.35 (dd, J=7.0, 2.7 Hz, 1H), 5.08 (m, 1H), 4.50 (t, J=6.9 Hz, 2H), 3.03-2.96 (m, 2H), 2.91 (s, 3H), 2.66-2.53 (m, 3H), 2.34-2.21 (m, 3H), 2.03-1.90 (m, 3H), 1.87-1.71 (m, 3H).

Example 208: N-methyl-1-(4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: methyl 2-(4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)acetate

A suspension of methyl 2-(4-chloropyridin-2-yl)acetate (300 mg, 1.62 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (407 mg, 1.94 mmol) and PdCl₂(dppf)-CH₂Cl₂(132 mg, 0.162 mmol) in DME (3 mL) was degassed by bubbling through N₂for 5 min. Aq. K₂CO₃(2.0 M, 2.42 ml, 4.85 mmol) was added and the mixture was degassed by bubbling through N₂for an additional 5 min. The mixture was heated to 90° C. and stirred for 1 h. The mixture was diluted with EtOAc (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 10% MeOH in DCM with 1% NH₄OH) to give the title compound as a brown liquid (154 mg, 41% yield). MS (ES⁺) C₁₃H₁₅NO₃requires: 233, found: 234 [M+H]⁺.

Step 2: methyl 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate

A reaction vessel was charged with methyl 2-(4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)acetate (150 mg, 0.643 mmol), 10% palladium on carbon (68 mg, 0.064 mmol) and EtOAc (6.4 mL) under an atmosphere of N₂. The suspension was degassed by bubbling through N₂for 5 min and purged with H₂for 5 min. The mixture was stirred under an atmosphere of H₂at 1 atm for 2 h. The reaction mixture was purged with N₂, filtered through Celite®, and concentrated under reduced pressure to give the title compound as a clear liquid (148 mg, 98%). MS (ES⁺) C₁₃H₁₇NO₃requires: 235, found: 236 [M+H]⁺.

Step 3: lithium 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate 2,2,2-trifluoroacetate

To a solution of methyl 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetate (140 mg, 0.595 mmol) in THF (2.4 mL) and MeOH (0.60 mL) was added aq. LiOH (2.0 M, 0.595 mL, 1.19 mmol) and the resulting mixture was stirred at 50° C. for 1 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=0-30%; 20 min; Column: C18) to give the title compound as a pale yellow residue (96 mg, 48% yield). MS (ES⁺) C₁₂H₁₅NO₃requires: 221, found: 222 [M+H]⁺.

Step 4: N-methyl-1-(4-(6-(2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 2-(4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)acetic acid 2,2,2-trifluoroacetate (36 mg, 0.11 mmol) and 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (30 mg, 0.11 mmol) in DMF (0.22 mL) was added T3P® (50 wt. % in EtOAc, 347 mg, 0.545 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-60%; 12 min; Column: C18) to give the title compound as an orange solid (19 mg, 32% yield) after neutralizing residual TFA with an Agilent StratoSpheres® PL-HCO₃MP resin column (19 mg, 32% yield). MS (ES⁺) C₂₄H₃₀N₈O₃requires: 478, found: 479 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.56 (s, 1H), 8.46-8.38 (m, 2H), 8.22 (d, J=9.1 Hz, 1H), 7.55 (d, J=9.1 Hz, 1H), 7.32 (s, 1H), 7.20 (dd, J=5.3 Hz, 1.6 Hz, 1H), 4.45 (t, J=7.0 Hz, 2H), 3.99-3.91 (m, 4H), 3.44 (td, J=11.5 Hz, 2.6 Hz, 2H), 2.91-2.74 (m, 6H), 1.94-1.84 (m, 2H), 1.73-1.62 (m, 6H).

Example 261: 1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 1-(4-(6-bromopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of copper (II) bromide (1850 mg, 8.27 mmol) in ACN (35 ml) at 0-5° C. was added dropwise tert-butyl nitrite (0.540 ml, 4.54 mmol) over 1 min. The dark mixture was stirred at 0-5° C. for 5 min, then 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (1020 mg, 3.70 mmol) was added all at once. The mixture was stirred at 0-5° C. for 5 min then RT for 90 h. To the mixture was added 10 mL of a 10% aq. NH₄Cl solution. The resulting mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a yellow-orange solid. The solid was triturated in hot MeOH (5 mL), and the mixture was then chilled in a freezer at −RT for 15 min. Precipitate was isolated by filtration, rinsing well with freezer-chilled MeOH and dried by sucking air through to afford the title compound as a yellow solid (76.1 mg, 6%). MS (ES⁺) C₁₂H₁₅BrN₆O requires: 338/340, found: 361/363 (M+Na)⁺.

Step 2: 1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

A degassed solution of 2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamide 2,2,2-trifluoroacetate (30 mg, 0.084 mmol), 1-(4-(6-bromopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (28 mg, 0.084 mmol), Pd(PPh₃)₄(9.73 mg, 8.42 μmol), Xantphos (9.8 mg, 0.017 mmol) and Cs₂CO₃(82 mg, 0.25 mmol) in 1,4-dioxane (1 ml) was stirred at 90° C. for 16 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as a white solid (10 mg, 19%). MS (ES⁺) C₂₃H₂₆F₂N₈O₃requires: 500, found: 501 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄) δ 8.66 (d, J=7.0 Hz, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.31 (s, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.51 (d, J=2.7 Hz, 1H), 7.45 (dd, J=6.7 Hz, 2.6 Hz, 1H), 5.15-5.09 (m, 1H), 4.50 (t, J=7.0 Hz, 2H), 3.35-3.26 (m, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.95-2.86 (m, 5H), 2.03-1.97 (m, 2H), 1.79-1.73 (m, 2H).

Example 188: N-methyl-1-(4-(6-(2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: methyl 2-(5-bromopyridin-3-yl)acetate Hydrochloride

To a solution of 2-(5-bromopyridin-3-yl)acetic acid (216 mg, 1.00 mmol) in MeOH (5 ml) was added thionyl chloride (0.219 ml, 3.00 mmol) and the resulting mixture was stirred at 90° C. for 2 h. The volatiles were removed under reduced pressure and the residue was lyophilized to give the title compound as a white solid (266 mg, 100%). MS (ES⁺) C₈H₈BrNO₂requires: 230, found: 231 [M+H]⁺.

Step 2: methyl 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetate

A degassed solution of methyl 2-(5-bromopyridin-3-yl)acetate hydrochloride (80 mg, 0.30 mmol), (3-(trifluoromethoxy)phenyl)boronic acid (74.2 mg, 0.360 mmol), PdCl₂(dppf)-CH₂Cl₂(12 mg, 0.015 mmol) and aq. K₂CO₃(2.0 M, 0.450 ml, 0.900 mmol) in DME (3 ml) was stirred at 90° C. for 1 h. Water (10 mL) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 50% EtOAc in hexanes) to give the title compound as a colorless liquid (82 mg, 88%). MS (ES⁺) C₁₅H₁₂F₃NO₃requires: 311, found: 312 [M+H]⁺.

Step 3: 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetic Acid

To a solution of methyl 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetate (80 mg, 0.26 mmol) in THF (1 ml) and water (1 ml) were added LiOH (12.3 mg, 0.514 mmol) and the resulting mixture was stirred at RT for 1 h then concentrated under reduced pressure. Water (3 ml) was added and the solution was acidified with 10% w/v aq. citric acid to pH 3. Precipitate was isolated by filtration to give the title compound as a white solid (58 mg, 76%). MS (ES⁺) C₁₄H₁₀F₃NO₃requires: 297, found: 298 [M+H]⁺.

Step 4: N-methyl-1-(4-(6-(2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

A solution of 2-(5-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)acetic acid (15 mg, 0.052 mmol), 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate (20 mg, 0.051 mmol), T3P® (50 wt. % in EtOAc, 165 mg, 0.260 mmol) and pyridine (0.021 mL, 0.26 mmol) in DMF (0.5 ml) was stirred at 80° C. for 0.5 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 20 min; Column: C18) to give the title compound as a white solid (18 mg, 52%). MS (ES⁺) C₂₆H₂₅F₃N₈O₃requires: 554, found: 555 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.39 (s, 1H), 8.89 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.46-8.41 (m, 1H), 8.23-8.18 (m, 2H), 7.81 (d, J=7.6 Hz, 1H), 7.77 (s, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 4.45 (t, J=6.9 Hz, 2H), 3.97 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.76 (d, J=4.8 Hz, 3H), 1.93-1.84 (m, 2H), 1.68-1.60 (m, 2H).

Example 243: cyclohexyl (6-(4-(4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)pyridazin-3-yl)carbamate

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To a solution of 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (30.0 mg, 0.109 mmol) and pyridine (0.013 ml, 0.16 mmol) in THF (1.0 ml) was added cyclohexyl carbonochloridate (21 mg, 0.13 mmol). The mixture was stirred at RT for 4 h, then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-60%; 12 min; Column: C18) to give the title compound as a yellow solid (7 mg, 16% yield). MS (ES⁺) C₁₉H₂₇N₇O₃requires: 401, found 402 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.54 (s, 1H), 8.42 (appar br s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 4.72-4.63 (m, 1H), 4.44 (t, J=7.0 Hz, 2H), 2.86 (t, J=7.4 Hz, 2H), 2.75 (d, J=4.6 Hz, 3H), 1.92-1.82 (m, 4H), 1.76-1.67 (m, 2H), 1.67-1.58 (m, 2H), 1.55-1.19 (m, 6H).

Example 269: (R)-1-(2-fluoro-4-(6-(2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine

To a suspension of NaH (60% in mineral oil, 168 mg, 4.21 mmol) in THF (5 ml) was added 3-(benzyloxy)cyclobutanol (500 mg, 2.81 mmol) and the resulting mixture was stirred at RT for 10 min. 2-chloro-4-fluoropyridine (369 mg, 2.81 mmol) was added, and the mixture was stirred at 60° C. for 2 h. The mixture was allowed to cool to RT, then diluted with EtOAc (20 mL), treated with sat. aq. NH₄Cl (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 40% EtOAc in hexanes) to give 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine as a colorless liquid (585 mg, 72%). MS (ES⁺) C₁₆H₁₆ClNO₂requires: 289, found: 290 [M+H]⁺.

Step 2: 3-((2-chloropyridin-4-yl)oxy)cyclobutanol

To a solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine (585 mg, 2.02 mmol) in DCM (10 ml) was added BF₃·Me₂S (525 mg, 4.04 mmol), and the resulting mixture was stirred at RT for 4 h then concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and sat. aq. NaHCO₃(50 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3×30 mL) and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 5% MeOH in DCM) to give the title compound as a colorless liquid (370 mg, 92%). MS (ES⁺) C₉H₁₀ClNO₂requires: 199, found: 200 [M+H]⁺.

Step 3: 2-chloro-4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridine

To a suspension of NaH (60% in mineral oil, 44.5 mg, 1.85 mmol) in THF (10 ml) was added 3-((2-chloropyridin-4-yl)oxy)cyclobutanol (370 mg, 1.85 mmol). After bubbling subsided, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.29 g, 5.56 mmol) was added and the resulting mixture was stirred at 60° C. for 5 h. The reaction mixture was diluted with EtOAc (30 mL), sat. aq. NH₄Cl (30 mL) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (3×20 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 30% EtOAc in hexanes) to give the title compound as a pale yellow liquid (195 mg, 37%). MS (ES⁺) C₁₁H₁₁ClF₃NO₂requires: 281, found: 282 [M+H]⁺.

Step 4: tert-butyl 2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate

A degassed mixture of 2-chloro-4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridine (195 mg, 0.692 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in THF (0.5 M, 2.77 mL, 1.38 mmol), Pd₂(dba)₃(31.7 mg, 0.0350 mmol) and X-Phos (16.5 mg, 0.0350 mmol) was stirred at 60° C. for 0.5 h. The mixture was diluted with EtOAc (20 mL). Sat. aq. NH₄Cl (20 mL) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (3×10 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (0% to 40% EtOAc in hexanes) to give the title compound as a pale yellow liquid (173 mg, 69%). MS (ES⁺) C₁₇H₂₂F₃NO₄requires: 361, found: 306 [M−t(Bu)+2H]⁺.

Step 5: methyl 2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate

To a solution of tert-butyl 2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate (172 mg, 0.476 mmol) in MeOH (5 ml) were added acetyl chloride (0.338 ml, 4.76 mmol) and the resulting mixture was stirred at 60° C. for 3 h then concentrated under reduced pressure. The reaction mixture was taken up in EtOAc (20 mL) and washed with sat. aq. NaHCO₃(20 mL). The organic layer was further washed with sat. aq. NaCl (10 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give the title compound as a pale yellow liquid (150 mg, 99%), which was used in the next step without further purification. MS (ES⁺) C₁₄H₁₆F₃NO₄requires: 319, found: 320 [M+H]⁺.

Step 6: 2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamide

A mixture of methyl 2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetate (150 mg, 0.470 mmol) and ammonia in MeOH (7 M, 2.01 mL, 14.1 mmol) was heated in a sealed tube at 80° C. for 16 h then concentrated under reduced pressure to give the title compound as a yellow solid (140 mg, 98%), which was used without further purification. MS (ES⁺) C₁₃H₁₅F₃N₂O₃requires: 304, found: 305 [M+H]⁺.

Step 7: (R)-1-(2-fluoro-4-(6-(2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

A degassed solution of 2-(4-(3-(2,2,2-trifluoroethoxy)cyclobutoxy)pyridin-2-yl)acetamide (22.6 mg, 0.0740 mmol), (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (30 mg, 0.074 mmol), (PPh₃)₂PdCl₂(5.21 mg, 7.42 μmol), Xantphos (8.59 mg, 0.0150 mmol) and Cs₂CO₃(48.4 mg, 0.148 mmol) in 1,4-dioxane (1 ml) was stirred at 80° C. for 16 h then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as a white solid (10 mg, 19%). MS (ES⁺) C₂₅H₂₈F₄N₈O₄requires: 580, found: 581 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄) δ 8.60 (d, J=7.0 Hz, 1H), 8.37-8.32 (m, 2H), 7.64 (d, J=9.2 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.37 (dd, J=7.0 Hz, 2.6 Hz, 1H), 5.24 (m, 1H), 4.98 (m, 1H), 4.82-4.69 (m, 2H), 4.44 (m, 1H), 3.91 (q, J=8.9 Hz, 2H), 3.18-3.07 (m, 2H), 2.92 (s, 3H), 2.71-2.65 (m, 2H), 2.62-2.56 (m, 2H), 2.23-2.02 (m, 2H).

Example 274: 1-(4-(6-(2-(4-(difluoromethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: 2-chloro-4-(difluoromethoxy)pyridine

To a solution of 2-chloropyridin-4-ol (1.0 g, 7.7 mmol) in DMF (8 ml) were added K₂CO₃(4.6 g, 33 mmol) and 2-chloro-2,2-difluoroacetic acid (1.0 ml, 10 mmol) (note: exothermic!) and the resulting mixture was stirred at RT for 1 h, then stirred at 80° C. for 2 h. An additional amount of 2-chloro-2,2-difluoroacetic acid (2.0 ml, 20 mmol) was added and the mixture was stirred for 16 h at 60° C. then for 30 min at 80° C. The mixture was allowed to cool, filtered, and the filtrate partitioned between EtOAc and water. The organic layer was washed twice with water, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (50% to 100% EtOAc in hexanes) to give the title compound as a pale yellow solid (157 mg, 11% yield). MS (ES⁺) C₆H₄ClF₂NO requires: 179, found: 180 [M+H]⁺.

Step 2: tert-butyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate 2,2,2-trifluoroacetate

A degassed solution of 2-chloro-4-(difluoromethoxy)pyridine (300 mg, 1.67 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride in Et₂O (0.5 M, 8.35 ml, 4.18 mmol), Pd₂(dba)₃(153 mg, 0.167 mmol), and X-Phos (40 mg, 0.084 mmol) in THF (3 ml) was stirred at 65° C. for 2 h. The mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue. The mixture was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with sat. aq. NaCl, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 16 min; Column: C18) to afford the title compound as a white solid (19 mg, 3% yield). MS (ES⁺) C₁₂H₁₅F₂NO₃requires: 259, found: 204 [M−(t−Bu)+2H]⁺.

Step 3: methyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate

To a solution of tert-butyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate (20 mg, 0.077 mmol) in MeOH (2.00 ml, 49.4 mmol) was added acetyl chloride (0.055 ml, 0.77 mmol) dropwise over 5 min. The resulting mixture was stirred at 60° C. for 4 h and was then concentrated under reduced pressure to give the title compound as a yellow liquid (16 mg, 96%). MS (ES⁺) C₉H₉F₂NO₃requires: 217, found 218 [M+H]⁺.

Step 4: 2-(4-(difluoromethoxy)pyridin-2-yl)acetamide

Methyl 2-(4-(difluoromethoxy)pyridin-2-yl)acetate (16 mg, 0.074 mmol) was treated with ammonia in MeOH (7 M, 1.0 ml, 7.0 mmol), and the reaction mixture was sealed in a reaction vessel and stirred at 60° C. for 16 h. The mixture was allowed to cool, then concentrated under reduced pressure to give the title compound as a yellow solid (12 mg, 81% yield). MS (ES⁺) C₈H₈F₂N₂O₂requires: 202, found: 203 [M+H]⁺.

Step 5: 1-(4-(6-(2-(4-(difluoromethoxy)pyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A suspension of 1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (24 mg, 0.059 mmol), 2-(4-(difluoromethoxy)pyridin-2-yl)acetamide (11 mg, 0.054 mmol), Xantphos (6.0 mg, 0.010 mmol), Pd(PPh₃)₄(6.0 mg, 0.0052 mmol) and Cs₂CO₃(56 mg, 0.17 mmol) in 1,4-dioxane (1.5 ml) was degassed by bubbling through N₂for 5 min. The reaction mixture was heated to 80° C. and stirred for 5 h, then stirred at RT for 16 h. The mixture was concentrated under reduced pressure, dissolved in DMSO, filtered and the filtrate directly purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column: C18) to give the title compound as a yellow solid. MS (ES⁺) C₂₀H₂₁F₃N₈O₃requires: 478, found: 479 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 11.35 (s, 1H), 8.55 (d, J=5.8 Hz, 1H), 8.52 (s, 1H), 8.47 (m, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.50 (t, J=73 Hz, 1H), 7.31 (s, 1H), 7.19 (d, J=4.5 Hz, 1H), 5.03 (m, 1H), 4.86-4.69 (m, 2H), 4.05 (s, 2H), 3.13-2.98 (m, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.21-1.96 (m, 2H).

Example 275: (R)-1-(4-(6-(2-(4-cyclopropylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: methyl 2-(4-cyclopropylpyridin-2-yl)acetate

A degassed solution of methyl 2-(4-bromopyridin-2-yl)acetate (500 mg, 2.17 mmol), cyclopropylzinc(II) bromide in THF (0.5 M, 2.17 mL, 10.9 mmol) and PdCl₂(dppf)-CH₂Cl₂(89 mg, 0.11 mmol) was stirred at 65° C. for 3 h. The mixture was diluted with EtOAc and washed with sat. aq. NH₄Cl. The organic layer was separated, dried over MgSO₄, and concentrated under reduced pressure to give the crude title compound, which was used without further purification. MS (ES⁺) C₁₁H₁₃NO₂requires: 191, found: 192 [M+H]⁺.

Step 2: 2-(4-cyclopropylpyridin-2-yl)acetamide

To a solution of methyl 2-(4-cyclopropylpyridin-2-yl)acetate (415 mg, 2.17 mmol) in MeOH (10 ml) was added ammonia in MeOH (7 M, 12.4 ml, 86.8 mmol) and the reaction mixture was stirred at RT for 2 d. The reaction mixture was concentrated under reduced pressure, and the residue was purified by SiO₂gel chromatography (0% to 20% MeOH in DCM) to give the title compound as a tan liquid (250 mg, 65% yield). MS (ES⁺) C₁₀H₁₂N₂O requires: 176, found: 177 [M+H]⁺.

