PCSK9 INHIBITORS AND THEIR METHODS OF USE

Description

RELATED APPLCIATIONS

[0001] This application claims the benefit of priority to U.S. Application No. 62 / 794,234, filed on January 18, 2019.BACKGROUND

[0002] PCSK9, also referred to as "proprotein convertase subtilisin / kexin 9", is a member of the secretory proprotein convertase family and plays an important role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol via the enhanced degradation of the LDL receptors independently of its catalytic activity. Secreted PCSK9 binds to the Epidermal Growth Factor domain A (EGFA) of the LDL receptor (LDLR) at the cell surface and the PCSK9 / LDL receptor complex is internalized into endosomal / lysosomal compartments. The enhanced binding affinity of PCSK9 to the LDL receptor at the acidic pH of late endosomes / lysosomes reduces LDL receptor recycling and instead targets LDL receptors for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events.

[0003] Another biological pathway involving the effect of PCSK9 on LDL receptors is the onset of septic shock. Septic shock is an often fatal complication of a severe microbial infection (sepsis) that triggers an uncontrolled systemic inflammatory response and subsequent organ failure. Sepsis originates with the microbial cell walls that contain pathogenic lipid moieties such as lipopolysaccharide (LPS; Gram-negative bacteria). LPS are potent ligands for mammalian innate immune receptors [Toll-like receptors (TLRs)] and thus figure prominently in the septic inflammatory response (septic shock, or sepsis).

[0004] PCSK9 reduces LPS uptake by the liver's LDL receptors, such that free LPS overstimulates the body's immune response to the pathogen leading to sepsis. Thus, inhibiting PCSK9 is beneficial in retaining liver LDL receptors to effect systemic pathogen clearance and detoxification in response to sepsis. However, beyond antibiotic therapy, there are currently no effective treatments for sepsis or septic shock.

[0005] For cardiovascular disease, few options exist for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and in human primary hepatocytes through the increased expression of SREBP-2, a transcription factor that upregulates both the LDLR and PCSK9 genes. Since an elevated level of PCSK9 decreases the abundance of LDL receptor on the cell surface, increasing doses of statins have failed to achieve proportional LDL-cholesterol lowering effects.

[0006] Two monoclonal antibodies (mAbs) that bind selectively to extracellular PCSK9 and prevent its interaction with the LDL receptor, alirocumab and evolocumab, have recently received FDA approval for lowering LDL-C levels. In clinical trials, alirocumab showed an about 50% decrease in LDL levels compared to placebo. Elbitar et al., Expert Opin Therapeutic Patents 2016 26:1377-1392. Patients taking evolocumab showed an about 60-75% decrease in LDL levels. The potency of these drugs demonstrates the potential for inhibitors of PCSK9 to be effective treatments for those with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and can cause allergic reactions or other deleterious immune responses in the body.

[0007] Shentao et. al. (European Journal of Medicinal Chemistry, 2018, vol. 162, pages 212-233) provides an overview of the development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and discloses different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules.

[0008] Cardiovascular diseases often require management over a person's lifetime, unlike an infection that could be episodic. Thus, ease of dosing and administration become key factors to patient compliance with maintenance drug treatments. There is a need for PCSK9 inhibitors with increased efficacy and greater ease of administration, which can be achieved with small molecule PCSK9 inhibitors.SUMMARY

[0009] A first embodiment of the present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is

[0010] The compound above is herein referred to as a compound of the invention or a pharmaceutically acceptable salt thereof.

[0011] A second embodiment of the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0012] A third embodiment of the present invention provides a compound of the invention for use as a medicament.

[0013] A fourth embodiment of the present invention provides a compound of the invention for use in the treatment of cardiovascular disease.

[0014] Disclosed herein are compounds for use in treating diseases and conditions that benefit from the inhibition of PCSK9. These diseases include, but are not limited to cardiovascular diseases, such as hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

[0015] A fifth embodiment of the present invention provides a compound of the invention for use in the treatment of cardiovascular disease, further comprising conjointly administering one or more additional therapeutic agents.

[0016] Provided herein are combination therapies of compounds of formula (I) with monoclonal antibodies, statins and other cardiovascular agents that can enhance the cardiovascular therapeutic benefit beyond the ability of the adjuvant therapy alone.DETAILED DESCRIPTION

[0017] Disclosed herein are compounds of Formula (I) wherein: A is selected from H, halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6< , and -C(O)NR 6< R 7< ; B is selected from H, alkyl, and halo, or A and B are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered heteroaryl; X is NR 5< or O; R 1< and R 1'< are each independently selected from H and alkyl; or if n is 0, R 1< and R 1'< , together with the atoms to which they are attached, form a 4-8 membered cycloalkyl or cycloalkenyl ring; R 2< is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, hydroxyalkyl, alkylamino, cyano, and hydroxy; or R 1< and R 2< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; or R 1'< and R 2< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; R 2'< is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, and cyano, or R 2< and R 2'< , taken together with the carbon atom to which they are attached, form a 3-to 8-membered cycloalkyl or heterocyclyl ring; each R 3< and R 4< is independently H or alkyl; or R 2< and R 3< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; and R 5< is H or alkyl; or R 1< and R 5< , together with the atoms to which they are attached, form a 6-8 membered cycloalkyl or heterocyclyl ring; or R 2< and R 5< , together with the atoms to which they are attached, form a 5-8 membered cycloalkyl or heterocyclyl ring; each R 6< and R 7< is independently H or alkyl; Y is selected from aryl, heteroaryl and heterocyclyl; and n is 0 or 1.

[0018] Disclosed herein are compounds of Formula (I') wherein: A is selected from H, halo, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, - C(O)OR 6< , and -C(O)NR 6< R 7< ; B is selected from H, alkyl, and halo; R 1< and R 1'< are each independently selected from H and alkyl; or if n is 0, R 1< and R 1'< , together with the atoms to which they are attached, form a 4-8 membered cycloalkyl ring; R 2< is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, hydroxyalkyl, alkylamino, cyano, and hydroxy; or R 1< and R 2< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; or R 1'< and R 2< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; R 2'< is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, and cyano, ; or R 2< and R 2'< , taken together with the carbon atom to which they are attached, form a 3-to 8-membered cycloalkyl or heterocyclyl ring; each R 3< and R 4< is independently H or alkyl; or R 2< and R 3< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring; and R 5< is H or alkyl; or R 1< and R 5< , together with the atoms to which they are attached, form a 6-8 membered cycloalkyl or heterocyclyl ring; or R 2< and R 5< , together with the atoms to which they are attached, form a 5-8 membered cycloalkyl or heterocyclyl ring; each R 6< and R 7< is independently H or alkyl; Het is heteroaryl or heterocyclyl; and n is 0 or 1.

[0019] All of the disclosures below and herein are understood to be disclosures of both Formula (I) and Formula (I').

[0020] In the disclosure A is selected from H, hydroxy, thioalkyl, alkyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6< , and -C(O)NR 6< R 7< . In the disclosure A is H, while in other disclosures, A is alkyl, such as thioalkyl. In the disclosure, A is selected from -SCH 3 , -SCHF 2 , and -OCHF 2 . In the disclosure, A is alkoxy. In the disclosure, A is cycloalkyl. In the disclosure, B is H.

[0021] In the disclosure, A and B are taken together with the carbon atoms to which they are attached to form a pyrrolyl or thienyl ring, which is unsubstituted or substituted with one or more alkyl.

[0022] In the disclosure, X is preferably NR5. In the disclosure, Y is preferably heteroaryl or heterocyclyl.

[0023] In the disclosure, R 1< and R 1< ' are each H. However, when n is 0, R 1< and R 1'< , together with the atoms to which they are attached, can form a 4- to 8-membered cycloalkyl ring. In the disclosure, the cycloalkyl is monocyclic or bicyclic. In the disclosure, R 1< and R 1'< , together with the atoms to which they are attached, can form a 4- to 8-membered cycloalkenyl ring. In the disclosure, the cycloalkyl ring is a cyclopentyl ring, such as S,S-cyclopentyl. In the disclosure, the cycloalkyl ring is substituted with hydroxyl or hydroxyalkyl.

[0024] In the disclosure, R 2< is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, alkylamino, cyano, and hydroxyl. In the disclosure, R 2< is C 1-3 alkyl. R 2< can be substituted with one or more substituents selected from amino, amido, cyano, hydroxy, and heterocyclyl. In the disclosure, R 2< is C 1-3 alkyl, while in the disclosure, R 2'< is H.

[0025] In the disclosure, R 1< and R 2< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring. In the disclosure, R 1'< and R 2< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring. In the disclosure, R 2< and R 2'< , taken together with the carbon atom to which they are attached, form a 3- to 8-membered cycloalkyl or heterocyclyl ring.

[0026] In the disclosure, R 3< is C 1-3 alkyl, while in other disclosures, R 3< is H. In the dsclosure, R 4< is H.

[0027] In the disclosure, R 2< and R 3< , together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocylcyl ring. In the disclosure, R 1< and R 5< , together with the atoms to which they are attached, form a 6-8 membered cycloalkyl or heterocyclyl ring. In the disclosure, R 2< and R 5< , together with the atoms to which they are attached, form a 5-8 membered cycloalkyl or heterocyclyl ring.

[0028] In the disclosure, Y is monocyclic heteroaryl, such as, but not limited to, pyridinyl, pyrazinyl, pyrimidinyl, and thiazolyl. In the disclosure, Y is monocyclic heteroaryl, such as, but not limited to, pyridinyl, pyrazinyl, and pyrimidinyl. In the disclosure, Y is selected from triazenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl and triazolyl. The monocyclic heteroaryl can be unsubstituted, or substituted with one or more substituents selected from alkyl, thioalkyl alkoxy, alkoxycarbonyl, amido, carboxy, cyano, halo, heteroaryl, nitro, sulfonamido, and thioalkyl. In the disclosure, Y is a monocyclic heteroaryl can be unsubstituted, or substituted with one or more substituents selected from alkyl, thioalkyl, alkoxy, alkoxycarbonyl, amido, carboxy, cyano, halo, aryl, heteroaryl, heterocyclyl, nitro, sulfonamido, and thioalkyl.

[0029] In the disclosure, the monocyclic heteroaryl is substituted with an aryl, heteroaryl or heterocyclyl selected from phenyl, pyridinyl, 2-hydroxypyridinyl, piperidinonyl, 2-hydroxy-1-methylpyridinyl, triazolyl, imidazolidinonyl, pyrimidonyl, 2-hydroxyisoquinolinyl, 3-hydroxypyridazinyl, pyrrolidinonyl, pyrazolyl, and morpholinonyl. In the disclosure, Y is a 6-membered monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is substituted with an heteroaryl or heterocyclyl that is substituted with one or more substituents selected from halo, CN, alkyl, alkoxy, hydroxy, carboxy, -CO 2 alkyl, and tetrazolyl. In the disclosure, the monocyclic heteroaryl is disposed on the para position of A relative to X.

