BR112017028309B1 - COMPOUND AND COMPOSITION - Google Patents

Abstract

COMPOUND, COMPOSITION, METHOD FOR INHIBITING THE ACTIVITY OF GLS1 IN A BIOLOGICAL SPECIMEN, METHODS FOR TREATING A DISORDER MEDIATED BY GLS1 IN A SUBJECT IN NEED THE SAME, AND USE OF A COMPOUND. Disclosed herein are compounds and compositions useful in treating GLS1-mediated diseases, such as cancer, which have the structure of Formula (I). Also provided are methods of inhibiting GLS1 activity in a human or animal.

Description

BACKGROUND

[001] This application claims the priority benefit of Provisional Applications No. U.S. 62/187,160, filed on June 30, 2015; and 62/270,355, filed on December 21, 2015, the disclosures of which are incorporated by reference as if written herein in their entirety.

[002] The present disclosure relates to new heterocyclic compounds and compositions and their application as pharmaceutical products for the treatment of diseases. Also provided are methods of inhibiting GLS1 activity in a human or animal for treating diseases, such as cancer.

[003] Metabolic dysregulation is a characteristic of cancer, since tumors present a greater 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 necessary to support proliferation and survival. Specifically, glutaminolysis, or the enzymatic conversion of glutamine to glutamate, provides proliferating cancer cells with a nitrogen source 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 since glutamate can be converted to glutathione, the main intracellular antioxidant.

[004] Glutaminolysis is regulated by mitochondrial glutaminase (GLS), the rate-limiting enzyme that catalyzes the conversion of Gln into glutamate and ammonia. Mammalian cells contain 2 genes that encode glutaminase: 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 main 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 believed to bind to the inner membrane of mitochondria 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 dependency of cancer cell lines, pharmacological inhibition of GLS offers the potential for Gln-dependent tumor targeting.

[005] Therefore, there is a need for glutaminase inhibitors that are specific and with the ability to be formulated for use in vivo.

[006] Consequently, new compositions and methods for inhibiting glutaminase activity are disclosed herein.

[007] The compound of structural formula I is provided

[008] or a salt thereof, wherein:

[009] n is chosen between 1 and 2;

[0010] R1 is chosen from NR3C(O)R3, NR3C(O)OR3, NR3C(O)N(R3)2, C(O)N(R3)2 and N(R3)2;

[0011] each R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups, wherein two groups R3, together with the atoms to which they are attached, optionally form a heteroaryl, or heterocycloalkyl, ring, which may be optionally substituted by one to three Rx groups;

[0012] R2 is chosen from NR4C(O)R4, NR4C(O)OR4, NR4C(O)N(R4)2, C(O)N(R4)2 and N(R4)2;

[0013] each R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups, wherein two groups R4, together with the atoms to which they are attached, optionally form a heteroaryl or heterocycloalkyl ring, which may be optionally substituted by one to three Rx groups;

[0014] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkyl larylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycle alkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N( R5)2, C(O)N(R5)2 and C(O)R5;

[0015] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups;

[0016] Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl;

[0017] A is a monocyclic heteroaryl, which can be optionally substituted by one to three Rz groups;

[0018] and Z is a monocyclic heteroaryl, which can be optionally substituted by one to three Rz groups.

[0019] A composition is provided which comprises a compound of Formula I and a pharmaceutically acceptable vehicle, adjuvant or carrier.

[0020] A method for inhibiting GLS1 activity in a biological sample is provided which comprises contacting the biological sample with a compound of Formula I.

[0021] A method for treating a GLS1-mediated disorder in a subject in need thereof is provided which comprises the step of administering to the subject a compound of Formula I.

[0022] There is provided a method for treating a GLS1-mediated disorder in a subject in need thereof characterized by the fact that it comprises the sequential administration or co-administration of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0023] A compound of any Formula I is provided for use in human therapy.

[0024] A compound of any Formula I is provided for use in treating GLS1-mediated disease.

[0025] The use of a compound of Formula I for the manufacture of a medicament for the treatment of a GLS1-mediated disease is provided.

DETAILED DESCRIPTION

[0026] Abbreviations and Definitions

[0027] To facilitate understanding of the disclosure, various terms and abbreviations, as used herein, are defined below as follows:

[0028] When introducing elements of the present disclosure or preferred embodiment (or embodiments) thereof, the articles "a", "an", "the" and "referred" are intended to mean that there is one or more of the elements . The terms "which comprises", "which includes" and "which has" are intended to be inclusive and mean that there may be other elements in addition to the elements listed.

[0029] 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 alone 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, that is, 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 .

[0030] When ranges of values are revealed, and the notation "from ni... to n2" or "between ni... and n2" is used, where n1 and n2 are the numbers, then unless If otherwise specified, this notation is intended to include the numbers themselves and the range between them. This interval may be integral or continuous between and including terminal 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 are presented in whole units. By way of example, compare 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., i .255 μM, 2.1 μM, 2.9999 μM, etc.).

[0031] The term "about", as used in this document, is intended to qualify the numerical values that it modifies, denoting such value as a variable within a margin of error. When no particular margin of error, such as a standard deviation from a mean value given in a graph or table of data, is cited, the term "about" should be understood to mean that the range that would encompass the quoted value and the range which would be included by rounding up or down to this figure as well, taking into account significant figures.

[0032] The term "acyl", as used herein, alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle or any other chemical moiety in which the bonded atom carbonyl is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the original molecular chemical moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0033] The term "alkenyl", as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical that has one or more double bonds and that contains from 2 to 20 carbon atoms . In some embodiments, the alkenyl will comprise 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system bonded 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.

[0034] The term "alkoxy", as used herein, alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

[0035] 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 additional embodiments, the alkyl will comprise 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 hydrocarbon bonded at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[0036] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the original molecular chemical moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylamino, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.

[0037] The term "alkylidene", as used herein, alone or in combination, refers to an alkenyl group in which a carbon atom of the carbon-carbon double bond belongs to the chemical moiety to which the alkenyl group is connected.

[0038] The term "alkylthio", as used herein, alone or in combination, refers to an alkyl thioether radical (R-S-) in which the term alkyl is as defined above and in which the sulfur can be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl and the like.

[0039] The term "alkynyl", as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical that has one or more triple bonds and that contains from 2 to 20 carbon atoms . In certain embodiments, the alkynyl comprises 2 to 6 carbon atoms. In additional embodiments, the alkynyl comprises 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond bonded 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, hexin-2-yl and the like. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.

[0040] The terms "starch" and "carbamoyl", as used herein, alone or in combination, refer to an amino group as described below linked to the original molecular chemical moiety through a carbonyl group or vice versa. The term "C-starch", as used herein, alone or in combination, refers to a group - C(O)N(RR') with R and R' as defined herein or as defined by the groups Specifically numbered "R" designated. The term "N-starch" as used herein, alone or in combination, refers to a group RC(O)N(R') with R and R' as defined herein or as defined by the groups " R" specifically numbered designated. The term "acylamino", as used herein, alone or in combination, encompasses an acyl group attached to the original chemical moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-).

[0041] 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 be optionally substituted. Additionally, R and R' can combine to form heterocycloalkyl, either of which can be optionally substituted.

[0042] 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" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthrile.

[0043] The term "arylalkenyl" or "aralkenyl", as used herein, alone or in combination, refers to an aryl group linked to the original molecular chemical moiety through an alkenyl group.

[0044] The term "arylalkoxy" or "aralkoxy", as used herein, alone or in combination, refers to an aryl group linked to the original molecular chemical moiety through an alkoxy group.

[0045] The term "arylalkyl" or "aralkyl", as used herein, alone or in combination, refers to an aryl group linked to the original molecular chemical moiety through an alkyl group.

[0046] The term "arylalkynyl" or "aralkynyl" as used herein, alone or in combination, refers to an aryl group linked to the original molecular chemical moiety through an alkynyl group.

[0047] 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, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl and the like.

[0048] The term "aryloxy", as used herein, alone or in combination, refers to an aryl group linked to the original molecular chemical moiety through an oxy.

[0049] 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.

[0050] The term "carbamate", as used herein, alone or in combination, refers to a carbamic acid ester (-NHCOO-) that can be linked to the original molecular chemical moiety of the acid or nitrogen end and which may be optionally replaced as defined in this document.

[0051] 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.

[0052] 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.

[0053] The term "carbonyl", as used herein, when alone, includes formyl [-C(O)H] and, in combination, is a -C(O)- group.

[0054] The term "carboxyl" or "carboxy", as used herein, refers to -C(O)OH or the corresponding "carboxylate" anion, as it is in a carboxylic acid salt. An "O-carboxy" group refers to an RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

[0055] The term "cyano", as used herein, alone or in combination, refers to -CN.

[0056] 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 in which each cyclic chemical moiety contains of 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system that is optionally substituted as defined herein. In some embodiments, the cycloalkyl will comprise 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 saturated or partially unsaturated multicyclic (multicentric) type. The last type of isomer is generally exemplified by bicyclo[1,1,1]pentane, camphor, adamantane and bicyclo[3,2,1]octane.

[0057] The term "ester", as used herein, alone or in combination, refers to a carboxy group that bridges two chemical moieties linked to carbon atoms.

[0058] The term "ether", as used herein, alone or in combination, refers to an oxy group that bridges two chemical moieties bonded to carbon atoms.

[0059] The term "halo" or "halogen", as used herein, alone or in combination, refers to a fluorine, chlorine, bromine or iodine.

[0060] The term "haloalkoxy", as used herein, alone or in combination, refers to a haloalkyl group linked to the original molecular chemical moiety through an oxygen atom.

[0061] The term "haloalkyl", as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above in which one or more hydrogens are replaced by a halogen. Monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are specifically covered. A monohaloalkyl radical, for example, may have an iodine, bromine, chlorine, or fluorine atom within the radical. Dihalo and polyhaloalkyl radicals can 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 bonded at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2 -), chloromethylene (-CHCl-) and the like.

[0062] 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 given number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N and S, and in which the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom (or heteroatoms) O, N and S can be placed in any interior position of the heteroalkyl group. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3.

[0063] The term "heteroaryl", as used herein, alone or in combination, refers to an unsaturated heteromonocyclic ring with 3 to 15 members 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 5 to 7 carbon atoms. The term also encompasses fused polycyclic groups, in which heterocyclic rings are fused to aryl rings, in which heteroaryl rings are fused to other heteroaryl rings, in which heteroaryl rings are fused to heterocycloalkyl rings, or in which heteroaryl rings are fused to 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, tetrahydroisoquine linyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and similar. Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0064] The terms "heterocycloalkyl" and, interchangeably, "heterocycle", as used herein, alone or in combination, each refer to a monocyclic, bicyclic or tricyclic saturated, partially unsaturated or completely unsaturated substance containing at least one heteroatom as a ring member, wherein each heteroatom may be independently selected from the group consisting of nitrogen, oxygen and sulfur. In certain embodiments, the heterocycloalkyl will comprise 1 to 4 heteroatoms as ring members. In additional embodiments, the heterocycloalkyl will comprise 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl will comprise 3 to 8 ring members in each ring. In additional embodiments, the heterocycloalkyl will comprise 3 to 7 ring members in each ring. In still other embodiments, the heterocycloalkyl will comprise 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 ring systems and benzo fused rings; Additionally, both terms also include systems in which 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, dihydrocinolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydrodropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl and the like. Heterocycle groups may be optionally substituted unless specifically prohibited.

[0065] The term "hydrazinyl", as used herein, alone or in combination, refers to two amino groups joined by a single bond, that is, -N-N-.

[0066] The term "hydroxy", as used herein, alone or in combination, refers to -OH.

[0067] The term "hydroxyalkyl", as used herein, alone or in combination, refers to a hydroxy group linked to the original molecular chemical moiety through an alkyl group.

[0068] The term "imino", as used herein, alone or in combination, refers to =N-.

[0069] The term "imino-hydroxy", as used herein, alone or in combination, refers to =N(OH) and =N-O-.

[0070] 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 for compounds of any of the formulas disclosed herein.

[0071] The term "isocyanate" refers to an -NCO group.

[0072] The term "isothiocyanate" refers to an -NCS group.

[0073] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

[0074] The term "lower", as used herein, alone or in a combination, when not specifically defined otherwise, means that it contains from 1 to and including 6 carbon atoms.

[0075] The term "lower aryl", as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.

[0076] 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 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 one and four heteroatoms selected from the group consisting of O, S and N .

[0077] The term "lower cycloalkyl", as used herein, alone or in combination, means a monocyclic cycloalkyl that has between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0078] The term "lower heterocycloalkyl", as used herein, alone or in combination, means a monocyclic heterocycloalkyl that has between three and six ring members, of which, between one and four may be heteroatoms selected from the group that consists of O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

[0079] 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 heteroalkyl bottom, any of which can be optionally replaced. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, any of which may be optionally substituted.

[0080] The term "mercaptil", as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.

[0081] The term "nitro", as used herein, alone or in combination, refers to - NO2.

[0082] The terms "oxy" or "oxa", as used herein, alone or in combination, refer to -O-.

[0083] The term "oxo", as used herein, alone or in combination, refers to =O.

[0084] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0085] The term "perhaloalkyl", as used herein, alone or in combination, refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0086] The terms "sulfonate", "sulfonic acid" and "sulfonic", as used herein, alone or in combination, refer to the -SO3H group, and its anion as sulfonic acid is used in salt formation .

[0087] The term "sulfanyl", as used herein, alone or in combination, refers to -S-

[0088] The term "sulfinyl", as used herein, alone or in combination, refers to

[0089] -S(O)-.

[0090] The term "sulfonyl", as used herein, alone or in combination, refers to -S(O)2-.

[0091] The term "N-sulfonamido" refers to a group RS(=O)2NR'- with R and R' as defined in this document.

[0092] The term "S-sulfonamido" refers to a group -S(=O)2NRR', with R and R' as defined in this document.

[0093] The terms "thia" and "thio", as used herein, alone or in combination, refer to an -S- group or an ether in which oxygen is replaced by sulfur. Oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thi and thio.

[0094] The term "thiol", as used herein, alone or in combination, refers to a -SH group.

[0095] The term "thiocarbonyl", as used herein, when alone, includes thioformyl -C(S)H and, in combination, is a -C(S)- group.

[0096] The term "N-thiocarbamyl" refers to a ROC(S)NR'- group, with R and R' as defined in this document.

[0097] The term "O-thiocarbamyl" refers to a group -OC(S)NRR', with R and R' as defined in this document.

[0098] The term "thiocyanate" refers to a -CNS group.

[0099] The term "trihalomethanesulfonamido" refers to a group X3CS(O)2NR- with X is a halogen and R as defined herein.

[00100] The term "trihalomethanesulfonyl" refers to a group X3CS (O)2 - where X is a halogen.

[00101] The term "trihalomethoxy" refers to a group X3CO- in which X is a halogen.

[00102] The term "trisubstituted silyl", as used herein, alone or in combination, refers to a silicone group substituted in its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

[00103] Any definition in this document can be used in combination with any other definition to describe a composite structural group. By convention, the last element in any such definition is the one that attaches to the original chemical moiety. For example, the compound alkylamido group would represent an alkyl group linked to the original molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group linked to the original molecule through an alkyl group.

[00104] When a group is defined as being "null", what is meant is that the group is absent.

[00105] The term "optionally substituted" means that the preceding group can 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 linked together to form a five-, six-, or seven-membered fused 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 between fully substituted and monosubstituted (e.g. , -CH2CF3). When substituents are cited without qualification as to substitution, both substituted and unsubstituted forms are covered. When a substituent is qualified as "substituted", the substituted form is specifically intended. Additionally, different steps of optional substituents to a particular chemical moiety can be defined as necessary; in these cases, the optional substitution will be as defined, often immediately following the phrase "optionally replaced by".

[00106] The term R or the term R', appearing alone and without a numerical designation, unless otherwise defined, refers to a chemical moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl , aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such groups R and R' are to be understood as being optionally substituted as defined herein. Whether a group R has a numerical designation or not, each group R, including R, R' and Rn where n = (1, 2, 3, ... n), each substituent and each term must be understood as being independent from each other in terms of selecting a group. If any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than once in a generic formula or structure, its definition in each occurrence is independent of the definition in each other occurrence. Those skilled in the art will further recognize that certain groups may be attached to an original molecule or may occupy a position in a chain of elements at either end as written. Thus, just as an example, an asymmetric group, such as -C(O)N(R)-, can be attached to the original chemical moiety on both carbon and nitrogen.

[00107] There are asymmetric centers in the compounds disclosed in this document. 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 that contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation, such as conversion of a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques , direct separation of enantiomers on chiral chromatographic columns or any other suitable 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 zusamen (Z) isomers as well as appropriate mixtures thereof. Additionally, compounds can exist as tautomers; all tautomeric isomers are provided by the present 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, solvated forms are considered equivalent to unsolvated forms.

[00108] The term "bond" refers to a covalent bond between two atoms or two chemical moieties when the atoms joined by the bond are considered part of the larger substructure. A bond can 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.

[00109] The term "disease" as used herein is intended to be generally synonymous with and is used interchangeably with the terms "disorder", "syndrome" and "condition" (as in medical condition), wherein all reflect an abnormal condition of the human or animal body or 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.

[00110] 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 the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of active ingredients or in multiple separate capsules for each active ingredient. Furthermore, this administration also encompasses the use of each type of therapeutic agent in a sequential manner. In both cases, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[00111] 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, no 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 the maximum level. Certain compounds disclosed herein have been found to exhibit inhibition against GLS1. In certain embodiments, the compounds will exhibit an IC50 relative to GLS1 of no greater than about 10 μM; in additional embodiments, the compounds will exhibit an IC50 relative to GLS1 no greater than about 5 μM; in still other embodiments, the compounds will exhibit an IC50 relative to GLS1 no greater than about 1 μM; In still other embodiments, the compounds will exhibit an IC50 relative to GLS1 of no greater than 200 nM, as measured in the GLS1 binding assay described herein.

[00112] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or in the effect of a clinical endpoint.

[00113] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with patient tissues without undue toxicity, irritation and allergic response , are proportionate to a reasonable risk/benefit ratio and are effective for their intended use.

[00114] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, that is, it may include prevention of the disease. Prevention of a disease may involve complete protection against the disease, for example, as in the case of preventing infection with a pathogen, or it may involve preventing the progression of the disease. For example, prevention of a disease may not mean the complete exclusion of any disease-related effects at any level, but instead may mean the prevention of symptoms of a disease at a clinically significant or detectable level. Disease prevention can also mean preventing the progression of a disease to a later stage of the disease.

[00115] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs and rabbits, and pets such as dogs, cats, rabbits and horses. Preferably, the patient is a human being.

[00116] 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 disclosed herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Furthermore, prodrugs can be converted into the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted into a compound when placed in a transdermal patch container with a suitable enzyme or chemical reagent. Prodrugs are often useful since, in some situations, they may be easier to administer than the original compound or drug. They may, for example, be bioavailable for oral administration while the original drug is not. The prodrug may also have improved solubility in pharmaceutical compositions relative to the original drug. A wide variety of prodrug derivatives are known in the art, such as those that depend on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound that is administered as an ester (the "prodrug"), but is then metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[00117] The compounds disclosed herein may exist as therapeutically acceptable salts. The present disclosure includes the 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 use in the preparation and purification of the compound in question. Base addition salts can also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich and Wermuth, Camile G., Wiley-VCHA, Zurich, Switzerland, 2002).