Step 3: (R)-1-(4-(6-(2-(4-cyclopropylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

A vial was charged with 2-(4-cyclopropylpyridin-2-yl)acetamide (21.8 mg, 0.124 mmol), (R)-1-(2-fluoro-4-(6-iodopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.12 mmol), Cs₂CO₃(81.0 mg, 0.247 mmol), Pd(PPh₃)₄(11.7 mg, 0.0120 mmol), Xantphos (14.3 mg, 0.0250 mmol), and 1,4-dioxane (1.24 mL). The mixture was evacuated and back-filled with N₂three times then stirred at 60° C. for 16 h. The mixture was diluted with sat. aq. NH₄Cl and extracted with DCM. The organic layer was concentrated under reduced pressure and the residue purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-30%; 12 min; Column: C18) to give the title compound as an off-white solid (9.0 mg, 16% yield). MS (ES⁺) C₂₂H₂₅FN₈O₂requires: 452, found: 453 [M+H]⁺. ¹H NMR (DMSO-d₆) δ 11.48 (s, 1H), 8.58 (d, J=5.2 Hz, 1H), 8.52 (s, 1H), 8.48 (q, J=4.6, Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.16 (s, 2H), 3.04 (m, 2H), 2.77 (d, J=5.7 Hz, 3H), 2.09 (m, 3H), 1.28 (m, 2H), 1.09 (m, 2H).

Example 605: N-methyl-1-(4-(6-(2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: 1-(4-(6-(2-(4-bromopyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (2.0 g, 7.2 mmol) and 2-(4-bromopyridin-2-yl)acetic acid (1.6 g, 7.2 mmol) in DMF (5 ml) were added T3P® (50 wt. % in EtOAc, 9.2 g, 14 mmol) and DIEA (2.7 g, 22 mmol). The mixture was stirred at RT for 3 h, then water (50 mL) was added, the mixture was stirred for 30 min, and precipitate was isolated by filtration to give the title compound as a yellow solid (1 g, 40%). MS (ES⁺) Cl₉H₂₁BrN₈O₂requires: 473, found: 474 [M+H]⁺.

Step 2: N-methyl-1-(4-(6-(2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(6-(2-(4-bromopyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (60 mg, 0.12 mmol), 2-(trifluoromethyl)phenylboronic acid (60 mg, 0.25 mmol), and Pd(PPh₃)₄(15 mg, 0.012 mmol) in 1,4-dioxane (2 ml) and water (0.2 ml) was added Cs₂CO₃(12.2 mg, 0.375 mmol), and the mixture was stirred at 100° C. for 16 h. The mixture was concentrated under reduced pressure, DMF (3 mL) was added, the mixture was filtered, and the filtrate was purified by preparatory HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to afford the title compound as a white solid (28 mg, 42%). MS (ES⁺) C₂₆H₂₅F₃N₈O₂requires: 538, found: 539 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 1.63 (m, 2H), 1.88 (m, 2H), 2.75 (d, J=6 Hz, 3H), 2.89 (t, J=9.5 Hz, 3H), 4.14 (s, 2H), 4.45 (t, J=8.5 Hz, 2H), 7.46 (appar m, 2H), 7.55 (s, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.76 (m, 2H), 7.91 (d, J=7.6 Hz, 1H), 8.23 (d, J=9.2 Hz, 1H), 8.45 (m, 1H), 8.56 (s, 1H), 8.68 (d, J=6.5 Hz, 1H), 11.42 (s, 1H).

Example 229: N-methyl-5-(4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide

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Steps 1 to 5

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Step 1: pent-4-ynehydrazide

A mixture of methyl pent-4-ynoate (100 g, 510 mmol) and hydrazine hydrate (100 mL, 1530 mmol) in EtOH (800 mL) was stirred at reflux under Ar for 16 h. The mixture was concentrated under reduced pressure, azeotroping with toluene (2×250 mL), to give the title compound as a white solid (61 g, 100%), which was used in the next step without further purification. MS (ES⁺) C₅H₈N₂O requires: 112, found: 113[M+H]⁺.

Step 2: ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate

To a mixture of pent-4-ynehydrazide (25.0 g, 223 mmol) and TEA (62.1 mL, 446 mmol) in DCM (500 mL) at 0° C. was added ethyl 2-chloro-2-oxoacetate (27.4 mL, 246 mmol). The mixture was stirred at RT for 30 min then filtered, washing with DCM (2×20 mL). The combined filtrates were concentrated under reduced pressure to give the title compound as a brown oil (60 g, >100%), which was used without further purification. MS (ES⁺) C₉H₁₂N₂O₄requires: 212, found: 213[M+H]⁺.

Step 3: ethyl 5-(but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl 2-oxo-2-(2-pent-4-ynoylhydrazinyl)acetate (17.5 g, 8.20 mmol) in toluene (350 mL) was stirred at 60° C. for 15 min, then P₂S₅(20 g, 9.0 mmol) was added in portions. The mixture was stirred at 60° C. for 15 min, then allowed to cool to RT. The toluene layer was separated, and the remaining residue was taken up in sat. aq. NaHCO₃(25 mL) and extracted with EtOAc (3×180 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by SiO₂gel chromatography (18% to 30% EtOAc in petroleum ether) to afford the title compound as a yellow solid (3.9 g, 22%). MS (ES⁺) C₉H₁₀N₂O₂S requires: 210, found: 211 [M+H]⁺.

Step 4: ethyl 5-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl 5-(but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate (13.6 g, 64.8 mmol), 6-iodopyridazin-3-amine (15.0 g, 68.0 mmol), Pd(PPh₃)₂Cl₂(4.55 g, 6.50 mmol), copper (I) iodide (2.47 g, 1.30 mmol) and TEA (27.0 mL, 194 mmol) in THF (200 mL) under Ar was stirred at 50° C. for 1 h, then filtered through a short SiO₂gel column, washing with THF (500 mL) and 4:1 v:v DCM/EtOH (800 mL). The filtrate was concentrated under reduced pressure to afford 44 g of a brown oil, which was washed with Et₂O (200 mL×2) and 8:1 v:v Et₂O/EtOAc (200 mL). The resulting brown oil was triturated with 95% EtOH (20 mL) and water (160 mL), solid was removed by filtration, and the filtrate was extracted with DCM (150 mL×3). The combined final organic layers were concentrated under reduced pressure to afford the title compound as a brown oil (18.9 g, 96%). MS (ES⁺) C₁₃H₁₃N₅O₂S requires: 303, found: 304 [M+H]⁺.

Step 5: ethyl 5-(4-(6-aminopyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxylate

A reaction vessel containing ethyl 5-(4-(6-aminopyridazin-3-yl)but-3-ynyl)-1,3,4-thiadiazole-2-carboxylate (18.9 g, 62.4 mmol) and Raney Ni (9.0 g) in EtOH (800 mL) was charged with H₂three times, stirred at 40° C. for 1.5 h, purged with N₂, filtered, washed with hot EtOH (400 mL, 70-80° C.), and concentrated under reduced pressure to afford 16 g of a brown oil. To this oil was added 40 mL of EtOAc, the mixture was stirred for 10 min, then Et₂O (200 mL) was added slowly. The mixture was stirred at RT for 30 min, and solid was isolated by filtration, washed with 1:5 v:v EtOAc/Et₂O (2×20), and dried to afford the title compound as a white solid (11.6 g, 61%). MS (ES⁺) C₁₃H₁₇N₅O₂S requires: 307, found: 308[M+H]⁺.

Steps 6 to 9

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Step 6: diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate

To a solution of 2-fluoro-4-(trifluoromethyl)pyridine (25 g, 0.15 mol) in DMSO (200 mL) were added Cs₂CO₃(97.5 g, 0.300 mol) and diethyl malonate (48 g, 0.30 mol), and the mixture was stirred under N₂at 80° C. for 3 h. The mixture was allowed to cool to RT, filtered, and the filtrate was treated with DCM (200 mL). Crude title compound crystallized from the solution as a white solid, which was used without further purification (40 g, 87%). MS (ES⁺) C₁₃H₁₄F₃NO₄requires: 305, found: 306 [M+H]⁺.

Step 7: ethyl 2-(4-(trifluoromethyl)pyridin-2-yl)acetate

To a solution of diethyl 2-(4-(trifluoromethyl)pyridin-2-yl)malonate (4.7 g, 0.015 mol) in DMSO (30 mL) was added lithium chloride (1.9 g, 0.046 mol) and the solution was stirred under N₂at 130° C. for 3 h, then allowed to cool to RT and treated with water (20 mL). The mixture was extracted with EtOAc (2×50 mL), and the combined organic layers were washed with sat. aq. NaCl, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (9% EtOAc in petroleum ether) to give the title compound as a yellow oil (1.7 g, 49%). MS (ES⁺) C₁₀H₁₀F₃NO₂requires: 233, found: 234 [M+H]⁺.

Step 8: ethyl lithium 2-(4-(trifluoromethyl)pyridin-2-yl)acetate

Lithium hydroxide (0.610 g, 14.4 mmol) was dissolved in ethanol (20 mL), then 2-(4-(trifluoromethyl)pyridin-2-yl)acetate (1.7 g, 7.2 mmol) was added slowly, and the reaction mixture was stirred at RT for 3 h. The mixture was concentrated under reduced pressure to give the crude title compound as a yellow solid, which was used without further purification (1.3 g, 86%). MS (ES⁺) C₈H₆F₃NO₂requires: 205, found: 206 [M+H]⁺.

Step 9: N-methyl-5-(4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazole-2-carboxamide 2,2,2-trifluoroacetate

To a solution of crude lithium 2-(4-(trifluoromethyl)pyridin-2-yl)acetate (21.7 mg, 0.103 mmol) in DMF (0.5 ml) were added 5-(4-(6-aminopyridazin-3-yl)butyl)-N-methyl-1,3,4-thiadiazole-2-carboxamide (30 mg, 0.10 mmol), HATU (42.9 mg, 0.113 mmol) and DIEA (0.054 ml, 0.31 mmol), and the resulting mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 12 min; Column: C18) to give the title compound as a white solid (3 mg, 5%). MS (ES⁺) C₂₀H₂₀F₃N₇O₂S requires: 479, found: 480 [M+H]⁺. ¹H NMR (600 MHz, MeOH-d₄) δ 8.77 (d, J=5.2 Hz, 1H), 8.54 (d, J=9.2 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J=5.3 Hz, 1H), 4.85 (s, 2H), 3.23 (t, J=6.8 Hz, 2H), 3.2 (t, J=7.4 Hz, 2H), 2.94 (s, 3H), 1.95-1.85 (m, 4H).

Example 508: 5-(3-fluoro-4-(4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide

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Step 1: pent-4-enehydrazide

Hydrazine hydrate (7.60 g, 152 mmol) was added to a solution of ethyl pent-4-enoate (19.5 g, 152 mmol) in 120 mL of MeOH. The mixture was stirred at RT for 48 h. The mixture was concentrated under reduced pressure to give the title compound as a white solid (11 g, 64%). MS (ES⁺) C₅H₁₀N₂O requires: 114, found: 115[M+H]⁺.

Step 2: ethyl 5-(but-3-enyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of pent-4-enehydrazide (1.14 g, 10.0 mmol) and TEA (2.1 mL, 15 mmol) in anhydrous THF (20 mL) at 0° C. was slowly added ethyl oxalyl chloride (1.34 mL, 12.0 mmol). The mixture was stirred at 0° C. for 30 min. The mixture was concentrated under reduced pressure and the residue dissolved in toluene (20 mL). P₂S₅(4.44 g, 20.0 mmol) was added, and the mixture was stirred at 60° C. for 20 min. The mixture was filtered and the residue was washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by SiO₂gel chromatography (20% EtOAc in petroleum ether) to give the title compound as a yellow oil (1.6 g, 76%). MS (ES⁺) C₉H₁₂N₂O₂S requires: 212, found: 213[M+H]⁺.

Step 3: ethyl 5-(4-azido-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl 5-(but-3-enyl)-1,3,4-thiadiazole-2-carboxylate (10.0 g, 47.2 mmol) and NaHCO₃(40.0 g, 476 mmol) in 10:1 v:v DCM/water (220 mL) was added m-chloroperbenzoic acid (10.0 g, 56.6 mmol). The mixture was stirred at RT for 40 min then additional m-chloroperbenzoic acid (6.00 g, 37.8 mmol) was added. The mixture was stirred at RT for 2 h then additional m-chloroperbenzoic acid (8.00 g, 47.2 mmol) was added. The mixture was stirred for 2 h, then quenched with water and partitioned between DCM and water. The aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with sat. aq. Na₂SO₃and sat. aq. NaHCO₃, dried and concentrated under reduced pressure to afford a crude product, which was dissolved in 80 mL of DMF. To the solution was slowly added NaN₃(9.20 g, 142 mmol). The mixture was stirred at 65° C. for 16 h, then diluted with water and extracted with EtOAc (3×150 mL). The combined organic layers were washed with sat. aq. NaCl, dried and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (25% to 50% EtOAc in petroleum ether) to give the title compound as a brown oil (10 g, 26%). MS (ES⁺) C₉H₁₃N₅O₃S requires: 271, found: 272[M+H]⁺.

Step 4: ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate

A mixture of ethyl 5-(4-azido-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate (1.0 g, 3.7 mmol), tert-butyl propiolate (558 mg, 4.40 mmol), CuSO₄(200 mg) and sodium ascorbate (400 mg) in 1:1 v:v t-BuOH/water (20 mL) was stirred at RT for 2 h. The mixture was diluted with water, then extracted with EtOAc (3×30 mL). The combined organic layers were dried and concentrated under reduced pressure to give the title compound as a yellow solid (1.4 g, 96%). MS (ES⁺) C₁₆H₂₃N₅O₅S requires: 397, found: 420[M+Na]⁺.

Step 5: ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1,3,4-thiadiazole-2-carboxylate

To a mixture of ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-hydroxybutyl)-1,3,4-thiadiazole-2-carboxylate (1.4 g, 3.5 mmol) and pyridine (0.150 mL, 1.86 mmol) in DCM (30 mL) at 0° C. was slowly added DAST (2.27 g, 14.1 mmol). The mixture was stirred at 0° C. for 30 min. The mixture was added slowly to an ice-cold saturated NaHCO₃solution, then extracted with DCM (3×30 mL). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (25% EtOAc in petroleum ether) to give the title compound as an orange solid (440 mg, 31%). MS (ES⁺) C₁₆H₂₂FN₅O₄S requires: 399, found: 422[M+Na]⁺.

The next steps outline the preparation of racemic EXAMPLE 508. For the preparation of enantiomeric enriched EXAMPLE 220 and EXAMPLE 221, a chiral separation was performed at this stage and the products carried through using the same general procedure. Ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1,3,4-thiadiazole-2-carboxylate was separated into its separate enantiomers using chiral SFC separation (column: IC 4.6*150 mm Sum; solvent: MeOH). Enantiomers are arbitrarily assigned in the final products.

Step 6: tert-butyl 1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of ethyl 5-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1,3,4-thiadiazole-2-carboxylate (150 mg, 0.38 mmol) and (4-(trifluoromethyl)pyridin-2-yl)methanamine (100 mg, 0.56 mmol) in MeOH (2 mL) was stirred at 80° C. for 3 d in a sealed tube. The mixture was concentrated under reduced pressure to afford the title compound as a yellow solid (195 mg, 98%). MS (ES⁺) C₂₁H₂₃F₄N₇O₃S requires: 529, found: 530[M+H]⁺.

Step 7: 1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

TFA (2 mL) was added to a solution of tert-butyl 1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (195 mg, 0.370 mmol) in DCM (3 mL). The mixture was stirred at RT for 3 h then concentrated under reduced pressure. MeOH was added to the residue, and precipitate was isolated by filtration to give the title compound as a beige solid (170 mg, 98%). MS (ES⁺) C₁₇H₁₅F₄N₇O₃S requires: 473, found: 474[M+H]⁺.

Step 8: 5-(3-fluoro-4-(4-(methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazole-2-carboxamide

A mixture of 1-(2-fluoro-4-(5-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.085 mmol), methylamine hydrochloride (9.0 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol) and DIEA (33 mg, 0.25 mmol) in DMF (1 mL) was stirred at RT for 2 h then treated with water. Precipitate was isolated by filtration and washed with MeOH to give the title compound as a white solid (20 mg, 49%). MS (ES⁺) C₁₈H₁₈F₄N₈O₂S requires: 486, found: 487[M+H]⁺; 1H NMR (500 MHz, DMSO-d₆) δ 9.81 (t, J=6.1 Hz, 1H), 8.81 (m, 1H), 8.53 (s, 1H), 8.50 (m, 1H), 7.73 (s, 1H), 7.69 (m, 1H), 5.06 (m, 1H), 4.88-4.73 (m, 2H), 4.70 (d, J=6.1 Hz, 2H), 3.34 (appar s, 2H), 2.76 (d, J=4.7 Hz, 3H), 2.36-2.07 (m, 2H).

Example 540: 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: 1,4-dibromo-2-fluorobutane

To a solution of 1,4-dibromobutan-2-ol (50.0 g, 216 mmol) in DCM (200 ml) at 0-5° C. was added DAST (38.2 g, 237 mmol). The mixture was allowed to warm to RT and stirred for 16 h. The mixture was added to a solution of sat. aq. NaHCO₃(200 ml) at 0-5° C. and extracted with DCM (2×200 ml). The combined organic layers were washed with sat. aq. NaCl (300 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the presumed title compound as a yellow oil (40.0 g, 80%).

Step 2: 5-bromo-4-fluoropentanenitrile

A solution of 1,4-dibromo-2-fluorobutane (5.0 g, 21 mmol) and NaCN (1.05 g, 21.0 mmol) in DMF (10 mL) was stirred at RT for 16 h. Water (50 ml) was added, and the mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the crude title compound as a yellow oil (3.78 g, 100%).

Step 3: 5-azido-4-fluoropentanenitrile

A solution of 5-bromo-4-fluoropentanenitrile (540 mg, 3.00 mmol) and sodium azide (195 mg, 3.00 mmol) in DMF (5 mL) was stirred at 70° C. for 16 h to give the title compound as a solution, which was used in the next step without purification (assumed 426 mg, 100% crude).

Step 4: ethyl 1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A solution of crude 5-azido-4-fluoropentanenitrile (426 mg, 3.00 mmol), ethyl propiolate (441 mg, 4.50 mmol) L-(+)-ascorbic acid (192 mg, 0.970 mmol) and CuSO₄-5H₂O (86 mg, 0.34 mmol) in 1:1 v:v t-BuOH/water (20 ml) was stirred at RT for 3 h, then extracted with EtOAc (3×60 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (450 mg, 62%). MS (ES⁺) C₁₀H₁₃FN₄O₂requires: 240, found: 241 [M+H]⁺.

Step 5: ethyl 1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A solution of ethyl 1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (450 mg, 1.88 mmol) and hydrazinecarbothioamide (341 mg, 3.75 mmol) in TFA (5 mL) was stirred at 70° C. for 16 h. The mixture was concentrated under reduced pressure, and to the residue was added sat. aq. NaHCO₃(20 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure to give a yellow solid, which was washed with water (20 mL) and Et₂O (30 mL) to give the title compound as a white solid (200 mg, 33%). MS (ES⁺) C₁₁H₁₅FN₆O₂S requires: 314, found: 315 [M+H]⁺.

Step 6: ethyl 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A solution of ethyl 1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (160 mg, 0.50 mmol), 2-(pyridin-2-yl)acetic acid hydrochloride (87 mg, 0.50 mmol), HATU (285 mg, 0.75 mmol) and K₂CO₃(207 mg, 1.50 mmol) in DMF (5 mL) was stirred at RT for 16 h. The mixture was diluted with water (30 mL), then extracted with 10:1 v:v DCM/MeOH (3×50 mL). The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a white solid (194 mg, 89%). MS (ES⁺) C₁₈H₂₀FN₇O₃S requires: 433, found: 434 [M+H]⁺.