[0030] In the disclosure, Y is bicyclic heteroaryl, such as, but not limited to, benzothiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl, thiazolopyrindinyl, quinolinyl, and quinoxalinyl. The bicyclic heteroaryl can be unsubstituted, or substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, thioalkyl, alkoxy, alkoxycarbonyl, amido, carboxy, cyano, halo, heteroaryl, nitro, and sulfonamido. In the disclosure, the bicyclic heteroaryl is unsubstituted, or substituted with one or more substituents selected from thioalkyl, alkoxycarbonyl, amido, carboxy, halo, and heteroaryl.

[0031] In the disclosure, Y is substituted with an amido substituent of the formula-C(O)NR 8< R 9< or -NR 9< C(O)R 10< , wherein R 8< and R 9< are each independently selected from H, alkyl, heterocyclyl and heteroaryl; or R 8< and R 9< , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocyclic or heteroaryl ring; and R 10< is alkyl.

[0032] In the disclosure, Y is substituted with a sulfonamido substituent of the formula-S(O) 2 NR 8< R 9< or -NR 9< S(O) 2 R 10< ; wherein R 8< and R 9< are each independently selected from H, alkyl, and heteroaryl; or R 8< and R 9< , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocyclic ring; and R 10< is alkyl.

[0033] The disclosure of variable Y in Formula (I) are understood to also be disclosures of variable Het in Formula (I').

[0034] In the disclosure, R 8< and R 9< are each independently selected from H, methyl, ethyl, triazolyl, and pyrazolyl. In the disclosure where one or both of R 8< and R 9< are alkyl, each alkyl is independently unsubstituted, or substituted with one or more substituents selected from methyl, methoxy, carboxy, cyano, hydroxy, dimethylamino, ethoxycarbonyl, phenyl, methoxyphenyl, oxadiazolyl, tetrazolyl, 2-methyl-tetrazolyl, triazolyl, 1-methyltriazolyl, 4-methyltriazolyl, and 2,4-dihydro-3H-1,2,4-triazol-3-onyl. In the disclosure, R 8< and R 9< , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from aziradine, isothiazolidine-1,1-dioxide, azetidine, thiazol-4(5Hn)-one, morpholine, piperidine, piperazine, pyrrolidine, thiomorpholine-1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane. In some embodiments, R 8< and R 9< , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from 2,8-diazaspiro[5,5]undecene, tetrahydroimidazo[1,2-a]pyrazine, octahydropyrazino[2,1-c][1,4]oxazine, tetrahydropyrido[3,4-d]pyrimidine, 2-oxa-8-azaspiro[4.5]decane, tetrahydropyrrolo[3,4-c]pyrazole, thiomorpholine, 2-oxa-7-azaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decan-3-one, tetrahydro-1,7-naphthyridine, 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, tetrahydropyrrolo[3,4-d]imidazole, pyrimidine, 8-oxa-2-azaspiro[4.5]decane, hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one, 1-oxa-7-azaspiro[3.5]nonane, octahydrocyclopenta[c]pyrrole, tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, 2,7-diazaspiro[4.4]nonane, 2,6-diazaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 1-oxa-8λ 2< -azaspiro[4.5]decane, 2-oxa-6-azaspiro[3.3]heptane, tetrahydrofuran, oxadiazole, triazole, pyridinone, tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one, piperidinone, 3,6-diazabicyclo[3.1.1]heptane, 5-oxa-2,7-diazaspiro[3.5]nonane, pyrazole, and pyridazin-3(2H)-one.

[0035] In the disclosure, the heterocyclic ring is unsubstituted, or substituted with one or more substituents selected from alkyl, alkoxycarbonyl, halo, hydroxy, cyano, carboxy, and heterocyclyl. In the disclosure, the heterocyclic ring is unsubstituted, or substituted with one or more substituents selected from methyl, ethoxycarbonyl, halo, hydroxy, cyano, carboxy, and oxetanyl.

[0036] The present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising a compound of the invention, and one or more pharmaceutically acceptable excipients. The pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein.Definitions

[0037] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0038] In this disclosure, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean " includes," "including," and the like; "consisting essentially of" or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0039] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural.

[0040] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0041] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0042] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0043] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0044] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0045] The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0046] An "alkyl" group or "alkane" is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C 1 -C 6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

[0047] Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, and the like.

[0048] The term "C x-y " when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term "C x-y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. C 0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "C 2-y alkenyl" and "C 2-y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0049] The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

[0050] The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0051] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0052] The term "amide", as used herein, refers to a group wherein each R 11< independently represents a hydrogen or hydrocarbyl group, or two R 11< are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0053] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R 11< independently represents a hydrogen or a hydrocarbyl group, or two R 11< are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term "aminoalkyl", as used herein, refers to an alkyl group substituted with an amino group.

[0054] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group.

[0055] The term "aryl" as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0056] The term "carbamate" is art-recognized and refers to a group wherein R 11< and R 12< independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R 11< and R 12< taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0057] The terms "carbocycle", and "carbocyclic", as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.

[0058] The term "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary disclosure, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. "Carbocycles" may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0059] A "cycloalkyl" group is a cyclic hydrocarbon which is completely saturated. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0060] The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted with a carbocycle group.

[0061] The term "carbonate" is art-recognized and refers to a group -OCO 2 -R 10< , wherein R 10< represents a hydrocarbyl group.

[0062] The term "carboxy", as used herein, refers to a group represented by the formula -CO 2 H.

[0063] The term "ester", as used herein, refers to a group -C(O)OR 10< wherein R 10< represents a hydrocarbyl group.

[0064] The term "ether", as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

[0065] The terms "halo" and "halogen" as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0066] The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl group substituted with a hetaryl group.

[0067] The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0068] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0069] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0070] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0071] The term "heterocyclylalkyl", as used herein, refers to an alkyl group substituted with a heterocycle group.

[0072] The term "hydrocarbyl", as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0073] The term "hydroxyalkyl", as used herein, refers to an alkyl group substituted with a hydroxy group.

[0074] The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In the disclosure, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0075] The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Each of the rings of the polycycle can be substituted or unsubstituted. In the disclosure, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0076] The term "silyl" refers to a silicon moiety with three hydrocarbyl moieties attached thereto.

[0077] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0078] The term "sulfate" is art-recognized and refers to the group -OSO 3 H, or a pharmaceutically acceptable salt thereof.

[0079] The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae wherein R 11< and R 12< independently represents hydrogen or hydrocarbyl, such as alkyl, or R 11< and R 12< taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0080] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 10< , wherein R 10< represents a hydrocarbyl.

[0081] The term "sulfonate" is art-recognized and refers to the group SO 3 H, or a pharmaceutically acceptable salt thereof.

[0082] The term "sulfone" is art-recognized and refers to the group -S(O) 2 -R 10< , wherein R 10< represents a hydrocarbyl.

[0083] The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group.

[0084] The term "thioester", as used herein, refers to a group -C(O)SR 10< or -SC(O)R 10< wherein R 10< represents a hydrocarbyl.

[0085] The term "thioether", as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0086] The term "urea" is art-recognized and may be represented by the general formula wherein R 11< and R 12< independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 11< taken together with R 12< and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0087] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[0088] Pharmaceutically acceptable isotopically-labelled compounds are described herein wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Compounds are enriched in such isotopically labeled substances (e.g., compounds wherein the distribution of isotopes in the compounds in the composition differ from a natural or typical distribution of isotopes).

[0089] Examples of isotopes suitable for inclusion in the compounds include isotopes of hydrogen, such as 2< H and 3< H carbon, such as 11< C, 13< C and 14< C, chlorine, such as 36< Cl, fluorine, such as 18< F, iodine, such as 123< I and 125< I, nitrogen, such as 13< N and 15< N, oxygen, such as 15< O, 17< O and 18< O, phosphorus, such as 32< P, and sulphur, such as 35< S.

[0090] Certain isotopically-labelled compounds as disclosed herein, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3< H, and carbon-14, i.e. 14< C, are useful for this purpose in view of their ease of incorporation and ready means of detection.

[0091] Substitution with heavier isotopes such as deuterium, i.e. 2< H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0092] Substitution with positron-emitting isotopes, such as 11< C, 18< F, 15< O and 13< N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0093] Compounds may be racemic. Compounds may be enriched in one enantiomer. For example, a compound may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. Compounds may have more than one stereocenter. Compounds may be enriched in one or more diastereomer. For example, a compound may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de.

[0094] The therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. The compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer.

[0095] The therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent.

[0096] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. Preferred subjects are humans.

[0097] As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0098] The term "treating" includes prophylactic and / or therapeutic treatments. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the subject of one or more of the disclosed compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0099] The term "prodrug" is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents. A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. The prodrug is converted by an enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs. Some or all of the compounds of Formula (I) in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid.

[0100] An "effective amount", as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A "therapeutically effective amount", as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.

[0101] A "response" to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others.Methods of Use

[0102] The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method of treatment of the human or animal body of therapy or for diagnosis.

[0103] The PCSK9 gene was identified using genetic mapping techniques on DNA from subjects with autosomal dominant hypercholesterolemia (Abifadel, et al. Nat. Genet. 2003 34: 154-6). The encoded protein is a serine protease that is mostly expressed in the liver, gut, kidney, and nervous system. While not wishing to be bound by any particular theory, studies on mutations in the gene indicated that its putative role was in reducing LDL receptors at the cell surface independently of its catalytic activity. (Abifadel, et al. Expert Opin. Ther. Pat. 2010 20:1547-71). Binding of PCSK9 to the receptors results in their lysosomal degradation. This enhanced degradation results in increases in the amount of circulating low-density lipoprotein LDL (LDL-c). PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonist, and insulin, but downregulated by dietary cholesterol, glucagon, ethinylestradiol, chenodeoxycholic acid and the bile acid-activated famesoid X receptor (FXR) (Maxwell, et al. J. Lipid Res. 2003 44:2109-19; Persson et al. Endocrinology 2009 150:1140-6; Langhi et al. FEBS Lett. 2008 582:949-55). Since an elevated level of PCSK9 decreases the abundance of LDL receptor on the cell surface, increasing doses of statins fail to achieve proportional LDL-cholesterol lowering results. Thus, disclosed herein are methods for treating a wide range of cardiovascular diseases and conditions that benefit from inhibiting PCSK9 thereby lowering LDL-c.

[0104] In the disclosure, the method of inhibiting PCSK9 occurs in a subject in need thereof, thereby treating a disease or disorder mediated by PCSK9.

[0105] Also, disclosed herein are methods of treating or preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Disclosed herein are methods of treating a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Disclosed herein are methods of preventing a disease or a disorder mediated by PCSK9 comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The prevention of cardiovascular events through the inhibition of PCSK9 has been described, e.g., in Robinson et al., Artherosclerosis 2015 243:593-597.

[0106] Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dimensia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure.

[0107] In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease. In certain embodiments, the disease is hypercholesterolemia, such as familial hypercholesterolemia or autosomal dominant hypercholesterolemia. In certain embodiments, the disease is hyperlipidemia. In certain embodiments, the disease is coronary artery disease.

[0108] In certain embodiments, the disclosed methods of treatment can decrease high levels of circulating serum cholesterol, such as LDL-cholesterol and VLDL-cholesterol. In addition, the disclosed methods are useful for decreasing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL and atherogenic lipoproteins. In certain embodiments, the diseases or conditions treated with the disclosed compounds and compositions include atherosclerosis and atherosclerotic plaque formation. Subjects having a gain-of-function mutation in the PCSK9 gene also benefit with treatment with the disclosed compounds and compositions counteracting the mutation through their inhibition of PCSK9.