[00118] The term "therapeutically acceptable salt", as used herein, represents salts or zwitterionic forms of the compounds disclosed herein that are soluble in water or oil or dispersible and therapeutically acceptable as defined herein. 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, gentilate, glutarate, glycerophosphate, glycolate , hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, 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. Furthermore, the 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 steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that 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 through coordination of compounds with an alkali or alkaline earth metal ion. Therefore, the present disclosure contemplates sodium, potassium, magnesium and calcium salts of the compounds disclosed herein and the like.

[00119] Base addition salts can be prepared during the final isolation and purification of 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 amine primary, secondary or tertiary organic. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic 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.

[00120] 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

[00121] The present disclosure provides a compound of structural Formula I:

[00122] or a salt thereof, wherein:

[00123] n is chosen from 1 and 2;

[00124] R1 is chosen from NR3C(O)R3, NR3C(O)OR3, NR3C(O)N(R3)2, C(O)N(R3)2 and N(R3)2;

[00125] each R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups, wherein two groups R3, together with the atoms to which they are attached, optionally form a heteroaryl, or heterocycloalkyl, ring, which may be optionally substituted by one to three Rx groups;

[00126] R2 is chosen from NR4C(O)R4, NR4C(O)OR4, NR4C(O)N(R4)2, C(O)N(R4)2 and N(R4)2;

[00127] each R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups, wherein two groups R4, together with the atoms to which they are attached, optionally form a heteroaryl or heterocycloalkyl ring, which may be optionally substituted by one to three Rx groups;

[00128] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, al kylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycle alkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, heterocycloalkyloxy,hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N( R5)2, C(O)N(R5)2 and C(O)R5;

[00129] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups;

[00130] Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl;

[00131] A is a monocyclic heteroaryl, which can be optionally substituted by one to three Rz groups; It is

[00132] Z is a monocyclic heteroaryl, which can be optionally substituted by one to three Rz groups.

[00133] In some embodiments, the compound has structural Formula II:

[00134] or a salt thereof, wherein:

[00135] n is chosen from 1 and 2;

[00136] A1 is chosen from S and HC=CH;

[00137] Z1 is chosen from S, CH and HC=CH;

[00138] Z2 is N when Z1 is CH, and Z2 is C when Z1 is S or HC=CH;

[00139] R1 is chosen from NR3C(O)R3, NR3C(O)OR3,NR3C(O)N(R3)2, C(O)N(R3)2 and N(R3)2;

[00140] each R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups, wherein two groups R3, together with the atoms to which they are attached, optionally form a heteroaryl, or heterocycloalkyl, ring, which may be optionally substituted by one to three Rx groups;

[00141] R2 is chosen from NR4C(O)R4, NR4C(O)OR4, NR4C(O)N(R4)2, C(O)N(R4)2 and N(R4)2;

[00142] each R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups, wherein two groups R4, together with the atoms to which they are attached, optionally form a heteroaryl or heterocycloalkyl ring, which may be optionally substituted by one to three Rx groups;

[00143] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, al kylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycle alkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkyl-haloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N( R5)2, C(O)N(R5)2 and C(O)R5;

[00144] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups; It is

[00145] Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl

[00146] In certain embodiments, A1 is S.

[00147] In certain embodiments, A1 is HC=CH.

[00148] In certain embodiments, Z1 is S; and Z2 is C.

[00149] In certain embodiments, Z1 is CH; and Z2 is N.

[00150] In certain embodiments, Z1 is HC=CH; and Z2 is C.

[00151] In certain embodiments, R1 is chosen from NR3C(O)R3 and C(O)N(R3)2.

[00152] In certain embodiments, R2 is chosen from NR4C(O)R4 and C(O)N(R4)2.

[00153] In some embodiments, the compound has structural Formula III:

[00154] or a salt thereof, wherein:

[00155] n is chosen from 1 and 2;

[00156] R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups;

[00157] R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups;

[00158] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, al kylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycle alkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N( R5)2, C(O)N(R5)2 and C(O)R5;

[00159] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups; It is

[00160] Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl.

[00161] In some embodiments, the compound has structural Formula IV:

[00162] or a salt thereof, in

[00163] n is chosen from 1

[00164] R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups;

[00165] R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups;

[00166] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, al kylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycle alkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N( R5)2, C(O)N(R5)2 and C(O)R5;

[00167] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups;

[00168] and Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl.

[00169] The compound as cited in claim 2, wherein the compound has structural Formula V:

[00170] or a salt thereof, wherein:

[00171] n is chosen from 1 and 2;

[00172] R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups;

[00173] R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups;

[00174] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, al kylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycle alkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy,heterocycloalkylhaloalkyl, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N(R5) 2, C(O)N(R5)2 and C(O)R5;

[00175] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups; It is

[00176] Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl.

[00177] The compound as cited in claim 2, wherein the compound has structural Formula VI:

[00178] or a salt thereof, wherein:

[00179] n is chosen from 1 and 2;

[00180] R3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R3 can be optionally substituted by one to three Rx groups;

[00181] R4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, wherein each R4 can be optionally substituted by one to three Rx groups;

[00182] each Rx group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, al kylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl la, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, halohetero cycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylahaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N( R5)2, C(O)N(R5)2 and C(O)R5;

[00183] each R5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, which can be optionally substituted by one to three Rz groups; It is

[00184] Rz is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl.

[00185] In particular embodiments, the compound, or a salt thereof, is chosen from Examples 1 to 53 as disclosed herein.

[00186] Embodiments are also provided in which any of the above modalities in paragraphs [0006] and [00107] to [0120] can be combined with any one or more of these modalities, provided that the combination is not mutually exclusive.

PHARMACEUTICAL COMPOSITIONS

[00187] Although it may be possible for the compounds of the disclosure in question to be administered as the raw chemical product, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations comprising 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 carriers. pharmaceutically acceptable thereof and, optionally, one or more other therapeutic ingredients. The carrier (or carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. The appropriate formulation is dependent on the chosen route of administration. Any of well-known techniques, carriers and excipients can be used as appropriate and as understood in the art; for example, in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, tableting, levigation, emulsification, encapsulation, capture or compression processes.

[00188] 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 appropriate route may depend, for example, on the affection 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, such methods include the step of bringing into association a compound of the present disclosure or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier constituting one or more accessory ingredients. In general, 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.

[00189] The compounds disclosed in this document can be administered as follows:

ORAL ADMINISTRATION

[00190] The compounds of the present invention can be administered orally, including swallowing, so that the compound enters the gastrointestinal tract, or is absorbed into the bloodstream directly from the mouth, including sublingual or buccal administration.

[00191] Compositions suitable for oral administration include solid formulations, such as tablets, pills, wafers, tablets and hard or soft capsules, which may contain liquids, gels, powders or granules.

[00192] In a tablet or capsule dosage form, the amount of drug present can be from about 0.05% to about 95% by weight, more typically, from about 2% to about 50% by weight. of the dosage form.

[00193] Additionally, tablets or capsules may contain a disintegrating agent comprising from about 0.5% to about 35% by weight, more typically, from about 2% to about 25% of the tablet form. dosage. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropyl cellulose, starch and the like.

[00194] 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.

[00195] Suitable surface active agents and gliding agents for use in a tablet or capsule may be present in amounts of about 0.1% to about 3% by weight and include polysorbate 80, dodecyl sulfate sodium, talc and silicon dioxide.

[00196] Suitable lubricants, for use in a tablet or capsule, may be present in amounts of about 0.1% to about 5% by weight and include calcium, zinc or magnesium stearate, sodium stearyl fumarate and similar.

[00197] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Pressed tablets may be prepared by compressing, in a suitable machine, the active ingredient into a free-flowing form, such as a powder or granules, optionally mixed with binding agents, inert diluents or lubricants, surface active agents or dispersants. . Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with a liquid diluent. Dyes or pigments can be added to tablets for identification or to characterize different dose combinations of active compound.

[00198] Liquid formulations can include emulsions, solutions, syrups, elixirs and suspensions that 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.

[00199] Compositions for oral administration can be formulated as immediate or modified release, including delayed or prolonged release, optionally, with enteric coating.

[00200] 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

[00201] The compounds of the present invention can be directly administered into the bloodstream, muscles or internal organs by injection, for example, by bolus injection or continuous infusion. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, intracranial and the like. Devices suitable for parenteral administration include injectors (including needle and needleless injectors) and infusion methods. Formulations may be presented in single-dose or multi-dose containers, e.g., ampoules and sealed vials.

[00202] Most parenteral formulations are aqueous solutions containing excipients, including salts, buffering agents, suspensions, stabilizers and/or dispersants, antioxidants, bacteriostats, preservatives and solutes that make the formulation isotonic with the blood of the intended recipient and carbohydrates. carbon.

[00203] Parenteral formulations can also be prepared in a dehydrated form (for example, by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable carrier, such as sterile water. Solubility enhancing agents can also be used in the preparation of parenteral solutions.

[00204] Compositions for parenteral administration can be formulated in immediate or modified release form, including delayed or prolonged release. The compounds may also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can 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.

TOPIC ADMINISTRATION

[00205] The compounds of the present invention can be administered topically (for example, to the skin, mucous membranes, ear, nose or eyes) or transdermally. Formulations for topical administration may 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 carried out, for example, by electroporation, iontophoresis, phonophoresis and the like.

[00206] Typically, the active ingredient for topical administration can 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.

[00207] Compositions for topical administration can be formulated in immediate or modified release form, including delayed or prolonged release.

RECTAL, ORAL AND SUBLINGUAL ADMINISTRATION

[00208] 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 solids at normal temperatures, but liquids at rectal temperatures and will therefore melt in the rectum and release the drug.

[00209] For buccal or sublingual administration, the compositions may take the form of tablets, tablets, lozenges or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base, such as sucrose and acacia or tragacanth.

ADMINISTRATION BY INHALATION

[00210] For administration by inhalation, the compounds can be conveniently administered from an insufflator, pressurized nebulizer packs or other convenient means of delivering an aerosol or powder spray. The pressurized packages 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 can 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 mixture of the compound and a suitable powder base, such as lactose or starch. The powder composition may be presented in unit dosage form, for example capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

[00211] Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the invention can be prepared by any of the techniques well known in pharmacy, such as effective formulation and administration procedures. Preferred unit dosage formulations are those that contain an effective dose, as cited herein, or an appropriate fraction thereof, of the active ingredient. The precise amount of compound administered to a patient will be the responsibility of the treating physician. The specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, timing of administration, route of administration, rate of excretion, combination of drugs, the precise disorder being treated, and the severity of the indication or condition being treated. Furthermore, the route of administration may vary depending on the condition and its severity. The foregoing considerations regarding effective formulations and administration processes are well known in the art and are disclosed in standard books. Drug formulation 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.I., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

TREATMENT METHODS

[00212] The present invention provides compounds and pharmaceutical compositions that inhibit glutaminase activity, in particular GLS1 activity and, thus, are useful in the treatment or prevention of disorders associated with GLS1. The compounds and pharmaceutical compositions of the present disclosure selectively modulate GLS1 and are thus useful in treating or preventing a variety of disorders associated with GLS1 and include, but are not limited to, cancer, immunological or neurological diseases associated with GLS1.

NEUROLOGICAL DISORDERS

[00213] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in treating or preventing neurological diseases.

[00214] The most common neurotransmitter is glutamate, derived from the enzymatic conversion of glutamine through glutaminase. High levels of glutamate have been shown to be neurotoxic. After the traumatic insult to neuronal cells, there is an increased release of neurotransmitters, particularly glutamate. Consequently, glutaminase inhibition has been hypothesized as a means of treatment following an ischemic insult such as stroke.

[00215] Huntington's disease is a fatal progressive neurological disease. In genetic mouse models of Huntington's disease, early manifestation of the disease was observed to be 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, activated microglia in Rett syndrome release glutamate causing neuronal damage. The release of excess glutamate has been associated with the upregulation of glutaminase (Maezawa et al., J. Neurosci, 2010). In mice bred to have reduced levels of glutaminase, sensitivity to psychotic stimulant drugs, such as amphetamines, was drastically reduced, thus suggesting that inhibition of glutaminase may be beneficial in the treatment of schizophrenia (Gaisler-Salomon et al., Neuropsychopharmacology, 2009). Bipolar disorder is a devastating illness that is marked by recurring episodes of depression and mania. This disease is treated with mood stabilizers such as lithium and valproate; however, chronic use of these drugs appears to increase the abundance of glutamate receptors (Nanavati et al., J. Neurochem., 2011), which may lead to a decrease in drug efficacy over time. Therefore, an alternative treatment may be to reduce the amount of glutamate by inhibiting glutaminase. This may or may not be in conjunction with mood stabilizers. Memantine, a partial antagonist of the N-methyl-D-aspartate receptor (NMDAR), is a therapeutic product approved for the treatment of Alzheimer's disease. Currently, research is being conducted considering 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 as well, it is not illogical 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 just some of the neurological diseases that have been correlated with increased glutamate levels. Thus, inhibition of glutaminase with a compound described herein can reduce or prevent neurological diseases. Therefore, in certain embodiments, the compounds can be used for the treatment or prevention of neurological diseases.

IMMUNE DISORDERS

[00216] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in treating or preventing immunological diseases.

[00217] Activation of T lymphocytes induces cell growth, proliferation and cytokine production, thus 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 having the ability 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 glutaminase inhibition may serve as a means of immune modulation. In multiple sclerosis, an autoimmune inflammatory disease, activated microglia exhibit upregulated glutaminase and release increased levels of extracellular glutamate. Glutamine levels are reduced by sepsis, injuries, burns, surgery, and resistance exercise (Calder et al., Amino Acids, 1999). These situations place the individual at risk of immunosuppression. In fact, in general, glutaminase gene expression and enzyme activity are both increased during T cell activity. Patients receiving glutamine after bone marrow transplantation resulted in a lower level of infection and reduced graft disease. versus host (Crowther, Proc. Nutr. Soc., 2009). T cell activation and proliferation are involved in many immunological diseases, such as inflammatory bowel disease, Crohn's disease, sepsis, psoriasis, arthritis (including rheumatoid arthritis), multiple sclerosis, graft-versus-host disease, infections, lupus, and diabetes. In one embodiment of the invention, the compounds described herein can be used to treat or prevent immunological diseases.

CANCER

[00218] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful in treating or preventing cancer.

[00219] In addition to serving as basic building blocks of protein synthesis, amino acids have been shown to contribute to many processes critical to cell growth and division, and this is particularly true for cancer cells. Almost all definitions of cancer include reference to unregulated proliferation. Numerous studies on glutamine metabolism in cancer indicate that many tumors are avid consumers of glutamine (Souba, Ann. Surg., 1993; Collins et al., J. Cell. Physiol., 1998; Medina, J. Nutr., 2001; Shanware et al., J. Mol. Med., 2011). One embodiment of the invention is the use of the compounds described herein for the treatment of cancer.

[00220] In some embodiments, the compounds of the present disclosure can 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, Related Cancers AIDS (Kaposi's Sarcoma and Lymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basel Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Tumors of the Brain and Spinal Cord, Brainstem Glioma, Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System, Embryonic Tumors of the Central Nervous System, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Meduloepithelioma , Pineal Parenchymal Tumors of Intermediate Differentiation, Supratentorial Neuroectodermal Tumors and Pineoblastoma), Breast Cancer, Bronchial Tumors, Burkit 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, Embryonic 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 Sézar Syndrome), Duct, Bile (Extrahepatic), Dutal Carcinoma In Situ (DCIS ), Embryonic 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 (such as Intraocular Melanoma, Retinoblastoma), Fibrous Histiocytoma of Bone (including Malignant and Osteosarcoma), Gallbladder Melanoma, Gastric Melanoma (Stomach, 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 Cancer (Liver), Histiocytosis, Langerhans Cell, Hodgkin's Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi's 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 Cells (Mycosis Fungoides and Sézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), Macroglobulinemia, Waldenstrom, 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, Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Cav Cancer age Nasal and Paranasal Sinus, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin's 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 such as Epithelial, Germ Cell Tumor and Low Malignant Potential Tumor), Pancreatic Cancer (including Islet Cell Tumors), Papillomatosis, Paraganglioma, Cancer of the Paranasal Sinus and Nasal Cavity, 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 (such as 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 Primary Occult, 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, Cell Cancer Transitional Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Unknown Primary, Uncommon Childhood Cancers, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Waldenstrom Macroglobulinemia or Wilms Tumor .

[00221] In certain embodiments, the cancer to be treated is one specific to T cells, such as T cell lymphoma and T cell lymphoblastic leukemia.

[00222] In some embodiments, the 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 that has developed resistance to chemotherapy drugs and/or ionizing radiation.

COMBINATIONS AND COMBINATION THERAPY

[00223] The compounds of the present invention can be used, alone or in combination with other pharmaceutically active compounds, for the treatment of conditions, such as those previously disclosed. The compound (or compounds) of the present invention and another pharmaceutically active compound (or compounds) 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.

[00224] In another embodiment, a pharmaceutical composition is provided that comprises one or more compounds of the present invention, one or more additional pharmaceutically active compounds and a pharmaceutically acceptable carrier.

[00225] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of anticancer drugs, antiproliferative drugs and anti-inflammatory drugs.

[00226] The GLS1 inhibitory compositions disclosed 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. . Initial administration is generally done according to established protocols and then, based on observed effects, dosage, modes of administration, and administration times subsequently modified. In certain cases, 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 efficacy of a GLS1 inhibitor is improved 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 efficacy of a compound described herein can be improved by administration of an adjuvant.

[00227] Therapeutically effective dosages vary when 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. Combined treatment also includes periodic treatments that start and stop at various times to assist in the patient's clinical management. In any case, the multiple therapeutic agents (one of which is a GLS1 inhibitor as described herein) can be administered in any order or simultaneously. If administered 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).

[00228] In some embodiments, one of the therapeutic agents is provided in multiple doses, or both are provided as multiple doses. If not administered simultaneously, the interval between multiple doses optionally varies from more than zero weeks to less than twelve weeks.

[00229] Furthermore, combination methods, compositions and formulations should not be limited to the use of just two agents, the use of multiple therapeutic combinations is also contemplated. It is understood that the dosage regimen for treating, preventing or alleviating the condition (or conditions) for which relief is intended is optionally modified in accordance with a variety of factors. These factors include the disorder the subject suffers from, as well as the subject's age, weight, gender, diet, and medical condition. Thus, the dosage regimen actually employed varies widely in some embodiments and therefore deviates from the dosage regimens presented herein.

[00230] The pharmaceutical agents that constitute the combination therapy disclosed herein are, optionally, a combined dosage form or are in separate dosage forms intended for substantially simultaneous administration. Pharmaceutical agents comprising combination therapy are optionally also administered sequentially, with either agent being administered by a regimen requiring two-step administration. The two-step administration regimen optionally requires sequential administration of the active agents or separate administration of the separate active agents. The time between multiple-step administration varies from a few minutes to several hours, depending on the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent.