Step 7: 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A solution of ethyl 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (150 mg, 0.35 mmol) and LiOH (17 mg, 0.70 mmol) in 1:1 v:v THF/H₂O (5 mL) was stirred at RT for 16 h. The solvent was removed, and the residue was purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to give the title compound as a white solid (120 mg, 66%). MS (ES⁺) C₁₆H₁₆FN₇O₃S requires: 405, found: 406 [M+H]⁺.

Step 8: 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

A solution of 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (41 mg, 0.10 mmol), (4-(trifluoromethyl)pyridin-2-yl)methanamine (18 mg, 0.10 mmol), HATU (57 mg, 0.15 mmol) and K₂CO₃(42 mg, 0.30 mmol) in DMF (1 mL) was stirred at RT for 16 h. The mixture was purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to afford the title compound as a white solid (25 mg, 45%). MS (ES⁺) C₂₃H₂₁F₄N₉O₂S requires: 563, found: 564 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br s, 1H), 9.25 (t, J=6.0 Hz, 1H), 8.81 (d, J=5.0 Hz, 1H), 8.65 (m, 1H), 8.61 (s, 1H), 8.06 (s, 1H), 7.74-7.62 (m, 3H), 7.54 (m, 1H) 5.06 (m, 1H), 4.89-4.65 (m, 4H), 4.15 (s, 2H), 3.17 (m, 2H), 2.25-1.98 (m, 2H).

Example 397: 1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

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Step 1: ethyl 1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of lithium 2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetate (0.104 g, 0.343 mmol) and ethyl 1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (0.073 g, 0.23 mmol) in DMF (2 ml) at 0° C. was added T3P® (50 wt. % in DMF, 0.55 ml, 0.86 mmol), and the mixture was stirred for 1 h at 0° C. then 1 h at RT. The resulting bright yellow-orange mixture was partitioned between EtOAc and water, and the organic layer was washed with water, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (2% to 5% MeOH in DCM) to give the title compound as a yellow solid (67 mg, 49% yield). MS (ES⁺) C₂₅H₂₃F₄N₇O₄S requires: 593, found: 594 [M+H]⁺.

Step 2: 1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 2,2,2-trifluoroacetate

To a solution of ethyl 1-(2-fluoro-4-(5-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (10 mg, 0.017 mmol) in 1,4-dioxane (0.2 ml) was added aq. methylamine (40% w/v, 0.10 mL, 1.3 mmol) and the mixture was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in DMSO and directly purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=30-70%; 12 min; Column: C18) to give the title compound as a white powder (7.0 mg, 60% yield). MS (ES⁺) C₂₄H₂₂F₄N₈O₃S requires: 578, found: 579 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 12.74 (s, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.51 (s, 1H), 8.48 (m, 1H), 7.87 (m, 2H), 7.82 (s, 1H), 7.73 (d, J=4.7 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 5.04 (m, 1H), 4.85-4.69 (m, 2H), 4.11 (s, 2H), 3.15 (m, 2H), 2.76 (d, J=4.6 Hz, 3H), 2.21-1.96 (m, 2H).

Example 250: (R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: (S)-2-hydroxybutane-1,4-diyl bis(4-methylbenzenesulfonate)

To a cooled 0° C. solution of (S)-butane-1,2,4-triol (2.10 ml, 23.6 mmol) in DCM (47 ml) was added 4-toluenesulfonyl chloride (11.2 g, 58.9 mmol) followed by pyridine (5.69 ml, 70.7 mmol). The resulting mixture was stirred at 0° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound as a colorless liquid (4.98 g, 51% yield). MS (ES⁺) C₁₈H₂₂O₇S₂requires: 414, found: 415 [M+H]⁺.

Step 2: (R)-2-fluorobutane-1,4-diyl bis(4-methylbenzenesulfonate)

To a cooled 0° C. solution of (S)-2-hydroxybutane-1,4-diyl bis(4-methylbenzenesulfonate) (4.98 g, 12.0 mmol) in DCM (60 ml) was added DAST (2.39 ml, 18.1 mmol) and the resulting mixture was stirred as it warmed to RT for 4 h. The mixture was filtered through a plug of SiO₂gel, eluting with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound as a red liquid (4.29 g, 85% yield). MS (ES⁺) C₁₈H₂₁FO₆S₂requires: 416, found: 439 [M+Na]⁺.

Step 3: (R)-4-cyano-2-fluorobutyl 4-methylbenzenesulfonate

To a solution of (R)-2-fluorobutane-1,4-diyl bis(4-methylbenzenesulfonate) (4.29 g, 10.3 mmol) in DMF (24 ml) was added KCN (0.957 g, 14.7 mmol) and the resulting mixture was stirred at 80° C. for 4 h. The mixture was allowed to cool to RT, diluted with EtOAc (24 mL), and filtered through a plug of SiO₂gel, eluting with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give the title compound as a colorless liquid (2.41 g, 86% yield). MS (ES⁺) C₁₂H₁₄FNO₃S requires: 271, found: 294 [M+Na]⁺.

Step 4: Ethyl (R)-1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-4-cyano-2-fluorobutyl 4-methylbenzenesulfonate (2.4 g, 8.8 mmol) in DMF (8.9 ml) was added NaN₃(0.690 g, 10.6 mmol) and the resulting mixture was stirred at 80° C. for 3 h. The reaction mixture was allowed to cool to RT and diluted with DCM (88 ml). DIEA (0.153 ml, 0.879 mmol), ethyl propiolate (1.34 ml, 13.2 mmol), and AcOH (0.050 ml, 0.879 mmol) were added to the reaction mixture. Copper (I) iodide (0.084 g, 0.44 mmol) was then added and the mixture was stirred for 15 h at RT. The reaction was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (0% to 100% EtOAc in hexanes) to give the title compound as a pale orange solid (675 mg, 32% yield). MS (ES⁺) C₁₀H₁₃FN₄O₂requires: 240, found: 241 [M+H]⁺.

Step 5: ethyl (R)-1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

To a suspension of (R)-ethyl 1-(4-cyano-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (675 mg, 2.81 mmol) in TFA (14 ml) was added hydrazinecarbothioamide (307 mg, 3.37 mmol) and the resulting mixture was stirred at 80° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (0% to 10% MeOH in DCM) to give the title compound as a pale yellow solid (550 mg, 62% yield). MS (ES⁺) C₁₁H₁₅FN₆O₂S requires: 314, found: 315 [M+H]⁺. Enantiopurity was analyzed by chiral SFC (30% MeOH/CO₂with 0.5% NH₄OH, ChiralPak IC column, 4.6×150 mm, 5 um, 3 mL/min), which indicated >98% ee.

Step 6: ethyl (R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a 0° C. solution of (R)-ethyl 1-(4-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.318 mmol) and 2-(pyridin-2-yl)acetic acid hydrochloride (61 mg, 0.35 mmol) in DMF (1.59 mL) was added triethylamine (0.133 mL, 0.954 mmol) and, after 5 min of stirring, T3P® (50 wt. % in DMF, 0.284 mL, 0.477 mmol) was added dropwise. The resulting mixture was stirred at RT for 15 h. The mixture was concentrated under reduced pressure and the residue was purified by SiO₂gel chromatography (0% to 10% MeOH in DCM with 1% NH₄OH) to give the title compound as a yellow solid (123 mg, 89% yield). MS (ES⁺) C₁₈H₁₀FN₇O₃S requires: 433, found: 434 [M+H]⁺.

Step 7: lithium (R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of (R)-ethyl 1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (123 mg, 0.284 mmol) in MeOH (0.284 mL) and THF (1.135 mL) was added aq. LiOH (2.0 M, 0.17 mL, 0.34 mmol) and the resulting mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to give the title compound as a yellow solid (126 mg, >100% yield), which was used without further purification. MS (ES⁺) C₁₆H₁₆FN₇O₃S requires: 405, found: 406 [M+H]⁺.

Step 8: (R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of lithium (R)-1-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (126 mg, 0.306 mmol), HATU (175 mg, 0.459 mmol), and (4-(trifluoromethyl)pyridin-2-yl)methanamine dihydrochloride (92 mg, 0.37 mmol) in DMF (1.53 mL) was added DIEA (0.160 mL, 0.919 mmol) and the resulting mixture was stirred at RT for 72 h. The mixture was concentrated under reduced pressure and the residue was adsorbed onto Celite® and purified by SiO₂gel chromatography (0% to 10% MeOH in DCM with 1% NH₄OH) to give the title compound as a tan solid (51 mg, 30% yield). MS (ES⁺) C₂₃H₂₁F₄N₉O₂S requires: 563, found: 564 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 12.72 (s, 1H), 9.23 (t, J=5.9 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.61 (s, 1H), 8.49 (d, J=4.8 Hz, 1H), 7.77 (appar t, J=7.7 Hz, 1H), 7.71-7.60 (m, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.29 (appar t, J=6.3 Hz, 1H), 5.08 (m, 1H), 4.89-4.70 (m, 2H), 4.67 (d, J=6.0 Hz, 2H), 4.01 (s, 2H), 3.22-3.10 (m, 2H), 2.26-1.98 (m, 2H).

Example 80: N-(3-(trifluoromethoxy)benzyl)-1-(4-(4-(((5-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

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Steps 1 to 8

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Step 1: 4-hydroxybutyl Benzoate

To a stirred solution of 1,4-butanediol (82.60 mL, 931.2 mmol) and TEA (43.26 mL, 310.4 mmol) in DCM (750 mL) at 0° C. was added benzoyl chloride (36 mL, 31 mmol). The resulting mixture was allowed to warm to RT and stirred for 6 h before quenching with sat. aq. NaHCO₃(150 mL). Layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with sat. aq. NH₄Cl (150 mL) and water (150 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (9% to 50% EtOAc in hexanes) to give the title compound as a colorless oil (49.6 g; 82% yield). MS (ES⁺) C₁₁H₁₄O₃requires: 194, found: 195 [M+H]⁺.

Step 2: 4-methylsulfonyloxybutyl Benzoate

To a stirred solution of 4-hydroxybutyl benzoate (20.0 g, 103 mmol) and TEA (28.70 mL, 205.9 mmol) in DCM (300 mL) at 0° C. was added methanesulfonyl chloride (11.95 mL, 154.5 mmol). The resulting mixture was allowed to warm to RT and stirred for 6 h before quenching with sat. aq. NaHCO₃(120 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂(2×60 mL). The combined organic layers were then washed with sat. aq. NaCl (150 mL×2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain the title compound as a colorless oil (28.02 g; 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.91-1.93 (m, 4H), 3.01 (s, 3H), 4.29-4.38 (m, 4H), 7.42-8.04 (m, 5H).

Step 3: 4-azidobutyl Benzoate

4-methylsulfonyloxybutyl benzoate (42.06 g, 154.4 mmol) was dissolved in DMF (300 mL). NaN₃(20.28 g, 308.9 mmol) was added cautiously. The solution was slowly heated to 65° C. and stirred for 16 h. The mixture was allowed to cool to RT, transferred to a separation funnel and diluted with Et₂O (600 mL), then washed with water (3×90 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a yellow oil, which was used without further purification (33.86 g; 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.74-1.89 (m, 4H), 3.37 (t, 2H), 4.35 (t, 2H), 7.42-8.05 (m, 5H).

Step 4: tert-butyl 1-(4-benzoyloxybutyl)triazole-4-carboxylate

To a solution of 1-(4-azidobutyl)-N-[[3-(trifluoromethoxy)phenyl]methyl]triazole-4-carboxamide (12.0 g, 54.7 mmol) in t-BuOH (100 mL) and water (100 mL) were added CuSO₄-5H₂O (1.38 g, 5.47 mmol), L-ascorbic acid sodium salt (2.20 g, 11.0 mmol) and tert-butyl prop-2-ynoate (8.29 g, 65.7 mmol). The suspension was stirred vigorously at RT for 16 h. The mixture was concentrated under reduced pressure to remove the organic layer, diluted with ice-cold water, and precipitate was isolated by filtration, washed with water and dried to give the title compound as a light brown solid (18.1 g; 96% yield). MS (ES⁺) C₁₈H₂₃N₃O₄requires: 345, found: 346 [M+H]⁺.

Step 5: tert-butyl 1-(4-hydroxybutyl)triazole-4-carboxylate

To a solution of tert-butyl 1-(4-benzoyloxybutyl)triazole-4-carboxylate (31 g; 90 mmol) in MeOH (300 mL) was added K₂CO₃(12.40 g, 89.75 mmol). The mixture was stirred at RT for 4 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (2% to 10% MeOH in DCM) to give the title compound as a light yellow oil (9.27 g, 43% yield). MS (ES⁺) C₁₁H₁₉N₃O₃requires: 241, found: 242 [M+H]⁺.

Step 6: tert-butyl 1-(4-methylsulfonyloxybutyl)triazole-4-carboxylate

To a stirred solution of tert-butyl 1-(4-hydroxybutyl)triazole-4-carboxylate (8.8 g, 36 mmol) and TEA (10.17 mL, 72.94 mmol) in DCM (120 mL) at 0° C. was added methanesulfonyl chloride (4.23 mL, 54.7 mmoles). The resulting mixture was allowed to warm to RT and stirred for 30 min before quenching with sat. aq. NaHCO₃(90 mL). The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were washed with sat. aq. NaCl (80 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to give the title compound as a colorless oil, which was used without further purification (11.27 g; 97% yield). MS (ES⁺) C₁₂H₂₁N₃O₅S requires: 319, found: 320[M+H]⁺.

Step 7: tert-butyl 1-(4-azidobutyl)triazole-4-carboxylate

Tert-butyl 1-(4-methylsulfonyloxybutyl)triazole-4-carboxylate (11.27 g, 35.29 mmol) was dissolved in DMF (80 mL). NaN₃(4.63 g, 70.6 mmol) was added cautiously. The solution was slowly heated to 60° C. and stirred for 16 h. The mixture was allowed to cool to RT, transferred to a separation funnel and diluted with Et₂O (250 mL), then washed with water (3×60 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound as a yellow oil (9.1 g; 97% yield), which was used without further purification. ¹H NMR (400 MHz, CDCl3) δ 1.61 (m, 11H), 2.03 (m, 2H), 3.35 (t, 2H), 4.45 (t, 2H), 8.01 (s, 1H).

Step 8: methyl 1-(4-(4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of tert-butyl 1-(4-azidobutyl)triazole-4-carboxylate (9.1 g, 34 mmol) in t-BuOH (40 mL) and water (40 mL) were added CuSO₄·5H₂O (862 mg, 3.42 mmol), L-ascorbic acid sodium salt (1.37 g, 6.83 mmol) and methyl prop-2-ynoate (2.87 g, 34.2 mmol). The suspension was stirred vigorously at RT for 16 h. The mixture was concentrated under reduced pressure to remove the organic layer, diluted with ice-cold water, and precipitate was isolated by filtration, washed with water and dried to give the title compound as a solid (9.64 g; 81% yield). MS (ES⁺) C₁₅H₂₂N₆O₄requires: 350, found: 351 [M+H]⁺.

Steps 9 to 12

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Step 9: 1-(4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

To a 0° C. solution of tert-butyl 1-(4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (1.00 g, 2.85 mmol) in DCM (28 ml) was added dropwise TFA (4.40 mL, 57.1 mmol), and the resulting mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure, azeotroping with toluene (3×25 mL), to give crude title compound, which was used without further purification. MS (ES⁺) C₁₁H₁₄N₆O₄requires: 294, found: 295 [M+H]⁺.

Step 10: methyl 1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of crude 1-(4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (840 mg, 2.85 mmol) in DMF (28 mL) were added (3-(trifluoromethoxy)phenyl)methanamine (0.650 mL, 3.43 mmol), HATU (1.3 g, 3.4 mmol), and DIEA (0.750 mL, 4.28 mmol). The resulting mixture was stirred at RT for 16 h. Precipitated solid was collected by filtration to give the title compound as an off-white powder (700 mg, 52% yield). MS (ES⁺) C₁₉H₂₀F₃N₇O₄requires: 467, found: 468 [M+H]⁺.

Step 11: 1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

To a solution of methyl 1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (100 mg, 0.214 mmol) in THF (1.8 mL) and water (0.18 mL) was added LiOH (51 mg, 2.1 mmol), and the resulting mixture was stirred at RT for 4 h. The solution was neutralized with HCl in MeOH (1.25 M, 1.7 mL, 2.12 mmol) and the mixture was concentrated under reduced pressure under reduced pressure to give the crude title compound as a white solid (96 mg, 99%), which was used as is. MS (ES⁺) C₁₈H₁₈F₃N₇O₄requires: 453, found: 454 [M+H]⁺.

Step 12: N-(3-(trifluoromethoxy)benzyl)-1-(4-(4-(((5-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-(4-((3-(trifluoromethoxy)benzyl)carbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (194 mg, 0.428 mmol) in DMF (4.3 mL) were added (5-(trifluoromethyl)pyridin-3-yl)methanamine dihydrochloride (117 mg, 0.471 mmol), HATU (244 mg, 0.642 mmol) and DIEA (0.262 mL, 1.49 mmol). The resulting mixture was stirred at RT for 18 h. Precipitated solid was collected by filtration and rinsed with MeOH to give the title compound as a white solid (180 mg, 69% yield). MS (ES⁺) C₂₅H₂₃F₆N₉O₃requires: 611, found: 612.5 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 9.27 (t, J=6.2 Hz, 1H), 9.19 (t, J=6.3 Hz, 1H), 8.89-8.82 (m, 2H), 8.61 (s, 1H), 8.60 (s, 1H), 8.12 (appar t, J=2.1 Hz, 1H), 7.45 (appar t, J=7.9 Hz, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.24 (m, 1H), 4.56 (d, J=6.1 Hz, 2H), 4.50-4.39 (m, 6H), 1.87-1.77 (m, 4H).

Example 475: 1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Step 1: methyl 1-(3-fluoro-4-(tosyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 2-fluorobutane-1,4-diyl bis(4-methylbenzenesulfonate) (20 g, 48 mol), NaN₃(3.1 g, 48 mmol), and DMF (100 ml) was stirred at 60° C. for 16 h, then water (500 mL) was added. The mixture was extracted with DCM (800 mL), and the organic layer was concentrated under reduced pressure. To the residue was added 1:1 v:v t-BuOH/water (200 mL), methyl propiolate (4.0 g, 48 mmol), CuSO₄(1.2 g, 7.5 mmol), and L-ascorbic acid (2.4 g, 14 mmol). The mixture was stirred at RT for 16 h, then concentrated under reduced pressure. To the residue was added water (150 mL), the mixture was stirred for 30 min, and precipitate was isolated by filtration to give the title compound as a white solid (12 g, 60%). MS (ES⁺) C₁₅H₁₈FN₃O₅S requires: 371, found: 372 [M+H]⁺.

Step 2: tert-butyl 1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of methyl 1-(3-fluoro-4-(tosyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate (8.9 g, 24 mmol), NaN₃(1.56 g, 24.0 mmol), and DMF (50 ml) was stirred at 80° C. for 16 h, then water (500 mL) was added. The mixture was extracted with DCM (600 mL), and the organic layer was concentrated under reduced pressure. To the residue was added 1:1 v:v t-BuOH/water (200 mL), tert-butyl propiolate (3.0 g, 24 mmol), CuSO₄(0.60 g, 3.8 mmol), and L-ascorbic acid (1.2 g, 6.8 mmol). The mixture was stirred at RT for 16 h then concentrated under reduced pressure. To the residue was added water (150 ml), the mixture was stirred for 30 min, and precipitate was isolated by filtration to give the title compound as a white solid (7 g, 80%). MS (ES⁺) C₁₅H₂₁FN₆O₄requires: 368, found: 369 [M+H]⁺.

Step 3: 1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of tert-butyl 1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (1.0 g, 2.7 mmol) and 1:1 v:v TFA/DCM (20 ml) was stirred at RT for 3 h, then concentrated under reduced pressure. To the residue was added water (100 ml), the mixture was stirred for 20 min, and precipitate was isolated by filtration to give the title compound as a white solid (500 mg, 64%). MS (ES⁺) C₁₁H₁₃FN₆O₄requires: 312, found: 313 [M+H]⁺.