[0109] Inhibition of PCSK9 has also shown therapeutic benefit in treating sepsis in a subject. Septic shock is an often fatal complication of a severe microbial infection (sepsis) that triggers an uncontrolled systemic inflammatory response and subsequent organ failure. Sepsis originates with the microbial cell walls that contain pathogenic lipid moieties such as lipopolysaccharide (LPS; Gram-negative bacteria). LPS are potent ligands for mammalian innate immune receptors [Toll-like receptors (TLRs)] and thus figure prominently in the septic inflammatory response (septic shock or sepsis). PCSK9 reduces LPS uptake by the liver's LDL receptors, such that free LPS overstimulates the body's immune response to the pathogen leading to sepsis. Inhibiting PCSK9 is beneficial in retaining liver LDL receptors to effect systemic pathogen clearance and detoxification in response to sepsis (See, e.g., Walley et al Sci. Translat. Med. 2014 6:1-10).

[0110] Disclosed herein are methods of treating sepsis or septic shock comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The disclosed methods of treatment are useful for increasing LPS uptake. The disclosure provides a method of decreasing the inflammatory response induced by sepsis or septic shock.Combination Treatments

[0111] Disclosed compounds and compositions may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of high levels of LDL and triglycerides. In certain embodiments, conjointly administering one or more additional therapeutic agents with a compound of the invention provides a synergistic effect. In certain embodiments, conjointly administering one or more additional therapeutic agents provides an additive effect.

[0112] In the disclosure, the method of treating a disease or a disorder mediated by PCSK9 comprises administering a PCSK9 inhibitor conjointly with one or more other therapeutic agent(s). In the disclosure, the PCSK9 inhibitor is a compound of Formula (I). Other therapeutic agents can include monoclonal antibodies such as alirocumab, evolocumab, bococizumab, RG7652, LY3015014, and mAb316P. Further exemplary antibodies include those described in WO / 2015 / 140079, WO / 2015 / 142668, WO / 2015 / 123423, WO / 2015 / 073494, WO / 2015 / 054619, WO / 2014 / 197752, WO / 2014 / 194111, WO / 2014 / 194168, WO / 2014 / 028354, WO / 2013 / 039969, WO / 2013 / 016648, WO / 2012 / 101251, WO / 2012 / 101253, WO / 2012 / 101252, WO / 2014 / 209384, WO / 2014 / 150983, WO / 2014 / 144080, WO / 2013 / 166448, WO / 2012 / 154999, WO / 2013 / 008185, WO / 2015 / 200438, WO / 2014 / 107739, WO / 2013 / 188855, WO / 2013 / 169886, WO / 2013 / 148284, WO / 2013 / 091103, WO / 2013 / 039958, WO / 2012 / 177741, WO / 2012 / 168491, WO / 2012 / 170607, WO / 2012 / 109530, WO / 2012 / 088313, WO / 2012 / 054438, WO / 2011 / 072263, WO / 2011 / 053759, WO / 2011 / 053783, and WO / 2011 / 037791. Other therapeutic agents that can be used in combination with the disclosed compounds and compositions include plant alkaloids and flavanoids known for their cholesterol-lowering activity, such as berberine and quercetin. In the disclosure, cholesterol-lowering small molecules, such as ezetimbe, and policosanol, can be administered as additional therapeutic agents. In the disclosure, polypeptides such as BMS-962476 and fibronectin-based scaffold domain proteins can be administered in combination with disclosed compounds and compositions. Further exemplary compounds include those described in WO / 2014 / 150326, WO / 2014 / 150395, WO / 2014 / 139008, WO / 2014 / 140210, WO / 2014 / 127316, WO / 2014 / 005224, WO / 2013 / 177536, WO / 2011 / 152508, WO / 2011 / 130354, WO / 2011 / 006000, and WO / 2015 / 077154.

[0113] In certain embodiments, additional therapeutic agents can be statins, such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. In other embodiments, disclosed compounds may be conjointly administered with an HMG-CoA reductase.

[0114] Any HMG-CoA reductase inhibitor may be used in the combination aspect of this invention. The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion.

[0115] The term HMG-CoA reductase inhibitor refers to compounds which inhibit the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by the enzyme HMG-CoA reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Meth. Enzymol. 1981; 71:455-509 and references cited therein). A variety of these compounds are described and referenced below however other HMG-CoA reductase inhibitors will be known to those skilled in the art. U.S. Pat. No. 4,231,938 discloses certain compounds isolated after cultivation of a microorganism belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Also, U.S. Pat. No. 4,739,073 discloses certain substituted indoles, such as fluvastatin. Also, U.S. Pat. No. 4,346,227 discloses ML-236B derivatives, such as pravastatin. Also, EP-491226A discloses certain pyridyldihydroxyheptenoic acids, such as cerivastatin. In addition, U.S. Pat. No. 5,273,995 discloses certain 6-[2- (substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin and any pharmaceutically acceptable form thereof (i.e. LIPITOR ®< ). Additional HMG-CoA reductase inhibitors include rosuvastatin and pitavastatin.

[0116] Atorvastatin calcium (i.e., atorvastatin hemicalcium), disclosed in U.S. Patent No. 5,273,995, is currently sold as Lipitor ®< .

[0117] Statins also include such compounds as rosuvastatin disclosed in U.S. RE37,314 E, pitivastatin disclosed in EP 304063 B1 and US 5,011,930, simvastatin, disclosed in U.S. 4,444,784, pravastatin, disclosed in U.S. 4,346,227; cerivastatin, disclosed in U.S. 5,502,199,; mevastatin, disclosed in U.S. 3,983,140,; velostatin, disclosed in U.S. 4,448,784 and U.S. 4,450,171,; fluvastatin, disclosed in U.S. 4,739,073; compactin, disclosed in U.S. 4,804,770; lovastatin, disclosed in U.S. 4,231,938; dalvastatin, disclosed in European Patent Application Publication No. 738510 A2; fluindostatin, disclosed in European Patent Application Publication No. 363934 A1; and dihydrocompactin, disclosed in U.S. 4,450,171.

[0118] Any HMG-CoA synthase inhibitor may be used in the combination aspect of this invention. The term HMG-CoA synthase inhibitor refers to compounds which inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth Enzymol. 1975; 35:155-160: Meth. Enzymol. 1985; 110:19-26 and references cited therein). A variety of these compounds are described and referenced below, however other HMG-CoA synthase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,120,729 discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). U.S. Pat. No. 4,847,271 discloses certain oxetane compounds such as 11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoic acid derivatives.

[0119] Any compound that decreases HMG-CoA reductase gene expression may be used in the combination aspect of this invention. These agents may be HMG-CoA reductase transcription inhibitors that block the transcription of DNA or translation inhibitors that prevent or decrease translation of mRNA coding for HMG-CoA reductase into protein. Such compounds may either affect transcription or translation directly, or may be biotransformed to compounds that have the aforementioned activities by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite that has the aforementioned activities. Such compounds may cause this effect by decreasing levels of SREBP (sterol regulatory element binding protein) by inhibiting the activity of site-1 protease (SI P) or agonizing the oxysterol receptor or antagonizing SCAP. Such regulation is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1985; 110:9-19). Several compounds are described and referenced below, however other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. U.S. Pat. No. 5,041,432 discloses certain 15- substituted Ianosterol derivatives.

[0120] Other oxygenated sterols that suppress synthesis of HMG-CoA reductase are discussed by E.l. Mercer (Prog.Lip. Res. 1993;32:357-416).

[0121] Any compound having activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the present invention. The term CETP inhibitor refers to compounds that inhibit the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343). A variety of CETP inhibitors will be known to those skilled in the art, for example, those disclosed in commonly assigned U.S. Patent Number 6,140,343 and commonly assigned U.S. Patent Number 6,197,786. CETP inhibitors are also described in U.S. Patent Number 6,723,752, which includes a number of CETP inhibitors including (2R)-3-{[3-(4-Chloro-3- ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol. Moreover, CETP inhibitors included herein are also described in U.S. PatentAppIication Number 10 / 807838 filed March 23, 2004. U.S. Patent Number 5,512,548 discloses certain polypeptide derivatives having activity as CETP inhibitors, while certain CETP-inhibitory rosenonolactone derivatives and phosphate-containing analogs of choIesteryl ester are disclosed in J. Antibiot, 49(8) 815-816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively.

[0122] Any PPAR modulator may be used in combination. The term PPAR modulator refers to compounds which modulate peroxisome proliferator activator receptor (PPAR) activity in mammals, particularly humans. Such modulation is readily determined by those skilled in the art according to standard assays known in the literature. It is believed that such compounds, by modulating the PPAR receptor, regulate transcription of key genes involved in lipid and glucose metabolism such as those in fatty acid oxidation and also those involved in high density lipoprotein (HDL) assembly (for example, apolipoprotein Al gene transcription), accordingly reducing whole body fat and increasing HDL cholesterol. By virtue of their activity, these compounds also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and their associated components such as apolipoprotein B in mammals, particularly humans, as well as increasing HDL cholesterol and apolipoprotein Al. Hence, these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia. A variety of these compounds are described and referenced below, however, others will be known to those skilled in the art. International Publication Nos. WO 02 / 064549 and 02 / 064130 and U.S. patent application 10 / 720942, filed November 24, 2003 and U.S. patent application 60 / 552114 filed March 10, 2004 disclose certain compounds which are PPARa activators.

[0123] Any other PPAR modulator may be used in the combination. In particular, modulators of PPARp and / or PPARy may be useful in combination. An example PPAR inhibitor is described in US2003 / 0225158 as {5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfany]-phenoxy}-acetic acid.

[0124] Any MTP / Apo B (microsomal triglyceride transfer protein and or apolipoprotein B) secretion inhibitor may be used in the combination aspect of this invention. The term MTP / Apo B secretion inhibitor refers to compounds which inhibit the secretion of triglycerides, cholesteryl ester, and phospholipids. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Wetterau, J. R. 1992; Science 258:999). A variety of MTP / Apo B secretion inhibitors will be known to those skilled in the art, including implitapide (Bayer) and additional compounds such as those disclosed in WO 96 / 40640 and WO 98 / 23593, (two exemplary publications).

[0125] Any squalene synthetase inhibitor may be used in the combination aspect of this invention. The term squalene synthetase inhibitor refers to compounds which inhibit the condensation of 2 molecules of famesylpyrophosphate to form squalene, catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1969; 15: 393-454 and Meth. Enzymol. 1985; 110:359-373 and references contained therein). A variety of these compounds are described in and referenced below however other squalene synthetase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,026,554 discloses fermentation products of the microorganism MF5465 (ATCC 74011) including zaragozic acid. A summary of other patented squalene synthetase inhibitors has been compiled (Curr. Op. Then Patents (1993) 861-4).