[00231] 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 administration of the composition containing a GLS1 inhibitor varies in some embodiments. Thus, for example, a GLS1 inhibitor is used as a prophylactic method 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 symptoms. Although embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that these 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 the practice of the invention.

[00232] A GLS1 inhibitor can be used in combination with anticancer drugs, including, but not limited to, the following classes: alkylating agents, antimetabolites, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, angiogenesis inhibitors and tyrosine inhibitors kinase.

[00233] For use in cancer and neoplastic diseases, a GLS1 inhibitor can ideally be used in conjunction 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) antimetabolites, 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), lapatininb (TYKERB), and axitinib (INLYTA).

[00234] When a subject is suffering from or at risk of suffering from an inflammatory condition, a GLS1 inhibitor compound described herein is optionally used in conjunction with one or more agents or methods to treat 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 (HUMlRA); (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

[00235] The compounds of the present invention can be prepared using the methods illustrated in the general synthetic schemes and experimental procedures detailed below. General synthetic schemes and experimental procedures are presented for illustration purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using routine methods known in the art.

LIST OF ABBREVIATIONS

[00236] Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCI3 = deuterated chloroform; CDI = 1.1‘- Carbonyldiimidazole; DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = diiso-butyl aluminum 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 aluminum hydride; 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-butyl lithium; 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 = tetracys(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; prep-HPLC = preparatory high-performance liquid chromatography; PyBop = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = ambient temperature; RuPhos = 2-dicyclohexylphosphino-2‘,6‘-diisopropoxybiphenyl; Sat. = saturated; ss = saturated solution; t-BuOH = tert-butanol; T3P = Propylphosphonic Anhydrous; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; Tol = toluene; TsCl = tosyl chloride; XPhos = 2-dicyclohexylphosphino-2‘,4‘,6‘- triisopropylbiphenyl.

GENERAL METHODS FOR PREPARING COMPOUNDS

[00237] The following schemes can be used to practice the present invention.

[00238] EXAMPLE 1: N-(6-(3-(5-Amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)-2-phenylacetamide

[00239] The title compound was synthesized by a procedure similar to Example 13. MS (ES+) C19H21N7OS requires: 395; found: 396 [M+H]+.

[00240] EXAMPLE 2: 2-Phenyl-N-(6-(3-(5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl )acetamide

[00241] The title compound was synthesized by a procedure similar to Example 14. MS (ES+) C27H27N7O2S requires: 513; found: 514 [M+H]+. 1H NMR (600 MHz, MeOD-d4) δ: 8.28 (d, J = 10.2 Hz, 1H), 7.92 (d, J = 10.2 Hz, 1H), 7.30-7, 37 (m, 8H), 7.22-7.29 (m, 2H), 4.30-4.37 (m, 1H), 4.01 (m, 1H), 3,753.83 (m, 5H) , 3.47-3.57 (m, 2H), 2.26-2.35 (m, 1H), 1.98-2.08 (m, 1H), 1.88-1.97 (m, 1H), 1.75-1.86 (m, 1H).

[00242] EXAMPLE 3: 2-Phenyl-N-(6-(3-(5-(2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2-yl)piperidin-1- il)pyridazin-3-yl)acetamide

[00243] The title compound was synthesized by a procedure similar to Example 14. MS (ES+) C26H26N8O2S requires: 514; found: 515 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 12.80 (s l, 1H), 11.03 (s l, 1H), 8.58 (d, J = 4.5 Hz, 1H), 8.09 ( d, J = 9.8 Hz, 1H), 7.93 (m, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.43 (m, 1H), 7.30-7.36 (m, 4H), 7.207.28 (m, 1H), 4.41 (d l, 1H), 3.99-4.13 (m, 3H), 3.72 (s, 2H), 3.35-3.50 (m, 2H), 3.25 (t l, 1H), 2.17 (m, 1H), 1.76- 1.93 (m, 2H), 1.58-1.72 (m, 1H).

[00244] EXAMPLE 4: N-(6-(3-(5-Acetamido-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)-2-phenylacetamide

[00245] The title compound was synthesized by Example 14. MS (ES+) C21H23N7O2S requires: 437; found: 438 [M+H]+.

[00246] EXAMPLE 6: N-Methyl-1-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1H-1,2, 3-triazole-4-carboxamide

[00247] The title compound was synthesized by a procedure similar to step 9 of Example 8. MS (ES+) C21H21F3N8O3 requires: 490; found: 491[M+H]+.

[00248] EXAMPLE 7: N-(Pyridin-2-ylmethyl)-1-(1-(6- (2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide

[00249] The title compound was synthesized by a procedure similar to Example 8, step 9. MS (ES+) C27H26F3N9O3 requires: 581; found: 582 [M+H]+.

[00250] EXAMPLE 8: N-(pyridin-2-ylmethyl)-1-(1-(6- (2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)- 1H-1,2,3-triazole-4-carboxamide Steps 1 to 9 Step 1: Benzyl (6-iodopyridazin-3-yl)carbamate

[00251] A mixture of 6-iodopyridazin-3-amine (3 g, 13.57 mmol) and DIEA (2.85 ml, 16.29 mmol) in chloroform (8 ml) under nitrogen in an ice bath was Benzyl chloroformate (2.78 g, 16.29 mmol) was added dropwise, and the reaction was stirred in the ice bath for 10 min, then the mixture was allowed to warm to room temperature overnight. The reaction mixture was filtered, and the resulting solid was washed with minimal DCM. More solid formed in the filtrate and was recovered by filtration. The off-white solid was washed with minimal DCM to give the product (2.46 g). Additional product was isolated from the filtrate after purification by silica gel chromatography (0 to 60% hexanes in EtOAc; 0.5 g as a white solid) to give the title compound (combined total, 3 g, 62 %) as an off-white solid. MS (ES+) C12H10IN3O2 requires: 355; found: 356 [M+H]+.Step 2: benzyl (6-(3-hydroxypyrrolidin-1-yl)pyridazin-3-yl)carbamate

[00252] To a vial containing benzyl (6-iodopyridazin-3-yl)carbamate (1 g, 2.82 mmol), pyrrolidin-3-ol (0.294 g, 3.38 mmol), L-proline, (65 mg, 0.563 mmol), K3PO4 (1.793 g, 8.45 mmol) and copper (I) iodide (0.054 g, 0.282 mmol), DMSO (5 ml) (previously degassed with nitrogen) was added, and the resulting mixture was stirred at 50 °C for 20 h. To the mixture, copper (I) iodide (0.108 g, 0.564 mmol) and K3PO4 (0.161 g, 1.69 mmol) and 2-(dimethylamino)acetic acid (0.058 g, 0.563 mmol) were added, and the reaction heated to 50 °C for 2 days. The reaction was poured into water (200 ml) and diluted with DCM (100 ml), and the resulting mixture was filtered, and the resulting black solid was washed with DCM. The filtrate mixture was separated, and the aqueous layer was extracted with DCM (3 x 100 ml). The organic layers were combined, washed with brine, dried with MgSO4, filtered through a sintered glass funnel, concentrated, and the residue was purified by silica gel chromatography (0 to 30% DCM/MeOH/NH4OH solution to 80/20/1 in DCM) to give the title compound (225 mg, 25%) as a white solid. MS (ES+) C16H18N4O3 requires: 314; found: 315 [M+H]+.Step 3: 1-(6-(((benzyloxy)carbonyl)amino)pyridazin-3-yl)pyrrolidin-3-yl methanesulfonate

[00253] A suspension of benzyl (6-(3-hydroxypyrrolidin-1-yl)pyridazin-3-yl)carbamate (61 mg, 0.194 mmol) and DIEA (0.051 ml, 0.291 mmol) in DCM (2 ml) was cooled under nitrogen in an ice bath, and methanesulfonyl chloride (0.023 ml, 0.291 mmol) was added, and the resulting mixture was stirred in the ice bath for 3 min, then removed and warmed to room temperature. To the reaction, DIEA (47 μl, 0.269 mmol) was added, cooled in the ice bath, methanesulfonyl chloride (14 μl, 0.180 mmol) was added, and the reaction was stirred and allowed to cool to room temperature over 4 h . The reaction was cooled in an ice bath, and DIEA (47 μl, 0.269 mmol) and methanesulfonyl chloride (14 μl, 0.180 mmol) were added, and the reaction was stirred and allowed to cool over 1 h. The completed reaction was diluted with DCM, washed with water and saturated NaCl, dried over MgSO4, filtered and concentrated to give the title compound (79 mg, 88%). MS (ES+) C17H20N4O4S requires: 392; found: 393 [M+H]+.Step 4: benzyl (6-(3-azidopyrrolidin-1-yl)pyridazin-3-yl)carbamate

[00254] To a solution of 1-(6-(((benzyloxy)carbonyl)amino)pyridazin-3-yl)pyrrolidin-3-yl methanesulfonate (76 mg, 0.194 mmol) in DMF (1 ml), was added sodium azide (25.2 mg, 0.387 mmol), and the resulting mixture was stirred at 50 °C for 60 h. The reaction was concentrated, diluted with DCM, washed with water and saturated NaCl, dried with MgSO4, filtered and concentrated to give the title compound (43.9 mg, 66%) as an off-white solid. MS (ES+) C16H17N7O2 requires: 339; found: 340 [M+H]+. Step 5: 1-(1-(6-(((benzyloxy)carbonyl)amino)pyridazin-3-yl)pyrrolidin-3-yl)-tert-butyl 1H-1,2,3-triazol-4-carboxylate

[00255] To a solution of benzyl (6-(3-azidopyrrolidin-1-yl)pyridazin-3-yl)carbamate (41 mg, 0.121 mmol), DIEA (2.110 μl, 0.012 mmol), AcOH (0.692 μl, 0.012 mmol) in DCM (1 ml), tert-butyl propiolate (18.29 mg, 0.145 mmol) and CuI (1.150 mg, 6.04 μmol) were added, and the resulting mixture was stirred at room temperature for 2 h . The reaction was diluted with DCM and washed with dilute aqueous NH4OH and saturated NaCl, dried over MgSO4, filtered and concentrated to give the title compound (45.6 mg, 81%) as a light brown solid. MS (ES+) C23H27N7O4 requires: 465; Found: 466 [M+H]+.Step 6: 1- (1- (6- (((benzyloxy)carbonyl)amino)pyridazin-3-yl)pyrrolidin-3-yl)- 1H-1.2 acid, 3-triazole-4-carboxylic acid

[00256] To a suspension of 1-(1-(6- (((benzyloxy)carbonyl)amino)pyridazin-3-yl)pyrrolidin-3-yl)- 1H-1,2,3-triazol-4-carboxylate of tert-butyl (41 mg, 0.088 mmol) in DCM (0.5 ml), TFA (0.339 ml, 4.40 mmol) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated and dried multiple times from DCM/toluene and DCM/hexanes to give the title compound as a TFA (1:1) salt (46 mg, 100%) as an off-white solid. MS (ES+) C19H19N7O4 requires: 409; found: 410 [M+H]+.Step 7:Example 5:(6- (3- (4- ((pyridin-2-ylmethyl)carbamoyl)-1H-1,2,3-triazol-1-yl) pyrrolidin-1-yl)pyridazin-3-yl)benzyl carbamate

[00257] To a solution of the acid compound 1-(1- (6-(((benzyloxy)carbonyl)amino)pyridazin-3-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol- 4-carboxylic acid with 2,2,2-trifluoroacetic acid (1:1) (23 mg, 0.044 mmol) in DMF (1 ml), pyridin-2-ylmethanamine (14.26 mg, 0.132 mmol), DIEA ( 46 μl, 0.264 mmol) and HATU (50 mg, 0.132 mmol), and the reaction was stirred at room temperature until completion. The reaction was concentrated, sustained, Celite and purified by silica gel chromatography (0 to 50% 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the title compound (11.7 mg, 53%) as an off-white solid. MS (ES+) C25H25N9O3 requires: 499; found: 500 [M+H]+.Step 8: 1-(1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl)-N-(pyridin-2-ylmethyl)-1H-1,2, 3-triazole-4-carboxamide

[00258] A solution of (6-(3-(4-((pyridin-2-ylmethyl)carbamoyl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)pyridazin-3- il)benzyl carbamate (9 mg, 0.018 mmol) in MeOH (1 ml) was purged with nitrogen, and then 10% palladium on carbon (2 mg, 1.8 μm) was added. The resulting mixture was exposed to hydrogen (0.1 MPa (1 atm)) for 4 h. The reaction was filtered through celite, rinsed with DCM/MeOH, and the filtrate concentrated. The residue was applied to the same hydrogenation procedure for 2 h with 10% palladium on carbon (3 mg, 2.8 μm), but with the addition of concentrated HCl (10 μl). The reaction was filtered through celite, the filter cake rinsed with DCM/MeOH, and the filtrate concentrated and dried with DCM/hexanes to give the title compound which was used as is for the next step. MS (ES+) C21H21F3N8O3 requires: 365; found: 366 [M+H]+.Step 9 :N- (pyridin-2-ylmethyl) -1- (1- (6- (2- (3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl) pyrrolidin-3 - yl)-1H-1,2,3-triazole-4-carboxamide

[00259] To a solution of 1-(1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl)-N-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4- carboxamide (9 mg, 0.025 mmol) in DMF (100 μl), 2-(3-(trifluoromethoxy)phenyl) acetic acid (10.84 mg, 0.049 mmol) and pyridine (11.95 μl, 0.148 mmol) were added, followed by T3P (50% solution in EtOAc, 62 μl, 0.099 mmol), and the resulting mixture was stirred at 80 °C for 3 h. To the reaction, 2-(3-(trifluoromethoxy)phenyl)acetic acid (33 mg, 0.15 mmol), pyridine (36 μl, 0.45 mmol) were added, followed by T3P (50% solution in EtOAc, 186 μl , 0.30 mmol), and the reaction was stirred at 80 °C overnight. The reaction was concentrated, sustained in celite and purified by flash chromatography (0 to 60% DCM/MeOH/NH4OH solution at 80/20/1 in DCM) to generate the product. The product was further purified by reverse phase preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 to 60%; 12 min; Column : Y) to give the title compound (2.3 mg, 16%) as an off-white solid. MS (ES+) C26H24F3N9O3 requires: 567; found: 568 [M+H] +. 1H NMR (600 MHz, DMSO-d6) δ: 11.02 (s l, 1H), 9.10 (t, J = 5.9 Hz, 1H), 8.75 (s, 1H), 8.54 ( d, J = 4.5 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.44-7, 50 (m, 1H), 7.31-7.40 (m, 4H), 7.20-7.28 (m, 2H), 5.55-5.57 (m, 1H), 4.58 ( d, J = 6.0 Hz, 2H), 3,994.10 (m, 2H), 3.81 (s, 2H), 3.68-3.74 (m, 2H), 2.64-2.69 (m, 1H), 2.54-2.61 (m, 1H).

[00260] EXAMPLE 9: 2-(pyridin-2-yl)-N-(6-(3-(5- (2-(pyridin-2-yl)acetamido)-1,3,4-thiadiazol-2- il)pyrrolidin-1-yl)pyridazin-3-yl)acetamide Steps 1 to 4 Step 1: 1-(6-aminopyridazin-3-yl)pyrrolidine-3-carbonitrile

[00261] To a vial containing 6-iodopyridazin-3-amine, pyrrolidine-3-carbonitrile hydrochloride, L-proline ((S)-pyrrolidine-2-carboxylic acid) (20.84 mg, 0.181 mmol), K3PO4 ( 768 mg, 3.62 mmol) and copper (I) iodide (17.24 mg, 0.090 mmol), DMSO (2 ml) (previously degassed with nitrogen) was added, and the resulting mixture was stirred at 50 °C for 8 p.m. The reaction was diluted with MeOH and acidified with AcOH. The mixture was loaded onto SCX resin, and the product isolated by a procedure similar to that described in Tetrahedron Letters, 55 (2014), 5,186 to 5,190 to generate the crude product (80 mg). The crude product was held in celite and purified by silica gel chromatography (0 to 100% DCM/MeOH/NH4OH 80/20/1 solution in DCM) to give the title compound (55 mg, 19% ) as a light yellow solid. MS (ES+) C9H11N5 requires: 189; found: 190 [M+H]+.Step 2: N-(6-(3-cyanopyrrolidin-1-yl)pyridazin-3-yl)-2-(pyridin-2-yl)acetamide

[00262] To a round bottom flask containing 1-(6-aminopyridazin-3-yl)pyrrolidine-3-carbonitrile (55 mg, 0.180 mmol), DMF (1 ml), 2-(pyridin- 2-yl)acetic acid (101 mg, 0.582 mmol) and DIEA (0.203 ml, 1.161 mmol), the solution was cooled in an ice bath under N2, and to it, T3P (50% solution in EtOAc, 0.370 ml, 0.581 mmol) by drip. The reaction was allowed to cool to room temperature overnight. To the reaction, saturated NaHCO3 (50 ml) was added, and the resulting mixture was stirred for 30 min, and the precipitate was removed by filtration and washed with water and hexanes. The yellow solid was dissolved in DCM/MeOH, adsorbed on Celite and purified by flash chromatography (0 to 100% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the title compound (26 mg, 46.8%) as a yellow solid. MS (ES+) C16H16N6O requires: 308; found: 309 [M+H]+.Step 3:N- (6- (3- (5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl) -2-(pyridin-2-yl)acetamide

[00263] To a solution of N-(6-(3-cyanopyrrolidin-1-yl)pyridazin-3-yl)-2-(pyridin-2-yl)acetamide (23 mg, 0.075 mmol) in TFA (200 μl , 2.60 mmol), hydrazinecarbothioamide (7.48 mg, 0.082 mmol) was added, and the resulting mixture was stirred at 60 °C for 17 h and 80 °C for 2 h. The reaction was concentrated and azeotroped from DCM/EtOH, DCM/MeOH/NH4OH and DCM/hexanes. The residue was adsorbed onto Celite and purified by flash chromatography (0 to 50% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the title compound (25 mg, 88%) as a off-white solid. MS (ES+) C17H18N8OS requires: 382; found: 383 [M+H]+.Step 4: 2-(pyridin-2-yl)-N-(6 -(3-(5-(2-(pyridin-2-yl)acetamido)-1,3 ,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)acetamide

[00264] To a suspension of N-(6-(3-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)-2-(pyridin- 2-yl)acetamide (20 mg, 0.052 mmol) in DMF (0.2 ml), 2-(pyridin-2-yl)acetic acid hydrochloride (18.16 mg, 0.105 mmol) and DIEA (0.037 ml) were added. , 0.209 mmol), and the resulting mixture was stirred at room temperature for 5 min until a light yellow solution was formed. The reaction was placed under N2 and cooled in an ice bath. To it, T3P (50% solution in EtOAc, 0.067 ml, 0.105 mmol) was added dropwise, and the reaction was allowed to cool to room temperature overnight. The reaction was concentrated, mixed with saturated aqueous NaHCO3, filtered, and the filter rinsed with water and DCM. The filtrate mixture containing the product was separated, and the aqueous layer extracted twice with DCM. The DCM layers were combined and washed with saturated NaCl, dried with MgSO4, filtered, concentrated, and the residue was adsorbed on celite and purified by flash chromatography (0 to 20% DCM/MeOH/NH4OH solution at 80 /20/1 in DCM to give the title compound (2.5 mg, 9%) as a white solid. MS (ES+) C24H23N9O2S requires: 501; found: 502 [M+H]+. 1H NMR (600 MHz, MeOD-d4) δ: 8.508.56 (m, 2H), 8.18 (d, J = 9.8 Hz, 1H), 7.78-7.82 (m, 2H), 7.42-7, 46 (m, 2H), 7.28-7.36 (m, 2H), 6.94 (d, J = 9.4 Hz, 1H), 4.00-4.09 (m, 4H), 3 .97 (s, 2H), 3.81-3.86 (m, 1H), 3,733.80 (m, 1H), 3.62-3.69 (m, 1H), 2.56-2.66 (m, 1H), 2.36-2.40 (m, 1H).