Step 4: methyl 1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 1-(2-fluoro-4-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (500 mg, 1.6 mmol), (4-(trifluoromethyl)pyridin-2-yl) methanamine (282 mg, 1.60 mmol), HATU (912 mg, 2.4 mmol), DIEA (600 mg, 4.8 mmol), and DMF (5 ml) was stirred at RTf or 2 h, then water (100 mL) was added and the mixture was stirred for 10 min. Precipitate was isolated by filtration to give the title compound as a light brown solid (700 mg, 90%). MS (ES⁺) C₁₈H₁₈F₄N₈O₃requires: 470, found: 471[M+H]⁺.

Step 5: 1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A mixture of methyl 1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (700 mg, 1.4 mmol), LiOH (70 mg, 2.8 mmol), and 1:1 v:v THF/H₂O (8 ml) was stirred at RT for 3 h, then concentrated under reduced pressure to remove organics. The pH value was adjusted to 4.0 with 1 M aq. HCl. Precipitate was isolated by filtration to give the title compound as a white solid (600 mg, 91%). MS (ES⁺) C₁₇H₁₆F₄N₈O₃requires: 456, found: 457[M+H]⁺.

Step 6: 1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(3-fluoro-4-(4-((4-(trifluoromethyl)pyridin-2-yl)methylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.085 mmol), methylamine hydrochloride (6 mg, 0.09 mmol), HATU (50 mg, 0.13 mmol), DIEA (33 mg, 0.26 mmol), and DMF (1 ml) was stirred at RT for 16 h, then purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to afford the title compound as a white solid (26 mg, 60%). MS (ES⁺) C₁₈H₁₉F₄N₉O₂requires: 469, found: 470 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 9.24 (t, J=6.0 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.60 (d, J=6.5 Hz, 2H), 8.46 (m, 1H), 7.77-7.50 (m, 2H), 5.00 (m, 1H), 4.89-4.71 (m, 2H), 4.65 (m, 2H), 4.59 (m, 2H), 2.76 (d, J=4.6 Hz, 3H), 2.38-2.10 (m, 2H).

Example 297: 1-[4-[4-[[2-(2-pyridyl)acetyl]amino]triazol-1-yl]butyl]-N-(2-pyridylmethyl)triazole-4-carboxamide

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Step 1: 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

A solution of tert-butyl 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylate (5 g, 14.5 mmol) in 1:1 v:v TFA/DCM (40 ml) was stirred at RT for 3 h, then concentrated under reduced pressure. Water (30 ml) was added, the mixture was stirred for 15 min, and precipitate was isolated by filtration then recrystallized from acetonitrile/water to afford the presumed title product as a white solid (3.8 g, 90%).

Step 2: 4-(4-(pyridin-2-ylmethylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl Benzoate

To a stirred solution of 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.00 g, 3.46 mmol) in DMF (10 mL) were added HATU (1.84 g, 4.84 mmol), DIEA (1.21 mL, 6.91 mmol) and 2-pyridinemethanamine (449 mg, 4.15 mmol). The reaction mixture was stirred at RT for 16 h. Water (90 mL) was added and precipitate was isolated by filtration, washed with water, and dried to give the title compound as a brown solid (1.27 g; 97% yield). MS (ES⁺) C₂₀H₂₁N₅O₃requires: 379, found: 380 [M+H]⁺.

Step 3: 1-(4-hydroxybutyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 4-(4-(pyridin-2-ylmethylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl benzoate (1.27 g, 3.35 mmol) in MeOH (80 mL) was added K₂CO₃(463 mg, 3.35 mmol). The suspension was stirred vigorously at RT for 3 d. The reaction mixture was extracted with DCM (3×45 mL), and the combined organic layers were dried over MgSO₄, filtered through of Celite® and concentrated under reduced pressure. The residue was purified by SiO₂gel chromatography (25% EtOAc in petroleum ether) to give the title compound as a white solid (0.86 g, 93% yield). MS (ES⁺) C₁₃H₁₇N₅O₂requires: 275, found: 276[M+H]⁺.

Step 4: 4-[4-(2-pyridylmethylcarbamoyl)triazol-1-yl]butyl methanesulfonate

To a stirred solution of 1-(4-hydroxybutyl)-N-(2-pyridylmethyl)triazole-4-carboxamide (0.85 g; 3.1 mmol) and TEA (0.861 mL, 6.17 mmol) in DCM (20 mL) at 0° C. was added methanesulfonyl chloride (0.358 mL, 14.6 mmol). The resulting mixture was allowed to warm to RT and stirred for 30 min before quenching with sat. aq. NaHCO₃(150 mL). Layers were separated and the aqueous layer was extracted with DCM (2×60 mL). The combined organic layers were washed with sat. aq. NaCl (150 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a colorless oil (1.09 g; 100% yield). MS (ES⁺) C₁₄H₁₉N₅O₄S requires: 353, found: 354 [M+H]⁺.

Step 5: 1-(4-azidobutyl)-N-(2-pyridylmethyl)triazole-4-carboxamide

4-[4-(2-Pyridylmethylcarbamoyl)triazol-1-yl]butyl methanesulfonate (1.09 g, 3.08 mmol) was dissolved in DMF (15 mL). NaN₃(405 mg, 6.17 mmol) was added cautiously. The solution was slowly heated to 65° C. and stirred for 16 h, then allowed to cool to RT. The mixture was transferred to a separation funnel and diluted with Et₂O (90 mL), then washed with water (3×30 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (0.9 g; 97% yield). MS (ES⁺) C₁₃H₁₆N₈O requires: 300, found: 301 [M+H]⁺.

Step 6: 1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a solution of 1-(4-azidobutyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide (900 mg, 3 mmol) in t-BuOH (10 mL) and water (10 mL) were added CuSO₄·5H₂O (75.6 mg, 0.303 mmol), L-ascorbic acid sodium salt (120 mg, 0.600 mmol) and 2-ethynylisoindoline-1,3-dione (513 mg, 3.00 mmol). This suspension was stirred vigorously at RT for 16 h, then concentrated under reduced pressure to remove the organic layer. The mixture was diluted with ice-cold water, and precipitate was isolated by filtration, washed with water, and dried to give the title compound as a solid (1.28 g, 91% yield). MS (ES⁺) C₂₃H₂₁N₉O₃requires: 471, found: 472 [M+H]⁺.

Step 7: 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide

To a suspension of 1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide (1.28 g, 2.71 mmol) in MeOH (45 mL) was added hydrazine monohydrate (0.660 mL, 13.6 mmol). The mixture was stirred at 60° C. for 30 min, then concentrated under reduced pressure to obtain a solid, which was washed with cold water (3×15 mL) to give the title compound as a brown solid (0.574 g, 62% yield). MS (ES⁺) C₁₅H₁₉N₉O requires: 341, found: 342 [M+H]⁺.

Step 8: 1-[4-[4-[[2-(2-pyridyl)acetyl]amino]triazol-1-yl]butyl]-N-(2-pyridylmethyl)triazole-4-carboxamide

To a solution of 2-pyridylacetic acid hydrochloride (27.9 mg, 0.159 mmol), HATU (77.5 mg, 0.197 mmol) and DIEA (0.460 mL, 0.264 mmol) in DMF (1 mL) was added 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazole-4-carboxamide (45.0 mg, 0.131 mmol), and the resulting mixture was stirred at RT for 16 h. The mixture was directly purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to give the title compound as a white solid (15 mg; 25% yield). MS (ES⁺) C₂₂H₂₄N₁₀O₂requires: 460, found: 461 [M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄) δ 8.52 (m, 2H), 8.40 (s, 1H), 8.12 (s, 1H), 7.82 (m, 2H), 7.53-7.26 (m, 4H), 4.71 (s, 2H), 4.51-4.43 (m, 4H), 3.96 (m, 2H), 1.94 (appar s, 4H).

Example 332: 1-(4-(4-(2-(4,4-difluoropiperidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: 4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl benzoate

A mixture of 1-(4-(benzoyloxy)butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.0 g, 3.5 mmol), (3-(trifluoromethoxy)phenyl)methanamine (0.66 g, 3.5 mmol), HATU (1.9 g, 5.2 mmol), and DIEA (1.3 g, 10 mmol) in DMF (10 ml) was stirred at RT for 16 h. Water (100 ml) was added, the mixture was stirred for 10 min, and precipitate was isolated by filtration to give the title compound as a white solid (1 g, 62%). MS (ES⁺) C₂₂H₂₁F₃N₄O₄requires: 462, found: 463 [M+H]⁺.

Step 2: 1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl benzoate (1.0 g, 2.2 mmol) and LiOH·H₂O (0.27 g, 6.6 mmol) in THF (5 ml) and water (5 ml) was stirred at RT for 16 h, then extracted with EtOAc (50 mL). The combined organic layers were concentrated under reduced pressure to afford the title compound as a white solid (600 mg, 77%). MS (ES⁺) C₁₅H₁₇F₃N₄O₃requires: 358, found: 359 [M+H]⁺.

Step 3: 1-(4-azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

To a stirred solution of 1-(4-hydroxybutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (600 mg, 1.68 mmol) and TEA (340 mg, 3.36 mmol) in DCM (5 ml) at RT was added methanesulfonyl chloride (240 mg, 2.1 mmol) in DCM (5 ml) dropwise. The mixture was stirred at RT for 30 min then treated with water (10 ml) and extracted with DCM (20 ml). The organic layer was concentrated under reduced pressure to afford a white solid (presumed crude 4-(4-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-1,2,3-triazol-1-yl)butyl methanesulfonate), which was dissolved in DMF (3 mL). To the solution was added NaN₃(110 mg, 1.68 mmol), and the mixture was stirred at 80° C. for 1 hr, then allowed to cool to RT. Water (20 ml) was added, the mixture was stirred for 15 min, and precipitate was isolated by filtration to give the title compound as a white solid (600 mg, 93%). MS (ES⁺) C₁₅H₁₆F₃N₇O₂requires: 383, found: 384 [M+H]⁺.

Step 4: 1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(4-azidobutyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (600 mg, 0.78 mmol), 2-ethynylisoindoline-1,3-dione (133 mg, 0.780 mmol), L(+)-ascorbic acid (40 mg, 0.23 mmol), and CuSO₄(20 mg, 0.12 mmol) in 1:1 v:v t-BuOH/H₂O (10 mL) was stirred at RT for 16 h, then concentrated under reduced pressure. Water (30 ml) was added, the mixture was stirred for 15 min, and precipitate was isolated by filtration to give the title compound as a white solid (600 mg, 71%). MS (ES⁺) C₂₅H₂₁F₃N₈O₄requires: 554, found: 555 [M+H]⁺.

Step 5: 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (500 mg, 0.90 mmol) and hydrazine hydrate (90 mg, 1.8 mmol) in MeOH (10 ml) was stirred at RT for 3 h, then concentrated under reduced pressure. To the residue was added EtOAc (50 mL), and the mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (300 mg, 86%). MS (ES⁺) C₁₇H₁₉F₃N₈O₂requires: 424, found: 425 [M+H]⁺.

Step 6: 1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (300 mg, 0.705 mmol), 2-chloroacetyl chloride (120 mg, 1.06 mmol) and DIEA (177 mg, 1.41 mmol) in DMF (5 ml) was stirred at RT for 2 h. Water (50 ml) was added, the mixture was stirred for 10 min, and precipitate was isolated by filtration to give the title compound as a yellow solid (220 mg, 63%). MS (ES⁺) C₁₉H₂₀ClF₃N₈O₃requires: 501, found: 502 [M+H]⁺.

Step 7: 1-(4-(4-(2-(4,4-difluoropiperidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide (30 mg, 0.06 mmol), 3-fluoroazetidine (7 mg, 0.09 mmol) and K₂CO₃(25 mg, 0.18 mmol) in DMF (1 ml) was stirred at 65° C. for 2 h. Precipitate was isolated by filtration and purified by preparative HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to afford the title compound as a white solid (12.7 mg, 57%). MS (ES⁺) C₂₄H₂₈F₅N₉O₃requires: 585, found: 586 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 1.78 (m, 4H), 2.24 (m, 4H), 3.16 (m, 4H), 3.90 (m, 2H), 4.40-4.49 (m, 6H), 7.24 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.46 (appar t, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.59 (s, 1H), 9.20 (t, J=6.0 Hz, 1H), 11.45 (br s, 1H).

Example 347: 1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: 1,4-dibromo-2-fluorobutane

To a solution of 1,4-dibromobutan-2-ol (10 g, 43 mmol) in DCM (140 mL) at 0° C. was slowly added DAST (13.9 g, 86.2 mmol). The mixture was stirred at RT for 16 h, then carefully quenched with sat. aq. NaHCO. The mixture was extracted with DCM (3×100 mL), and the combined organic layers were dried and concentrated under reduced pressure to give the presumed title compound (9.5 g, 94%) as a yellow oil.

Step 2: tert-butyl 1-(4-bromo-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of 1,4-dibromo-2-fluorobutane (5.0 g, 21 mmol) and NaN₃(1.32 g, 20.3 mmol) in DMF (10 mL) was stirred at 70° C. for 1 h then allowed to cool to RT. DCM (100 mL) was added, followed by AcOH (130 mg, 2.14 mmol), DIEA (280 mg, 2.14 mmol), tert-butyl propiolate (4.04 g, 32.1 mmol) and copper(I) iodide (203 mg, 1.10 mmol). The mixture was stirred at RT for 5 h, diluted with water, and extracted with DCM (2×80 mL). The combined organic layers were dried and concentrated under reduced pressure, and solid was washed with Et₂O and isolated by filtration to give the title compound as a brown solid (3.5 g, 51%). MS (ES⁺) C₁₀H₁₇BrFN₃O₂requires: 321/323, found: 322/324[M+H]⁺.

Step 3: tert-butyl 1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl 1-(4-bromo-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (1.0 g, 3.1 mmol) and NaN₃(400 mg, 6.2 mmol) in DMF (2 mL) was stirred at 70° C. for 16 h, then allowed to cool to RT. DCM (20 mL) was added, followed by AcOH (19 mg, 0.31 mmol), DIEA (40 mg, 0.31 mmol), 2-ethynylisoindoline-1,3-dione (640 mg, 3.73 mmol) and copper(I) iodide (30 mg, 0.16 mmol). The mixture was stirred at RT for 5 h, then diluted with water and treated with sat. aq. NH₄OH (2 mL). The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were dried and concentrated under reduced pressure to give the title compound as a yellow oil (1.3 g, 92%). MS (ES⁺) C₂₁H₂₂FN₇O₄requires: 455, found: 456[M+H]⁺.

Step 4: tert-butyl 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

Hydrazine hydrate (715 mg, 14.3 mmol) was added to a solution of tert-butyl 1-(4-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (1.3 g, 2.9 mmol) in MeOH (15 mL). The mixture was stirred at RT for 1 h, then concentrated under reduced pressure and the residue purified by SiO₂gel chromatography (10% MeOH in DCM) to give the title compound as a yellow solid (650 mg, 70%). MS (ES⁺) C₁₃H₂₀FN₇O₂requires: 325, found: 326 [M+H]⁺.

Step 5: tert-butyl 1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (350 mg, 1.08 mmol), 2-(pyridin-2-yl)acetic acid (220 mg, 1.62 mmol), HATU (614 mg, 1.62 mmol) and DIEA (209 mg, 1.62 mmol) in DMF (10 mL) was stirred at RT for 2 h. The mixture was diluted with water and extracted with 10:1 v:v DCM/MeOH. The organic layer was dried and concentrated under reduced pressure to afford the title compound as a brown oil (500 mg, 60%). MS (ES⁺) C₂₀H₂₅FN₈O₃requires: 444, found: 445[M+H]⁺.

Step 6: 1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

TFA (2 mL) was added to a solution of tert-butyl 1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (500 mg, 1.13 mmol) in DCM (5 mL). The mixture was stirred at 50° C. for 16 h. Water was added and the mixture was concentrated under reduced pressure to remove the organic layer. The aqueous mixture was washed with EtOAc (3×20 mL), then concentrated under reduced pressure. The residue was washed with MeOH and solid was isolated by filtration to give the title compound as a beige solid (300 mg, 68%). MS (ES⁺) C₁₆H₁₇FN₈O₃requires: 388, found: 389 [M+H]⁺.

Step 7: 1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(3-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(3-fluoro-4-(4-(2-(pyridin-2-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.10 mmol), (3-(trifluoromethoxy)phenyl)methanamine (24 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol) in DMF (1 mL) was stirred at RT for 2 h. Water (10 mL) was added, and precipitated solid was isolated by filtration and washed with MeOH to give the title compound as a white solid. MS (ES⁺) C₂₄H₂₃F₄N₉O₃requires: 561, found: 562[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.17 (s, 1H), 9.20 (t, J=6.1 Hz, 1H), 8.63 (s, 1H), 8.48 (m, 1H), 8.12 (s, 1H), 7.75 (t, J=8.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.36 (dd, J=17.6, 7.8 Hz, 2H), 7.31-7.20 (m, 3H), 4.94 (m, 1H), 4.68 (m, 2H), 4.58 (t, J=6.9 Hz, 2H), 4.48 (d, J=6.2 Hz, 2H), 3.87 (s, 2H), 2.36-2.09 (m, 2H).

Example 372: 1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

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Step 1: tert-butyl 1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate

To a mixture of tert-butyl 1-(4-(4-amino-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (800 mg, 2.46 mmol) and DIEA (635 mg, 4.92 mmol) in THF (10 mL) at 0° C. was added 2-chloroacetyl chloride (556 mg, 4.92 mmol). The mixture was stirred at 0° C. for 30 min. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and H₂O. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried and concentrated under reduced pressure to afford the title compound as a yellow oil (950 mg, 96%). MS (ES⁺) C₁₅H₂₁ClFN₇O₃requires: 401, found: 402[M+H]⁺.

Step 2: tert-butyl 1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate

A mixture of tert-butyl 1-(4-(4-(2-chloroacetamido)-1H-1,2,3-triazol-1-yl)-3-fluorobutyl)-1H-1,2,3-triazole-4-carboxylate (450 mg, 1.12 mmol), 3-fluoroazetidine hydrochloride (138 mg, 1.23 mmol) and K₂CO₃(310 mg, 2.24 mmol) in ACN (5 mL) was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure and the residue purified by SiO₂gel chromatography (10% MeOH in DCM) to give the title compound as a yellow solid (330 mg, 67%). MS (ES⁺) C₁₈H₂₆F₂N₈O₃requires: 440, found: 441[M+H]⁺.

Step 3: 1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic Acid

TFA (2 mL) was added to a solution of tert-butyl 1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylate (330 mg, 0.75 mmol) in DCM (10 mL). The mixture was stirred at 50° C. for 4 h. Water was added and the mixture lyophilized to give the title compound as a yellow oil (350 mg, 94%). MS (ES⁺) C₁₄H₁₈F₂N₈O₃requires: 384, found: 385[M+H]⁺.

Step 8: 1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-1,2,3-triazole-4-carboxamide

A mixture of 1-(3-fluoro-4-(4-(2-(3-fluoroazetidin-1-yl)acetamido)-1H-1,2,3-triazol-1-yl)butyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.1 mmol), (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine (25 mg, 0.12 mmol), HATU (59 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol) in DMF (1 mL) was stirred at RT for 2 h. Water was added, and precipitated solid was isolated by filtration and purified by preparatory HPLC (Mobile phase: A=0.1% ammonium hydroxide/H₂O, B=acetonitrile; Gradient: B=5%-95% in 18 min; Column: C18) to give the title compound as a white solid (6 mg, 10%). MS (ES⁺) C₂₂H₂₃F₆N₉O₃requires: 575, found: 576[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.64 (s, 1H), 9.17 (t, J=6.1 Hz, 1H), 8.64 (s, 1H), 8.16 (s, 1H), 7.36-7.30 (m, 3H), 5.18 (m, 1H), 4.96 (m, 1H), 4.73-4.63 (m, 2H), 4.59 (t, J=6.9 Hz, 2H), 4.50 (d, J=5.8 Hz, 2H), 3.71-3.63 (m, 2H), 3.29-3.24 (m, 4H), 2.33-2.13 (m, 2H).