[0126] Any squalene epoxidase inhibitor may be used in the combination aspect of this invention. The term squalene epoxidase inhibitor refers to compounds which inhibit the bioconversion of squalene and molecular oxygen into squalene-2,3-epoxide, catalyzed by the enzyme squalene epoxidase. Such inhibition is readily determined by those skilled in the art according to standard assays (Biochim. Biophys. Acta 1984; 794:466-471). A variety of these compounds are described and referenced below, however other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,011,859 and 5,064,864 disclose certain fluoro analogs of squalene. EP publication 395,768 A discloses certain substituted allylamine derivatives. PCT publication WO 9312069 A discloses certain amino alcohol derivatives. U.S. Pat. No. 5,051,534 discloses certain cyclopropyloxy-squalene derivatives.

[0127] Any squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention. The term squalene cyclase inhibitor refers to compounds which inhibit the bioconversion of squalene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalene cyclase. Such inhibition is readily determined by those skilled in the art according to standard assays (FEBS Lett. 1989; 244:347-350). In addition, the compounds described and referenced below are squalene cyclase inhibitors, however other squalene cyclase inhibitors will also be known to those skilled in the art. Pd publication WO9410150 discloses certain 1,2,3,5,6,7,8,8a-octahydro-5,5,8(beta)-trimethyl-6- isoquinolineamine derivatives, such as N-trifluoroacetyl-1,2,3,5,6,7,8,8a-octahydro-2- allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolineamine. French patent publication 2697250 discloses certain beta, beta-dimethyl-4-piperidine ethanol derivatives such as 1-(1,5,9-trimethyldecyl)-beta,beta- dimethyl-4-piperidineethanol

[0128] Any combined squalene epoxidase / squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention. The term combined squalene epoxidase / squalene cyclase inhibitor refers to compounds that inhibit the bioconversion of squalene to lanosterol via a squalene-2,3-epoxide intermediate. In some assays it is not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors; however, these assays are recognized by those skilled in the art. Thus, inhibition by combined squalene epoxidase / squalene cyclase inhibitors is readily determined by those skilled in art according to the aforementioned standard assays for squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referenced below, however other squalene epoxidase / squalene cyclase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,084,461 and 5,278,171 disclose certain azadecalin derivatives. EP publication 468,434 discloses certain piperidyl ether and thio-ether derivatives such as 2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethyl sulfide. PCT publication WO 9401404 discloses certain acyl-piperidines such as 1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)-ethyl)piperidine. U.S. Pat. No. 5,102,915 discloses certain cyclopropyloxy-squalene derivatives.

[0129] The compounds of the present invention can also be administered in combination with naturally occurring compounds that act to lower plasma cholesterol levels. These naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract and niacin. A slow-release form of niacin is available and is known as Niaspan. Niacin may also be combined with other therapeutic agents such as lovastatin, or another HMG-CoA reductase inhibitor. This combination therapy with lovastatin is known as ADVICOR ™< (Kos Pharmaceuticals Inc.).

[0130] Any cholesterol absorption inhibitor can be used as an additional compound in the combination aspect of the present invention. The term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from entering into the intestinal cells and / or passing from within the intestinal cells into the lymph system and / or into the blood stream. Such cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res. (1993) 34: 377-395). Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94 / 00480. An example of a cholesterol absorption inhibitor is ZETIA ™< (ezetimibe) (Schering- Plough / Merck).

[0131] Any ACAT inhibitor may be used in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to compounds that inhibit the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acy!transferase. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Journal of Lipid Research., 24:1127 (1983). A variety of these compounds are known to those skilled in the art, for example, U.S. Patent No. 5,510,379 discloses certain carboxysulfonates, while WO 96 / 26948 and WO 96 / 10559 both disclose urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as Avasimibe (Pfizer), CS-505 (Sankyo) and Eflucimibe (Eli Lilly and Pierre Fabre).

[0132] A lipase inhibitor may be used in the combination therapy. A lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides or plasma phospholipids into free fatty acids and the corresponding glycerides (e.g. EL, HL, etc.). Under normal physiological conditions, Iipolysis occurs via a two-step process that involves acylation of an activated serine moiety of the lipase enzyme. This leads to the production of a fatty acid-lipase hemiacetal intermediate, which is then cleaved to release a diglyceride. Following further deacylation, the lipase-fatty acid intermediate is cleaved, resulting in free lipase, a glyceride and fatty acid. In the intestine, the resultant free fatty acids and monoglycerides are incorporated into bile acid-phospholipid micelles, which are subsequently absorbed at the level of the brush border of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Such lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

[0133] Pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the 1- and 3-carbon positions. The primary site of the metabolism of ingested fats is in the duodenum and proximal jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Because pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and the other related conditions. Such pancreatic lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

[0134] Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids needed to trigger pancreatic lipase activity in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, C.K. Abrams, et al., Gastroenterology, 92,125 (1987). Such gastric lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

[0135] A variety of gastric and / or pancreatic lipase inhibitors are known to one of ordinary skill in the art. Preferred lipase inhibitors are selected from lipstatin, tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A, and ebelactone B. The compound tetrahydrolipstatin is especially preferred. The lipase inhibitor, N-3-trifluoromethylphenyl-N'-3-chloro-4'-trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in U.S. Patent No. 4,405,644. The lipase inhibitor, esteracin, is disclosed in U.S. Patent Nos. 4,189,438 and 4,242,453. The lipase inhibitor, cyclo-0,0'-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and the various bis(iminocarbonyl)dioximes related thereto may be prepared as described in Petersen et al., Liebig's Annalen, 562, 205-229 (1949).

[0136] A variety of pancreatic lipase inhibitors are described herein below. The pancreatic lipase inhibitors lipstatin, (2S, 3S, 5S, 7Z, 10Z)-5-[(S)-2-formamido-4-methyl- valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), (2S, 3S, 5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic 1,3 acid lactone, and the variously substituted N-formylleucine derivatives and stereoisomers thereof, are disclosed in U.S. Patent No. 4,598,089. For example, tetrahydrolipstatin is prepared as described in, e.g., U.S. Patent Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. The pancreatic lipase inhibitor, FL-386, 1-[4-(2- methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]-ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in U.S. Patent No. 4,452,813. The pancreatic lipase inhibitor, WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl- carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in U.S. Patent Nos. 5,512,565; 5,391,571 and 5,602,151. The pancreatic lipase inhibitor, valilactone, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650 (1987). The pancreatic lipase inhibitors, ebelactone A and ebelactone B, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG7-G1, are disclosed in Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980). The use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in Japanese Kokai 08-143457, published June 4, 1996.

[0137] Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis include bile acid sequestrants, such as Welchol ®< , Colestid ®< , LoCholest ®< and Questran ®< ; and fibric acid derivatives, such as Atromid ®< , Lopid ®< and Tricor ®< .

[0138] Given the association between diabetes and atherosclerosis (e.g., Metabolic Syndrome) the compounds of formula I may be administered with antidiabetic compounds. Diabetes can be treated by administering to a patient having diabetes (especially Type II), insulin resistance, impaired glucose tolerance, metabolic syndrome, or the like, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound combination with other agents (e.g., insulin) that can be used to treat diabetes. This includes the classes of anti-diabetic agents (and specific agents) described herein.

[0139] Any glycogen phosphorylase inhibitor can be used as the second agent in combination with a compound. The term glycogen phosphorylase inhibitor refers to compounds that inhibit the bioconversion of glycogen to glucose-1-phosphate which is catalyzed by the enzyme glycogen phosphorylase. Such glycogen phosphorylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety of glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96 / 39384 and WO 96 / 39385.

[0140] Any aldose reductase inhibitor can be used in combination with a compound. The term aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase. Aldose reductase inhibition is readily determined by those skilled in the art according to standard assays (e.g., J. Malone, Diabetes, 29:861-864 (1980). "Red Cell Sorbitol, an Indicator of Diabetic Control"). A variety of aldose reductase inhibitors are known to those skilled in the art, such as those described in U.S. Patent No. 6,579,879, which includes 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.

[0141] Any sorbitol dehydrogenase inhibitor can be used in combination with a compound . The term sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose which is catalyzed by the enzyme sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitor activity is readily determined by those skilled in the art according to standard assays (e.g., Analyt. Biochem (2000) 280: 329-331). A variety of sorbitol dehydrogenase inhibitors are known, for example, U.S. Patent Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase.

[0142] Any glucosidase inhibitor can be used in combination with a compound . A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, into bioavailable simple sugars, for example, glucose. The rapid metabolic action of glucosidases, particularly following the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to enhanced secretion of insulin, increased fat synthesis and a reduction in fat degradation. Following such hyperglycemias, hypoglycemia frequently occurs, due to the augmented levels of insulin present. Additionally, it is known chyme remaining in the stomach promotes the production of gastric juice, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors are known to have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. Furthermore, the conversion of carbohydrates into lipids of the fatty tissue and the subsequent incorporation of alimentary fat into fatty tissue deposits is accordingly reduced or delayed, with the concomitant benefit of reducing or preventing the deleterious abnormalities resulting therefrom. Such glucosidase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Biochemistry (1969) 8: 4214).

[0143] A generally preferred glucosidase inhibitor includes an amylase inhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen into maltose. Such amylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. (1955) 1: 149). The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom.

[0144] A variety of glucosidase inhibitors are known to one of ordinary skill in the art and examples are provided below. Preferred glucosidase inhibitors are selected from acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. The glucosidase inhibitor, acarbose, and the various amino sugar derivatives related thereto are disclosed in U.S. Patent Nos. 4,062,950 and 4,174,439 respectively. The glucosidase inhibitor, adiposine, is disclosed in U.S. Patent No. 4,254,256. The glucosidase inhibitor, voglibose, 3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, and the various N- substituted pseudo-aminosugars related thereto, are disclosed in U.S. Patent No. 4,701,559. The glucosidase inhibitor miglitol, (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2- (hydroxymethyl)-3,4,5-piperidinetriol, and the various 3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S. Patent No. 4,639,436. The glucosidase inhibitor emiglitate, ethyl p-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate, the various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 5,192,772. The glucosidase inhibitor MDL-25637, 2,6-dideoxy-7-0-13-D-glucopyrano- syl-2,6-imino-D-glycero-L-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 4,634,765. The glucosidase inhibitor camiglibose, methyl 6-deoxy-6- [(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-a-D-glucopyranoside sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and synthetic methods for the preparation thereof, are disclosed in U.S. Patent Nos. 5,157,116 and 5,504,078. The glycosidase inhibitor salbostatin and the various pseudosaccharides related thereto are disclosed in U.S. Patent No. 5,091,524.

[0145] A variety of amylase inhibitors are known to one of ordinary skill in the art. The amylase inhibitor, tendamistat and the various cyclic peptides related thereto, are disclosed in U.S. Patent No. 4,451,455. The amylase inhibitor AI-3688 and the various cyclic polypeptides related thereto are disclosed in U.S. Patent No. 4,623,714. The amylase inhibitor trestatin, consisting of a mixture of trestatin A, trestatin B and trestatin C and the various trehalose-containing aminosugars related thereto are disclosed in U.S. Patent No. 4,273,765.

[0146] Additional anti-diabetic compounds, which can be used as the second agent in combination with a compound, includes, for example, the following: biguanides (e.g., metformin), insulin secretagogues (e.g., sulfonylureas and glinides), glitazones, non-glitazone PPARy agonists, PPARp agonists, inhibitors of DPP- IV, inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists, inhibitors of f-1,6- BPase(Metabasis / Sankyo), GLP-1 / analogs (AC 2993, also known as exendin-4), insulin and insulin mimetics (Merck natural products). Other examples would include PKC-P inhibitors and AGE breakers.