[00265] EXAMPLE 10: N-(pyridin-2-ylmethyl)-5-(1- (6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)- 1,3,4-thiadiazol-2-carboxamide-2,2,2-trifluoroacetate Steps 1 to 4 Step 1:5-bromo-N-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide

[00266] To a suspension of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (483 mg, 2.037 mmol), pyridin-2-ylmethanamine (0.210 ml, 2.037 mmol) was added, and the mixture The resulting mixture was stirred at room temperature overnight. The reaction was evaporated, and the residue was purified by silica gel chromatography (25 to 100% EtOAc in hexanes, Rf=0.7 100% EtOAc) to give the title compound (300 mg, 49%) as a white solid. MS (ES+) C9H7BrN4OS requires: 299; found: 299, 301 [M+H]+.Step 2:3-(5-((pyridin-2-ylmethyl)carbamoyl)- 1,3,4-thiadiazol-2-yl)-2,5-di- tert-butyl hydro-1H-pyrrole-1-carboxylate

[00267] A suspension of tert 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate butyl (296 mg, 1.003 mmol), 5-bromo-N-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide (300 mg, 1.003 mmol) and 2M sodium carbonate in water (1 .5 ml, 3.01 mmol) under N2 was treated with PdCl2(dppf)-DCM (82 mg, 0.100 mmol) and heated to 90 °C and stirred for 2.5 h. The mixture was evaporated, and the residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes to give the title compound (262 mg, 67%) as a yellow amorphous material. MS (ES+) C18H21N5O3S requires: 387 found: 388 [M+H]+.Step 3: N-(pyridin-2-ylmethyl)-5-(pyrrolidin-3-yl)- 1,3,4-thiadiazol-2-carboxamide

[00268] To a solution of 3-(5-((pyridin-2-ylmethyl)carbamoyl)-1,3,4-thiadiazol-2-yl)-2,5-dihydro-1H-pyrrole-1- tert-butyl carboxylate (55 mg, 0.142 mmol) in Ethanol (1.5 ml), palladium on carbon (10%, 7.5 mg, 0.071 mmol) was added (after subjecting to 3 iterations of vacuum and nitrogen), and the resulting mixture was subjected to 3 iterations of vacuum and nitrogen stirring followed by hydrogen (0.31 MPa (45 psi)) in a Parr shaker for 6 h. The catalyst was removed by filtration, and to the solution, palladium on carbon (10%, 50 mg) and acetic acid (0.033 ml, 0.568 mmol) were added. The reaction mixture was subjected to hydrogen (0.28 MPa (40 psi)) in the Parr shaker for 48 h. The reaction was filtered through Celite, and the filtrate was evaporated. The residue was directly dissolved in 1.6 ml of DCM and 0.4 ml of TFA, and the mixture was stirred for 20 min. The reaction was evaporated, and the residue dissolved in methanol and neutralized by elution with MeOH rinses through an MP-HCO3 cartridge (Agilent PL3540-C603, PL-HCO3 MP SPE 500 mg/6 ml). The eluent was evaporated under vacuum to give the title compound as a yellow solid. MS (ES+) C13H15N5OS requires: 289 found: 290 [M+H]+. Step 4: N-(pyridin-2-ylmethyl)-5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1,3 ,4-thiadiazol-2-carboxamide 2,2,2-trifluoroacetate

[00269] To a solution of N-(pyridin-2-ylmethyl)-5-(pyrrolidin-3-yl)-1,3,4-thiadiazol-2-carboxamide (7.05 mg, 0.024 mmol) in acetonitrile ( 0.5 ml), N-(6-bromopyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (11 mg, 0.029 mmol) and TEA (3.40 μl, 0.024 mmol) were added, and the resulting mixture was heated in a microwave at 160 °C for 2 h. The mixture was filtered and purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 12 min; Column: C18) to generate the title compound (0.94 mg, 1.346 μmol, 5%) as a brown solid. MS (ES+) C26H23F3N8O3S requires: 584 found: 585 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 11.10 (s, 1H), 9.75 (t, J = 5.5 Hz, 1H), 8.57-8.52 (m, 1H), 8.21-8.15 (m, 1H), 7.86-7.81 (m, 1H), 7.58-7.18 (m, 6H), 7.26 (d, J = 8.4 Hz, 1H), 4.634.59 (m, 2H), 4.30-4.23 (m, 1H), 4.11-4.05 (m, 1H), 3.90-3.84 (m, 1H), 3.82 (s, 2H), 3.75-3.61 (m, 2H), 2.66-2.59 (m, 1H), 2.38-2.30 (m, 1H) .

[00270] EXAMPLE 11: N-(6-(3-(4-acetamido-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)pyridazin-3-yl)-2-(3 - (trifluoromethoxy)phenyl)acetamide Steps 1 to 7 Step 1:3 - tert-butyl((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

[00271] A stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2 g, 10.68 mmol) in DCM (93 ml) was cooled to 0°C. DIEA (3.73 ml, 21.36 mmol) was added followed by methanesulfonyl chloride (1.835 g, 16.02 mmol) under nitrogen. After 45 min, the reaction mixture was diluted with saturated sodium bicarbonate, extracted with DCM (3 times), washed with brine, dried with sodium sulfate and concentrated to give the title compound (2.8 g, 99%) as a thick amber oil. MS (ES+) C10H19NO5S requires: 265; found: 288 [M+Na]+.Step 2: tert-butyl 3-azidopyrrolidine-1-carboxylate

[00272] To a stirring solution of tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (1.417 g, 5.34 mmol) in DMF (25 ml), sodium azide (0.694 g, 10. 68 mmol) was added, and the reaction was stirred at 40 °C for 19 h. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate and DCM (100 ml) were added, and the layers were separated. The aqueous phase was extracted with DCM (3 x 100 ml), and the organic layers were combined, washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (1.8 g, 98 % yield). MS (ES+) C9H16N4O2 requires: 212; found: 235 [M+Na] +.Step 3: 3-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate tert-butyl

[00273] To a solution of tert-butyl 3-azidopyrrolidine-1-carboxylate (500 mg, 2.356 mmol) in DCM (4.7 ml), 2-ethynylisoindoline-1,3-dione (484 mg, 2 .83 mmol), DIEA (0.041 ml, 0.236 mmol), acetic acid (0.013 ml, 0.236 mmol), and copper(I) iodide (31.4 mg, 0.165 mmol), and the reaction was allowed to stir at room temperature for 4 p.m. The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel chromatography (0 to 10% MeOH in DCM) to give the title compound (823 mg, 91%) as a white solid. MS (ES+) C19H21N5O4 requires: 383; found: 384 [M+H]+.Step 4: tert-butyl pyrrolidine-1-carboxylate

[00274] To a stirring solution 3-(4-(1,3-dioxoisoindolin-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1-tert-butyl carboxylate (617 .7 mg, 1.611 mmol) in MeOH (16 ml), hydrazine hydrate (0.157 ml, 3.22 mmol) was added, and the reaction was heated to 80 °C until completion. The reaction mixture was concentrated, diluted with MeOH and acidified with TFA added dropwise. The resulting white solid was removed by filtration, and the filtrate was diluted with water and lyophilized to give the title compound (500 mg, 73%) as an off-white semisolid. MS (ES+) C11H19N5O2 requires: 253; found: 254 [M+H]+.Step 5:3- tert-butyl (4-acetamido-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate

[00275] To a stirred solution of tert-butyl 3-(4-amino-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.395 mmol) in DMF (2 ml ), pyridine (0.064 ml, 0.790 mmol) was added, and the reaction was cooled in an ice bath. To the reaction, acetyl chloride (0.056 ml, 0.790 mmol) was added, and the reaction mixture was allowed to warm to room temperature over 20 h. The reaction mixture was concentrated, diluted with DCM and washed with water (3x), saturated sodium bicarbonate (3x) and brine. The organic layer was dried with magnesium sulfate, and concentrated to give the title compound (54.5 mg, 46.7%) as an off-white solid. MS (ES+) C13H21N5O3 requires: 295; found: 318 [M+Na]+.Step 6: N-(1-(Pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)acetamide

[00276] To a stirred solution of tert-butyl 3-(4-acetamido-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (54.5 mg, 0.185 mmol) in DCM ( 0.923 ml), TFA (0.284 ml, 3.69 mmol) was added dropwise, and the reaction was allowed to stir for 3 h. The reaction mixture was concentrated to give the title compound (51 mg, 90%) as a light yellow solid. MS (ES+) C8H13N5O requires: 195; found: 196 [M+H]+.Step 7: N-(6-(3-(4-Acetamido-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)pyridazin-3- il)-2-(3-(trifluoromethoxy)phenyl)acetamide

[00277] A vial containing N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (20 mg, 0.060 mmol), N-(1-(pyrrolidin-3-yl)- 1H-1,2,3-triazol-4-yl)acetamide (11.77 mg, 0.060 mmol) and TEA (84 μl, 0.603 mmol) was stirred and heated at 100 °C for 48 h. The reaction was diluted with MeOH/DMSO, acidified with TFA and purified by mass-activated preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 20 to 50%; 12 min; Column: C18) to generate the title compound as a yellow powder. MS (ES+) C21H21F3N8O3 requires: 490 found: 491 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 10.97 (s l, 1H), 10.86 (s, 1 H), 8.20 (s, 1 H), 8.06 (s l, 1 H) , 7.40-7.49 (m, 1 H), 7.33-7.39 (m, 2 H), 7.18-7.30 (m, 2 H), 5.42 (s l, 1 H), 3.89-4.05 (m, 2H), 3.80 (s, 2H), 3.613.70 (m, 2H), 2.57-2.65 (m, 2H), 2.03 (s, 3 H).

[00278] EXAMPLE 12: N-(6-(3-(5-acetamido-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)-2-(pyridin-2 - il)acetamide

[00279] The title compound was synthesized by a procedure similar to that used for Example 14. MS (ES+) C19H20N8O2S requires: 424; found: 425 [M+H]+.

[00280] EXAMPLE 14: 2-(pyridin-2-yl)-N-(5-(1-(6- (2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-3- il)-1,3,4-thiadiazol-2-yl)acetamide Steps 1 to 4 Step 1: N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

[00281] To a round-bottom flask containing 2-(3-(trifluoromethoxy)phenyl)acetic acid (13.59 g, 61.8 mmol), thionyl chloride (9.01 ml, 124 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was concentrated and then azeotroped with mixtures of DCM/toluene and then DCM/hexanes. To a round bottom flask containing 6-chloropyridazin-3-amine (4 g, 30.9 mmol) mixed with NMP (50 ml), 2-(3-(trifluoromethoxy) chloride was added dropwise through an addition funnel. )phenyl)acetyl (7.37 g, 30.9 mmol) dissolved in NMP (10 ml). The reaction was stirred at room temperature overnight. The reaction was then heated to 50 °C for 3.5 h. The reaction mixture was dropped into a solution of saturated NaHCO3 (200 ml) and ice. The mixture was transferred to a larger flask, diluted with more saturated NaHCO3 and water and stirred until all the ice had melted and the mixture had warmed to room temperature. The solid was filtered off and washed with saturated NaHCO3, water and hexanes to give the title compound (6.24 g, 61%) as an off-white solid. MS (ES+) C13H9ClF3N3O2 requires: 331; found: 332 [M+H]+.Step 2: N-(6-(3-cyanopiperidin-1-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

[00282] To a vial, N-(6-chloropyridazin-3-yl)-2-phenylacetamide (2 g, 6.03 mmol) piperidine-3-carbonitrile (0.731 g, 6.63 mmol) and TEA ( 1 ml, 7.24 mmol), and the reaction was stirred and heated in a sand bath at 100 °C overnight. The reaction was then heated in a microwave reactor for 2.5 h at 150 °C. To the reaction, piperidine-3-carbonitrile (0.44 g, 4.0 mmol) and TEA (0.5 ml, 3.6 mmol) were added, and it was heated in a dry block at 120 °C for one day. To the other. The reaction was diluted with DCM and saturated NaHCO3, the phases separated, and the DCM layer was washed with water and brine. Each aqueous layer was extracted twice with DCM. The organic layers were combined, dried over MgSO4, filtered, concentrated, and the residue was dissolved in minimal DCM and purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give the title compound (397 mg , 16%) as a light yellow solid. MS (ES+) C19H18F3N5O2 requires: 405; found: 406 [M+H]+.Step 3: Example 13: N-(6-(3-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3 -yl)-2 - (3- (trifluoromethoxy)phenyl)acetamide

[00283] To a round bottom flask containing N-(6-(3-cyanopiperidin-1-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (396 mg, 0.977 mmol), TFA (2 ml, 26 mmol) and hydrazinecarbothioamide (116 mg, 1.28 mmol) were added. The reaction was heated in a dry block at 80 °C for 30 min (cooled to room temperature overnight) and 60 °C for 4 h, then cooled to room temperature over 2 days. The reaction was heated to 80 °C for 30 min and then cooled to room temperature, diluted with EtOH and concentrated. The thick oil was concentrated from DCM/hexanes, and the residue was adsorbed onto celite and purified by flash chromatography (0 to 50% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to generate the title compound (381 mg, 81%) as a yellow solid. MS (ES+) C20H20F3N7O2S requires: 479; found: 480 [M+H]+.Step 4 :2- (pyridin-2-yl) -N- (5- (1- (6- (2- (3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3 -yl)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00284] A vial containing N-(6-(3-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)-2-(3- ( trifluoromethoxy)phenyl)acetamide, DIEA (146 μl, 0.834 mmol) and 2-(pyridin-2-yl)acetic acid hydrochloride (72.4 mg, 0.417 mmol) dissolved in DMF (2 ml) was placed under nitrogen and cooled in an ice bath. To this mixture, T3P (50% solution in DMF, 131 μl, 0.417 mmol) was added dropwise. The reaction was allowed to cool to room temperature over 4.5 h. The reaction was diluted with MeOH and water, and the yellow solution was concentrated to a thick oil. The residue was adsorbed on silica gel and purified by flash chromatography (Hexanes, then 0 to 50% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to generate the title compound (64, 9 mg, 52.0%) as a yellow solid. MS (ES+) C27H25F3N8O3S requires: 598; found: 599 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 12.73 (s, 1H), 10.97 (s, 1H), 8.49 (dd, J = 4.9, 0.8 Hz, 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.77 (t d, J = 7.6, 1.7 Hz, 1H), 7.44-7.49 (m, 1H), 7 .33-7.44 (m, 4H), 7.23-7.31 (m, 2H), 4.43 (d l, J = 11.0 Hz, 1H), 3.97-4.08 (m , 3H), 3.80 (s, 2H), 3.33-3.38 (m, 2H), 3.11-3.21(m, 1H), 2.12-2.20 (m, 1H ), 1,741.89 (m, 2H), 1.54-1.69 (m, 1H).

[00285] EXAMPLE 15: N-(6-(3-(5-acetamido-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridazin-3-yl)-2-(3- ( trifluoromethoxy)phenyl)acetamide

[00286] The title compound was synthesized by a procedure similar to Example 14. MS (ES+) C22H22F3N7O3S requires: 521; found: 522 [M+H]+.

[00287] EXAMPLE 17: 2-(Pyridin-2-yl)-N-(5-(1-(6-(2-(3-trifluoromethoxy)phenyl)acetamido)pyridazin-2,2,2-trifluoroacetate 3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide Steps 1 to 3 Step 1: N-(6-(3-cyanopyrrolidin-1-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

[00288] A microwave flask was charged with N-(6-chloropyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (1,000 mg, 3.01 mmol), pyrrolidine-3 hydrochloride -carbonitrile (600 mg, 4.52 mmol), cesium fluoride (458 mg, 3.01 mmol), and DMSO (4 ml) were added. The vial was sealed, and the reaction mixture was heated to 130 °C in a microwave reactor for 6 h (60% conversion). The mixture was evaporated and taken up in EtOAc washed with saturated NaHCO3 and brine and dried with Na2SO4. The residue was purified by silica gel chromatography (0 to 100% EtOAc in DCM to give the title compound (240 mg, 20%) as a green solid. MS (ES+) C18H16F3N5O2 requires: 391; found: 392 [M+H]+.Step 2: Example 19: N-(6-(3-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl) -2 -(3- (trifluoromethoxy)phenyl)acetamide

[00289] To a solution of N-(6-(3-cyanopyrrolidin-1-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (240 mg, 0.613 mmol) in TFA (1 ml), hydrazinecarbothioamide (61.5 mg, 0.675 mmol) was added, and the resulting mixture was stirred at 70 °C for 6 h. The mixture was evaporated and dissolved in DCM containing methanol (10 to 15%) and then washed with saturated NaHCO3:H2O in a 1:1 mixture. The aqueous phase was then washed with DCM, and all organic phases were combined and evaporated in vacuo. The residue was purified by silica gel chromatography (0 to 7% MeOH in DCM and then 7% isocratic methanol in DCM) to give the title compound (182 mg, 64%) as a yellow solid. MS (ES+) C18H16F3N5O2S requires: 465; found: 466 [M+H]+.Step 3: 2-(pyridin-2-yl)-2,2,2-trifluoroacetate- N-(5-(1-(6-(2-(3(trifluoromethoxy) phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00290] To a solution of N-(6-(3-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)-2-(3- (trifluoromethoxy)phenyl)acetamide (40 mg, 0.086 mmol) in DMF (0.5 ml), 2-(pyridin-2-yl)acetic acid hydrochloride (44.8 mg, 0.258 mmol) and DIEA (0.090) were added. ml, 0.516 mmol) at 0°C, then T3P (50% DMF, 0.149 ml, 0.258 mmol), and the mixture was allowed to reach room temperature. After 3 h, the mixture was diluted with water and extracted with DCM/MeOH (10 to 15%). The organic phase was evaporated, redissolved in DMSO, acidified with aqueous HCl (6 N, a few drops) and purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% of TFA/MeCN; Gradient: B = 20 to 60%; 20 min; Column: C18) to give the title compound (23 mg, 0.033 mmol, 38% yield) as a light yellow solid. MS (ES+) C26H23F3N8O3S requires: 584, found: 585 [M+H]+. 1H NMR (600 MHz, d6-DMSO) δ: 12.82 (s, 1H), 11.13 (s l, 1H), 8.53 (d, J = 4.6 Hz, 1H), 8.21 ( d l, J = 5.8 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.49-7.43 (m, 3H), 7.38-7.33 (m , 3H), 7.26 (d, J = 7.4 Hz, 1H), 4.12-4.06 (m, 1H), 4.06 (s, 2H), 4.05-3.99 ( m, 1H), 3.87-3.82 (m, 1H), 3.82 (s, 2H), 3.74-3.68 (m, 1H), 3.67-3.61 (m, 1H), 2.59-2.51 (m, 1H), 2.35-2.26 (m, 1H).