Non-limiting examples include the following compounds and pharmaceutically acceptable salts thereof:

TABLE 1

Synthesized Examples

Ex.

No.
Structure
Name

10

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N-(propan-2-yl)-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl)acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

11

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N-(cyclopropylmethyl)-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

12

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N-(oxolan-3-ylmethyl)-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

13

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1-{4-[5-(2-phenylacetamido)-1,3,4- thiadiazol-2-yl]butyl}-N-(2- phenylethyl)-1H-1,2,3-triazole-4- carboxamide

14

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N-[2-(4-hydroxypiperidin-1-yl)ethyl]- 1-{4-[5-(2-phenylacetamido)-1,3,4- thiadiazol-2-yl]butyl}-1H-1,2,3- triazole-4-carboxamide

15

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N-benzyl-1-{4-[5-(2- phenylacetamido)-1,3,4-thiadiazol-2- yl]butyl}-1H-1,2,3- triazole-4-carboxamide

16

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N-benzyl-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

17

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N-(2-hydroxyethyl)-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

18

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N-(2-phenylpropan-2-yl)-1-[4-(5-{2- [3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

19

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N-(pyridin-2-ylmethyl)-1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

20

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1-[4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

21

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N-[(1R)-2-hydroxy-1-phenylethyl]-1- [4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

22

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N-[(2,4-dimethoxyphenyl)methyl]-1- [4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

23

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N-[(1S)-2-hydroxy-1-phenylethyl]-1- [4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

24

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N-(2-methylpropyl)-1-{4-[6-(2- phenylacetamido)pyridazin-3- yl]butyl}-1H-1,2,3- triazole-4-carboxamide

25

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5-(4-{6-[(2S)-2-hydroxy-2- phenylacetamido]pyridazin-3- yl}butyl)-N-(2-phenylethl)-1,3,4- thiadiazole-2-carboxamide

26

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5-{4-[6-(2- phenylacetamido)pyridazin-3- yl]butyl}-N-(2-phenylethyl)-1,3,4- thiadiazole-2-carboxamide

27

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N-(2-phenylethyl)-5-(4-{6-[2-(pyridin- 3-yl)acetamido]pyridazin-3-yl}butyl)- 1,3,4-thiadiazole-2-carboxamide

28

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N-benzyl-5-{4-[6-(2- phenylacetamido)pyridazin-3- yl]butyl}-1,3,4- thiadiazole-2-carboxamide

29

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N-benzyl-5-(4-{6-[(2S)-2-hydroxy-2- phenylacetamido]pyridazin-3- yl}butyl)-1,3,4- thiadiazole-2-carboxamide

30

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N-benzyl-5-(4-{6-[2-(pyridin-3- yl)acetamido]pyridazin-3-yl}butyl)- 1,3,4- thiadiazole-2-carboxamide

31

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N-(2-methylpropyl)-5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

32

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N-(pyridin-2-ylmethyl)-5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

33

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N-(oxetan-3-ylmethyl)-5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

34

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N-(2-hydroxy-2-methylpropyl)-5-[4- (6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

34

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N-[2-(pyrrolidin-1-yl)ethyl]-5-[5-(6- {2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

36

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N-benzyl-5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

37

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N-(2-hydroxyethyl)-5-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1,3,4- thiadiazole-2-carboxamide

38

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(propan-2-yl)- 1,3,4- thiadiazole-2-carboxamide

39

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4- thiadiazole-2-carboxamide

40

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(pyridin-2- ylmethyl)-1,3,4- thiadiazole-2-carboxamide

41

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2- hydroxyethyl)-1,3,4- thiadiazole-2-carboxamide

42

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2- methylpropyl)-1,3,4- thiadiazole-2-carboxamide

43

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N-(propan-2-yl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

44

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N-(2-methylpropyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

45

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N-(2-hydroxyethyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2- carboxamide

46

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N-{[3- (trifluoromethoxy)phenyl]methyl}-5- {4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

47

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N-(pyridin-2-ylmethyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

48

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N-(2-hydroxy-2-methylpropyl)-5-{4- [4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

49

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N-[2-(pyrrolidin-1-yl)ethyl]-5-{4-[4- ({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

50

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N-(oxetan-3-ylmethyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

51

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N-(oxetan-3-yl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4- thiadiazole-2-carboxamide

52

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2- methoxyethyl)-1,3,4-thiadiazole-2- carboxamide

53

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tert-butyl 4-[(4-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazol-1- yl)methyl]piperidine-1-carboxylate

54

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ethyl N-[(1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazol-4- yl)methyl]carbamate

55

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1-(4-{4-[(3- methylbutanamido)methyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

56

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2-methylpropyl N-[(1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazol-4- yl)methyl]carbamate

57

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1-(4-(4-((isopentylamino)methyl)-1H- 1,2,3-triazol-1-yl)butyl)-N-(3- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

58

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1-(4-(4-(propionamidomethyl)-1H- 1,2,3-triazol-1-yl)butyl)-N-(3- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

59

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N-(cyclopropylmethyl)-5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2- carboxamide

60

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N-[(6-methylpyridin-3-yl)methyl]-5- {4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2- carboxamide

61

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5-[4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

62

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5-[4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-(pyridin-2- ylmethyl)-1,3,4-thiadiazole-2- carboxamide

63

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N-(cyclopropylmethyl)-5-[4-(4-{[(6- methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1,3,4-thiadiazole-2- carboxamide

64

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N-[(6-methylpyridin-3-yl)methyl]-5- [4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1,3,4-thiadiazole-2- carboxamide

65

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5-(4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

66

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N-(pyridin-2-ylmethyl)-5-(4-{4- [(pyridin-2-ylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-1,3,4- thiadiazole-2-carboxamide

67

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N-[(6-methylpyridin-3-yl)methyl]-5- (4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-1,3,4-thiadiazole- 2-carboxamide

68

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N-(cyclopropylmethyl)-5-(4-{4- [(pyridin-2-ylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-1,3,4- thiadiazole-2-carboxamide

69

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5-(4-{4- [(cyclopropylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-(pyridin-2- ylmethyl)-1,2,3-thiadiazole-2- carboxamide

70

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5-(4-{4- [(cyclopropylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-[(6- methylpyridin-3-yl)methyl]-1,3,4- thiadiazole-2-carboxamide

71

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N-(pyridin-2-ylmethyl)-1-(4-{4- [(pyridin-2-ylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

72

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1-[4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

73

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tert-butyl 3-{[(5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazol-2- yl)formamido]methyl}azetidine-1- carboxylate

74

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tert-butyl 3-[({5-[4-(4-{[(6- methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1,3,4-thiadiazol-2- yl}formamido)methyl]azetidine-1- carboxylate

75

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5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

76

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5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

77

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5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

78

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5-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

79

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tert-butyl 3-{[(1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazol-4- yl)formamido]methyl}azetidine-1- carboxylate

80

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1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

81

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1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

82

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1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

83

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N-{[3- (trifluoromethoxy)phenyl]methyl}-1- {4-[4-({[4-(trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

84

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N-(cyclopentylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

85

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1-(4-{4- [(cyclobutylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

86

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1-(4-{4-[(oxolan-3- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

87

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1-(4-{4-[(oxetan-3- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

88

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1-{4-[4-(methylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

89

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1-(4-{4- [(cyclopropylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

90

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1-(4-{4- [(cyclohexylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazol-4- carboxamide

91

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N-(oxetan-3-ylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

92

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N-(oxolan-2-ylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide

93

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N-(cyclobutylmethyl)-1-{4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

94

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N-(oxan-4-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

95

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N-methyl-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

96

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1-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

97

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1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

98

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1-[4-(4-{[(1R)-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

99

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1-[4-(4-{[(1S)-1- phenyethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

100

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1-[4-(4-{[(1R)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

101

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1-[4-(4-{[(1S)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

102

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1-[4-(4-{[(2R)-7- oxabicyclo[2.2.1]heptan-2- ylmethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

103

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1-[4-(4-{[(2S)-7- oxabicyclo[2.2.1]heptan-2- ylmethyl]carbamoyl}-1H-1,2,3- triazol-1-yl]butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

104

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1-{4-[4-(cyclopentylcarbamoyl)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

105

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1-[4-(4-{[(3- cyclopropylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl) butyl]-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

106

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N-[(4-cyclopropylpyridin-2- yl)methyl]-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl}- carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

107

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1-[4-(4-{[(2-chloro-5- fluorophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

108

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1-[4-(4-{[(3- methoxyphenyl)methyl]carbamoyl}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

109

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1-{4-[4-({1-[3- (trifluoromethoxy)phenyl]ethyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

110

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tert-butyl N-[(3-{[(1-{4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazol-4-yl)formamido]methyl} phenyl)methyl]carbamate

111

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1-[4-(4-{[(3- chlorophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

112

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1-[4-(4-{[(3- fluorophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

113

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1-{4-(4-({[3- (hydroxymethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

114

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1-(4-{4-[(oxan-2- ylmethyl)carbamoyl]-1H-1,2,3-triazol- 1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

115

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N-{7-oxabicyclo[2.2.1]heptan-2- ylmethyl}-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

116

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N-{7-oxabicyclo[2.2.1]heptan-2- ylmethyl}-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

117

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N-(oxan-3-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

118

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N-(oxan-2-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

119

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N-(oxan-3-ylmethyl)-1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

120

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N-(oxan-4-ylmethyl)-1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

121

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N-(oxan-2-ylmethyl)-1-{4-[4-({[3- (trifluoromethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

122

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1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[2-(trifluoromethyl) pyridin-4-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

123

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N-[(3-cyclopropylphenyl)methyl]-1- {4-[4-({[6-(2-hydroxypropan-2- yl)pyridin-3-yl]methyl}carbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-1H- 1,2,3-triazole-4-carboxamide

124

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1-{4-[4-({[3-(pyrrolidin-1- yl)phenyl]methyl}carbamoyl)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

125

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1-{4-[4-({[3-(2- methoxyethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

126

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N-(pyrazin-2-ylmethyl)-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

127

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1-(4-{4-[(pyridazin-4- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl] methyl}-1H-1,2,3-triazole-4- carboxamide

128

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N-[(3-cyclopropylphenyl)methyl]-1- [4-(4-{[(4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

129

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N-[(3-cyclopropylphenyl)methyl]-1- [4-(4-{[(4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)-3-fluorobutyl]-1H-1,2,3- triazole-4-carboxamide

130

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1-[2-fluoro-4-(4-{[(1S)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

131

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1-[2-fluoro-4-(4-{[(1R)-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

132

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1-{4-[4-({[3- (difluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

133

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1-[4-(4-{[(3- cyclopropylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1- yl)butyl]-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

134

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1-[4-(4-{[(3- cyclopropylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl)- 3-fluorobutyl]-N-[(4-cyclopropyl- pyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

135

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1-[4-(4-{[(4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

136

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1-[4-(4-{[(2,2-dimethyl-2H-1,3- benzodioxol-5-yl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl) butyl]-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

137

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1-[4-(4-{[(2,2-dimethyl-2H-1,3- benzodioxol-5-yl)methyl] caramoyl}-1H-1,2,3-triazol-1-yl) butyl]-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

138

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N-[(2S)-2-hydroxy-2-phenylethyl]-1- {4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

139

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N-[(2R)-2-hydroxy-2-phenylethyl]-1- {4-[4-({[3-(trifluoromethoxy) phenyl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide

140

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N-{[5-(trifluoromethyl)pyridin-3- yl]methyl}-1-{4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

141

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1-{4-[4-({[4-(trifluoromethyl)pyridin- 2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

142

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1-{4-[4-({[5-(trifluoromethyl)pyridin- 2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

143

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N-{[5-(trifluoromethyl)pyridin-3- yl]methyl}-1-{4-[4-({[6- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide

144

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1-{4-[4-({[6-(trifluoromethyl)pyridin- 2-yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

145

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1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

146

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N-{[5-(3,3-difluoroazetidin-1- yl)pyridin-3-yl]methyl}-1-{4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

147

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1-[4-(4-{[(4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)-3-fluorobutyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

148

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1-[4-(4-{[(4-cyclopropylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)-2-fluorobutyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

149

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1-{2-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H- 1,2,3-triazole-4-carboxamide

150

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1H-1,2,3- triazole-4-carboxamide

151

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1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H- 1,2,3-triazole-4-carboxamide

152

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N-[(4-cyclopropylpyridin-2- yl)methyl]-1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

153

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1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1H-1,2,3-triazole- 4-carboxamide

154

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N-ethyl-1-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide

155

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1-{3-fuoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{imidazo[2,1- b][1,3]thiazol-6-ylmethyl}-1H-1,2,3- triazole-4-carboxamide

156

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1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

157

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N-methyl-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

158

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N-{[4-(trifluoromethyl)pyridin-2- yl]methyl}-1-{4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1,2,3-triazole- 4-carboxamide

159

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1-[2-fluoro-4-(4-{[(4-methylpyridin-2- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

160

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1-[4-(6-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-N-methyl-1H- 1,2,3-triazole-4-carboxamide

161

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N-methyl-1-{4-[6-(2- phenylacetamido)pyridazin-3- yl]butyl}-1H-1,2,3- triazole-4-carboxamide

162

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1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1H-1,2,3-triazole- 4-carboxamide

163

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1-(3-fluoro-4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide

164

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1-[4-(4-{[(5-cyclopropylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)-3-fluorobutyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide

165

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1-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]-3-fluorobutyl}-N-methyl- 1H-1,2,3-triazole-4-carboxamide

166

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tert-butyl N-[(3-{[(1-{2-fluoro-4-[4- (methylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazol-4-yl)formamido]methyl} phenyl)methyl]carbamate

167

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N-methyl-1-(4-{6-[2-(pyridin-2- yl)acetamido]pyridazin-3-yl}butyl)- 1H-1,2,3-triazole-4-carboxamide

168

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N-(cyanomethyl)-1-{3-fluoro-4-[4- ({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1H-1,2,3-triazole-4- carboxamide

169

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1-(4-{6-[2-(pyridin-2- yl)acetamido]pyridazin-3-yl}butyl)- N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

170

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1-(3-fuoro-4-{4-[(quinolin-3- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide

171

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1-(3-fluoro-4-{4-[(isoquinolin-4- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide

172

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tert-butyl N-[(3-{[(6-{4-[4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl]butyl}pyridazin-3- yl)carbamoyl]methyl}phenyl)methyl] carbamate

173

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1-[4-(6-{2-[3-(2- methoxyethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-N-methyl- 1H-1,2,3- triazole-4-carboxamide

174

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1-[4-(6-acetamidopyridazin-3- yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

175

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1-[4-(6-acetamidopyridazin-3- yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

176

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1-[4-(6-cyclopropaneamidopyridazin- 3-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

177

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1-[4-(6-cyclopropaneamidopyridazin- 3-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

178

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N-methyl-1-[4-(6-{2-[3-(morpholin-4- yl)phenyl]acetamido}pyridazin-3- yl)butyl]-1H-1,2,3-triazole-4- carboxamide

179

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N-methyl-1-(4-{6-[(2S)-2- phenylpropanamido]pyridazin-3- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

180

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1-(4-{6-[2-(3-chloro-2- fluorophenyl)acetamido]pyridazin-3- yl}butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

181

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1-{4-[4-({[4- (difluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl]-3- fluorobutyl}-N-methyl-1H-1,2,3- triazole-4-carboxamide

182

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1-[4-(4-{[(3- cyanophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)-3-fluorobutyl]-N- methyl-1H-1,2,3-triazole-4- carboxamide

183

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1-[3-fluoro-4-(4-{[3- methanesulfonylphenyl)methyl] carbamoyl}-1H-1,2,3-triazol-1-yl) butyl]-N-methyl-1H-1,2,3-triazole-4- carboxamide

184

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1-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H- 1,2,3-triazole-4-carboxamide

185

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methyl 3-{[(1-{2-fluoro-4-[4- (methylcarbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazol-4-yl)formamido]methyl} benzoate

186

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1-{3-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1H- 1,2,3-triazole-4-carboxamide

187

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1-[3-fluoro-4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-methyl-1H- 1,2,3-triazole-4-carboxamide

188

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N-methyl-1-{4-[6-(2-{5-[3- (trifluoromethoxy)phenyl]pyridin-3- yl}acetamido)pyridazin-3-yl]butyl}- 1H-1,2,3-triazole-4-carboxamide

189

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5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

190

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1-(4-{6-[2-(4-cyclopropylpyridin-2- yl)acetamido]pyridazin-3-yl}butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

191

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1-(4-{6-[2-(4-chloropyridin-2- yl)acetamido]pyridazin-3-yl}butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

192

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N-methyl-1-{4-[6-(2-{4-[3- (trifluoromethoxy)phenyl]pyridin-2- yl}acetamido)pyridazin-3-yl]butyl}- 1H-1,2,3-triazole-4-carboxamide

193

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(S)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide

194

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(S)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide

195

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1-(2-fluoro-4-(5-(2-(5-(3- (trifluoromethoxy)phenyl)pyridin-3- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

196

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tert-butyl 3-((5-(3-fluoro-4-(4- (methylcarbamoyl)-1H-1,2,3-triazol- 1-yl)butyl)-1,3,4-thiadiazole-2- carboxamido)methyl)piperidine-1- carboxylate

197

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(S)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

198

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(R)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

199

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1-(4-(6-(2-(3-(3,6-dihydro-2H-pyran- 4-yl)phenyl)acetamido)pyridazin-3- yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide

200

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1-(4-(6-(2-(4-bromopyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

201

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(R)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-((5- (trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

202

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1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

203

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1-(4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- ((4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-1,2,3-triazole-4- carboxamide

204

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1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

205

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1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-((4- methoxypyridin-2-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide

206

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1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yL)butyl)-N-((6- methoxypyridin-2-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide

207

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N-methyl-1-(4-(6-(2-(4-(2 (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

208

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N-methyl-1-(4-(6-(2-(4-(tetrahydro- 2H-pyran-4-yl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

209

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5-(3-fluoro-4-(4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-N-(3- (piperidin-1-yl)benzyl)-1,3,4- thiadiazole-2-carboxamide

210

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N-methyl-1-(4-(6-(2-(4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

211

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1-(2-fluoro-4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- ((4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-1,2,3-triazole-4- carboxamide

212

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tert-butyl 4-(3-(2-((6-(4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl)butyl)pyridazin-3-yl)amino)-2- oxoethyl)phenyl)-3,6-dihydropyridine- 1(2H)-carboxylate

213

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tert-butyl 4-(3-(2-((6-(4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl)butyl)pyridazin-3-yl)amino)-2- oxoethyl)phenyl)piperidine-1- carboxylate

214

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N-methyl-1-(4-(6-(2-(2-oxopiperidin- 1-yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

215

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N-methyl-1-(4-(6-(2-(4- phenylpiperidin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

216

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N-methyl-5-(4-(6-(2-(5-(3- (trifluoromethoxy)phenyl)pyridin-3- yl)acetamido)pyridazin-3-yl)butyl)- 1,2,3-thiadiazole-2-carboxamide

217

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N-methyl-1-(4-(6-(2-(3-(tetrahydro- 2H-pyran-2- yl)phenyl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4- carboxamide

218

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1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N- (pyridin-3-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

219

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1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thidiazol-2-yl)butyl)-N-((6- methoxypyridin-3-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide

220

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(S)-5-(3-fluoro-4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1,3,4-thiadiazole-2-carboxamide

221

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(R)-5-(3-fluoro-4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1,3,4-thiadiazole-2-carboxamide

222

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1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-((5- methoxypyridin-3-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide

223

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1-(2-fluoro-4-(5-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-((2- methoxypyridin-3-yl)methyl)-1H- 1,2,3-triazole-4-carboxamide

224

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methyl 6-(4-(4-(((4- (trifluoromethyl)pyridin-2- yl)methyl)carbamoyl)-1H-1,2,3- triazol-1-yl)butyl)pyridazin-3- yl)carbamate

225

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N-methyl-1-(4-(6-(2-(4-(2,2,2- trifluoroethoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

226

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1-(2-fluoro-4-(5-(2-(4- (trifluoromethyl)pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide

227

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N-methyl-1-(4-(6-(2-(2-oxo-4-(3- (trifluoromethoxy)phenyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

228

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N-methyl-1-(4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

229

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N-methyl-5-(4-(6-(2-(4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1,3,4-thiadiazole-2-carboxamide

230

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1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3- yl)acetamido)pyridazin-3-yl)butyl)-N- ((4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-1,2,3-triazole-4- carboxamide

231

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1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3- yl)acetamido)pyridazin-3-yl)butyl)-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

232

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N-methyl-1-(4-(6-(2-(4-(4- (trifluoromethoxy)phenyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

233

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N-methyl-1-(4-(6-(2-(4-(4- (trifluoromethoxy)phenyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

234

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5-(3-fluoro-4-(4-((pyridin-2- ylmethyl)carbamoyl)-1H-1,2,3-triazol- 1-yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1,3,4-thiadiazole-2-carboxamide

235

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5-(3-fluoro-4-(4-(((4- (trifluoromethyl)pyridin-2- yl)methyl)carbamoyl)-1H-1,2,3- triazol-1-yl)butyl)-N-(pyridin-2- ylmethyl)-1,3,4-thiadiazole-2- carboxamide

236

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1-(4-(6-acetamidopyridazin-3-yl)-2- fluorobutyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

237

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1-(4-(6-(2-(3- (dimethylamino)phenyl)acetamido) pyridazin-3-yl)butyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide

238

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(S)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

239

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(S)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide

240

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(R)-1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide

241

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1-(2-fluoro-4-(6-(2-(2-oxo-4-(3- (trifluoromethoxy)phenyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

242

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1-(2-fluoro-4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

243

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cyclohexyl (6-(4-(4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl)butyl)pyridazin-3-yl)carbamate

244

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1-(2-fluoro-4-(6-(2- phenylacetamido)pyridazin-3- yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide

245

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1-(4-(6-(2-(5-(3,3- difluorocyclobutoxy)pyridin-3- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

246

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N-(2-hydroxyethyl)-1-(4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

247

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N-methyl-1-(4-(6-(2-(2-oxo-4-(3- (trifluoromethoxy)benzyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

248

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1-(2-fluoro-4-(6-(2-(4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

249

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N-methyl-1-(4-(6-(2-(2-oxo-4-(2- (trifluoromethoxy)phenyl)piperazin-1- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

250

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(R)-1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

251

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1-(4-(6-(2-(4-cyclobutoxypyridin-2- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

252

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1-(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

253

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1-(2-fluoro-4-(6-(2-(4-(tetrahydro-2H- pyran-4-yl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

254

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(R)-1-(2-fluoro-4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

255

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(R)-1-(2-fluoro-4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

256

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(S)-1-(2-fluoro-4-(6-(2-(pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

257

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(S)-1-(2-fluoro-4-(6-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

258

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N-methyl-1-(4-(6-(2-(4-(1,1,1- trifluoropropan-2-yl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

259

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(R)-1-(2-fluoro-4-(6-(2-(4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

260

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(S)-1-(2-fluoro-4-(6-(2-(4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

261

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1-(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

262

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1-(2-fluoro-4-(6-(2-(4-(2,2,2- trifluoroethoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

263

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1-(4-(6-(2-(6-cyclopropyl-4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

264

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1-(2-fluoro-4-(6-(2-(6-methyl-4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

265

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1-(2-fluoro-4-(5-(2-(4-(tetahydro-2H- pyran-4-yl)pyridin-2-yl)acetamido)- 1,3,4-thiadiazol-2-yl)butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide

266

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1-(2-fluoro-4-(6-(2-(4-((1,1,1- trifluoropropan-2-yl)oxy)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

267

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(R)-1-(4-(6-(2-(4- (cyclopropyldifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

268

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(R)-1-(2-fluoro-4-(6-(2-(6-methyl-4- (trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

269

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(R)-1-(2-fluoro-4-(6-(2-(4-(3-(2,2,2- trifluoroethoxy)cyclobutoxy)pyridin- 2-yl)acetamido)pyridazin-3-yl)butyl)- N-methyl-1H-1,2,3-triazole-4- carboxamide

270

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(R)-1-(2-fluoro-4-(6-(2-(1-(3- (tifluoromethoxy)phenyl)-1H- imidazol-4-yl)acetamido)pyridazin-3- yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide

271

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(R)-1-(2-fluoro-4-(6-(2-(4- ((tetrahydro-2H-pyran-4- yl)oxy)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3-triazole-4- carboxamide

272

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(R)-1-(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

273

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(R)-1-(2-fluoro-4-(6-(2- phenylacetamido)pyridazin-3- yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide

274

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1-(4-(6-(2-(4- (difluoromethoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1,2,3- triazole-4-carboxamide

275

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(R)-1-(4-(6-(2-(4-cyclopropylpyridin- 2-yl)acetamido)pyridazin-3-yl)-2- fluorobutyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

276

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1-{4-[4-(2-cyclopropylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

277

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1-{4-[4-(cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4- carboxamide

278

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1-{4-[4-(2-cyclopropylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4- carboxamide

279

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N-(pyridin-2-ylmethyl)-1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

280

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4- carboxamide

281

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N-(cyclohexylmethyl)-1-{4-[4-(2- cyclopropylacetamido)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3- triazole-4-carboxamide

282

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N-(cyclohexylmethyl)-1-{4-[4-(2- cyclopentylacetamido)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

283

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N- (cyclohexylmethyl)-1H-1,2,3-triazole- 4-carboxamide

284

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N-(cyclohexylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide

285

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N-(cyclohexylmethyl)-1-(4-{4-[2- (pyridin-2-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide

286

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N-(cyclohexylmethyl)-1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

287

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N-(cyclopentylmethyl)-1-{4-[4-(2- cyclopropylacetamido)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

288

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1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N- (cyclopentylmethyl)-1H-1,2,3- triazole-4-carboxamide

289

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N- (cyclopentylmethyl)-1H-1,2,3- triazole-4-carboxamide

290

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N-(cyclopentylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

291

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N-(cyclopentylmethyl)-1-(4-{4-[2- (pyridin-2-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide

292

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N-(cyclopentylmethyl)-1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

293

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1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

294

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1-(4-{4-[2-(pyridin-3-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

295

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1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

296

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

297

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1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

298

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N-(pyridin-2-ylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3-triazole- 4-carboxamide

299

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N-[(6-methylpyridin-3-yl)methyl]-1- [4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

300

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1-{4-[4-(2-cyclopropylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

301

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N-(cyclopropylmethyl)-1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

302

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N-(cyclopropylmethyl)-1-(4-{4-[2- (pyridin-2-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

303

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N-(cyclopropylmethyl)-1-(4-{4-[2- (pyridin-3-yl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

304

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1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N- (cyclopropylmethyl)-1H-1,2,3- triazole-4-carboxamide

305

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N- (cyclopropylmethyl)-1H-1,2,3- triazole-4-carboxamide

306

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1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

307

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N-(pyridin-3-ylmethyl)-1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

308

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1-{4-[4-(2-cyclopropylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(pyridin-3- ylmethyl)-1H-1,2,3- triazole-4-carboxamide

309

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1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(pyridin-3- ylmethyl)-1H-1,2,3- triazole-4-carboxamide

310

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-(pyridin-3- ylmethyl)-1H-1,2,3- triazole-4-carboxamide

311

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N-(cyclopentylmethyl)-1-(4-{4-[2-(6- methylpyridin-3-yl)acetamido]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

312

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N-(cyclohexylmethyl)-1-(4-{4-[2-(6- methylpyridin-3-yl)acetamido]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

313

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1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

314

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N-[(6-methylpyridin-3-yl)methyl]-1- (4-{4-[2-(pyridin-2-yl)acetamido]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

315

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N-[(6-methylpyridin-3-yl)methyl]-1- (4-{4-[2-(pyridin-3-yl)acetamido]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

316

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1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

317

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1-{4-[4-(2-cyclopentylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

318

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1-{4-[4-(2-cyclohexylacetamido)-1H- 1,2,3-triazol-1-yl]butyl}-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

319

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N-(cyclopropylmethyl)-1-(4-{4-[2-(6- methylpyridin-3-yl)acetamido]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

320

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1-(4-{4-[2-(pyridin-3-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N- (pyridin-3-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

321

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1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-N- (pyridin-3-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

322

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1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-3-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

323

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

324

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1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

325

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1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

326

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1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

327

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

328

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

329

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1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

330

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

331

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1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

332

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1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

333

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N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1- [4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

334

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

335

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N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1- (4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

336

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(6-methylpyridin-3- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3- triazole-4-carboxamide

337

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N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1- (4-{4-[2-(pyridin-2-yl)acetamido]-1H- 1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

338

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(pyridin-2-yl)acetamido]- 1H-1,2,3-triazol-1-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

339

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

340

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

341

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

342

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1-(3-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

343

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1-(3-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methy}- 1H-1,2,3-triazole-4-carboxamide

344

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1-(3-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

345

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1-(3-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3- triazole-4-carboxamide

346

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1-(3-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl-1H-1,2,3- triazole-4-carboxamide

347

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1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

348

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1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

349

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

350

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N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1- (4-{4-[2-(3-fluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

351

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

352

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

353

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

354

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1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

355

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

356

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1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

357

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1-(4-{4-[2-(3,3-difluoropyrrolidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

358

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1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

359

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-1H-1,2,3-triazole-4- carboxamide

360

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1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

361

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1-(4-{4-[2-(4,4-difluoropiperidin-1- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

362

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1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

363

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1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

364

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1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

365

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1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

366

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1-(4-{4-[2-(4-chloro-2- fluorophenyl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4- carboxamide

367

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1-[4-(4-{2-[2-fluoro-4- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethy)-1H-1,2,3- triazole-4-carboxamide

368

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

369

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

370

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1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

371

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1-(3-fluoro-4-{4-[2-(3-fluoroazetidin- 1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

372

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1-(3-fluoro-4-{4-[2-(3-fluoroazetidin- 1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

373

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1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

374

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1-(3-fluoro-4-{4-[2-(3-fluoroazetidin- 1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

375

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

376

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

377

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

378

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

379

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

380

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1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

381

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1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

382

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1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

383

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1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

384

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N-[(5-chloro-2-fluorophenyl)methyl]- 1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

385

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1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

386

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1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

387

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1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

388

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1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

389

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1-(3-fluoro-4-{4-[2-(3-fluoroazetidin- 1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-(pyridin-2-ylmethyl)-1H- 1,2,3-triazole-4-carboxamide

390

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

391

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

392

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4- carboxamide

393

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-[(6-methylpyridin-3- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

394

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

395

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

396

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1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

397

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1-(2-fluoro-4-(5-(2-(4-(3- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3-triazole- 4-carboxamide

398

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1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

399

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1-(3-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

400

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1-(3-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

401

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1-(3-fluoro-4-{4-[2-(3-fluoroazetidin- 1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

402

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

403

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1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

404

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1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[2- fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

405

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1-(2-fluoro-4-{4-[2-(6-methylpyridin- 3-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

406

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1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

407

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1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

408

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1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

409

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1-(3-fluoro-4-{4-[2-(3-fluoroazetidin- 1-yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

410

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1-(4-{4-[2-(3,3-difluoroazetidin-1- yl)acetamido]-1H-1,2,3-triazol-1-yl}- 3-fluorobutyl)-N-[(3-fluoropyridin-2- yl)methyl]-1H-1,2,3-triazole-4- carboxamide

411

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[6- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

412

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[6- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

413

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1-[4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

414

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1-[4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

415

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1-(4-{4-[2-(5-chloro-2- fluorophenyl)acetamido]-1H-1,2,3- triazol-1-yl}butyl)-N-[(5-chloro-2- fluorophenyl)methyl]-1H-1,2,3- triazole-4-carboxamide

416

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1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

417

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1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

418

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1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

419

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1-(2-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1H-1,2,3-triazol-1- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

420

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5-[3-fluoro-4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

421

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1-{2-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

422

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1-{2-fluoro-4-[5-({[6- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

423

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

424

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

425

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

426

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

427

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

428

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

429

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

430

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

431

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

432

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1-{2-fluoro-4-[4-({[4- (tifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

433

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1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

434

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1-[2-fluoro-4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

435

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

436

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

437

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1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

438

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1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[6-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

439

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1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

440

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1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

441

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1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

442

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl) methyl]-1,3,4-thiadiazole-2- carboxamide

443

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5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(6-methylpyridin-3-yl) methyl]-1,3,4-thiadiazole-2- carboxamide

444

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1-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(3-fluoropyridin-2-yl) methyl]-1H-1,2,3-triazole-4- carboxamide

445

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

446

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

447

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5-[3-fluoro-4-(4-{[(6-methylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

448

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

449

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

450

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N-benzyl-1-{2-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-1H-1,2,3-triazole- 4-carboxamide

451

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5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

452

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1S)-2-hydroxy-1- phenylethyl]-1H-1,2,3-triazole-4- carboxamide

453

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1R)-2-hydroxy-1- phenylethyl]-1H-1,2,3-triazole-4- carboxamide

454

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1-[2-fluoro-4-(4-{[(2- fluorophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

455

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1-{2-fluoro-4-[4-({[3- (trifluoromethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

456

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1-(4-{4- [(cyclohexylmethyl)carbamoyl]-1H- 1,2,3-triazol-1-yl}-2-fluorobutyl)-N- {[4-(trifluoromethyl)pyridin-2- yl]methyl}-1H-1,2,3-triazole-4- carboxamide

457

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1-(2-fluoro-4-{4-[(oxan-4- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

458

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1-[2-fluoro-4-(4-{[(1S)-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3-triazole-4- carboxamide

459

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1-[2-fluoro-4-(4-{[(4- fluorophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

460

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1-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]-2-fluorobutyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

461

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1R)-2-hydroxy-1- phenylethyl]-1H-1,2,3-triazole-4- carboxamide

462

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-[(1S)-2-hydroxy-1- phenylethyl]-1H-1,2,3- triazole-4-carboxamide

463

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

464

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

465

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5-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

466

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1-[2-fluoro-4-(4-{[(3- fluorophenyl)methyl]carbamoyl}-1H- 1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

467

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1-[2-fluoro-4-(4-{[(1R)-2-hydroxy-1- phenylethyl]carbamoyl}-1H-1,2,3- triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

468

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1-[2-fluoro-4-(4-{[(3- methoxyphenyl)methyl]carbamoyl}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

469

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1-{2-fluoro-4-[4-({[4- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

470

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1-{2-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3- triazole-4-carboxamide

471

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1-(4-{4- [(cyclopentylmethyl)carbamoyl]- 1H-1,2,3-triazol-1-yl}-2- fluorobutyl)-N-{[4- (trifluoromethyl)pyridin-2- yl]methyl}-1H-1,2,3-triazole-4- carboxamide

472

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1-(2-fluoro-4-{4-[(oxan-2- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

473

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1-(2-fluoro-4-{4-[(oxan-3- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3- triazole-4-carboxamide

474

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1-{2-fluoro-4-[4-({[6- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl] methyl}-1H-1,2,3- triazole-4-carboxamide

475

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1-{2-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

476

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1-{2-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

477

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1-{2-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

478

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1-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

479

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1-{2-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

480

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3- (trifluoromethyl)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

481

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5-[4-(4-{[(6-cyclopropylpyridin-3- yl)methyl]carbamoyl}-1H-1,2,3- triazol-1-yl)-3-fluorobutyl]-N-{[3- (trifluoromethyl)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

482

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

483

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

484

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5-{3-fluoro-4-[4-({[3- (trifluoromethyl)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-{[5-(trifluoromethyl) pyridin-3-yl]methyl}-1,3,4- thiadiazole-2-carboxamide

485

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

486

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-{[5- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

487

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl-N-{[6- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

488

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide

489

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide

490

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[6- (trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide

491

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[6- (trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide

492

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[6- (trifluoromethyl)pyridin-2-yl] methyl}-1,3,4-thiadiazole-2- carboxamide

493

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl) butyl]-N-{[5-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

494

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl) butyl]-N-{[6-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

495

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl) butyl]-N-{[4-(trifluoromethyl) pyridin-2-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

496

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

497

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1-(2-fluoro-4-(5-(2-(3- (trifluoromethoxy)phenyl) acetamido)-1,3,4-thiadiazol-2-yl) butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

498

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl] acetamido}-1,3,4-thiadiazol-2-yl) butyl]-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl}-1H-1,2,3- triazole-4-carboxamide

499

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2,2,2- trifluoroethyl)-1,3,4-thiadiazole-2- carboxamide

500

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(2,2,2- trifluoroethyl)-1,3,4-thiadiazole-2- carboxamide

501

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5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

502

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5-(3-fluoro-4-{4-[(3,3,3- trifluoropropyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

503

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1,3,4- thiadiazole-2-carboxamide

504

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1,3,4-thiadiazole-2- carboxamide

505

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N-(cyanomethyl)-1-[2-fluoro-4-(5-{2- [3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

506

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5-(3-fluoro-4-{4-[(2,2,2- trifluoroethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[5- (trifluoromethyl)pyridin-3-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

507

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-methyl-1,3,4- thiadiazole-2-carboxamide

508

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5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

509

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5-(3-fluoro-4-{4-[(2,2,2- trifluoroethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

510

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5-(3-fluoro-4-{4-[(3,3,3- trifluoropropyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

511

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamooyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(3,3,3- trifluoropropyl)-1,3,4-thiadiazole-2- carboxamide

512

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5-{3-fluoro-4-[4-({[5- (trifluoromethyl)pyridin-3- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-(3,3,3- trifluoropropyl)-1,3,4-thiadiazole-2- carboxamide

513

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1-(2-fluoro-4-{5-[2-(pyridin-2- yl)acetamido]-1,3,4-thiadiazol-2- yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

514

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1-(2-fluoro-4-{4-[2-(pyridin-2- yl)acetamido]-1,3,4-thiadiazol-2- yl}butyl)-N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

515

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N-(cyanomethyl)-5-{3-fluoro-4-[4- ({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2- carboxamide

516

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1-[2-fluoro-4-(5-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-{[5- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

517

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1-[2-fluoro-4-(5-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1H-1,2,3-triazole-4-carboxamide

518

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1-[2-fluoro-4-(5-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide

519

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1-(2-fluoro-4-{5-[2-(pyridin-2- yl)acetamido]-1,3,4-thiadiazol-2- yl}butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

520

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5-{3-fluoro-4-[4-({[4- (trifluoromethyl)pyridin-2- yl]methyl}carbamoyl)-1H-1,2,3- triazol-1-yl]butyl}-N-{[4- (trifluoromethyl)pyridin-2-yl]methyl}- 1,3,4-thiadiazole-2-carboxamide

521

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2- carboxamide

522

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N-ethyl-5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-1,3,4-thiadiazole-2- carboxamide

523

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5-{3-fluoro-4-[4-({[3- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-(2-methoxyethyl)-1,3,4- thiadiazole-2-carboxamide

524

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1-[3-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N- methyl-1H-1,2,3-triazole-4- carboxamide

525

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1-[3-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide

526

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N-(propan-2-yl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

527

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N-(cyanomethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

528

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N-(2-hydroxyethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

529

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N-(pyridin-2-ylmethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl] acetamido}pyridazin-3-yl)butyl]- 1H-1,2,3-triazole-4-carboxamide

530

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

531

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N-ethyl-1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