[0147] The compounds can also be used in combination with cardiovascular agents such as antihypertensive agents. Any anti-hypertensive agent can be used as the second agent in such combinations and examples are provided herein. Such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements).

[0148] AmLodipine and related dihydropyridine compounds are disclosed in U.S. Patent No. 4,572,909, as potent anti-ischemic and antihypertensive agents. U.S. Patent No. 4,879,303, discloses amLodipine benzenesulfonate salt (also termed amLodipine besylate). AmLodipine and amLodipine besylate are potent and long lasting calcium channel blockers. As such, amLodipine, amLodipine besylate, amLodipine maleate and other pharmaceutically acceptable acid addition salts of amLodipine have utility as antihypertensive agents and as antiischemic agents. AmLodipine besylate is currently sold as Norvasc ®< .

[0149] Calcium channel blockers include, but are not limited to: bepridil, which may be prepared as disclosed in U.S. Patent No. 3,962, 238 or U.S. Reissue No. 30,577; clentiazem, which may be prepared as disclosed in U.S. Patent No. 4,567,175; diltiazem, which may be prepared as disclosed in U.S. Patent No. 3,562, fendiline, which may be prepared as disclosed in U.S. Patent No. 3,262,977; gallopamil, which may be prepared as disclosed in U.S. Patent No. 3,261,859; mibefradil, which may be prepared as disclosed in U.S. Patent No. 4,808,605; prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; semotiadil, which may be prepared as disclosed in U.S. Patent No. 4,786,635; terodiline, which may be prepared as disclosed in U.S. Patent No. 3,371,014; verapamil, which may be prepared as disclosed in U.S. Patent No. 3,261,859; aranipine, which may be prepared as disclosed in U.S. Patent No.4,572,909; barnidipine, which may be prepared as disclosed in U.S. Patent No. 4,220,649; benidipine, which may be prepared as disclosed in European Patent Application Publication No. 106,275; cilnidipine, which may be prepared as disclosed in U.S. Patent No. 4,672,068; efonidipine, which may be prepared as disclosed in U.S. Patent No.4,885,284; elgodipine, which may be prepared as disclosed in U.S. Patent No. 4,952,592; felodipine, which may be prepared as disclosed in U.S. Patent No. 4,264,611; isradipine, which may be prepared as disclosed in U.S. Patent No. 4,466,972; lacidipine, which may be prepared as disclosed in U.S. Patent No.4,801,599; lercanidipine, which may be prepared as disclosed in U.S. Patent No. 4,705,797; manidipine, which may be prepared as disclosed in U.S. Patent No. 4,892,875; nicardipine, which may be prepared as disclosed in U.S. Patent No. 3,985,758; nifedipine, which may be prepared as disclosed in U.S. Patent No. 3,485,847; nilvadipine, which may be prepared as disclosed in U.S. Patent No. 4,338,322; nimodipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; nisoldipine, which may be prepared as disclosed in U.S. Patent No. 4,154,839; nitrendipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; cinnarizine, which may be prepared as disclosed in U.S. Patent No. 2,882,271; flunarizine, which may be prepared as disclosed in U.S. Patent No. 3,773,939; lidoflazine, which may be prepared as disclosed in U.S. Patent No. 3,267,104; lomerizine, which may be prepared as disclosed in U.S. Patent No. 4,663,325; bencyclane, which may be prepared as disclosed in Hungarian Patent No. 151,865; etafenone, which may be prepared as disclosed in German Patent No. 1,265,758; and perhexiline, which may be prepared as disclosed in British Patent No. 1,025,578. Examples of presently marketed products containing antihypertensive agents include calcium channel blockers, such as Cardizem ®< , Adalat ®< , Calan ®< , Cardene ®< , Covera ®< , Dilacor ®< , DynaCirc ®< ' Procardia XL ®< , Sular ®< , Tiazac ®< , Vascor ®< , Verelan ®< , Isoptin ®< , Nimotop ®< ' Norvasc ®< , and Plendil ®< ; angiotensin converting enzyme (ACE) inhibitors, such as Accupril ®< , Altace ®< , Captopril ®< , Lotensin ®< , Mavik ®< , Monopril ®< , Prinivil ®< , Univasc ®< , Vasotec ®< and Zestril ®< .

[0150] Angiotensin Converting Enzyme Inhibitors (ACE-Inhibitors) w include, but are not limited to: alacepril, which may be prepared as disclosed in U.S. Patent No. 4,248,883; benazepril, which may be prepared as disclosed in U.S. Patent No. 4,410,520; captopril, which may be prepared as disclosed in U.S. Patent Nos. 4,046,889 and 4,105,776; ceronapril, which may be prepared as disclosed in U.S. Patent No. 4,452,790; delapril, which may be prepared as disclosed in U.S. Patent No. 4,385,051; enalapril, which may be prepared as disclosed in U.S. Patent No. 4,374,829; fosinopril, which may be prepared as disclosed in U.S. Patent No. 4,337,201; imadapril, which may be prepared as disclosed in U.S. Patent No. 4,508,727; lisinopril, which may be prepared as disclosed in U.S. Patent No. 4,555,502; moveltopril, which may be prepared as disclosed in Belgian Patent No. 893,553; perindopril, which may be prepared as disclosed in U.S. Patent No. 4,508,729; quinapril, which may be prepared as disclosed in U.S. Patent No. 4,344,949; ramipril, which may be prepared as disclosed in U.S. Patent No. 4,587,258; spirapril, which may be prepared as disclosed in U.S. Patent No. 4,470,972; temocapril, which may be prepared as disclosed in U.S. Patent No. 4,699,905; and trandolapril, which may be prepared as disclosed in U.S. Patent No. 4,933,361.

[0151] Angiotensin-Il receptor antagonists (A-ll antagonists) include, but are not limited to: candesartan, which may be prepared as disclosed in U.S. Patent No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Patent No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S. Patent No. 5,270,317; losartan, which may be prepared as disclosed in U.S. Patent No. 5,138,069; and valsartan, which may be prepared as disclosed in U.S. Patent No. 5,399,578.

[0152] Beta-adrenergic receptor blockers (beta- or (3-blockers) include, but are not limited to: acebutolol, which may be prepared as disclosed in U.S. Patent No. 3,857,952; alprenolol, which may be prepared as disclosed in Netherlands PatentAppIication No. 6,605,692; amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,305; arotinolol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; atenolol, which may be prepared as disclosed in U.S. Patent No. 3,663,607 or 3,836,671; befunolol, which may be prepared as disclosed in U.S. Patent No. 3,853,923; betaxolol, which may be prepared as disclosed in U.S. Patent No. 4,252,984; bevantolol, which may be prepared as disclosed in U.S. Patent No. 3,857,981; bisoprolol, which may be prepared as disclosed in U.S. Patent No. 4,171,370; bopindolol, which may be prepared as disclosed in U.S. Patent No. 4,340,541; bucumolol, which may be prepared as disclosed in U.S. Patent No. 3,663,570; bufetolol, which may be prepared as disclosed in U.S. Patent No. 3,723,476; bufuralol, which may be prepared as disclosed in U.S. Patent No. 3,929,836; bunitrolol, which may be prepared as disclosed in U.S. Patent Nos. 3,940,489 and 3,961,071; buprandolol, which may be prepared as disclosed in U.S. Patent No. 3,309,406; butiridine hydrochloride, which may be prepared as disclosed in French Patent No. 1,390,056; butofilolol, which may be prepared as disclosed in U.S. Patent No. 4,252,825; carazolol, which may be prepared as disclosed in German Patent No. 2,240,599; carteolol, which may be prepared as disclosed in U.S. Patent No. 3,910,924; carvedilol, which may be prepared as disclosed in U.S. Patent No. 4,503,067; celiprolol, which may be prepared as disclosed in U.S. Patent No. 4,034,009; cetamolol, which may be prepared as disclosed in U.S. Patent No. 4,059,622; cloranolol, which may be prepared as disclosed in German Patent No. 2,213,044; dilevalol, which may be prepared as disclosed in Clifton et al., Journal of Medicinal Chemistry, 1982, 25, 670; epanolol, which may be prepared as disclosed in European Patent Publication Application No. 41,491; indenolol, which may be prepared as disclosed in U.S. Patent No. 4,045,482; labetalol, which may be prepared as disclosed in U.S. Patent No. 4,012,444; levobunolol, which may be prepared as disclosed in U.S. Patent No. 4,463,176; mepindolol, which may be prepared as disclosed in Seeman et al., Helv. Chim. Acta, 1971,54, 241; metipranolol, which may be prepared as disclosed in Czechoslovakian PatentAppIication No. 128,471; metoprolol, which may be prepared as disclosed in U.S. Patent No. 3,873,600; moprolol, which may be prepared as disclosed in U.S. Patent No. 3,501,7691; nadolol, which may be prepared as disclosed in U.S. Patent No. 3,935, 267; nadoxolol, which may be prepared as disclosed in U.S. Patent No. 3,819,702; nebivalol, which may be prepared as disclosed in U.S. Patent No. 4,654,362; nipradilol, which may be prepared as disclosed in U.S. Patent No. 4,394,382; oxprenolol, which may be prepared as disclosed in British Patent No. 1,077,603; perbutolol, which may be prepared as disclosed in U.S. Patent No. 3,551,493; pindolol, which may be prepared as disclosed in Swiss Patent Nos. 469,002 and 472,404; practolol, which may be prepared as disclosed in U.S. Patent No. 3,408,387; pronethalol, which may be prepared as disclosed in British Patent No. 909,357; propranolol, which may be prepared as disclosed in U.S. Patent Nos. 3,337,628 and 3,520,919; sotalol, which may be prepared as disclosed in Uloth et al., Journal of Medicinal Chemistry, 1966, 9, 88; sufinalol, which may be prepared as disclosed in German Patent No. 2,728,641; talindol, which may be prepared as disclosed in U.S. Patent Nos. 3,935,259 and 4,038,313; tertatolol, which may be prepared as disclosed in U.S. Patent No. 3,960,891; tilisolol, which may be prepared as disclosed in U.S. Patent No. 4,129,565; timolol, which may be prepared as disclosed in U.S. Patent No. 3,655,663; toliprolol, which may be prepared as disclosed in U.S. Patent No. 3,432,545; and xibenolol, which may be prepared as disclosed in U.S. Patent No. 4,018,824.

[0153] Alpha-adrenergic receptor blockers (alpha- or a-blockers) include, but are not limited to: amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,307; arotinolol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S. Patent No. 4,252,721; doxazosin, which may be prepared as disclosed in U.S. Patent No. 4,188,390; fenspiride, which may be prepared as disclosed in U.S. Patent No. 3,399,192; indoramin, which may be prepared as disclosed in U.S. Patent No. 3,527,761; labetolol, which may be prepared as disclosed above; naftopidil, which may be prepared as disclosed in U.S. Patent No. 3,997,666; nicergoline, which may be prepared as disclosed in U.S. Patent No. 3,228,943; prazosin, which may be prepared as disclosed in U.S. Patent No. 3,511,836; tamsulosin, which may be prepared as disclosed in U.S. Patent No. 4,703,063; tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161,938; trimazosin, which may be prepared as disclosed in U.S. Patent No. 3,669,968; and yohimbine, which may be isolated from natural sources according to methods well known to those skilled in the art.