[00291] EXAMPLE 18: IACS-005992 2-(1-Methyl-1H-pyrazol-4-yl)-N-(5-(1-(6-(2-(3-) (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00292] The compound was prepared by the procedure of Example 20, 2-(2-fluorophenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy))phenyl 2,2,2-trifluoroacetate )acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 20 to 60%; 20 min; Column: C18) to give the title compound (8 mg, 26%) as a light yellow solid. MS (ES+) C25H24F3N9O3S requires: 587; found: 588 [M+H]+.

[00293] EXAMPLE 20: 2-(2-fluorophenyl)-N-(5-(1-(6-(2-(3-trifluoromethoxy)phenyl)acetamido)pyridazin-3-2,2,2-trifluoroacetate il)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00294] To a solution of N-(6-(3-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)-2-(3- (trifluoromethoxy)phenyl)acetamide (15 mg, 0.032 mmol) in DMF (0.5 ml), 2-(2-fluorophenyl)acetic acid (14.90 mg, 0.097 mmol) and DIEA (0.034 ml, 0.193 mmol) were added. ) at 0°C, then T3P (50% DMF, 0.056 ml, 0.097 mmol), and the mixture was allowed to reach room temperature over 30 min. The reaction was concentrated and purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to give the title compound (10 mg, 43%) as a light yellow solid. MS (ES+) C27H23F4N7O3S requires: 601; found: 602 [M+H] +1H NMR (600 MHz, DMSO-d6) δ: 12.79 (s, 1H), 11.00 (s l, 1H), 8.06 (s l, 1H), 7, 46 (t, J = 7.9 Hz, 1H), 7.40-7.30 (m, 4H), 7.26 (d, J = 8.2 Hz, 1H), 7.24-7.03 (m, 3H), 4.07-4.01 (m, 1H), 3.98-3.91 (m, 1H), 3.89 (s, 2H), 3.80 (s, 2H), 3,793.73 (m, 2H), 3.68-3.52 (m, 1H), 2.35-2.48 (m, 1H), 2.29-2.22 (m, 1H).

[00295] EXAMPLE 21: 2-(pyridin-2-yl)-N-(5-(3-(6- (2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-1- il)-1,3,4-thiadiazol-2-yl)acetamide Steps 1 and 2 Step 1: N-(6-(1-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-3-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl )acetamide

[00296] The compound was prepared by the procedure of Example 22, Step 5. The mixture was taken up in EtOAc and washed with water. The combined organic layers were washed with saturated NaCl, dried with Na2SO4, filtered and concentrated under reduced pressure to give the title compound (used directly for the next step). MS (ES+) C19H18F3N7O2S requires: 465; found: 466 [M+H] +. Step 2:2-(pyridin-2-yl)-N-(5-(3-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)- 1,3,4-thiadiazol-2-yl)acetamide

[00297] To a solution of N-(6-(1-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-3-yl)pyridazin-3-yl)-2-(3- (trifluoromethoxy)phenyl)acetamide (20 mg, 0.043 mmol) in DMF (0.5 ml), 2-(pyridin-2-yl)acetic acid hydrochloride (22.38 mg, 0.129 mmol) and DIEA (0.045) were added. ml, 0.258 mmol) and cooled in an ice bath. To the reaction, T3P (50% solution in DMF, 0.075 ml, 0.129 mmol) was added, and the mixture was allowed to reach RT. Upon completion, volatile products were removed under reduced pressure, and the residue was purified by mass-activated preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 40 to 60%; 20 min; Column: C18) to generate the title compound (2.4 mg, 9%). MS (ES+) C26H23F3N8O3S requires: 584; found: 585 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 12.44 (s l, 1H), 11.37 (s, 1H), 8.60 (d, J = 4.4 Hz, 1H), 8.25 (d , J = 9.2 Hz, 1H), 8,017.94 (m, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H ), 7.50-7.43 (m, 2H), 7.40-7.34 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 4.05 (s, 2H), 3.93-3.80 (m, 2H), 3.86 (s, 2H), 3.72-3.65 (m, 1H), 3.65-3.58, (m, 1H ), 3.58-3.51 (m, 1H), 2.52-2.44 (m, 1H), 2.30-2.22 (m, 1H).

[00298] EXAMPLE 22: N-(pyridin-2-ylmethyl)-5-(3-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)- 1,3,4-thiadiazol-2-carboxamide Steps 1 to 5 Step 1: tert-butyl 3-(6-aminopyridazin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[00299] A suspension of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate of tert- butyl (500 mg, 1.694 mmol), 6-bromopyridazin-3-amine (246 mg, 1.412 mmol) and 2 M sodium carbonate (2.117 ml, 4.23 mmol) were treated with PdCl2(dppf)-DCM adduct (115 mg, 0.141 mmol), stirred and heated to 90 °C for 2.5 h. The volatile products were removed under reduced pressure, and the residue was purified by silica gel chromatography (0 to 10% MeOH in DCM) to give the title compound (263 mg, 71%). MS (ES+) C13H18N4O2 requires: 262; found: 263 [M+H]+.Step 2: tert-butyl 3-(6-aminopyridazin-3-yl)pyrrolidine-1-carboxylate

[00300] A reaction vessel was charged with tert-butyl 3-(6-aminopyridazin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (263 mg, 1.003 mmol), acid acetic acid (0.115 ml, 2.005 mmol) and ethanol (3.0 ml) under a nitrogen atmosphere. The suspension was degassed with nitrogen and purged with hydrogen (3x). The reaction mixture was subjected to hydrogen at 0.28 MPa (40 psi) for 48 h in a Parr shaker. The reaction mixture was purged with nitrogen and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% MeOH in DCM) to give the title compound (140 mg, 52%) as an off-white amorphous material. MS (ES+) C13H20N4O2 requires: 264; found: 265 [M+H]+.Step 3:3-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidine-tert-butyl 1-carboxylate

[00301] To a solution of tert-butyl 3-(6-aminopyridazin-3-yl)pyrrolidine-1-carboxylate (70 mg, 0.265 mmol) in DMF (1 ml), 2-(3-( trifluoromethoxy)phenyl)acetic acid (117 mg, 0.530 mmol), HATU (151 mg, 0.397 mmol) and DIEA (0.185 ml, 1.059 mmol), and the resulting mixture was stirred at RT overnight. Volatile products were removed under reduced pressure. The residue was taken up in EtOAc and washed with water. The aqueous phase was extracted, and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% MeOH in DCM) to give the title compound as an orange solid which was used as such in the next step. MS (ES+) C22H25F3N4O4 requires: 466; found: 467 [M+H]+.Step 4: N-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

[00302] A solution of tert-butyl 3-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate in DCM (0.8 ml) was treated with TFA (0.2 ml) and stirred for 1 h. Volatile products were removed under reduced pressure. The residue was dissolved in MeOH and neutralized using an MP-HCO3 cartridge. The eluent was concentrated under reduced pressure to give the title compound (100 mg, 100%). MS (ES+) C17H17F3N4O2 requires: 366; found: 367 [M+H]+.Step 5:N- (pyridin-2-ylmethyl) -5- (3- (6- (2- (3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl) pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide

[00303] A microwave flask was charged with N-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (15 mg, 0.041 mmol), 5-Bromo-N-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide (12.25 mg, 0.041 mmol) (synthesized by a similar procedure to 5-Bromo-N-(3- (trifluoromethoxy)benzyl)-1,3,4-thiadiazol-2-carboxamide), CsF (6.22 mg, 0.041 mmol) and DMSO (0.25 ml). The vial was sealed, and the reaction mixture was heated in the microwave at 120 °C for 20 min. The mixture was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to generate the title compound (2.6 mg, 10%) as a light yellow amorphous material. MS (ES+) C26H23F3N8O3S requires: 584; found: 585 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.43 (t, J = 6.0 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H ), 8.26 (d, J = 9.3 Hz, 1H), 8.09 (t, J = 7.6 Hz, 1H), 7.73 (d,J = 9.2 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 6.1 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7, 40-7.35 (m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 4.65 (d, J = 6.1 Hz, 2H), 4.03-3.97 (m, 1H), 3.97-3.90 (m, 1H), 3.87 (s, 2H), 3.82-3.77 (m, 1H), 3.73-3.67 (m , 1H), 3.67-3.61 (m, 1H), 2.55-2.50 (m, 1H), 2.35-2.27 (m, 1H).

[00304] EXAMPLE 23: 2-(2-fluorophenyl)-N-(5-(1-(6- (2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)piperidin-3-yl) -1,3,4-thiadiazol-2-yl)acetamide

[00305] The title compound was synthesized by a procedure similar to Example 14. MS (ES+) C28H25F4N7O3S requires: 615; found: 616 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 12.75 (s l, 1H), 10.97 (s, 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.44- 7.50 (m, 1H), 7.31-7.43 (m, 5H), 7.25 (d, J = 7.9 Hz, 1H), 7.157.21 (m, 2H), 4.43 (d, J = 11.0 Hz, 1H), 4.03 (d, J = 12.8 Hz, 1H), 3.89 (s, 2H), 3.79 (s, 2H), 3.36 -3.45 (m, 1H), 3.12-3.21 (m, 1H), 2.53-2.60 (m, 1H), 2.10-2.21 (m, 1H), 1 .73-1.90 (m,2H), 1.57-1.69 (m, 1H).

[00306] EXAMPLE 24: 2-(1-Methyl-1H-pyrazol-4-yl)- N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin- 3- il)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00307] The title compound was synthesized by a procedure similar to Example 14. MS (ES+) C26H26F3N9O3S requires: 601; found: 602 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 12.59 (s l, 1H), 10.97 (s, 1H), 8.00 (d, J = 9.8 Hz, 1H), 7.59 ( s, 1H), 7.44-7.49 (m, 1H), 7.41 (d, J = 9.8 Hz, 1H), 7.34-7.38 (m, 2H), 7.32 (s, 1H), 7.25 (d l, 1H), 4.42 (d, J = 10.6 Hz, 1H), 4.03 (d l, 1H), 3.75-3.83 (m, 6H), 3.61 (s, 2H), 3.303.35 (m, 1H), 3.12-3.21 (m, 1H), 2.11-2.20 (m, 1H), 1.74 -1.90 (m, 2H), 1.57-1.68 (m, 1H).

[00308] EXAMPLE 25: N-(5-(3-(5-acetamido-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-1,3,4-thiadiazol-2-yl) -2-(3-(trifluoromethoxy)phenyl)acetamide

[00309] The title compound was synthesized by a procedure similar to Example 26, step 4 (3.6 mg, 23%). MS (ES+) C20H20F3N7O3S2 requires: 527; found: 528 [M+H]+.

[00310] EXAMPLE 26: 2-(pyridin-2-yl)-N-(5-(1-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2 - il)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide Steps 1 to 4 Step 1:1 - (5-amino-1,3,4-thiadiazol-2-yl)piperidine-3-carbonitrile

[00311] To a microwave flask containing 5-bromo-1,3,4-thiadiazol-2-amine (200 mg, 1.111 mmol), piperidine-3-carbonitrile (245 mg, 2.222 mmol) and K2CO3 (307 mg, 2.222 mmol), DMF (1 ml) was added. The flask was heated in a microwave reactor at 120 °C for 30 min. The reaction mixture was concentrated, diluted with DCM and washed with saturated sodium bicarbonate. The aqueous layer was extracted with DCM (2x). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated to give the crude product as a dark green semisolid. The aqueous layer containing the product was diluted with MeOH, and the resulting precipitate was removed by filtration. The filtrate was concentrated and triturated with DCM to generate additional crude product. The two batches of raw product were combined to generate a light brown semisolid. The residue was purified by silica gel chromatography in (0 to 50% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the title compound as a light gray semisolid. MS (ES+) C8H11N5S requires: 209; found: 210 [M+H]+.Step 2:N-(5-(3-cyanopiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl )acetamide

[00312] To a solution of 2-(3-(trifluoromethoxy)phenyl)acetic acid (245 mg, 1.112 mmol) in acetonitrile (2 ml), CDI (180 mg, 1.112 mmol) was added, and the reaction stirred at temperature environment for 1 h. To the reaction, 1-(5-amino-1,3,4-thiadiazol-2-yl)piperidine-3-carbonitrile (194 mg, 0.927 mmol) was added, and the reaction was stirred and heated to 60 °C for 1 h and then 40 °C for 20 h. The reaction mixture was concentrated, diluted with DCM and washed with saturated sodium bicarbonate. The aqueous layer was extracted with DCM (2x). The organic layers were combined, washed with brine, dried with sodium sulfate and concentrated to give the crude product as a yellow semisolid. The residue was purified by silica gel chromatography (0 to 25% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the desired product. Isolated impure fractions were repurified by the same procedure and combined with the first isolation to generate the title compound (74 mg, 19%) as a white solid. MS (ES+) C17H16F3N5O2S requires: 411; found: 412 [M+H]+.Step 3: Example 16: N-(5-(3-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-1, 3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide cyanopiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy) phenyl)acetamide

[00313] To a vial containing N-(5-(3-cyanopiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (49.1 mg, 0.119 mmol), TFA (211 μl, 2.75 mmol) and hydrazinecarbothioamide (15.23 mg, 0.167 mmol) were added, and the reaction was stirred at 80 °C for 1 h and then allowed to cool to RT. one day to the next. The reaction was then heated to 80 °C for 21 h. The reaction mixture was concentrated and purified by silica gel chromatography (0 to 50% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the title compound (39 mg, 68% ). MS (ES+) C18H18F3N7O2S2 requires: 485; found: 486 [M+H]+.Step 4:2- (pyridin-2-yl) -N- (5- (1- (5- (2- (3- (trifluoromethoxy)phenyl)acetamido)-1, 3,4-thiadiazol-2-yl)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00314] To a stirred solution of N-(5-(3-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-1,3,4-thiadiazol-2- yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (19.4 mg, 0.040 mmol) in DMF (0.200 ml) cooled in an ice bath, 2-(pyridin-2-yl) acid hydrochloride was added acetic acid (24.97 mg, 0.144 mmol), followed by T3P (50% solution in DMF, 0.105 ml, 0.180 mmol) added drip, and then TEA (0.050 ml, 0.360 mmol) added drip, and the reaction was warmed to room temperature and stirred for 15 h. The reaction mixture was concentrated, diluted with DCM, washed with sodium bicarbonate (2x), brine and concentrated to reveal a bright yellow solid. The crude product was adsorbed on silica gel and purified by silica gel chromatography (0 to 50% of an 80/20/1 DCM/MeOH/NH4OH solution in DCM) to give the title compound (12 mg , 51%) as a light yellow solid. MS (ES+) C25H23F3N8O3S2 requires: 604; found: 605 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 12.74 (s l, 1H), 12.34 (s l, 1H), 8.49 (d, J = 4.53 Hz, 1 H), 7.77 (t, J = 7.55 Hz, 1 H); 7.43-7.49 (m, 1 H); 7.39 (d, J = 7.93 Hz, 1 H); 7,317.35 (m, 2H); 7.24-7.30 (m, 2H); 4.02-4.06 (m, 1 H); 4.01 (s, 2H); 3.82 (s, 2H); 3.57-3.67 (m, 1H); 3.2-3.5 (m, 3 H), 2.06-2.17 (m, 1 H), 1.64-1.87 (m, 3 H).

[00315] EXAMPLE 27: N-(6-(1-(5-acetamido-1,3,4-thiadiazol-2-yl)pyrrolidin-3-yl)pyridazin-3-yl)-2-(3- ( trifluoromethoxy)phenyl)acetamide

[00316] A solution of N-(6-(1-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidin-3-yl)pyridazin-3-yl)-2-(3- ( trifluoromethoxy)phenyl)acetamide (20 mg, 0.043 mmol) in pyridine (0.5 ml) was cooled in an ice bath, and acetic anhydride (4.46 μl, 0.047 mmol) was added dropwise. The resulting mixture was stirred and warmed to room temperature over 1 h. Volatile products were removed under reduced pressure, and the residue was purified by mass-activated preparative HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to give the title compound (2.6 mg, 12%) as a light yellow foamy solid. MS (ES+) C21H20F3N7O3S requires: 507; found: 508 [M+H]+. 1H NMR (600 MHz, TFA+DMSO-d6) δ 12.81 (s l, 1H), 11.46 (s, 1H), 8.32 (d, J = 9.3 Hz, 1H), 7.77 (d, J = 9.3 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.41-7.35 (s, 2H), 7.25 (d, J = 8.2 Hz, 1H), 4.12-4.06 (m, 1H), 4.04-3.93 (m, 2H), 3.89 (s, 2H), 3.81-3.72 (m, 2H), 2.63-2.57 (m, 1H), 2.38-2.30 (m, 1H), 2.21 (s, 3H).

[00317] EXAMPLE 28: [This example is intentionally left blank]

[00318] EXAMPLE 29: N-(6-(3-(5-acetamido-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)-2-(3- ( trifluoromethoxy)phenyl)acetamide

[00319] The compound was prepared by the same procedure as Example 27. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN ; Gradient: B = 30 to 70%; 20 min; Column: C18) to generate the title compound (5.5 mg, 10.84 μmol, 16.8% yield) as a light yellow solid. MS (ES+) C21H20F3N7O3S requires: 507; found: 508 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 12.49 (s, 1H), 11.13 (s l, 1H), 8.20 (d l, J = 9.7 Hz, 1H), 7.53-7 .41 (m, 2H), 7.39-7.33 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 4.11-4.00 (m, 2H), 3.85-3.79 (m, 1H), 3.82 (s, 2H), 3.74-3.68 (m, 1H), 3.67-3.60 (m, 1H), 2, 59-2.52 (m, 1H), 2.34-2.25 (m, 1H), 2.17 (s, 3H).

[00320] EXAMPLE 30: 2-(2-phenylthiazol-4-yl)-N-(5- (1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin- 3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00321] The compound was prepared by the same procedure as Example 21, Step 2. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to generate the title compound (6.8 mg, 24%). MS (ES+) C30H25F3N8O3S2 requires: 666; found: 667 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.98 (s l, 1H), 8.06 (s l, 1H), 7.90 (d, J = 7.8 Hz , 2H), 7.57 (s, 1H), 7.52-7.44 (m, 4H), 7.38-7.33 (m, 2H), 7.25 (d, J = 8.7 Hz, 1H), 7.16 (s l, 1H), 4.08-4.03 (m, 1H), 4.05 (s, 2H), 3,993.92 (m, 1H), 3.79 (s , 2H), 3.78-3.73 (m, 1H), 3.68-3.62 (m, 1H), 3.61-3.55 (m, 1H), 2.57-2.47 (m, 1H), 2.31-2.24 (m, 1H).