532

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-(2- methoxyethyl)-1H-1,2,3- triazole-4-carboxamide

533

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N- (pyridin-2-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

534

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N-cyclopropyl-1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

535

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N-(cyclopropylmethyl)-1-[2-fluoro-4- (5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

536

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-(2,2,2- trifluoroethyl)-1H-1,2,3-triazole-4- carboxamide

537

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-[(3- fluoropyridin-2-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

538

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1-[2-fluoro-4-(4-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide

539

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1-[2-fluoro-4-(4-{2-[2-fluoro-5- (trifluoromethoxy)phenyl]acetamido}- 1H-1,2,3-triazol-1-yl)butyl]-N-methyl- 1H-1,2,3-triazole-4-carboxamide

540

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1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

541

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N-methyl-1-(5-{6-[2-(pyridin-3- yl)acetamido]pyridazin-3-yl}butyl)- 1H-1,2,3-triazole-4-carboxamide

542

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1-(4-{6-[2-(3- bromophenyl)acetamido]pyridazin-3- yl}butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

543

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1-(4-{6-[2-(3- methanesulfonylphenyl)acetamido] pyridazin-3-yl}butyl)-N-methyl- 1H-1,2,3-triazole-4-carboxamide

544

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1-(4-{6-[2-(6-chloropyridin-3- yl)acetamido]pyridazin-3-yl}butyl)-N- methyl-1H-1,2,3- triazole-4-carboxamide

545

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N-methyl-1-[4-(6-{2-[3-(pyridin-2- yl)phenyl]acetamido}pyridazin-3- yl)butyl]-1H-1,2,3- triazole-4-carboxamide

546

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1-(4-{6-[2-(5-bromopyridin-3- yl)acetamido]pyridazin-3-yl}butyl)-N- methyl-1H- triazole-4-carboxamide

547

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N-methyl-1-(4-{6-[2-(oxan-4- yl)acetamido]pyridazin-3-yl}butyl)- 1H-1,2,3-triazole-4-carboxamide

548

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1-{4-[6-(2- cyclopentylacetamido)pyridazin-3- yl]butyl}-N-methyl-1H-1,2,3- triazole-4-carboxamide

549

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N-(2-hydroxy-2-methylpropyl)-1-[4- (6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

550

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N-(oxetan-3-ylmethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

551

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N-(2-methoxyethyl)-1-[4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

552

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N-[3-hydroxy-2- (hydroxymethyl)propyl]-1-[4-(6-{2- [3- (trifluoromethoxy)phenyl]acetamido}- pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

553

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1-(4-{5-[2-(pyridin-2-yl)acetamido]- 1,3,4-thiadiazol-2-yl}butyl)-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1H-1,2,3-triazole-4-carboxamide

554

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N-{[2-fluoro-5- (trifluoromethoxy)phenyl]methyl}-1- (4-{5-[2-(pyridin-2-yl)acetamido]- 1,3,4-thiadiazol-2-yl}butyl)-1H-1,2,3- triazole-4-carboxamide

555

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N-{3-fluoro-4-[4-({[2-fluoro-5- (trifluoromethoxy)phenyl]methyl} carbamoyl)-1H-1,2,3-triazol-1-yl] butyl}-N-methyl-1,3,4-thiadiazole-2- carboxamide

556

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5-{4-[4-(benzylcarbamoyl)-1H-1,2,3- triazol-1-yl]-3-fluorobutyl}-N-methyl- 1,3,4-thiadiazole-2-carboxamide

557

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5-(3-fluoro-4-{4-[(pyridin-2- ylmethyl)carbamoyl]-1H-1,2,3- triazol-1-yl}butyl)-N-methyl-1,3,4- thiadiazole-2-carboxamide

558

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N- (oxetan-3-ylmethyl)-1H-1,2,3- triazole-4-carboxamide

559

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1-[2-fluoro-4-(5-{2-[3- (trifluoromethoxy)phenyl]acetamido}- 1,3,4-thiadiazol-2-yl)butyl]-N-[(6- methylpyridin-3-yl)methyl]-1H-1,2,3- triazole-4-carboxamide

560

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N-(3-hydroxy-2,3-dimethylpropyl)-1- [4-(6-{2-[3- (trifluoromethoxy)phenyl]acetamido} pyridazin-3-yl)butyl]-1H-1,2,3- triazole-4-carboxamide

561

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5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[3- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

562

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5-{3-fluoro-4-[4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl]butyl}-N-{[2- fluoro-5- (trifluoromethoxy)phenyl]methyl}- 1,3,4-thiadiazole-2-carboxamide

563

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N-benzyl-5-{3-fluoro-4-[4- (methylcarbamoyl)-1H-1,2,3-triazol-1- yl]butyl}-1,3,4-thiadiazole-2- carboxamide

564

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1-(4-{5-[2-(5-chloro-3-fluoropyridin- 2-yl)acetamido]-1,3,4-thiadiazol-2- yl}-2-fluorobutyl)-N-methyl-1H- 1,2,3-triazole-4-carboxamide

565

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N-methyl-1-(4-(6-(2-(3-(pyrrolidin-1- yl)phenyl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4- carboxamide

566

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1-(4-(5-acetamido-1,3,4-thiadiazol-2- yl)-2-fluorobutyl)-N-(3- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

567

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1-(4-(5-acetamido-1,3,4-thiadiazol-2- yl)-2-fluorobutyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

568

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1-(4-(5-(cyclopropanecarboxamido)- 1,3,4-thiadiazol-2-yl)-2-fluorobutyl)- N-(3-(trifluoromethoxy)benzyl)-1H- 1,2,3-triazole-4-carboxamide

569

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1-(4-(5-(cyclopropanecarboxamido)- 1,3,4-thiadiazol-2-yl)-2-fluorobutyl)- N-((4-(trifluoromethyl)pyridin-2- yl)methyl)-1H-1,2,3- triazole-4-carboxamide

570

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5-(3-fluoro-4-(4-(methylcarbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-N- (pyridin-2-ylmethyl)-1,3,4- thiadiazole-2-carboxamide

571

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1-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-((5- (trifluoromethyl)pyridin-3-yl) methyl)-1H-1,2,3- triazole-4-carboxamide

572

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N-methyl-5-(4-(6-(2-(3- (trifluoromethoxy)phenyl) acetamido)pyridazin-3-yl)butyl)- 1,3,4-thiadiazole-2-carboxamide

573

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1-(2-fluoro-4-(5-(2-(thiazol-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

574

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1-(2-fluoro-4-(5-(tetrahydro-2H- pyran-2-carboxamido)-1,3,4- thiadiazol-2-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

575

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1-(4-(5-(2-(1H-pyrazol-5- yl)acetamido)-1,3,4-thiadiazol-2-yl)-2- fluorobutyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

576

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1-(2-fluoro-4-(5-(2-(1-methyl-1H- imidazol-4-yl)acetamido)-1,3,4- thiadiazol-2-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

577

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N-(5-(3-fluoro-4-(4-((2-fluoro-5- (trifluoromethoxy)benzyl)carbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazol-2-yl)nicotinamide

578

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1-(2-fluoro-4-(5-(2-(pyridin-3- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-methyl-1H-1,2,3- triazole-4-carboxamide

579

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N-methyl-1-(4-(6-(2-(pyrazin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

580

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1-(4-(5-(2-(4-cyclopropylpyridin-2- yl)acetamido)-1,3,4-thiadiazol-2-yl)-2- fluorobutyl)-N-((5- (trifluoromethyl)pyridin-3-yl)methyl)- 1H-1,2,3-triazole-4-carboxamide

581

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1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(oxetan-3-yl)- 1H-1,2,3-triazole-4-carboxamide

582

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1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(oxetan-2- ylmethyl)-1H-1,2,3- triazole-4-carboxamide

583

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N-cyclopropyl-1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-1H-1,2,3- triazole-4-carboxamide

584

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1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(2- methoxyethyl)-1H-1,2,3- triazole-4-carboxamide

585

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1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(pyridin-2- ylmethyl)-1H-1,2,3-triazole-4- carboxamide

586

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1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(pyridin-3- ylmethyl)-1H-1,2,3- triazole-4-carboxamide

587

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1-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(pyridin-4- ylmethyl)-1H-1,2,3- triazole-4-carboxamide

588

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N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1-(4-(6-(2- (pyridin-2-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4- carboxamide

589

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N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1-(4-(6-(2- (pyridin-3-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3- triazole-4-carboxamide

590

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N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1-(4-(6-(2- (pyridin-4-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3-triazole-4- carboxamide

591

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1-(4-(6- (cyclopropanecarboxamido)pyridazin- 3-yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

592

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1-(2-fluoro-4-(5-(2-(6-fluoropyridin-2- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

593

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1-(2-fluoro-4-(5-(2-(thiazol-5- yl)acetamido)-1,3,4-thiadiazol-2- yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1H-1,2,3- triazole-4-carboxamide

594

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N-(5-(3-fluoro-4-(4-((2-fluoro-5- (trifluoromethoxy)benzyl)carbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazol-2-yl)isonicotinamide

595

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N-(5-(3-fluoro-4-(4-((2-fluoro-5- (trifluoromethoxy)benzyl)carbamoyl)- 1H-1,2,3-triazol-1-yl)butyl)-1,3,4- thiadiazol-2-yl)picolinamide

596

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1-(4-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-1H-1,2,3- triazole-4-carboxamide

597

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5-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-(2- hydroxyethyl)-1,3,4-thiadiazole-2- carboxamide

598

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5-(4-(6-(2-(2-fluoro-5- (trifluoromethoxy)phenyl)acetamido) pyridazin-3-yl)butyl)-N-methyl-1,3,4- thiadiazole-2-carboxamide

599

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5-(4-(6-acetamidopyridazin-3- yl)butyl)-N-(3- (trifluoromethoxy)benzyl)-1,3,4- thiadiazole-2-carboxamide

600

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5-(4-(6-acetamidopyridazin-3- yl)butyl)-N-(2-fluoro-5- (trifluoromethoxy)benzyl)-1,3,4- thiadiazole-2-carboxamide

601

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5-(4-(6-acetamidopyridazin-3- yl)butyl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)- 1,3,4-thiadiazole-2-carboxamide

602

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5-(4-(6-acetamidopyridazin-3- yl)butyl)-N-((5- (trifluoromethyl)pyridin-3-yl)methyl)- 1,3,4-thiadiazole-2-carboxamide

603

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N-methyl-5-(4-(4-(((4- (trifluoromethyl)pyridin-2- yl)methyl)carbamoyl)-1H-1,2,3- triazol-1-yl)butyl)-1,3,4-thiadiazole-2- carboxamide

604

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N-methyl-1-(4-(6-(2-(1-(3- (trifluoromethoxy)phenyl)-1H- imidazol-4-yl)acetamido)pyridazin-3- yl)butyl)-1H-1,2,3- triazole-4-carboxamide

605

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N-methyl-1-(4-(6-(2-(4-(2- (trifluoromethyl)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)- 1H-1,2,3-triazole-4-carboxamide

606

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1-(4-(6-(2-(4-(4-fluoro-2- (trifluoromethyl)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3- triazole-4-carboxamide

607

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1-(4-(6-(2-(4-(2-fluoro-3- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3- triazole-4-carboxamide

608

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1-(4-(6-(2-(4-(3-chloro-2- (trifluoromethoxy)phenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3- triazole-4-carboxamide

609

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1-(4-(6-(2-(4-(5-fluoro-2- methylphenyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N- methyl-1H-1,2,3- triazole-4-carboxamide

Table 2 below reports the calculated observed molecular weight of each Example, as well as the method by which each compound may be made by reference to each Example whose synthesis is substantially similar that one skilled in the art could produce the compound using, if necessary, variations know in the art.

TABLE 2

Observed Molecular Weight and Synthesis for Examples

Ex. No.
Calc. Mass
Obs Mass
Method as in Ex.

10
511
512
1

11
523
524
1

12
553
554
1

13
489
490
1

14
512
513
1

15
475
476
1

16
559
560
1

17
513
514
1

18
587
588
1

19
560
561
1

20
643
644
1

21
589
590
1

22
619
620
1

23
589
590
1

24
435
435
5

25
516
517
6

26
500
501
6

27
501
502
6

28
486
487
6

29
502
503
6

30
487
488
6

31
536
537
6

32
571
572
6

33
550
551
6

34
552
553
6

34
577
578
6

36
570
571
6

37
524
525
6

38
427
428
7

39
559
560
7

40
476
477
7

41
429
430
7

42
441
442
7

43
511
512
7

44
525
526
7

45
513
514
7

46
643
644
7

47
560
561
7

48
541
542
7

49
566
567
7

50
539
540
7

51
525
526
7

52
443
444
7

53
606
607
8

54
510
511
9

55
522
523
9

56
538
539
9

57
508
509
9

58
494
495
9

59
523
524
7

60
574
575
7

61
574
575
7

62
491
492
7

63
454
455
7

64
505
506
7

65
560
561.5
7

66
477
478
7

67
491
491
7

68
440
441
7

69
440
441
7

70
454
455
7

71
460
461
80

72
557
558
80

73
638
639
7

74
569
570
7

75
628
629
7

76
628
629
7

77
628
629
7

78
628
629
7

79
621
622
80

80
611
612
80

81
611
612
80

82
611
612
80

83
611
612
80

84
519
520
80

85
505
506
80

86
521
522
80

87
507
508
80

88
451
452
80

89
491
492
80

90
533
534
80

91
507
508
80

92
521
522
80

93
505
506
80

94
550
551
80

95
466
467
80

96
527
528
80

97
595
596
80

98
541
542
80

99
541
542
80

100
557
558
80

101
557
558
80

102
547
548
80

103
547
548
80

104
505
506
80

105
567
568
80

106
583
584
80

107
579
580
80

108
557
558
80

109
625
626
80

110
656
657
80

111
561
562
80

112
545
546
80

113
557
558
80

114
535
536
80

115
562
563
80

116
562
563
80

117
550
551
80

118
550
551
80

119
534
535
80

120
534
535
80

121
534
535
80

122
611
612
80

123
557
558
80

124
596
597
80

125
601
602
80

126
544
545
80

127
544
545
80

128
539
540
80

129
557
558
475

130
575
576
475

131
559
560
475

132
593
594
80

133
567
568
80

134
557
558
475

135
568
569
80

136
599
600
80

137
599
600
80

138
572
573
80

139
572
573
80

140
596
597
80

141
596
597
80

142
596
597
80

143
596
597
80

144
596
597
80

145
614
615
475

146
634
635
80

147
601
602
475

148
601
602
475

149
469
470
475

150
502
503
475

151
469
470
475

152
586
587
475

153
502
503
475

154
483
484
475

155
591
592
475

156
614
615
475

157
477
478
157

158
596
597
80

159
560
561
475

160
495
496
157

161
393
394
157

162
484
485
475

163
401
402
475

164
441
442
475

165
400
401
475

166
529
530
475

167
394
395
157

168
527
528
475

169
554
555
157

170
451
452
475

171
451
452
475

172
522
523
157

173
467
468
157

174
477
478
157

175
462
463
157

176
503
504
157

177
488
489
157

178
478
479
157

179
407
408
157

180
445
446
157

181
466
467
475

182
425
426
475

183
478
479
475

184
469
470
475

185
458
459
475

186
469
470
475

187
415
416
475

188
554
555
188

189
486
487
508

190
434
435
192

191
428
429
192

192
554
555
192

193
501
502
250

194
501
502
250

195
578
579
195

196
524
525
540

197
596
597
250

198
596
597
250

199
475
476
192

200
472
473/475
192

201
563
564
250

202
500
501
192

203
539
540
157

204
596
597
540

205
626
627
540

206
626
627
540

207
554
555
192

208
478
479
192

209
500
501
540

210
462
463
192

211
557
558
211

212
574
575
192

213
576
577
192

214
414
415
192

215
476
477
192

216
571
572
229

217
477
478
192

218
596
597
540

219
626
627
540

220
486
487
508 +

separation

221
486
487
508 +

separation

222
626
627
540

223
626
627
540

224
478
479
157

225
492
493
192

226
486
487
540

227
575
576
211

228
561
562
228

229
479
480
229

230
645
646
157

231
577
578
157

232
561
562
228

233
464
465
233

234
563
564
508

235
563
564
508

236
480
481
259

237
436
437
192

238
563
564
250

239
501
502
250

240
501
502
250

241
593
594
259

242
572
573
242

243
401
402
243

244
411
412
259

245
518
519
259

246
584
585
157

247
589
612 (M +
211

Na+)