[0154] The term "vasodilator," where used herein, is meant to include cerebral vasodilators, coronary vasodilators and peripheral vasodilators. Cerebral vasodilatorsinclude, but are not limited to: bencyclane, which may be prepared as disclosed above; cinnarizine, which may be prepared as disclosed above; citicoline, which may be isolated from natural sources as disclosed in Kennedy et al., Journal of the American Chemical Society, 1955, 77, 250 or synthesized as disclosed in Kennedy, Journal of Biological Chemistry, 1956, 222, 185; cyclandelate, which may be prepared as disclosed in U.S. Patent No. 3,663,597; ciclonicate, which may be prepared as disclosed in German Patent No. 1,910,481; diisopropylamine dichloroacetate, which may be prepared as disclosed in British Patent No. 862,248; ebumamonine, which may be prepared as disclosed in Hermann et al., Journal of the American Chemical Society, 1979, 101, 1540; fasudil, which may be prepared as disclosed in U.S. Patent No. 4,678,783; fenoxedil, which may be prepared as disclosed in U.S. Patent No. 3,818,021; flunarizine, which may be prepared as disclosed in U.S. Patent No. 3,773,939; ibudilast, which may be prepared as disclosed in U.S. Patent No. 3,850,941; ifenprodil, which may be prepared as disclosed in U.S. Patent No. 3,509,164; lomerizine, which may be prepared as disclosed in U.S. Patent No. 4,663,325; nafronyl, which may be prepared as disclosed in U.S. Patent No. 3,334,096; nicametate, which may be prepared as disclosed in Blicke et al., Journal of the American Chemical Society, 1942, 64, 1722; nicergoline, which may be prepared as disclosed above; nimodipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; papaverine, which may be prepared as reviewed in Goldberg, Chem. Prod. Chem. News, 1954, 17, 371; pentifylline, which maybe prepared as disclosed in German Patent No. 860,217; tinofedrine, which may be prepared as disclosed in U.S. Patent No. 3,563,997; vincamine, which may be prepared as disclosed in U.S. Patent No. 3,770,724; vinpocetine, which may be prepared as disclosed in U.S. Patent No. 4,035,750; and viquidil, which may be prepared as disclosed in U.S. Patent No. 2,500,444.

[0155] Coronary vasodilators include, but are not limited to: amotriphene, which may be prepared as disclosed in U.S. Patent No. 3,010,965; bendazol, which may be prepared as disclosed in J. Chem. Soc. 1958, 2426; benfurodil hemisuccinate, which may be prepared as disclosed in U.S. Patent No. 3,355,463; benziodarone, which may be prepared as disclosed in U.S. Patent No. 3,012,042; chloracizine, which may be prepared as disclosed in British Patent No. 740,932; chromonar, which may be prepared as disclosed in U.S. Patent No. 3,282,938; clobenfural, which may be prepared as disclosed in British Patent No. 1,160,925; clonitrate, which may be prepared from propanediol according to methods well known to those skilled in the art, e.g., see Annalen, 1870, 155, 165; cloricromen, which may be prepared as disclosed in U.S. Patent No. 4,452,811; dilazep, which may be prepared as disclosed in U.S. Patent No. 3,532,685; dipyridamole, which may be prepared as disclosed in British Patent No. 807,826; droprenilamine, which may be prepared as disclosed in German Patent No. 2,521,113; efloxate, which may be prepared as disclosed in British Patent Nos. 803,372 and 824,547; erythrityl tetranitrate, which may be prepared by nitration of erythritol according to methods well-known to those skilled in the art; etafenone, which may be prepared as disclosed in German Patent No. 1,265,758; fendiline, which may be prepared as disclosed in U.S. Patent No. 3,262,977; floredil, which may be prepared as disclosed in German Patent No. 2,020,464; ganglefene, which may be prepared as disclosed in U.S.S.R. Patent No. 115,905; hexestrol, which may be prepared as disclosed in U.S. Patent No. 2,357,985; hexobendine, which may be prepared as disclosed in U.S. Patent No. 3,267,103; itramin tosylate, which may be prepared as disclosed in Swedish Patent No. 168,308; khellin, which may be prepared as disclosed in Baxter et al., Journal of the Chemical Society, 1949, S 30; lidoflazine, which may be prepared as disclosed in U.S. Patent No. 3,267,104; mannitol hexanitrate, which may be prepared by the nitration of mannitol according to methods well-known to those skilled in the art; medibazine, which may be prepared as disclosed in U.S. Patent No. 3,119,826; nitroglycerin; pentaerythritol tetranitrate, which may be prepared by the nitration of pentaerythritol according to methods well-known to those skilled in the art; pentrinitrol, which may be prepared as disclosed in German Patent No. 638,422-3; perhexilline, which may be prepared as disclosed above; pimefylline, which may be prepared as disclosed in U.S. Patent No. 3,350,400; prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; propatyl nitrate, which may be prepared as disclosed in French Patent No. 1,103,113; trapidil, which may be prepared as disclosed in East German Patent No. 55,956; tricromyl, which may be prepared as disclosed in U.S. Patent No. 2,769,015; trimetazidine, which may be prepared as disclosed in U.S. Patent No. 3,262,852; trolnitrate phosphate, which may be prepared by nitration of triethanolamine followed by precipitation with phosphoric acid according to methods well-known to those skilled in the art; visnadine, which may be prepared as disclosed in U.S. Patent Nos. 2,816,118 and 2,980,699.

[0156] Peripheral vasodilators include, but are not limited to: aluminum nicotinate, which may be prepared as disclosed in U.S. Patent No. 2,970,082; bamethan, which may be prepared as disclosed in Corrigan et al., Journal of the American Chemical Society, 1945, 67, 1894; bencyclane, which may be prepared as disclosed above; betahistine, which may be prepared as disclosed in Walter et al.; Journal of the American Chemical Society, 1941, 63, 2771; bradykinin, which maybe prepared as disclosed in Hamburg et al., Arch. Biochem. Biophys., 1958, 76, 252; brovincamine, which may be prepared as disclosed in U.S. Patent No. 4,146,643; bufeniode, which may be prepared as disclosed in U.S. Patent No. 3,542,870; buflomedil, which may be prepared as disclosed in U.S. Patent No. 3,895,030; butalamine, which may be prepared as disclosed in U.S. Patent No. 3,338,899; cetiedil, which may be prepared as disclosed in French Patent Nos. 1,460,571; ciclonicate, which may be prepared as disclosed in German Patent No. 1,910,481; cinepazide, which may be prepared as disclosed in Belgian Patent No. 730,345; cinnarizine, which may be prepared as disclosed above; cyclandelate, which may be prepared as disclosed above; diisopropylamine dichloroacetate, which may be prepared as disclosed above; eledoisin, which may be prepared as disclosed in British Patent No. 984,810; fenoxedil, which may be prepared as disclosed above; flunarizine, which may be prepared as disclosed above; hepronicate, which may be prepared as disclosed in U.S. Patent No. 3,384,642; ifenprodil, which may be prepared as disclosed above; iloprost, which may be prepared as disclosed in U.S. Patent No. 4,692,464; inositol niacinate, which may be prepared as disclosed in Badgett et al., Journal of the American Chemical Society, 1947, 69, 2907; isoxsuprine, which may be prepared as disclosed in U.S. Patent No. 3,056,836; kallidin, which may be prepared as disclosed in Biochem. Biophys. Res. Commun., 1961, 6, 210; kallikrein, which may be prepared as disclosed in German Patent No. 1,102,973; moxisylyte, which may be prepared as disclosed in German Patent No. 905,738; nafronyl, which may be prepared as disclosed above; nicametate, which may be prepared as disclosed above; nicergoline, which may be prepared as disclosed above; nicofuranose, which may be prepared as disclosed in Swiss Patent No. 366,523; nylidrin, which may be prepared as disclosed in U.S. Patent Nos. 2,661,372 and 2,661,373; pentifylline, which may be prepared as disclosed above; pentoxifylline, which may be prepared as disclosed in U.S. Patent No. 3,422,107; piribedil, which may be prepared as disclosed in U.S.Patent No. 3,299,067; prostaglandin E-i, which may be prepared by any of the methods referenced in the Merck Index, Twelfth Edition, Budaveri, Ed., New Jersey, 1996, p. 1353; suloctidil, which may be prepared as disclosed in German Patent No. 2,334,404; tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161,938; and xanthinol niacinate, which may be prepared as disclosed in German Patent No. 1,102,750 or Korbonits et al., Acta. Pharm. Hung., 1968, 38, 98.

[0157] The term "diuretic,", is meant to include diuretic benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils and other diuretics such as amanozine, which may be prepared as disclosed in Austrian Patent No. 168,063; amiloride, which may be prepared as disclosed in Belgian Patent No. 639,386; arbutin, which may be prepared as disclosed in Tschitschibabin, Annalen, 1930, 479, 303; chlorazanil, which may be prepared as disclosed in Austrian Patent No. 168,063; ethacrynic acid, which may be prepared as disclosed in U.S. Patent No. 3,255,241; etozolin, which may be prepared as disclosed in U.S. Patent No. 3,072,653; hydracarbazine, which may be prepared as disclosed in British Patent No. 856,409; isosorbide, which may be prepared as disclosed in U.S. Patent No. 3,160,641; mannitol; metochalcone, which may be prepared as disclosed in Freudenberg et al., Ber., 1957, 90, 957; muzolimine, which may be prepared as disclosed in U.S. Patent No. 4,018,890; perhexiline, which may be prepared as disclosed above; ticrynafen, which may be prepared as disclosed in U.S. Patent No. 3,758,506; triamterene which may be prepared as disclosed in U.S. Patent No. 3,081,230; and urea.

[0158] Diuretic benzothiadiazine derivatives include, but are not limited to: althiazide, which may be prepared as disclosed in British Patent No. 902,658; bendroflumethiazide, which may be prepared as disclosed in U.S. Patent No. 3,265,573; benzthiazide, McManus et al., 136th Am. Soc. Meeting (Atlantic City, September 1959), Abstract of papers, pp 13-0; benzylhydrochlorothiazide, which may be prepared as disclosed in U.S. Patent No. 3,108,097; buthiazide, which may be prepared as disclosed in British Patent Nos. 861,367 and 885,078; chlorothiazide, which may be prepared as disclosed in U.S. Patent Nos. 2,809,194 and 2,937,169; chlorthalidone, which may be prepared as disclosed in U.S. Patent No. 3,055,904; cyclopenthiazide, which may be prepared as disclosed in Belgian Patent No. 587,225; cyclothiazide, which may be prepared as disclosed in Whitehead et al., Journal of Organic Chemistry, 1961,26, 2814; epithiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911; ethiazide, which may be prepared as disclosed in British Patent No. 861,367; fenquizone, which may be prepared as disclosed in U.S. Patent No. 3,870,720; indapamide, which may be prepared as disclosed in U.S. Patent No. 3,565,911; hydrochlorothiazide, which may be prepared as disclosed in U.S. Patent No. 3,164,588; hydroflumethiazide, which may be prepared as disclosed in U.S. Patent No. 3,254,076; methyclothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960, 82, 1132; meticrane, which may be prepared as disclosed in French Patent Nos. M2790 and 1,365,504; metolazone, which may be prepared as disclosed in U.S. Patent No. 3,360,518; paraflutizide, which may be prepared as disclosed in Belgian Patent No. 620,829; polythiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911; quinethazone, which may be prepared as disclosed in U.S. Patent No. 2,976,289; teclothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960, 82, 1132; and trichlormethiazide, which may be prepared as dislcosed in deStevens et al., Experientia, 1960, 16, 113.