[00322] EXAMPLE 31: 2-(thiazol-4-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3- il)-1,3,4-thiadiazol-2-yl)acetamide

[00323] The compound was prepared by the same procedure as Example 21, Step 2. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 40 to 60%; 20 min; Column: C18) to generate the title compound (3.9 mg, 15%) MS (ES+) C24H21F3N8O3S2 requires: 590; found: 591 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 12.80 (s l, 1H), 11.22 (s, 1H), 9.04 (d, J = 1.9 Hz, 1H), 8.28 (d , J = 9.9 Hz, 1H), 7.63 (d l, J = 9.2 Hz, 1H), 7.58-7.56 (m, 1H), 7.47 (t, J = 7, 9 Hz,1H), 7.38-7.34 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 4.14-4.03 (m, 2H), 4, 03 (s, 2H), 3.91-3.85 (m, 1H), 3.84 (s, 2H), 3.77-3.71 (m, 1H), 3.71-3.64 ( m, 1H), 2.61-2.53 (m, 1H), 2.35-2.27 (m, 1H).

[00324] EXAMPLE 32: IACS-006086 2-(pyridin-2-yl)- N-(5-(1-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4- thiadiazol-2-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00325] The title compound was synthesized by a procedure similar to Example 26. MS (ES+) C24H21F3N8O3S2 requires: 590; found: 591 [M+H]+.

[00326] EXAMPLE 33: 2-(2,4-difluorophenyl)-N-(5- (1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3- il)-1,3,4-thiadiazol-2-yl)acetamide

[00327] The compound was synthesized by a procedure similar to Example 20. 2-(2-fluorophenyl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy) )phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to generate the title compound (2 mg, 6%). MS (ES+) C27H22F5N7O3S requires: 619; found: 620 [M+H]+

[00328] EXAMPLE 34: 2-(tetrahydro-2H-pyran-2-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3- il)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00329] The compound was synthesized by a procedure similar to Example 20. 2-(2-fluorophenyl)-N-(5-(1-(6-(2-(3-trifluoromethoxy) )phenyl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to give the title compound (7 mg, 16%) as a white solid. MS (ES+) C26H28F3N7O4S requires: 591; found: 592 [M+H] + . 1H NMR (600 MHz, dg-DMSO) δ: 12.46 (s, 1H), 11.00 (s l, 1H), 8.07 (s l, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.38-7.30 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.25-7.08 (m, 1H), 4.07 -4.01 (m, 1H), 3.98-3.91 (m, 1H), 3.80 (s, 2H), 3.82-3.74 (m, 1H), 3.73-3 .65 (m, 2H), 3.62-3.54 (m, 1H), 3,343.25 (m, 2H), 2.62-2.49 (m, 3H), 2.32-2.23 (m, 1H), 1.79-1.72 (m, 1H), 1.62-1.57 (m, 1H), 1.51-1.35 (m, 3H), 1.27-1 .17 (m, 1H).

[00330] EXAMPLE 36: 2-(benzo[d]isoxazol-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl) pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide

[00331] The compound was synthesized by a procedure similar to Example 20. MS (ES+) C28H23F3N8O4S requires: 624; found: 625 [M+H]+.

[00332] EXAMPLE 37: N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl )pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide Steps 1 to 3 Step 1: tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate

[00333] To a solution of tert-butyl 3-(6-aminopyridazin-3-yl)pyrrolidine-1-carboxylate (180 mg, 0.681 mmol), 2-(pyridin-2-yl)acetic acid hydrochloride (236 mg, 1.362 mmol) and DIEA (0.476 ml, 2.72 mmol) in DMF (2 ml), cooled in an ice bath, T3P (50% solution in DMF, 0.867 ml, 1.362 mmol) was added, and the reaction it was stirred for 15 min, allowed to reach RT and stirred for 2 h. The mixture was taken up in DCM/MeOH (10%) and washed with water. The aqueous phase was extracted twice with DCM/MeOH (10%). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography (0 to 10% MeOH in DCM) to give the title compound (244 mg, 93%). MS (ES+) C20H25N5O3 requires: 383; found: 384 [M+H]+.Step 2 :2- (pyridin-2-yl) -N- (6- (pyrrolidin-3-yl)pyridazin-3-yl)acetamide

[00334] To a solution of tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin 3-yl)pyrrolidine-1-carboxylate (244 mg, 0.636 mmol) in DCM (1. 5 ml), TFA (0.75 ml) was added, and the resulting mixture was stirred at RT for 1 h. Volatile products were removed under reduced pressure. Water was added to the residue, and the aqueous layer was extracted 3 times with EtOAc/MeOH (10%). The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to give the title compound which was used as is. MS (ES+) C15H17N5O requires: 283; found: 284 [M+H]+.Step 3: N-((1-methyl-1H-pyrazol-3-yl)methyl)-5-(3- (6 -(2 -(pyridin-2-yl) acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide

[00335] The compound was prepared by the procedure of Example 22, Step 5. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% and TFA/ MeCN; Gradient: B = 10 to 40%; 20 min; Column: C18) to generate the title compound (13.4 mg, 37%) as a light yellow amorphous material. MS (ES+) C23H24N10O2S requires: 504; found: 505 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.06 (t, J = 6.1 Hz, 1H), 8.74 (d, J = 5.1 Hz, 1H ), 8.29-8.16 (m, 2H), 7.80-7.73 (m, 2H), 7.69-7.64 (m, 1H), 7.587.55 (m, 1H), 6.12 (d, J = 1.8 Hz, 1H), 4.36 (d, J = 6.1 Hz, 2H), 4.22 (s, 2H), 4.02-3.89 (m , 2H), 3.81-3.78 (m, 1H), 3.77 (s, 3H), 3.73-3.58 (m, 2H), 2.55-2.48 (m, 1H ), 2.34-2.27 (m, 1H).

[00336] EXAMPLE 38: 5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-((4-(trifluoromethyl)pyridin- 2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00337] The compound was prepared by the procedure of Example 37, step 3. N-((1-methyl-1H-pyrazol-3-yl)methyl)-5- (3-(6-(2-(pyridin-2 -yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide was prepared from 5-bromo-N-((4-(trifluoromethyl)pyridin-2 -yl)methyl)-1,3,4-thiadiazol-2-carboxamide (synthesized by a similar procedure to 5-Bromo-N-(3-(trifluoromethoxy)benzyl)-1,3,4-thiadiazol-2-carboxamide ). The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 to 30%; 20 min; Column: C18) to give the title compound (9.5 mg, 24%) as a white powder. MS (ES+) C25H22F3N9O2S requires: 569; found: 570 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.42 (t, J = 6.0 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H ), 8.66 (d l, J = 4.2 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.06 (s l, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.69-7.61 (m, 3H), 7.54 (s l, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.14 (s, 2H), 4.03-3.90 (m, 2H), 3.83-3.77 (m, 1H), 3.74-3.59 (m, 2H), 2.57-2 .47 (m, 1H), 2.35-2.27 (m, 1H).

[00338] EXAMPLE 39: 5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide

[00339] The compound was prepared by a procedure similar to Example 37, step 3, from 5-bromo-1,3,4-thiadiazol-2-carboxamide (synthesized by a procedure similar to 5-Bromo-N-( 3-(trifluoromethoxy)benzyl)-1,3,4-thiadiazol-2-carboxamide). MS (ES+) C18H18F3N8O2S requires: 410; found: 411 [M+H]+.

[00340] EXAMPLE 40: N-methyl-5-(3-(6-(2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetamido)pyridazin-3-yl)pyrrolidin -1-yl)-1,3,4-thiadiazol-2-carboxamide Steps 1 to 5 Step 1:2- (1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)methyl acetate

[00341] To a solution of 1-bromo-3-(trifluoromethoxy)benzene (2.6 g, 10.8 mmol), methyl 2-(1H-imidazol-4-yl)acetate (1.5 g, 10 .8 mmol), CuI (205 mg, 1.08 mmol), picolinic acid (133 mg, 1.08 mmol), Cs2CO3 (10.5 g, 32.4 mmol) in DMSO (50 ml) were added, washed with argon, stirred at 120 °C overnight. The reaction was diluted with water (100 ml), and the solution was washed with EtOAc. The organic phase was separated, and the aqueous layer was extracted with EtOAc (100 ml x 3). The organic layers were combined, washed with brine (100 ml), concentrated and purified by silica gel column chromatography (30% to 70% EtOAc in Hexanes) to give the title compound as a light brown solid (980 mg, 25%). MS (ES+) C13H11F3N2O3 requires: 300; found: 301 [M+H]+.Step 2: 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetic acid (MDA3462)

[00342] A mixture of methyl 2-(1-(3-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)acetate (980 mg, 3.27 mmol) in HCl (4N, 10 ml) was stirred at 75°C overnight and monitored by LCMS. The mixture was concentrated to give the title compound as a light yellow solid (900 mg, 90%). MS (ES+) C12H9F3N2O3 requires: 286; found: 287 [M+H]+.Steps 3 and 4: N-(6-(pyrrolidin-3-yl)pyridazin-3-yl)- 2-(1-(3-(trifluoromethoxy)phenyl)-1H- imidazol-4-yl)acetamide

[00343] The compound was synthesized by a procedure similar to Example 37, step 1. Step 5j N-methyl-5- (3- (6- (2- (1- (3-(trifluoromethoxy)phenyl)-1H-imidazole -4-yl)acetamido)pyridazin- 3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide

[00344] The compound was prepared by a procedure similar to Example 8, Step 5, from 5-bromo-N-methyl-1,3,4-thiadiazol-2-carboxamide (synthesized by a procedure similar to 5-Bromo -N-(3-(trifluoromethoxy)benzyl)-1,3,4-thiadiazol-2-carboxamide). The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 10 to 40%; 20 min; Column: C18) to give the title compound (2.5 mg, 12%) as an orange solid. MS (ES+) C24H22F3N9O3S requires: 573; found: 574 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.98 (l-s, 1H), 8.75-8.69 (m, 1H), 8.28 (d, J = 9.1 Hz, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.01-3.89 (m, 4H), 3.78 (t, J = 8.2 Hz, 1H), 3.72-3.60 (m, 2H), 2.76 (d, J = 4.7 Hz, 3H), 2, 54-2.47 (m, 1H), 2.34-2.26 (m, 1H).

[00345] EXAMPLE 41: N-methyl-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazole -2-carboxamide

[00346] The compound was prepared by a procedure similar to Example 37, step 3. MS (ES+) C19H20F3N8O2S requires: 424; found: 425[M+H]+.

[00347] EXAMPLE 42: 2-(pyridin-2-yl)-N-(6-(3-(5-(2-(3-(trifluoromethoxy)phenyl)acetamido)-1,3,4-thiadiazol-2 - il)pyrrolidin-1-yl)pyridazin-3-yl)acetamide

[00348] The compound was prepared using the procedure of Example 17 to generate the title compound. MS (ES+) C26H23F3N8O3S requires: 584; found: 585 [M+H]+.

[00349] EXAMPLE 43: 5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-(3-(trifluoromethoxy)benzyl)- 1,3,4-thiadiazol-2-carboxamide Step 1

[00350] The compound was prepared by a procedure similar to Example 22, Step 5. The mixture was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 20 min; Column: C18) to give the title compound (1.6 mg, 3%) as a white solid. MS (ES+) C26H23F3N8O3S requires: 584; found: 585 [M+H]+.

[00351] EXAMPLE 44: (R)-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-((4- ( trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide Steps 1 to 10 Step 1:4-(tert-butyltrifluoromethylsulfonyloxy)-2,3-dihydropyrrole-1-carboxylate

[00352] To a stirred solution of sodium bis(trimethylsilyl) amide (2M in THF, 27.5 ml, 55 mmol) in THF (200 ml), a solution of tert 3-oxopyrrolidine-1-carboxylate was added dropwise. -butyl (9.25 g, 50 mmol) in THF (100 ml) at -78 °C. After stirring for 15 min, trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (17.8 g, 50 mmol) in THF (100 ml) was added, and the reaction mixture was stirred for 3 h at -78 °C and then at RT for 1 h. The reaction mixture was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The crude product was purified by silica gel chromatography (20 to 25% EtOAc in petroleum ether) to give the title compound (14.5 g, 92%) as a yellow oil. MS (ES+) C10H14F3NO5S requires: 317; found: 262 [M-56+H]+.Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H tert-butyl-pyrrole-1-carboxylate

[00353] A mixture of tert-butyl 4-(trifluoromethylsulfonyloxy)-2,3-dihydropyrrole-1-carboxylate (14.5 g, 45.7 mmol), 4,4,4',4',5 ,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.8 g, 50.3 mmol), KOAc (13.4 g, 137 mmol) and Pd (dppf)Cl2 (1.67 g, 2.3 mmol) in dioxane (200 ml) was heated at 80 °C for 16 h under Ar. The reaction mixture was cooled to RT, and the mixture was purified by silica gel chromatography (20 to 25% EtOAc in Petroleum Ether) to give the title compound as a yellow oil (12.5 g, 93%). MS (ES+) C15H26BNO4 requires: 295;found: 240 [M-56+H]+. Step 3: Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate

[00354] To an aqueous hydrobromic acid solution (48%, 17 ml) at 5 °C was added ethyl 5-amino-1,3,4-thiadiazol-2-carboxylate (5.71 g, 33 mmol) followed by per bromine (12.8 ml, 0.24 mol) at a rate such that the reaction mixture is maintained at a temperature < 11 °C. A solution of sodium nitrite (6.0 g, 85 mmol) in water (8.5 ml) was added at a rate such that the reaction mixture was maintained at ~5 T. The reaction mixture was maintained at 0 T for 2 h. Water was added, and it was extracted with EtOAc. The organic layer was washed with saturated Na2S2O3 and brine, dried and concentrated. The crude product was purified by silica gel chromatography (20 to 25% EtOAc in Petroleum Ether) to provide the title compound (3.2 g, 41%) as a white solid. MS (ES+) C5H5BrN2O2S requires: 236; found: 237 [M+H]+.Step 4: 5-bromo-N-((4-(trifluoromethyl)pyridin-2 - yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00355] A mixture of ethyl 5-bromo-1,3,4-thiadiazol-2-carboxylate (2.0 g, 8.4 mmol), (4-(trifluoromethyl)pyridin-2-yl dihydrochloride salt )methanamine (2.1 g, 8.4 mmol) and Et3N (2.13 g, 21.1 mmol) in MeOH (30 ml) was stirred at RT overnight. The mixture was purified by silica gel chromatography (20 to 35% EtOAc in Petroleum Ether) to provide the title compound as a beige solid (2.0 g, 65%). MS (ES+) C10H6BrF3N4OS requires: 366; found: 367 [M+H]+.Step 5: N-(6-bromopyridazin-3-yl)-2-(pyridin-2-yl)acetamide

[00356] A mixture of 2-(pyridin-2-yl)acetic acid hydrochloride salt (28 g, 160 mmol), 6-bromopyridazin-3-amine (23.3 g, 134 mmol), T3P (102 g , 161 mmol, 50 wt% in DMF) and DIPEA (26 g, 200 mmol) in DMF (400 ml) was stirred at RT overnight. The reaction was added slowly to a mixture of saturated NaHCO3 (300 ml) and ice (300 ml). The precipitated solid was collected by filtration to give the title compound (29 g, 74%) as a brown solid. MS (ES+) C11H9BrN4O requires: 292; found: 293 [M+H]+.Step 6: 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)-2H-pyrrole-1(5H)-tert-carboxylate butyl

[00357] A mixture of N-(6-bromopyridazin-3-yl)- 2-(pyridin-2-yl)acetamide (25.6 g, 87.4 mmol), 4-(4,4,5,5 - tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrrole-1-carboxylate (38.6 g, 131 mmol), Na2CO3 (37 g, 350 mmol) and Pd(dppf)Cl2 (6.0 g, 8.2 mmol) in 1,4-dioxane (500 ml) and H2O (25 ml) was heated to 110 °C overnight under Ar. The reaction was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel chromatography (2 to 5% MeOH in DCM) to give the title compound as a beige solid (17.2 g, 52%). MS (ES+) C20H23N5O3 requires: 381; found: 382 [M+H]+.Step 7: tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin- 3-yl)pyrrolidine-1-carboxylate

[00358] A mixture of tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)-2H-pyrrole-1(5H)-carboxylate (7.0 g, 18 mmol) and Pd/C (3 g) in MeOH (1400 ml) was stirred at RT overnight under H2. The mixture was filtered, and the filtrate was concentrated to provide the title compound as a brown oil (6.5 g, 93%). MS (ES+) C20H25N5O3 requires: 383; found: 384 [M+H]+.Step 8: (S)-tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate and (R)-tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate

[00359] tert-Butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate (1.0 g) was separated by chiral SFC (Thar/Waters SFC-80, column: OJ 4.6 x 250 mm, CO2/MeOH 80:20 with 0.2% NH3, flow rate 80 g/min) to generate the title compounds as off-white solids (1a elution: 270 mg, 27%; 2nd elution: 230 mg, 23%).Step 9: (R)-2-(pyridin-2-yl)-N-(6-(pyrrolidin-3-yl)pyridazin-3 -il)acetamide

[00360] A mixture of tert-butyl 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate (230 mg, 0.60 mmol, 1st product elution from step 8) and TFA (1 ml) in DCM (1 ml) was stirred at RT for 2 h. The reaction mixture was concentrated to provide the title compound as a brown oil (238 mg, 100%, TFA salt) which was used in the next step without purification. MS (ES+) C15H17N5O requires: 283; found: 284 [M+H]+.