248
480
481
259

249
575
576
211

250
563
564
250

251
482
483
251

252
518
519
272

253
496
497
253

254
412
413
259

255
572
573
242

256
412
413
259

257
572
573
242

258
490
491
258

259
480
481
259

260
480
481
259

261
500
501
261

262
510
511
262

263
520
521
268

264
494
495
268

265
502
503
540

266
524
525
262

267
502
503
267

268
494
495
268

269
580
581
269

270
561
562
270

271
512
513
271

272
518
519
272

273
411
412
259

274
478
479
274

275
452
453
275

276
506
507
297

277
451
452
297

278
423
424
297

279
543
544
297

280
465
466
297

281
428
429
297

282
456
457
297

283
470
471
297

284
465
466
297

285
465
466
297

286
548
549
297

287
414
415
297

288
442
443
297

289
456
457
297

290
451
452
297

291
451
452
297

292
534
535
297

293
543
544
297

294
543
544
297

295
534
535
297

296
548
549
297

297
460
461
297

298
460
461
297

299
557
558
297

300
437
438
297

301
506
507
297

302
423
424
297

303
423
424
297

304
414
415
297

305
428
429
297

306
474
475
297

307
543
544
297

308
423
424
297

309
451
452
297

310
465
466
297

311
465
466
297

312
479
480
297

313
557
558
297

314
474
475
297

315
474
475
297

316
488
489
297

317
465
466
297

318
479
480
297

319
437
438
297

320
460
461
297

321
460
461
297

322
474
475
297

323
474
475
332

324
456
457
332

325
488
489
332

326
502
503
332

327
561
562
347

328
575
576
347

329
539
540
332

330
557
558
332

331
571
572
332

332
585
586
332

333
644
645
297

334
594
595
297

335
575
576
297

336
525
526
297

337
561
562
297

338
511
512
297

339
644
645
347

340
662
663
347

341
579
580
347

342
575
576
347

343
593
594
347

344
492
493
347

345
510
511
347

346
506
507
347

347
561
562
347

348
470
471
332

349
507
508
332

350
557
558
332

351
488
489
332

352
525
526
332

353
575
576
332

354
502
503
332

355
539
540
332

356
589
590
332

357
506
507
332

358
516
517
332

359
553
554
332

360
603
604
332

361
520
521
332

362
478
479
347

363
579
580
347

364
492
493
347

365
496
497
347

366
511
512
347

367
561
562
347

368
593
594
475

369
579
580
475

370
593
594
475

371
557
558
372

372
575
576
372

373
579
580
347

374
488
489
372

375
579
580
347

376
593
594
347

377
680
681
347

378
597
598
347

379
662
663
347

380
644
645
297

381
662
663
297

382
579
580
297

383
575
576
297

384
612
613
297

385
594
595
297

386
612
613
297

387
529
530
297

388
525
526
297

389
474
475
372

390
593
594
372

391
575
576
372

392
492
493
372

393
506
507
372

394
629
630
347

395
647
648
347

396
575
576
347

397
578
579
t397

398
579
580
347

399
546
547
347

400
560
561
347

401
542
543
372

402
560
561
372

403
561
562
372

404
680
681
347

405
593
594
347

406
579
580
347

407
629
630
347

408
644
645
347

409
492
493
372

410
510
511
372

411
629
630
347

412
647
648
347

413
629
630
297

414
611
612
297

415
562
563
297

416
662
663
347

417
597
598
347

418
647
648
347

419
579
580
347

420
592
593
508

421
647
648
475

422
647
648
475

423
647
648
475

424
647
648
475

425
647
648
475

426
647
648
475

427
597
598
475

428
629
630
475

429
579
580
475

430
575
576

431
629
630
475

432
647
648
475

433
629
630
475

434
575
576
475

435
629
630
475

436
629
630
475

437
629
630
475

438
629
630
475

439
629
630
475

440
579
580
475

441
647
648
475

442
592
593
508

443
610
611
508

444
597
598
475

445
646
647
508

446
646
647
508

447
610
611
508

448
664
665
508

449
664
665
508

450
545
546
475

451
664
665
508

452
608
609
475

453
608
609
475

454
563
564
475

455
613
614
475

456
551
552
475

457
553
554
475

458
559
560
475

459
563
564
475

460
545
546
475

461
590
591
475

462
590
591
475

463
646
647
508

464
646
647
508

465
664
665
508

466
563
564
475

467
575
576
475

468
575
576
475

469
629
630
475

470
614
615
475

471
537
538
475

472
553
554
475

473
553
554
475

474
614
615
475

475
469
470
475

476
614
615
475

477
629
630
475

478
629
630
475

479
647
648
475

480
630
631
508

481
602
603
508

482
646
647
508

483
646
647
508

484
630
631
508

485
631
632
508

486
629
630
347

487
629
630
347

488
631
632
508

489
631
632
508

490
631
632
508

491
631
632
508

492
631
632
508

493
646
647
540

494
646
647
540

495
646
647
540

496
646
647
540

497
501
502
540

498
646
647
540

499
554
555
508

500
554
555
508

501
486
487
508

502
568
569
508

503
486
487
508

504
501
502
508

505
526
527
508

506
554
555
508

507
486
487
508

508
486
487
508

509
554
555
508

510
568
569
508

511
568
569
508

512
568
569
508

513
578
579
540

514
596
597
540

515
526
527
540

516
664
665
540

517
664
665
540

518
519
520
540

519
418
419
540

520
631
632
508

521
487
488
508

522
515
516
508

523
545
546
508

524
484
485
347

525
502
503
347

526
505
506
157

527
502
503
157

528
507
508
157

529
554
555
157

530
487
488
540

531
515
516
540

532
545
546
540

533
578
579
540

534
527
528
540

535
541
542
540

536
569
570
540

537
596
597
540

538
484
485
347

539
502
503
347

540
563
564
540

541
394
395
192

542
471
472
192

543
471
472
192

544
428
429
192

545
470
471
192

546
472
473
192

547
401
402
192

548
385
386
192

549
535
536
157

550
533
534
157

551
521
522
157

552
551
552
157

553
560
561
540

554
578
579
540

555
519
520
508

556
417
418
508

557
418
419
508

558
557
558
540

559
592
593
540

560
549
550
157

561
501
502
508

562
519
520
508

563
417
418
508

564
470
471
540

565
462
463
192

566
501
502
540

567
486
487
540

568
527
528
540

569
512
513
540

570
418
419
508

571
563
564
540

572
494
495
6

573
602
603
540

574
589
590
540

575
585
586
540

576
599
600
540

577
582
583
540

578
418
419
540

579
395
396
192

580
603
604
540

581
537
538
157

582
551
552
157

583
521
522
157

584
539
540
157

585
572
573.1907
157

586
572
573
157

587
572
573
157

588
572
573
192

589
572
573
192

590
572
573
192

591
521
522
192

592
614
615
540

593
602
603
540

594
582
583
540

595
582
583
540

596
463
464
157

597
542
543
6

598
512
513
6

599
494
495
229

600
512
513
229

601
479
480
229

602
479
480
229

603
468
469
7

604
543
544
192

605
538
539
605

606
556
557
605

607
572
573
605

608
588
589
605

609
502
503
605

PROPHETIC EXAMPLES

The prophetic examples shown below further illustrate the scope of this disclosure. Non-limiting prophetic examples include the following compounds and pharmaceutically acceptable salts thereof:

Example 610: (R)-1-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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Example 611: (R)-1-(4-(6-(2-(4-cyclopropyl-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide

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It is believed that a person of skill in the art would know how to synthesize the claimed compounds based, in part, on the provided Schemes 6 and 7.

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Biological Activity Assays

The following are assays that may be used to evaluate the biological efficacy of compounds of Formula (I).

GLS1 Enzymatic Activity Assay

The inhibition of purified recombinant human GAC by varying concentrations of inhibitors is assessed via a dual-coupled enzymatic assay. The glutamate produced by the glutaminase reaction is used by glutamate oxidase to produce α-ketoglutarate, ammonia, and hydrogen peroxide, with this hydrogen peroxide subsequently being used by horseradish peroxidase to produce resorufin in the presence of Amplex UltraRed. The assay buffer consisted of 50 mM Hepes (pH 7.4), 0.25 mM EDTA and 0.1 mM Triton X-100. GAC was incubated with potassium phosphate (10 minutes at room temperature) prior to incubation with inhibitor (10 minutes at room temperature). The final reaction conditions were as follows: 2 nM GAC, 50 mM potassium phosphate, 100 mU/mL glutamate oxidase (Sigma), 1 mM glutamine (Sigma), 100 mU/mL horseradish peroxidase (Sigma), 75 μM Amplex UltraRed (Life Technologies), and 1% (v/v) DMSO. The production of resorufin was monitored on a Perkin Elmer Envision plate reader (excitation 530 nm, emission 590 nm) either in a kinetics or endpoint mode (at 20 minutes). IC50 values were calculated using a four-parameter logistic curve fit.

Proliferation Assay

A549 cells were routinely maintained in RPMI 1640 media (Gibco catalog number 11875-093) supplemented with 10% dialyzed fetal bovine serum using a humidified incubator (37° C., 5% CO₂and ambient O₂). In preparation for the viability assay, cells were inoculated into 384-well black CulturPlates (Perkin Elmer) at a density of 1000 cells/well in a volume of 40 uL. Following a 24-hour incubation at 37° C., 5% CO2 and ambient O2, cells were treated with compound (10 uL) in a final DMSO concentration of 0.5% (v/v). The microplates were then incubated for 72 hours (37° C., 5% CO2 and ambient O2). Cell Titer Fluor (Promega) was subsequently added (10 uL of 6× reagent) and mixed for 15 minutes at room temperature. The plates were then incubated for 30 minutes (37° C., 5% CO2 and ambient O2) and fluorescence was subsequently read on the Perkin Elmer Envision plate reader. IC50 values were calculated using a four-parameter logistic curve fit.

Non-limiting examples include the following compounds and pharmaceutically acceptable salts thereof. Table 3 below reports the IC₅₀against GLS1 and the EC₅₀against A549 cell proliferation, both in nanomolar, and both wherein A<100 nM, B=100-500 nM, C>500-5000 nM, and D>5000 nM. “ND” indicates no data. Compounds disclosed herein and not yet tested are expected to demonstrate activity in these assays as well.

TABLE 3

Biological Data

Ex. No.
GLS1 IC₅₀
A549 EC₅₀

1
A
A

2
A
A

3
B
B

4
B
B

5
A
A

6
A
A

7
B
B

8
B
N.D.

9
C
N.D.

10
B
N.D.

11
A
B

12
A
A

13
A
C

14
C
N.D.

15
A
B

16
A
A

17
B
B

18
B
B

19
A
A

20
A
A

21
A
B

22
A
B

23
A
B

24
A
A

25
A
B

26
A
A

27
A
A

28
A
B

29
A
A

30
A
A

31
A
A

32
A
A

33
A
A

34
A
B

34
B
B

36
A
A

37
A
A

38
C
N.D.

39
N.D.
B

40
B
N.D.

41
C
C

42
N.D.
N.D.

43
N.D.
B

44
N.D.
B

45
B
C

46
A
A

47
A
B

48
C
C

49
C
D

50
B
C

51
B
C

52
C
D

53
C
N.D.

54
B
BN.D.

55
B
C

56
A
A

57
C
N.D.

58
C
N.D.

59
B
C

60
A
A

61
A
A

62
B
C

63
B
C

64
A
C

65
A
B

66
C
N.D.

67
B
N.D.

68
C
N.D.

69
C
N.D.

70
C
N.D.

71
C
N.D.

72
A
A

73
A
A

74
B
N.D.

75
A
A

76
A
A

77
A
A

78
A
A

79
A
A

80
A
A

81
A
A

82
A
A

83
A
A

84
B
B

85
C
C

86
C
D

87
C
D

88
C
C

89
C
C

90
B
B

91
C
D

92
C
C

93
B
C

94
B
B

95
B
B

96
B
B

97
A
A

98
C
C

99
C
C

100
C
D

101
C
C

102
C
C

103
B
C

104
C
C

105
A
A

106
A
A

107
A
A

108
A
B

109
A
B

110
A
A

111
A
A

112
B
B

113
A
C

114
C
C

115
C
C

116
A
B

117
B
B

118
B
B

119
B
B

120
B
C

121
B
B

122
A
A

123
A
B

124
A
A

125
A
B

126
B
B

127
B
C

128
A
A

129
A
A

130
B
B

131
B
B

132
A
A

133
A
A

134
A
A

135
A
A

136
A
A

137
A
A

138
B
B

139
B
B

140
A
A

141
A
A

142
A
A

143
A
A

144
A
A

145
A
A

146
A
A

147
A
A

148
A
A

149
B
C

150
B
B

151
B
C

152
A
A

153
A
B

154
C
C

155
A
C

156
A
A

157
A
B

158
A
A

159
A
B

160
A
A

161
A
A

162
B
B

163
C
C

164
A
B

165
B
C

166
A
B

167
A
B

168
A
B

169
A
A

170
B
C

171
B
C

172
A
A

173
B
B

174
A
B

175
A
B

176
A
B

177
A
B

178
A
B

179
A
C

180
A
B

181
B
C

182
B
D

183
B
D

184
C
D

185
B
C

186
B
C

187
B
D

188
A
A

189
C
D

190
A
B

191
A
B

192
A
A

193
A
C

194
A
A

195
A
A

196
C
C

197
A
A

198
A
A

199
A
B

200
A
B

201
A
B

202
A
B

203
A
A

204
A
A

205
A
A

206
A
A

207
A
A

208
A
B

209
B
B

210
A
B

211
A
A

212
A
A

213
A
A

214
B
D

215
B
C

216
A
A

217
A
B

218
A
A

219
A
A

220
B
C

221
B
B

222
A
A

223
A
A

224
B
B

225
A
B

226
A
A

227
A
A

228
A
A

229
A
A

230
A
A

231
A
A

232
A
A

233
A
A

234
A
B

235
A
B

236
A
A

237
A
B

238
A
B

239
A
B

240
A
A

241
A
A

242
A
A

243
B
B

244
A
A

245
A
A

246
A
A

247
A
A

248
A
A

249
A
A

250
A
A

251
A
A

252
A
A

253
A
A

254
A
B

255
A
A

256
A
B

257
A
A

258
A
A

259
A
A

260
A
A

261
A
A

262
A
A

263
A
A

264
A
A

265
A
A

266
A
A

267
A
A

268
A
A

269
A
A

270
A
A

271
A
A

272
A
A

273
A
A

274
A
A

275
A
A

276
B
B

277
B
C

278
C
N.D.

279
A
B

280
B
C

281
C
N.D.

282
C
N.D.

283
C
N.D.

284
B
C

285
C
C

286
A
B

287
C
N.D.

288
B
C

289
C
N.D.

290
C
N.D.

291
C
N.D.

292
B
C

293
A
B

294
A
B

295
A
A

296
A
A

297
C
N.D.

298
C
N.D.

299
A
A

300
C
D

301
B
C

302
C
N.D.

303
C
N.D.

304
C
N.D.

305
C
C

306
B
C

307
A
B

308
C
N.D.

309
B
B

310
A
B

311
B
C

312
B
C

313
A
A

314
B
C

315
B
C

316
A
C

317
B
B

318
A
A

319
C
D

320
B
C

321
C
C

322
B
C

323
C
N.D.

324
C
N.D.

325
C
N.D.

326
C
N.D.

327
A
A

328
A
A

329
B
C

330
A
B

331
A
B

332
A
B

333
C
N.D.

334
A
A

335
A
A

336
A
B

337
A
A

338
A
B

339
A
A

340
A
A

341
A
B

342
A
A

343
A
A

344
B
D

345
B
D

346
A
C

347
A
A

348
C
N.D.

349
B
N.D.

350
B
B

351
C
N.D.

352
B
C

353
A
B

354
C
N.D.

355
B
B

356
A
A

357
C
N.D.

358
C
N.D.

359
B
B

360
A
A

361
C
N.D.

362
C
N.D.

363
A
A

364
B
C

365
C
N.D.

366
B
C

367
A
B

368
A
A

369
A
A

370
A
A

371
A
B

372
A
B

373
A
A

374
B
N.D.

375
A
A

376
A
A

377
A
A

378
A
A

379
A
A

380
A
A

381
A
A

382
A
B

383
A
A

384
A
A

385
A
A

386
A
A

387
B
C

388
A
B

389
C
D

390
A
A

391
A
B

392
C
D

393
C
C

394
A
A

395
A
A

396
A
A

397
A
A

398
A
A

399
A
B

400
A
B

401
B
C

402
B
C

403
A
A

404
A
A

405
A
A

406
A
A

407
A
A

408
A
A

409
C
D

410
C
C

411
A
A

412
A
A

413
A
A

414
A
A

415
A
A

416
A
A

417
A
A

418
A
A

419
A
A

420
A
B

421
A
A

422
A
A

423
A
A

424
A
A

425
A
A

426
A
A

427
A
A

428
A
A

429
A
B

430
A
A

431
A
A

432
A
A

433
A
A

434
A
A

435
A
A

436
A
A

437
A
A

438
A
A

439
A
A

440
A
B

441
A
A

442
A
A

443
A
A

444
A
A

445
A
A

446
A
A

447
A
A

448
A
A

449
A
A

450
A
B

451
A
A

452
A
B

453
A
B

454
A
B

455
A
A

456
A
A

457
C
C

458
B
B

459
A
B

460
B
B

461
B
C

462
A
B

463
A
A

464
A
A

465
A
A

466
A
A

467
B
B

468
A
A

469
A
A

470
A
A

471
A
B

472
B
B

473
B
B

474
A
A

475
B
B

476
A
A

477
A
A

478
A
A

479
A
A

480
A
A

481
A
A

482
A
A

483
A
A

484
A
A

485
A
A

486
A
A

487
A
A

488
A
A

489
A
A

490
A
A

491
A
A

492
A
B

493
A
A

494
A
A

495
A
A

496
A
A

497
A
B

498
A
A

499
B
B

500
B
B

501
B
B

502
B
B

503
B
C

504
A
B

505
A
B

506
B
B

507
B
B

508
B
B

509
B
B

510
B
C

511
B
C

512
B
B

513
A
A

514
A
A

515
A
B

516
A
A

517
A
A

518
A
A

519
B
C

520
A
A

521
B
B

522
A
B

523
B
C

524
A
B

525
A
B

526
B
C

527
A
A

528
A
C

529
A
A

530
A
C

531
A
B

532
A
B

533
A
A

534
A
B

535
A
B

536
A
B

537
A
B

538
A
B

539
A
B

540
A
A

541
A
C

542
A
B

543
A
C

544
A
B

545
A
B

546
A
B

547
B
C

548
B
C

549
B
C

550
A
B

551
A
B

552
C
D

553
A
A

554
A
A

555
A
B

556
B
C

557
C
C

558
A
C

559
A
B

560
A
B

561
A
B

562
A
B

563
C
C

564
A
C

565
A
B

566
A
B

567
A
B

568
A
B

569
A
B

570
B
C

571
A
A

572
A
B

573
A
A

574
A
A

575
A
B

576
A
A

577
A
C

578
A
C

579
B
C

580
A
A

581
A
B

582
A
B

583
A
A

584
A
B

585
A
A

586
A
A

587
A
A

588
A
A

589
A
A

590
A
A

591
A
B

592
A
A

593
A
A

594
A
C

595
A
A

596
A
B

597
A
B

598
A
A

599
A
A

600
A
A

601
A
A

602
A
A

603
C
D

604
A
A

605
A
A

606
A
A

607
A
A

608
A
A

609
A
A

Other Embodiments

The detailed description set-forth above is provided to aid those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the disclosure. Any equivalent embodiments are intended to be within the scope of this disclosure. Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

Number	Name	Date	Kind
4399140	Gacek	Aug 1983	A
4720447	De Keyzer	Jan 1988	A
6153628	Jin	Nov 2000	A
6239137	Karmali	May 2001	B1
7956070	Alcaraz	Jun 2011	B2
7985548	Lorenzi	Jul 2011	B2
9809588	Di Francesco	Nov 2017	B2
10125128	Lewis	Nov 2018	B2
10150753	Jones	Dec 2018	B2
10344025	Di Francesco	Jul 2019	B2
10722487	Heffernan	Jul 2020	B2
10738043	Lewis	Aug 2020	B2
10766892	Di Francesco	Sep 2020	B2
10899740	Jones	Jan 2021	B2
11045443	Heffernan	Jun 2021	B2
11370786	Di Francesco	Jun 2022	B2
11603365	Jones	Mar 2023	B2
11713313	Lewis	Aug 2023	B2
20020115698	Newcomb	Aug 2002	A1
20090215750	Bamberg	Aug 2009	A1
20100255117	Biswal	Oct 2010	A1
20110229984	Lorenzi	Sep 2011	A1
20120202776	Wang	Aug 2012	A1
20130157998	Li	Jun 2013	A1
20140050699	Li	Feb 2014	A1
20140142081	Lemieux	May 2014	A1
20150344466	Mitsudera	Dec 2015	A1
20150368240	Bleisch	Dec 2015	A1
20160002204	Di Francesco	Jan 2016	A1
20160002248	Di Francesco	Jan 2016	A1
20160009704	Di Francesco	Jan 2016	A1
20160058759	Heffernan	Mar 2016	A1
20160097040	Gao	Apr 2016	A1
20170001996	Lewis	Jan 2017	A1
20170174661	Jones	Jun 2017	A1
20170291895	Di Francesco	Oct 2017	A1
20190031651	Lewis	Jan 2019	A1
20190134032	Heffernan	May 2019	A1
20190144425	Jones	May 2019	A1
20190270736	Di Francesco	Sep 2019	A1
20190274993	Heffernan	Sep 2019	A1
20200368196	Heffernan	Nov 2020	A1
20210122744	Lewis	Apr 2021	A1
20210206745	Jones	Jul 2021	A1
20220016069	Heffernan	Jan 2022	A1
20230250081	Jones	Aug 2023	A1

Number	Date	Country
1991009848	Jul 1991	WO
1996037492	Nov 1996	WO
1998043962	Oct 1998	WO
1999026945	Jun 1999	WO
2008083238	Jul 2008	WO
2010023946	Mar 2010	WO
2010099527	Sep 2010	WO
2010111504	Sep 2010	WO
2011089995	Jul 2011	WO
2011143160	Nov 2011	WO
2013078123	May 2013	WO
2014078645	May 2014	WO
2014079150	May 2014	WO
2014081925	May 2014	WO
2014089048	Jun 2014	WO
2014119696	Aug 2014	WO
2015101957	Jul 2015	WO
2015101958	Jul 2015	WO
2016004404	Jan 2016	WO
2016004413	Jan 2016	WO
2016004417	Jan 2016	WO
2016004418	Jan 2016	WO
2017004359	Jan 2017	WO
2017112831	Jun 2017	WO
2019079632	Apr 2019	WO

	Number	Date	Country
Parent	15624168	Jun 2017	US
Child	16412050		US

GLS1 inhibitors for treating disease

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

Field of Search

CPC

International Classifications

Disclaimer

Abstract

Description

Claims

Parent Case Info

US Referenced Citations (46)

Foreign Referenced Citations (25)

Non-Patent Literature Citations (121)

Related Publications (1)

Provisional Applications (1)

Divisions (1)

Continuations (3)

	Number	Date	Country
Parent	16925974	Jul 2020	US
Child	17660541		US
Parent	16412050	May 2019	US
Child	16925974		US
Parent	14791186	Jul 2015	US
Child	15624168		US

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