[0159] Diuretic sulfonamide derivatives include, but are not limited to: acetazolamide, which may be prepared as disclosed in U.S. Patent No. 2,980,679; ambuside, which may be prepared as disclosed in U.S. Patent No. 3,188,329; azosemide, which may be prepared as disclosed in U.S. Patent No. 3,665,002; bumetanide, which may be prepared as disclosed in U.S. Patent No. 3,634,583; butazolamide, which may be prepared as disclosed in British Patent No. 769,757; chloraminophenamide, which may be prepared as disclosed in U.S. Patent Nos. 2,809,194, 2,965,655 and 2,965,656; clofenamide, which may be prepared as disclosed in Olivier, Rec. Trav. Chim., 1918, 37, 307; clopamide, which may be prepared as disclosed in U.S. Patent No. 3,459,756; clorexolone, which may be prepared as disclosed in U.S. Patent No. 3,183,243; disulfamide, which may be prepared as disclosed in British Patent No. 851,287; ethoxolamide, which may be prepared as disclosed in British Patent No. 795,174; furosemide, which may be prepared as disclosed in U.S. Patent No. 3,058,882; mefruside, which may be prepared as disclosed in U.S. Patent No. 3,356,692; methazolamide, which may be prepared as disclosed in U.S. Patent No. 2,783,241; piretanide, which may be prepared as disclosed in U.S. Patent No. 4,010,273; torasemide, which may be prepared as disclosed in U.S. Patent No. 4,018,929; tripamide, which may be prepared as disclosed in Japanese Patent No. 73 05,585; and xipamide, which may be prepared as disclosed in U.S. Patent No. 3,567,777. Other additional agents for combination with compounds disclosed herein include PCSK9 translation inhibitors as described in WO2016 / 055901.

[0160] In some embodiments, additional therapeutic agents include an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP / Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase / squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, a bile acid sequestrant, and a PCSK9 translation inhibitor.

[0161] For the treatment of sepsis or septic shock, disclosed methods may include an additional therapeutic agent, such as an antibiotic. In the disclosure, the antibiotic is an aminoglycoside such as, but not limited to, kanamycin, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, streptomycin, and neomycins B, C, and E. Other antibiotics include carbapenems such as, but not limited to, imipenum, meropenum, ertapenem, doripenum, panipenum, biapenem, razupenum, tebipenum, lenapenum, tomopenum, and thienpenum.

[0162] Further antibiotics include quinolones such as, but not limited to, ciprofloxacin, garenoxacin, gatifloxacin, gemifloxaicin, levofloxacin, cinoxacin, nalidixic acid, moxifloxacin, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, sitafloxacin, trovafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, nemonoxacin, and zabofloxacin.

[0163] Further antibiotics include tetracyclines such as, but not limited to, doxycycline, tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, and tigecycline.

[0164] Additional antibiotics useful in the methods disclosed herein include, but are not limited to, ampicillin, amoxicillin, augmentin, piperacillin, tazobactam, chloramphenicol, and ticarcillin.Pharmaceutical Compositions

[0165] The compositions and methods of the present invention may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0166] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0167] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0168] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0169] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In the disclosure a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0170] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0171] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0172] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0173] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0174] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0175] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

[0176] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0177] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0178] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0179] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0180] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0181] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0182] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0183] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0184] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0185] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0186] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0187] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124,. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0188] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0189] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0190] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0191] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0192] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0193] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0194] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0195] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0196] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0197] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882).

[0198] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0199] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. The active compound may be administered two or three times daily. The active compound may be administered once daily.

[0200] The compound of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. The different therapeutic compounds can be administered within one hour, 12 h, 24 h, 36 h, 48 h, 72 h, or a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.

[0201] In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., compound of formula I or Ia) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).

[0202] This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

[0203] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0204] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0205] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.Examples and Reference Examples

[0206] Examples and reference examples of compounds of Formula (I), or pharmaceutically acceptable salts thereof, having useful biological activity are listed in Tables 1-10. 1< H NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency), equipped with: a self-shielded z-gradient coil 5 mm 1H / nX broad band probehead for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with transmitter offset frequency shift. Chemical shift are reported as δ values in ppm relative to trimethylsilane (TMS) as an internal standard. Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following abbreviation (s= singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=not determined).A. Analytical methodsMethod 1 (acid FA)UPLC Setup

[0207] Solvents: - A Water (High purity via PureLab Option unit) with 0.1% formic acid B Acetonitrile (Far UV grade) with 0.1% (V / V) formic acid Column:- Acquity UPLC HSS C18 1.8 um 100 x 2.1 mm. (Plus guard cartridge)Flow Rate:- 0.5 mL / min Gradient:

[0208] Time (min)%A%B0.009551.29553.501004.9010059556955 Injections 0.5-2 uL UV detection via Waters DAD Start Range (nm)210End Range (nm)400Resolution (nm)1.2 MS detection: Waters SQD2, single quadrapole UPLC-MS Scan range for MS Data (m / z) Start (m / z)100End (m / z)700 or 1500 when required With +ve / -ve switching Ionisation is ESI.

[0209] ESI voltages and temperatures are: Source 150C3.5KV capillary25V cone Method 2 (basic FA)UPLC SetupSolvents: - Acetonitrile (Far UV grade)Water (High purity via PureLab Option unit) with 10 mM ammonium bicarbonate (ammonium hydrogen carbonate)

[0210] Column: -Acquity UPLC BEH Shield RP18 1.7 um 100 x 2.1 mm. (Plus guard cartridge)Flow Rate: -0.5 mL / minGradient: -A: Water / BasicB: MeCN / Basic TimeA%B%0.009551.209553.501004.9001005.009556.00955 Typical Injections 0.5-2 uL (concentration ~ 0.2 -1 mg / mL). UV detection via Waters DAD Start Range (nm)210End Range (nm)400Resolution (nm)1.2 Other wavelength traces are extracted from the DAD data. MS detection: Waters SQD2, single quadrapole UPLC-MS Flow splitter gives approximately 300ul / min to mass spec Scan range for MS Data (m / z) Start (m / z)100End (m / z)700 or 1500 when required With +ve / -ve switching Preparative reverse-phase HPLC conditions Preparative HPLC Waters Micromass ZQ / Sample manager 2767 Photodiode array detector 2996; Column: XTerra Prep MS C18 Column (5 µm, 19 x 150 mm, Waters) Flow rate: 20 mL / min with MS detection UV wavelength: 254 nm. Mobile phase: Solvent A (water:MeCN:HCO2H 95:5:0.05); Solvent B (water:MeCN:HCO2H 5:95:0.05) Gradient: Time (min)%A%B0.00100.00.001.001000.0010.000.00100.011.000.00100.012.00100.00.00

[0211] Flash chromatography is carried out using an Isolera MPLC system (manufactured by Biotage) using pre-packed silica gel or reverse-phase cartridges (supplied by Biotage or Interchim).B. Chemical Syntheses

[0212] The general procedures used in the methods to prepare the compounds are described below: 2-Chloro-5-(methylthio)pyrimidine (100B)

[0213] Dimethyl disulphide (13.96 mL, 155.4 mmol, 1.0 eq) was added under nitrogen to a - 75 °C cooled solution of 5-bromo-2-chloropyrimidine (100A) (30 g, 155.4 mmol, 1.0 eq) in anhydrous tetrahydrofuran (700 mL). To this mixture was added a solution of n-butyl lithium (2.5 M, 68.4 mL, 170.9 mmol, 1.0 eq) dropwise over 1.5 h, with the internal temperature maintained at -70 °C to -75 °C throughout the addition. After complete addition, the mixture was stirred at -75 °C for 4.5 h and was then quenched by the slow addition of a saturated solution of ammonium chloride (100 mL). The cooling bath was removed and the reaction was allowed to warm to room temperature under nitrogen over 18 h. The reaction mixture was diluted with ethyl acetate (500 mL), washed with water (50 mL) and then saturated brine (50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude pale yellow oil obtained was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-50%) to give the desired product 2-chloro-5-(methylthio)pyrimidine as a waxy pale yellow solid (100B). Yield: 7.39 g (29%). 1< H NMR (CDCl 3 ) δ 8.48 (2H, s), 2.54 (3H, s); MS (ESI+) m / z 161 (M+H) +< .General Method 1 tert-Butyl (2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (100C)

[0214] tert-Butyl(3-amino-2-methylpropyl)carbamate (4.79 g, 25.52 mmol, 1.05 eq) was added to a stirred suspension of 2-chloro-5-(methylthio)pyrimidine (100B) (3.89 g, 24.31 mmol, 1.0 eq) and cesium carbonate (11.85 g, 36.46 mmol, 1.4 eq) in anhydrous dimethylformamide (50 mL). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to ~20 mL. The liquor was diluted with ethyl acetate (100 mL), washed with water (75 mL) and brine (50 mL) and then dried over magnesium sulfate. The solvents were removed under vacuum to afford a crude residue that was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-50%) to give the desired product tert-butyl (2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) carbamate (100C) as a pale yellow oil. Yield: 6.59 g (86%). MS (ESI+) m / z 313 (M+H) +< .tert-Butyl (S)-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) carbamate (100D)

[0215] Racemic tert-butyl (2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (100C) (5 g) was purified by chiral SFC using the following conditions: YMC amylose-C 30 / 70 MeOH / CO 2 , 100 mL / min, 120 bar, 40 °C, GLS 40 psi, System 3900 psi, drop 140 bar, Stacker, DAD 245 nm.

[0216] First-eluting isomer, 1.3 minutes. tert-Butyl (R)-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate Yield: 2.05 g. 1< H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 2H), 5.79 (dd, J=6.7, 6.7 Hz, 1H), 5.18 (dd, J=5.8, 5.8 Hz, 1H), 3.50 - 3.39 (m, 1H), 3.33 - 3.14 (m, 2H), 3.04 - 2.94 (m, 1H), 2.36 (s, 3H), 1.94 - 1.85 (m, 1H), 1.45 (s, 9H), 0.95 (d, J=6.9 Hz, 3H). MS (ESI+) m / z 313 (M+H) +< .