[00361] To determine the absolute stereochemistry of the two enantiomers, the Mosher amide protocol was followed according to Hoye, TR and Renner, MK, J. Org. Chem. 1996, 61, 2056 to 2064 and J. Org. Chem. 1996, 61, 8489 to 8495. Step 9a: 2-(pyridin-2-yl)-N-(6-((R)-1-((S)-3,3,3-trifluoro-2-methoxy- 2-phenylpropanoyl)pyrrolidin-3-yl)pyridazin-3-yl)acetamide (S-Mosher amide)

[00362] To a solution of 2-(pyridin-2-yl)-N-(6-(pyrrolidin-3-yl)pyridazin-3-yl)acetamide 2,2,2-trifluoroacetate (25 mg, 0.063 mmol ) and DIEA (38 μl, 0.22 mmol) in CH2Cl2 (629 μl) at RT, (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (29.4 μl, 0.157 mmol), and the resulting mixture was stirred at RT for 1 h. Volatile products were removed under reduced pressure. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 30 to 70%; 12 min; Column: C18) to generate the title compound as a light yellow solid (TFA salt, ~90% purity). The product was repurified by silica gel chromatography (0 to 100% EtOAc (with 10% MeOH) in hexanes) to give the title compound (23 mg, 73%) as a colorless amorphous material. MS (ES+) C25H24F3N5O3 requires: 499; found: 500 [M+H]+. 1H NMR (500 MHz, Chloroform-d, ~1:1 mixture of syn/anti rotamers) δ 11.12 (br s, 0.5H), 11.07 (br s, 0.5H), 8, 67 (dd, J = 5.0, 1.0 Hz, 1H), 8.43 (d, J = 9.2 Hz, 0.5H, anti), 8.20 (d, J = 9.2 Hz , 0.5H, syn), 7.74 — 7.68 (m, 1H), 7.58 — 7.52 (m, 1H), 7.45 - 7.36 (m, 2.5H), 7 .33 - 7.20 (m, 4H), 6.74 (d, J = 9.2 Hz, 0.5H, syn), 4.13 (dd, J = 12.6, 7.9 Hz, 0 .5H, anti), 3.97 (s, 2H), 3.96 - 3.87 (m, 1H), 3.82 (dd, J = 11.9, 6.9 Hz, 0.5H, syn ), 3.73 - 3.60 (m, 4H), 3.57 - 3.51 (m, 0.5H, syn), 3.48 - 3.41 (m, 0.5H, anti), 2 .92 (dd, J = 11.8, 6.3 Hz, 0.5H, syn), 2.64 (dt, J = 11.5, 7.3 Hz, 0.5H, anti), 2.28 - 2.14 (m, 1.5H), 2.08 (dtd, J = 12.5, 7.0, 5.6 Hz, 0.5H, anti).Step 9b: 2-(pyridin-2- yl)-N-(6-((R)-1-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)yl)pyridazin-3-yl)acetamide (R-amide Mosher)

[00363] Using the procedure for the S-Mosher amide above, starting with (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (39.7 mg, 0.157 mmol), the title compound was obtained as colorless amorphous material (8.0 mg, 26%). MS (ES+) C25H24F3N5O3 requires: 499; found: 500 [M+H]+. 1H NMR (500 MHz, Chloroform-d, ~1:1 mixture of syn/anti rotamers) δ 11.12 (br s, 0.5H, syn), 11.08 (br s, 0.5H, anti ), 8.70 - 8.64 (m, 1H), 8.40 (d, J = 9.2 Hz, 0.5H, anti), 8.37 (d, J = 9.2 Hz, 0, 5H, syn), 7.74 - 7.68 (m, 1H), 7.57 - 7.51 (m, 2H), 7.40 - 7.35 (m, 3H), 7.31 - 7, 24 (m, 1.5H), 7.17 (d, J = 9.2 Hz, 0.5H, syn), 4.12 (dd, J = 12.5, 8.0 Hz, 0.5H, anti), 3.96 (s, 1H, anti), 3.94 (s, 1H, syn), 3.93 - 3.89 (m, 0.5H, syn), 3.86 (dd, J = 12.5, 8.9 Hz, 0.5H, anti), 3.76 - 3.69 (m, 1.5H), 3.65 - 3.60 (m, 1.5H), 3.59 - 3.52 (m, 0.5H, anti), 3.39 (ddd, J = 11.6, 9.6, 6.6 Hz, 0.5H, anti), 3.29 (dd, J = 11 .6, 7.3 Hz, 0.5H, syn), 3.20 (tt, J = 9.5, 6.9 Hz, 0.5H, syn), 3.02 (ddd, J = 11.4 , 7.8, 3.3 Hz, 0.5H, anti), 2.30 - 2.09 (m, 1.5H), 2.01 - 1.90 (m, 0.5H, anti).

[00364] Proton assignments for H1-H8 were made using DEPT, COZY, NOESY and HSQC spectra in combination with expected chemical shift predictions (ChemDraw Professional, v15.0). The syn/anti rotamers were grouped using these data, and the presumption that the Mosher amide phenyl ring would displace protons adjacent to the upper field, specifically for the (S)-Mosher amide: syn = H2(down) shielded and anti = H5(up) shielded; for the (R)-Mosher amide: syn = H2(up) shielded and anti = H5(down) shielded.

[00365] Using Mosher's amide protocol, the calculated δ(SR) values were higher in the syn rotamers in H2, H3 and H7/8, whereas, with the anti rotamers, only H5 was significantly affected. These values are in accordance with the stereochemistry in H3 being (R) as drawn.Step 10 :(R) -5- (3- (6- (2- (pyridin-2-yl)acetamido)pyridazin-3-yl) pyrrolidin-1-yl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00366] A mixture of (R)-2-(pyridin-2-yl)-N-(6-(pyrrolidin-3-yl)pyridazin-3-yl)acetamide 2,2,2-trifluoroacetate (240 mg , 0.60 mmol), 5-bromo-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide (184 mg, 0.500 mmol) and K2CO3 ( 276 mg, 2.00 mmol) in DMF (3 ml) was stirred at 40°C overnight. The reaction mixture was diluted with EtOAc and washed successively with water and brine. The organic layer was dried and concentrated. The crude product was washed with EtOAc to provide the title compound as a beige solid (230 mg, 81%). MS (ES+) C25H22F3N9O2S requires: 569; found: 570 [M+H]+. 1H NMR (500 MHz, DMSO) δ 11.37 (s, 1H), 9.44 (t, J = 6.0 Hz, 1H), 8.82 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 4.4 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 7.78-7.67 (m, 4H), 7.41 (d , J = 7.8 Hz, 1H), 7.29 (dd, J = 6.9, 5.4 Hz, 1H), 4.67 (d, J = 6.0 Hz, 2H), 4.08 - 3.87 (m, 4H), 3.85 - 3.77 (m, 1H), 3.75 - 3.60 (m, 2H), 2.60 - 2.52 (m, 1H), 2 .39 - 2.25 (m, 1H). Analysis by chiral HPLC (EtOH/Hexanes 50:50 with 0.1% diethylamine, column: ChiralPak IA, 4.6x250 mm, 5 uM, 1.0 ml/min, temperature: 40 °C): >99% of ee, Rt = 18.2 min.

[00367] EXAMPLE 45: (S)-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-(pyridin-2- ylmethyl)-1,3,4-thiadiazol-2-carboxamide

[00368] Using the procedure of Example 44, steps 9 and 10, starting from 3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate of (S)-tert-butyl (230 mg, 0.60 mmol, 2nd elution from Example 44, step 8), the title compound was obtained as a beige solid (250 mg, 73%). MS (ES+) C25H22F3N9O2S requires: 569; found: 570 [M+H]+. Analysis by chiral HPLC (EtOH/Hexanes 50:50 with 0.1% diethylamine, column: ChiralPak IA, 4.6x250 mm, 5 uM, 1.0 ml/min, temperature: 40 °C): >99% of ee, Rt = 14.3 min.

[00369] EXAMPLE 46: (R)-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-(pyridin-2- ylmethyl)-1,3,4-thiadiazol-2-carboxamide Step 1:5-bromo-N-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide

[00370] To a solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (150 mg, 0.633 mmol) and pyridin-2-ylmethanamine hydrochloride (91 mg, 0.63 mmol) in MeOH (2.5 ml), iPr2NEt (276 μl, 1.58 mmol) was added, and the resulting mixture was stirred at RT for 2 h. The mixture was concentrated. The residue was purified by silica gel chromatography (0 to 100% EtOAc (with 10% MeOH) in hexanes) to give the title compound (169 mg, 89%) as a white solid. MS (ES+) C9H7BrN4OS requires: 298; found: 299 [M+H]+.Step 2 :(R) -5- (3- (6- (2- (pyridin-2- yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)- N-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide

[00371] To a suspension of (R)-2-(pyridin-2-yl)-N-(6-(pyrrolidin-3-yl)pyridazin-3-yl)acetamide dihydrochloride (50 mg, 0.14 mmol ) in DMF (638 μl), 5-bromo-N-(pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide (38 mg, 0.13 mmol) and potassium carbonate (70 mg, 0.51 mmol), and the resulting mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with EtOAc (3 ml) and washed with water (3 ml) and brine (3 ml) before drying with MgSO4. Volatile products were removed under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% MeOH in DCM with 0.5% NH4OH) to give the title compound (25 mg, 39%) as a yellow solid. MS (ES+) C24H23N9O2S requires: 501; found: 502 [M+H]+. 1H NMR (600 MHz, DMSO-d 6) δ 11.36 (s, 1H), 9.31 (t, J = 6.1 Hz, 1H), 8.56 - 8.47 (m, 2H), 8.28 (d, J = 9.2 Hz, 1H), 7.79 - 7.71 (m, 3H), 7.41 (d, J = 7.8 Hz, 1H), 7.32 (d , J = 7.8 Hz, 1H), 7.30 - 7.25 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.04 - 3.98 (m, 3H), 3.98 - 3.90 (m, 1H), 3.80 (dd, J = 9.8, 7.7 Hz, 1H), 3.75 - 3.68 (m, 1H), 3 .68 - 3.60 (m, 1H), 2.57 - 2.51 (m, 1H), 2.36 - 2.26 (m, 1H).

[00372] EXAMPLE 47: (R)-N-((4-cyclopropylpyridin-2-yl)methyl)-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl )pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide Step 1: (4-cyclopropylpyridin-2-yl)methanamine

[00373] A degassed solution of (4-bromopyridin-2-yl)methanamine (200 mg, 1.07 mmol), cyclopropylzinc(II) bromide (10.7 ml, 5.35 mmol, 0.5 M in THF ) and PdCl2(dppf)-CH2Cl2 adduct (44 mg, 0.054 mmol) was stirred at 65 °C for 3 h. Volatile products were removed under reduced pressure. The residue was purified by mass-activated preparatory HPLC (Mobile phase: A = 0.1% TFA/H2O, B = 0.1% TFA/MeCN; Gradient: B = 0 to 30%; 20 min; Column: C18) to give the title compound (99 mg, 35%, TFA salt) as an off-white solid. MS (ES+) C9H12N2 requires: 148; found: 149 [M+H]+.Step 2: 5-bromo-N-((4-cyclopropylpyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00374] Using the procedure in Example 46, step 1, the title compound was obtained as a light yellow solid (101 mg, 78%). MS (ES+) C12H11BrN4OS requires: 338; found: 339 [M+H]+. Step 3: (R)-N-((4-cyclopropylpyridin-2-yl)methyl)-5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin- 1-yl)-1,3,4-thiadiazol-2-carboxamide

[00375] Using the procedure in Example 46, step 2, the title compound was obtained as a yellow solid (7 mg, 9%). MS (ES+) C27H27N9O2S requires: 541; found: 542 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.22 (t, J = 6.1 Hz, 1H), 8.51 (d, J = 3.4 Hz, 1H ), 8.32 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 7.4, 4.9 Hz, 1H), 7.07 (s, 1H), 6.96 (d, J = 3.6 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H), 4.03 - 3.98 (m, 3H), 3.98 - 3.90 (m, 1H), 3.80 (dd, J = 9.8, 7.6 Hz, 1H), 3.74 - 3.67 (m, 1H), 3.67 - 3.61 (m, 1H), 2.57 - 2.51 (m, 1H), 2.36 - 2.26 (m, 1H), 1.97 - 1.87 (m, 1H), 1.09 - 1.01 (m, 2H), 0, 80 - 0.72 (m, 2H).

[00376] EXAMPLE 48: (R)-N-((6-methyl-4-(trifluoromethyl)pyridin-2-yl)methyl)-5-(3-(6-(2-(pyridin-2-yl) acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide Step 1: tert-butyl((6-methyl-4-(trifluoromethyl)pyridin-2-yl)methyl)carbamate

[00377] To a solution of 6-methyl-4-(trifluoromethyl)picolinonitrile (100 mg, 0.537 mmol, prepared according to document EP 1362850 A1, 2003, page 38), di-tert-butyl dicarbonate (176 mg , 0.806 mmol) and nickel(II) chloride hexahydrate (31.9 mg, 0.134 mmol) in MeOH (2.7 ml) at 0 °C, NaBH4 (81 mg, 2.1 mmol) was added in portions . The resulting mixture was stirred at 0 °C for 30 min and allowed to cool to RT. N1-(2-aminoethyl)ethane-1,2-diamine (58 μl, 0.54 mmol) was then added, stirred at RT for 30 min and concentrated. The residue was partitioned between EtOAc (6 ml) and water (6 ml). The organic layer was separated and washed with aqueous NaHCO3 (6 ml), brine (6 ml) and dried over MgSO4. Volatile products were removed under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% EtOAc in hexanes) to give the title compound (138 mg, 88%) as a light yellow liquid. MS (ES+) C13H17F3N2O2 requires: 290; found: 235 [M-tBu+H]+.Step 2:(6-methyl-4-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride

[00378] HCl in dioxane (538 μl, 2.15 mmol, 4 M in dioxane) was added to tert-butyl ((6-methyl-4-(trifluoromethyl)pyridin-2-yl)methyl)carbamate (125 mg , 0.431 mmol) at RT, and the resulting solution was allowed to stir for 1 h. The reaction mixture was concentrated, and the residue was triturated with Et2O (2 x 4 ml) to give the title compound (98 mg, 100%) as an off-white solid. MS (ES+) C8H9F3N2 requires: 190; found: 191 [M+H]+.Step 3:5-bromo-N- ((6-methyl-4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00379] Using the procedure in Example 46, step 1, the title compound was obtained as an off-white solid (106 mg, 67%). MS (ES+) C11H8BrF3N4OS requires: 380; found: 381 [M+H]+.Step 4: (R)-N-((6-methyl-4-(trifluoromethyl)pyridin- 2-yl)methyl)-5-(3-(6-(2- (pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide

[00380] Using the procedure in Example 46, step 2, the title compound was obtained as a yellow solid (24 mg, 32%). MS (ES+) C26H24F3N9O2S requires: 583; found: 584 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.43 (t, J = 6.2 Hz, 1H), 8.51 (d, J = 4.9 Hz, 1H ), 8.28 (d, J = 9.2 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.55 (s, 1H), 7.43 — 7.38 (m, 2H), 7.28 (dd, J = 7.4, 5.1 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.03 - 3.97 (m, 3H ), 3.97 - 3.90 (m, 1H), 3.80 (dd, J = 9.9, 7.6 Hz, 1H), 3.73 - 3.67 (m, 1H), 3, 67 - 3.61 (m, 1H), 2.58 (s, 3H), 2.56 - 2.51 (m, 1H), 2.35 - 2.27 (m, 1H).

[00381] EXAMPLE 49: 5-(3-(6-(2-(6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-((4-(trifluoromethyl) pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide Steps 1 to 5 Step 1: N-(6-chloropyridazin-3-yl)-2-(6-methylpyridin-2-yl)acetamide

[00382] A vial (20 ml, Teflon septum) was charged with 2-(6-methylpyridin-2-yl)acetamide (200 mg, 1.33 mmol), 3-chloro-6-iodopyridazine (352 mg, 1 .46 mmol), cesium carbonate (868 mg, 2.66 mmol), allylpalladium chloride dimer (24 mg, 0.067 mmol), Xantphos (154 mg, 0.266 mmol) and Dioxane (6.6 ml). The mixture was degassed by bubbling N2 through the suspension for 5 min and then heated to 50 °C with stirring for 12 h. The reaction was filtered, and volatile products were removed under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% EtOAc (with 10% MeOH) in hexanes) to give the title compound (283 mg, 81%) as a brown amorphous material. MS (ES+) C12H11ClN4O requires: 262; found: 285 [M+Na]+.Step 2:3- (6- (2- (6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2,5-dihydro-1H-pyrrole -1- tert-butyl carboxylate

[00383] To a vial (20 ml, Teflon septum) containing N-(6-chloropyridazin-3-yl)-2-(6-methylpyridin-2-yl)acetamide (200 mg, 0.761 mmol), 3-( tert-butyl 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (337 mg, 1.14 mmol ), Cs2CO3 (248 mg, 0.761 mmol) and PdCl2(dppf)-CH2Cl adduct (62 mg, 0.076 mmol), dioxane (3.8 ml) and water (69 μl, 3.8 mmol) were added. The reaction mixture was purged with N2 for 5 min and stirred at 50 °C overnight. The reaction mixture was cooled, diluted with DCM (10 ml) and filtered. Volatile products were removed under reduced pressure. The residue was purified by flash chromatography (0 to 100% EtOAc (with 10% MeOH) in Hexanes) to give the title compound (151 mg, 50%) as a brown solid. MS (ES+) C21H25N5O3 requires: 395; found: 396 [M+H]+.Step 3:3- (6- (2- (6-methylpyridin-2-tert-butyl

[00384] A reaction vessel was charged with 10% Pd-C (81 mg, 0.076 mmol), 3-(6-(2-(6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)- tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (150 mg, 0.379 mmol) and Ethanol (3.8 ml) under an N2 atmosphere. The suspension was degassed with N2 for 5 minutes and purged with H2 for 5 minutes. The reaction mixture was stirred under an atmosphere of H2 at 0.1 MPa (1 atm) for 2 h at 40 °C. The reaction mixture was purged with N2, filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 10% DCM in MeOH with 0.5% NH4OH) to give the title compound (126 mg, 84%) as an orange amorphous material. MS (ES+) C21H27N5O3 requires: 397; found: 398 [M+H]+.Step 4: 2-(6-methylpyridin-2-yl)-N-(6-(pyrrolidin-3-yl)pyridazin-3-yl 2,2,2-trifluoroacetate )acetamide

[00385] To a solution of tert-butyl 3-(6-(2-(6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate (120 mg, 0.302 mmol) in CH2Cl2 (604 μl), trifluoroacetic acid (581 μl, 7.55 mmol) was added, and the resulting mixture was stirred at RT for 30 min. The volatile products were removed under reduced pressure to give the title compound (124 mg, 100%) as a brown oil. MS (ES+) C16H19N5O requires: 297; found: 298 [M+H] +.Step 5 :5- (3- (6- (2- (6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N- ((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00386] Using the procedure in Example 46, step 2, the title compound was obtained as an off-white solid (42 mg, 71%). MS (ES+) C26H24F3N9O2S requires: 583; found: 584 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.44 (t,J = 6.1 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H ), 8.27 (s, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.70 - 7.63 (m, 3H), 7.20 (d, J = 7, 6 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.04 - 3.98 (m, 1H) , 3.97 - 3.90 (m, 3H), 3.85 - 3.78 (m, 1H), 3.74 - 3.68 (m, 1H), 3.68 - 3.61 (m, 1H), 2.57 - 2.51 (m, 1H), 2.45(s, 3H), 2.36 - 2.26 (m, 1H).

[00387] EXAMPLE 50: 5-(3-(6-(2-(6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N-((6-methylpyridin-2 -yl)methyl)-1,3,4-thiadiazol-2-carboxamide Step 1: 5-bromo-N-((6-methylpyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00388] Using the procedure in Example 46, step 1, the title compound was obtained as a yellow liquid (117 mg, 59%). MS (ES+) C10H9BrN4OS requires: 312; found: 313 [M+H]+.Step 2:5- (3- (6- (2- (6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-N- ((6-methylpyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00389] Using the procedure in Example 46, step 2, the title compound was obtained as a light yellow amorphous material (22 mg, 41%). MS (ES+) C26H27N9O2S requires: 529; found: 530 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.32 (t, J = 6.1 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H ), 7.74 (d, J = 9.3 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 8.3 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 4.49 (d, J = 6.1 Hz, 2H), 4.03 - 3 .97 (m, 1H), 3.97 - 3.91 (m, 3H), 3.80 (dd, J = 9.8, 7.7 Hz, 1H), 3.73 - 3.67 (m , 1H), 3.67 - 3.60 (m, 1H), 2.57 - 2.51 (m, 1H), 2.45 (s, 3H), 2.45 (s, 3H), 2, 35 - 2.27 (m, 1H).

[00390] EXAMPLE 51: 5-(3-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl) -N-(pyridin-2-ylmethyl)-1,3,4-thiadiazole-2-carboxamide Steps 1 to 4 Step 1: 2,6-dichloro-4-(3,3-difluorocyclobutoxy)pyridine.

[00391] To a suspension of NaH (8.88 g, 60% in mineral oil, 222 mmol) in THF (800 ml) at 0 °C, 3,3-difluorocyclobutanol (20 g, 19 mmol) was added dropwise over a 10 min period. After completion of the addition, 2,6-dichloro-4-nitropyridine (35.7 g, 185 mmol) was added portionwise, and the resulting mixture was stirred at 0 °C for 1 h. Saturated aqueous NH4Cl (200 ml) and water (800 ml) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 500 ml), and the combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 8% EtOAc in hexanes) to give the title compound as a white crystalline solid (45.0 g, 96%). MS (ES+) C9H7Cl2F2NO requires: 253; found: 254 [M+H]+. Step 2: 2-chloro-4-(3,3-difluorocyclobutoxy)-6-methylpyridine.

[00392] To a solution of 2,6-dichloro-4-(3,3-difluorocyclobutoxy)pyridine (45 g, 177 mmol), THF (800 ml), NMP (200 ml) and ferric acetylacetonate (1.87 g , 5.31 mmol) at 0 °C, methylmagnesium bromide (3 M in ether, 77 ml, 230 mmol) was added dropwise, and the resulting mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with saturated aqueous NH4Cl (100 ml) to 0 °C, water (900 ml) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 500 ml), and the combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% EtOAc in hexanes) to give the title compound as a colorless liquid (36.5 g, 88%). MS (ES+) C10H10ClF2NO requires: 233; found: 234 [M+H]+. Step 3: ethyl 2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetate.

[00393] A degassed solution of 2-chloro-4-(3,3-difluorocyclobutoxy)-6-methylpyridine (33.0 g, 141 mmol), (2-ethoxy-2-oxoethyl)zinc(II) bromide ( 0.5 M in THF, 706 ml, 350 mmol), Pd2(dba)3 (6.47 g, 7.06 mmol) and XPhos (3.37 g, 7.06 mmol) was stirred at 50 °C for 1 hr. The reaction mixture was allowed to cool to RT, and saturated aqueous NH4Cl (100 ml) and water (900 ml) were added. The precipitate was removed by filtration, and the filtrate layers were separated. The aqueous phase was extracted with EtOAc (3 x 500 ml), and the combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 60% EtOAc in hexanes) to give the title compound as a yellow liquid (27.8 g, 69%). MS (ES+) C14H17F2NO3 requires: 285; found: 286 [M+H]+. Step 4:2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamide.

[00394] A solution of ethyl 2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetate (27.8 g, 97.0 mmol) and NH3 in MeOH (7 M, 557 ml, 390 mmol) in a pressure bottle was stirred at 85 °C for 20 h. The reaction mixture was allowed to cool to RT, then concentrated under reduced pressure. The resulting solid was triturated with ether and isolated by filtration to give the title compound as an off-white solid (22.4 g, 90%). MS (ES+) C12H14F2N2O2 requires: 256; Found: 257 [M+H]+.Step 5:N-(6-chloropyridazin-3-yl)-2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamide

[00395] Using the procedure in Example 49, step 1, the title compound was obtained as a brown liquid (278 mg, 77%). MS (ES+) C16H15ClF2N4O2 requires: 368; found: 369 [M+H]+. Step 6: 3-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)-2,5-dihydro-1H-pyrrole tert-butyl -1-carboxylate

[00396] Using the procedure in Example 49, step 2, the title compound was obtained as an orange solid (243 mg, 72%). MS (ES+) C25H29F2N5O4 requires: 501; found: 502 [M+H]+. Step 7: tert-butyl 3-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidine-1-carboxylate

[00397] Using the procedure in Example 49, step 3, the title compound was obtained as an orange solid (210 mg, 87%). MS (ES+) C25H31F2N5O4 requires: 503; found: 504 [M+H]+.Step 8: 2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)-N-(6-(pyrrolidin)-2,2,2-trifluoroacetate -3- yl)pyridazin-3-yl)acetamide

[00398] Using the procedure in Example 49, step 4, the title compound was obtained as an orange solid (206 mg, 100%). MS (ES+) C20H23F2N5O2 requires: 403; found: 404 [M+H]+. Step 9: 5-(3-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)- N- (pyridin-2-ylmethyl)-1,3,4-thiadiazol-2-carboxamide

[00399] Using the procedure in Example 46, step 2, the title compound was obtained as a yellow solid (19 mg, 32%). MS (ES+) C29H29F2N9O3S requires: 621; found: 622 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.31 (t, J = 6.1 Hz, 1H), 8.51 (d, J = 4.0 Hz, 1H ), 8.27 (d, J = 9.2 Hz, 1H), 7.81 - 7.66 (m, 2H), 7.32 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 6.4, 4.8 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 4 .88 - 4.77 (m, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.00 (dd, J = 9.9, 7.6 Hz, 1H), 3, 94 (dt, J = 15.2, 7.4 Hz, 1H), 3.89 (s, 2H), 3.80 (dd, J = 9.8, 7.6 Hz, 1H), 3.73 - 3.68 (m, 1H), 3.67 - 3.61 (m, 1H), 3.28 - 3.19 (m, 2H), 2.77 - 2.65 (m, 2H), 2 .56 - 2.51 (m, 1H), 2.40 (s, 3H), 2.35 - 2.26 (m, 1H).

[00400] EXAMPLE 52: 5-(3-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl) -N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00401] Using the procedure in Example 46, step 2, the title compound was obtained as a light yellow solid (20 mg, 30%). MS (ES+) C30H28F5N9O3S requires: 689; found: 690 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.36 (s,1H), 9.43 (t, J = 6.1 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H ), 8.27 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.71 - 7.63 (m, 2H), 6.80 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 4.88 - 4.78 (m, 1H), 4.66 (d, J = 6.1 Hz, 2H), 4.00 (dd, J = 9.9,7.6 Hz, 1H), 3.97 - 3.91 (m, 1H), 3.89 (s, 2H), 3.80 (dd, J = 9.9, 7.6 Hz, 1H), 3.74 - 3.68 (m, 1H), 3.68 - 3.61 (m, 1H), 3.29 - 3.19 (m, 2H), 2.76 - 2.65 (m, 2H), 2.56 - 2.51 (m, 1H), 2.40 (s, 3H), 2.36 - 2, 27 (m, 1H).

[00402] EXAMPLE 53: 5-(3-(6-(2-(4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl) -N-((6-methylpyridin-2-yl)methyl)-1,3,4-thiadiazol-2-carboxamide

[00403] Using the procedure in Example 46, step 2, the title compound was obtained as a light yellow solid (23 mg, 32%). MS (ES+) C30H31F2N9O3S requires: 635; found: 636 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.30 (t, J = 6.1 Hz, 1H), 8.25 (d, J = 9.2 Hz, 1H ), 7.75 (d, J = 9.2 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.03 - 6.81 (m, 2H), 4.90 (s, 1H), 4.50 (d, J = 6.1 Hz , 2H), 4.04 - 3.90 (m, 4H),3.80 (dd, J = 9.8, 7.6 Hz, 1H), 3.73 - 3.61 (m, 2H), 3.30 -3.21 (m, 2H), 2.82 - 2.70 (m, 2H), 2.56 - 2.51 (m, 1H), 2.48- 2.44 (m, 6H ), 2.35 - 2.27 (m, 1H). Table 1: Synthesized Compounds

[00404] Table 2 below reports the observed molecular ion (ES+) (Mass Spectrometry) [M+H]+ of each Example, as well as the method by which each compound can be made in reference to each Example whose synthesis is substantially similar so that one skilled in the art can produce the compound using, if necessary, variations known in the art. Table 2: Observed Molecular Weight and Synthesis for Examples

ADDITIONAL COMPOUNDS

[00405] The following compounds, which may not yet have been produced or tested, can be produced as disclosed herein and are expected to have similar activity to those produced and tested.

[00406] EXAMPLE 54: (R)-N-((4-(3,3-difluorocyclobutoxy)-6-methylpyridin-2-yl)methyl)-5-(3-(6-(2-(pyridin-2 -yl)acetamido)pyridazin-3-yl)pyrrolidin-1-yl)-1,3,4-thiadiazol-2-carboxamide

BIOLOGICAL ACTIVITY TESTS

[00407] The following are assays that can be used to evaluate the biological efficacy of compounds of Formula (I).

GLS1 ENZYME ACTIVITY ASSAY

[00408] Inhibition of purified recombinant human GAC by varying inhibitor concentrations is assessed using a double-coupling enzymatic assay. Glutamate produced by the glutaminase reaction is used by glutamate oxidase to produce α-ketoglutarate, ammonia and peroxide of hydrogen, 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) before incubation with inhibitor (10 minutes at room temperature). 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. Resorufin production was monitored on a Perkin Elmer Envision plate reader (excitation 530 nm, emission 590 nm) in either a kinetic or endpoint mode (within 20 minutes). IC50 values were calculated using a four-parameter logistic curve fit.

PROLIFERATION ASSAY

[00409] A549 cells were routinely maintained in RPMI 1640 medium (Gibco catalog number 11875-093) supplemented with 10% dialyzed fetal bovine serum using a humidified incubator (37 ° C, 5% CO2 and ambient O2). . In preparation for the viability assay, cells were seeded into 384-well black CulturPlates (Perkin Elmer) at a density of 1,000 cells/well in a volume of 40 μl. After a 24-hour incubation at 37°C, 5% CO2, and ambient O2, cells were treated with the compound (10 μl) at a final DMSO concentration of 0.5% (in 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 μl of 6x 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. EC50 values were calculated using a four-parameter logistic curve fit.

[00410] Table 3 below reports the IC50 against GLS1 and the EC50 against A549 cell proliferation, both in nanomolar, and both where A = < 100 nM, B = 100 to 500 nM and C = 500 to 5,000 nM. Table 3: IC50 data of GLS1 and EC50 data of A549

OTHER MODALITIES

[00411] The detailed description presented above is provided to assist those skilled in the art in practicing the present disclosure. However, the disclosure described and claimed herein should not be limited in scope by the specific embodiments disclosed herein due to the fact that these embodiments are intended to illustrate various aspects of the disclosure. Any equivalent embodiments are intended to be within the scope of the present invention. In fact, various modifications of the disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the above-mentioned description, without departing from the spirit or scope of the present inventive disclosure. Such modifications are also intended to fall within the scope of the appended claims.

Claims (14)

1. COMPOUND, of structural Formula II, or a salt thereof, characterized in that: n is 1; A1 be chosen from S and HC=CH; Z1 be chosen from S, CH and HC=CH; Z2 is N when Z1 is CH, and Z2 is C when Z1 is S or HC=CH; R1 is chosen from NR3C(O)R3, NR3C(O)OR3, NR3C(O)N(R3)2, C(O)N(R3)2 and N(R3)2; each R3 will be independently chosen from C1-6 alkyl, 3-7 membered aryl, aryl(3-7 membered) C1-6alkyl, C3-12cycloalkyl, (C3-12cycloalkyl) C1-6alkyl, H, C1-6haloalkyl, heteroaryl 3- to 7-membered, (3- to 7-membered heteroaryl) C1-6alkyl, C3-12heterocycloalkyl, (C3-12heterocycloalkyl) C1-6alkyl, wherein each R3 may be optionally substituted by one to three Rx groups, wherein two groups R3, together with the atoms to which they are attached, optionally form a 3- to 7-membered heteroaryl or C3-12 heterocycloalkyl ring, which may be optionally substituted by one to three Rx groups; R2 is chosen from NR4C(O)R4, NR4C(O)OR4, NR4C(O)N(R4)2, C(O)N(R4)2 and N(R4)2; each R4 will be independently chosen from alkyl, 3- to 7-membered aryl, (3- to 7-membered aryl) C1-6alkyl, C3-12cycloalkyl, (C3-12cycloalkyl)C1-6alkyl, H, C1-6haloalkyl, 3- to 7-membered, (3- to 7-membered heteroaryl) C1-6alkyl, C3-12heterocycloalkyl and (C3-12heterocycloalkyl)C1-6alkyl, wherein each R4 may be optionally substituted by one to three Rx groups, wherein two R4 groups, in together with the atoms to which they are attached, they optionally form a 3 to 7 membered heteroaryl or C3-12 heterocycloalkyl ring, which may be optionally substituted by one to three Rx groups; each Rx group is independently chosen from C1-6alkoxy, (C1-6alkoxy)C1-6alkyl, (C1-6alkoxy)aryl 3 to 7 members, (C1-6alkoxy)arylalkyl 3 to 7 members, (C1-6alkoxy)C3 -12cycloalkyl, (C1-6alkoxy)C3-12cycloalkylalkyl, (C1-6alkoxy)C1-6haloalkyl, (C1-6alkoxy)3- to 7-membered heteroaryl, C1-6alkoxy(3- to 7-membered heteroaryl)C1-6alkyl, (C1 -6alkoxy)C3-12heterocycloalkyl, C1-6alkoxy(C3- 12heterocycloalkyl)C1-6alkyl, C1-6alkyl, (C1- 6alkyl)3- to 7-membered aryl, C1-6alkyl(3 to 7-membered aryl)C1-6alkyl, ( ( C1-6alkyl)C3-12heterocycloalkyl, C1-6alkyl(C3- 12heterocycloalkyl)C1-6alkyl, 3-7 membered aryl, (3-7 membered aryl)C1-6alkyl, (3-7 membered aryl)C1-6alkyloxy , (3-7 membered aryl)C1-6haloalkyl, 3-7 membered aryloxy, cyano, C3-12cycloalkyl, (C3-12cycloalkyl)C1-6alkyl, (C3-12cycloalkyl)C1-6alkyloxy, (C3-12cycloalkyl)C1 -6haloalkyl, C3-12cycloalkyloxy, halo, C1-6haloalkoxy, C1-6haloalkoxy, C1-6alkyl, (C1-6haloalkoxy)3- to 7-membered aryl, C1-6haloalkoxy(3- to 7-membered aryl)C1- 6alkyl, (C1- 6haloalkoxy)C3-12cycloalkyl, C1-6haloalkoxy(C3- 12cycloalkyl)C1-6alkyl, (C1-6haloalkoxy)3- to 7-membered heteroaryl, C1-6haloalkoxy(3- to 7-membered heteroaryl)C1- 6alkyl, (C1-6haloalkoxy) C3-12heterocycloalkyl, C1- 6haloalkoxy(C3-12heterocycloalkyl)C1-6alkyl, C1- 6haloalkyl, (C1-6haloalkyl)3- to 7-membered aryl, C1- 6haloalkyl(3- to 7-membered aryl)C1-6alkyl, (C1- 6haloalkyl)C3-12cycloalkyl, C1-6haloalkyl(C3- 12cycloalkyl)C1-6alkyl, (C1-6haloalkyl)3- to 7-membered heteroaryl, C1-6haloalkyl(3- to 7-membered heteroaryl)C1- 6alkyl, (C1-6haloalkyl) C3-12heterocycloalkyl, C1-6haloalkyl(C3-12heterocycloalkyl)C1-6alkyl, 3-7 membered haloaryl, (3-7 membered haloaryl)C1-6alkyl, (3-7 membered haloaryl) C1-6alkyloxy, 3-haloaryloxy ( 3- to 7-membered haloheteroaryl)C1-6alkyloxy, 3- to 7-membered haloheteroaryloxy, C3-12haloheterocycloalkyl, (C3-12haloheterocycloalkyl)C1-6alkyl, (C3-12haloheterocycloalkyl)C1-6alkyloxy, C3-12haloheterocycloalkyloxy, 3- to 7-membered haloheteroaryl 7 members , (3- to 7-membered heteroaryl)C1-6alkyl, (3 to 7-membered heteroaryl)C1-6alkyloxy, (3- to 7-membered heteroaryl)C1- 6haloalkyl, 3- to 7-membered heteroaryloxy, C3- 12heterocycloalkyl, (C3- 12heterocycloalkyl)C1-6alkyl, (C3- 12heterocycloalkyl)C1-6alkyloxy, (C3-12heterocycloalkyl)C1- 6haloalkyl, C3-12heterocycloalkyloxy, hydroxyl, oxo, N(R5)2, NR5C(O)R5, NR5C(O)OR5, NR5C(O)N(R5)2, C(O)N(R5)2 and C(O)R5; each R5 is independently chosen from C1-6alkyl, 3- to 7-membered aryl, (3- to 7-membered aryl)C1-6alkyl, C3-12cycloalkyl, (C3-12cycloalkyl)C1-6alkyl, H, C1-6haloalkyl, heteroaryl of 3 to 7 members, (3 to 7 member heteroaryl)C1-6alkyl, C3-12heterocycloalkyl and (C3-12heterocycloalkyl)C1-6alkyl, which may be optionally substituted by one to three Rz groups; and Rz is chosen from C1-6alkyl, 3- to 7-membered aryl, (3- to 7-membered aryl)C1-6alkyl, cyano, C3-12cycloalkyl, (C3-12cycloalkyl)C1-6alkyl, H, halo, C1-6haloalkyl , 3- to 7-membered heteroaryl, (3- to 7-membered heteroaryl)C1-6alkyl, C3-12heterocycloalkyl and (C3-12heterocycloalkyl)C1-6alkyl; wherein heteroaryl is an 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 chosen from O, S and N; and heterocycloalkyl is a saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom can be chosen independently of nitrogen, oxygen and sulfur. 2. COMPOUND, according to claim 1, or a salt thereof, characterized in that: A1 is S. 3. COMPOUND, according to claim 1, or a salt thereof, characterized in that: Z1 is HC=CH; and Z2 be C. 4. COMPOUND, according to claim 1, or a salt thereof, characterized in that: R1 is chosen from NR3C(O)R3 and C(O)N(R3)2 5. COMPOUND, according to claim 1, or a salt thereof, characterized in that: R2 is chosen from NR4C(O)R4 and C(O)N(R4)2. 6. COMPOUND, according to claim 1, characterized by having structural formula IV: or a salt thereof. 7. COMPOUND, according to claim 1, characterized by having structural formula V: or a salt thereof. 8. COMPOUND, according to claim 1, or a salt thereof, characterized in that it is chosen from among 9. COMPOSITION, characterized in that it comprises a compound, as defined in claim 1, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 10. COMPOUND according to claim 1, characterized in that it is for use in treating a GLS1-mediated disease, comprising the step of administering to a subject the compound according to claim 1. 11. COMPOUND according to claim 10, characterized in that the GLS1-mediated disorder is cancer. 12. COMPOUND, according to claim 11, characterized in that the cancer is chosen from Non-Small Cell Lung Cancer, Ovarian Cancer and Small Cell Lung Cancer, or a variant thereof. 13. COMPOUND according to claim 10, characterized in that it is for use, wherein the GLS1-mediated disorder is a neurological disorder. 14. COMPOUND according to claim 13, characterized in that it is for use, in which the neurological disorder is chosen from Alzheimer's disease, bipolar disorder, HIV-associated dementia, Huntington's disease, ischemic insult, Parkinson's disease, schizophrenia, stroke, traumatic insult and vascular dementia.