[0217] Second-eluting isomer, 1.7 minutes. tert-Butyl (S)-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (100D) Yield: 2.48 g. 1< H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 2H), 5.77 - 5.69 (m, 1H), 5.15 (dd, J =6.5, 6.5 Hz, 1H), 3.50 - 3.40 (m, 1H), 3.33 - 3.16 (m, 2H), 3.03 - 2.94 (m, 1H), 2.36 (s, 3H), 1.95 - 1.85 (m, 1H), 1.47 (s, 9H), 0.95 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 313 (M+H) +< .General Method 2 (R)-2-Methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E)

[0218] A solution of hydrogen chloride (15 mL, 4M in 1,4-dioxane) was added to tert-butyl (S)-(2-ethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (100D) (600 mg, 2.48 mmol) and the mixture was stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford the desired product (R)-2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) as a pale yellow semi-solid. Yield: 548 mg (100%) HCl salt. 1< H NMR (400 MHz, DMSO) δ 8.39 (s, 2H), 8.00 - 7.96 (m, 3H), 7.72 - 7.72 (m, 1H), 3.32 - 3.18 (m, 2H), 2.88 - 2.80 (m, 1H), 2.66 - 2.55 (m, 1H), 2.38 (s, 3H), 2.13 - 2.00 (m, 1H), 0.96 (d, J=6.8 Hz, 3H); MS (ESI+) m / z 213 (M+H) +< .General Method 3 Ethyl (5)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d]thiazole-6-carboxylate (100F)

[0219] Ethyl-2-chlorobenzothiazole-6-carboxylate (600 mg, 2.48 mmol, 1.0 eq) was added to a stirred solution of (R)-2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) (548 mg, 2.48 mmol, 1.0 eq) and triethylamine (1.73 mL, 12.44 mmol, 5.0 eq) in anhydrous dimethylformamide (20 mL) under nitrogen. The mixture was stirred at room temperature for 48 h and then concentrated under vacuum to ~5 mL. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (25 mL) then dried over magnesium sulfate. The solvents were removed under vacuum to give a crude yellow oil which was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-100%) to give the desired ethyl (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d] thiazole-6-carboxylate (100F) as an off white solid. Yield: 647 mg (62%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 8.27 (d, J=1.5 Hz, 1H), 7.99 (dd, J=1.8, 8.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.02 - 6.98 (m, 1H), 5.83 (dd, J=6.7, 6.7 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.67 - 3.47 (m, 2H), 3.42 - 3.24 (m, 2H), 2.37 (s, 3H), 2.20 - 2.11 (m, 1H), 1.40 (dd, J=7.2, 7.2 Hz, 3H), 1.07 (d, J=7.0 Hz, 3H); MS (ESI+) m / z 418 (M+H) +< .General Method 4 (S)-2-((2-Methyl-3-((5-(methylthio)pytimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxylic acid (Reference Example 1)

[0220] Lithium hydroxide monohydrate (318 mg, 7.75 mmol, 5.0 eq) was added to a stirred solution of ethyl (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d]thiazole-6-carboxylate (100F) (647 mg, 1.55 mmol, 1.0 eq) in ethanol (7 mL) and water (5 mL). The mixture was stirred at ambient temperature for 18 h and then concentrated under reduced pressure. Water (5 mL) was added to the residue and this mixture was acidified to pH ~3 with a solution of aqueous hydrochloric acid (2M). A precipitate that formed was collected by filtration, washed with water and then dried under high vacuum to give the desired product (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)benzo[d]thiazole-6-carboxylic acid (Reference Example 1) as a pale yellow solid.General Method 5 Methyl (5)-2-methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)benzo [d]thiazole-6-carboxamido)propanoate (100G)

[0221] 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 146 mg, 0.385 mmol, 1.5 eq) was added to a solution of (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d] thiazole-6-carboxylic acid (1) (100 mg, 0.257 mmol, 1.0 eq), triethylamine (0.36 mL, 2.57 mmol, 10.0 eq) and methyl-2-amino-2-methylpropanoate hydrochloride (196 mg, 1.28 mmol, 4.9 eq) in dimethylformamide (5 mL) and the reaction mixture was stirred at room temperature for 18 h. The solvents were removed under reduced pressure and the crude residue obtained was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-75%) to give the desired methyl (S)-2-methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)benzo[d] thiazole-6-carboxamido) propanoate (G) as an off-white solid. Yield: 120 mg (95%). 1< H NMR (400 MHz, MeOD) δ 8.34 (s, 2H), 8.10 (d, J=1.8 Hz, 1H), 7.77 (dd, J=1.9, 8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), 3.45 (dd, J=6.3, 22.4 Hz, 4H), 2.34 (s, 3H), 2.29 - 2.16 (m, 1H), 1.59 (s, 6H), 1.08 (d, J=6.9 Hz, 3H) NH exchangeable protons not observed; MS (ESI+) m / z 489 (M+H) +< .(S)-2-Methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)benzo[d] thiazole-6-carboxamido)propanoic acid (Reference Example 2) Method analogous to General Method 4

[0222] Lithium hydroxide mono-hydrate (50 mg, 1.22 mmol, 5.0 eq) was added to a stirred solution of methyl (S)-2-methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d] thiazole-6-carboxamido) propanoate (100G) (120 mg, 0.245 mmol, 1.0 eq) in ethanol (5 mL) and water (5 mL) and the mixture was stirred at room temperature for 1 hour. The solvents were removed under vacuum and the residue was diluted with water (3 mL) and acidified to pH ~3 with aqueous solution of hydrochloride acid (2M). A precipitate that formed was collected by filtration, washed with water and then dried under high vacuum to give the title compound as an off-white solid.

[0223] Using the above procedures, the following examples were synthesized: Table 1 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 1 1< H NMR (400 MHz, DMSO) δ 8.43 (dd, J = 4.8, 4.8 Hz, 1H), 8.33 (s, 2H), 8.26 (d, J =1.8 Hz, 1H), 7.81 (dd, J = 1.8, 8.5 Hz, 1H), 7.53 (dd, J = 5.6, 5.6 Hz, 1H), 7.38 (d, J =8.4 Hz, 1H), 3.35 - 3.23 (m, 4H), 2.34 (s, 3H), 2.17 - 2.07 (m, 1H), 0.96 (d, J =6.7 Hz, 3H).390 Reference 2 1< H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 2H), 8.00 (d, J = 1.1 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.20 - 7.20 (m, 1H), 3.54 - 3.48 (m, 1H), 3.43 - 3.27 (m, 3H), 2.36 (s, 3H), 2.19 - 2.13 (m, 1H), 1.74 (d, J = 3.2 Hz, 6H), 1.03 (d, J = 6.9 Hz, 3H) NH protons not observed.475 Reference 3 1< H NMR (400 MHz, DMSO) δ 8.90 (dd, J = 6.0, 6.0 Hz, 1H), 8.34 (s, 2H), 8.30 (dd, J =5.5, 5.5 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 1.8, 8.4 Hz, 1H), 7.52 (dd, J =5.8, 5.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.33 (d, J =4.4 Hz, 4H), 7.27 - 7.22 (m, 1H), 4.48 (d, J =6.0 Hz, 2H), 3.48 - 3.41 (m, 1H), 3.31 - 3.23 (m, 3H), 2.34 (s, 3H), 2.17 - 2.00 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).479 Reference 4 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.73 (d, J =1.3 Hz, 1H), 7.51 (d, J =8.3 Hz, 1H), 7.39 (dd, J =1.5, 8.3 Hz, 1H), 6.77 (s, 1H), 5.77 - 5.74 (m, 1H), 3.89 - 3.85 (m, 2H), 3.71 (s, 2H), 3.63 - 3.47 (m, 2H), 3.42 - 3.25 (m, 2H), 3.12 (s, 3H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.06 (d, J =6.8 Hz, 3H) NH protons not observed.447 Reference 5 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.67 (d, J =1.5 Hz, 1H), 7.51 (d, J =8.1 Hz, 1H), 7.32 (dd, J =1.8, 8.1 Hz, 1H), 6.67 - 6.64 (m, 1H), 5.70 (dd, J =6.8, 6.8 Hz, 1H), 4.02 - 3.95 (m, 2H), 3.63 - 3.49 (m, 2H), 3.42 - 3.29 (m, 4H), 2.37 (s, 3H), 2.20 - 2.09 (m, 1H), 1.95 - 1.88 (m, 2H), 1.06 (d, J =6.8 Hz, 3H) NH protons not observed.473 Reference 6 1< H NMR (400 MHz, DMSO) δ 8.38 (s, 2H), 8.36 - 8.30 (m, 2H), 8.18 (d, J =1.8 Hz, 1H), 7.76 (dd, J =1.9, 8.5 Hz, 1H), 7.56 (dd, J =6.1, 6.1 Hz, 1H), 7.40 (d, J =8.6 Hz, 1H), 3.52 - 3.44 (m, 1H), 3.34 - 3.27 (m, 3H), 2.83 (d, J =4.5 Hz, 3H), 2.39 (s, 3H), 2.22 - 2.10 (m, 1H), 1.00 (d, J =6.8 Hz, 3H).403 Reference 7 1< H NMR (400 MHz, DMSO) δ 8.34 (s, 2H), 8.26 (dd, J =5.6, 5.6 Hz, 1H), 7.85 (s, 1H), 7.51 (dd, J =5.8, 5.8 Hz, 1H), 7.37 (s, 2H), 3.94 - 3.83 (m, 4H), 3.48 - 3.40 (m, 1H), 3.31 - 3.24 (m, 8H), 2.34 (s, 3H), 2.14 - 1.99 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).507 Reference 8 1< H NMR (400 MHz, DMSO) δ 8.34 (s, 2H), 8.31 (d, J =5.6 Hz, 2H), 8.17 (d, J =1.8 Hz, 1H), 7.73 (dd, J =1.8, 8.4 Hz, 1H), 7.52 (dd, J =5.9, 5.9 Hz, 1H), 7.37 (d, J =8.4 Hz, 1H), 3.76 (d, J =5.1 Hz, 2H), 3.49 - 3.40 (m, 1H), 3.33 - 3.22 (m, 3H), 2.34 (s, 3H), 2.17 - 2.07 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).447 Reference 9 1< H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 2H), 8.02 (s, 1H), 7.72 (dd, J =1.4, 8.5 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J =8.3 Hz, 1H), 6.20 - 6.18 (m, 1H), 3.73 - 3.58 (m, 3H), 3.49 (dd, J =4.2, 13.8 Hz, 1H), 3.40 - 3.20 (m, 2H), 3.01 - 2.91 (m, 2H), 2.59 (s, 6H), 2.36 (s, 4H), 2.20 - 2.13 (m, 1H), 1.07 (d, J =6.8 Hz, 3H).460 Reference 10 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.69 (d, J =1.5 Hz, 1H), 7.51 (d, J =8.3 Hz, 1H), 7.36 (dd, J = 1.8, 8.3 Hz, 1H), 6.75 - 6.74 (m, 1H), 5.70 (dd, J =6.4, 6.4 Hz, 1H), 3.63 - 3.47 (m, 2H), 3.42 - 3.25 (m, 2H), 3.08 (s, 6H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.06 (d, J =6.9 Hz, 3H).417 Reference 11 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 8.32 (s, 1H), 7.68 (s, 1H), 7.50 (d, J =8.3 Hz, 1H), 7.35 - 7.30 (m, 1H), 5.90 (dd, J =5.8, 5.8 Hz, 1H), 3.76 (s, 4H), 3.62 - 3.53 (m, 1H), 3.48 (dd, J =4.8, 13.8 Hz, 1H), 3.43 - 3.35 (m, 1H), 3.29 (dd, J =7.5, 13.7 Hz, 1H), 3.05 - 2.98 (m, 4H), 2.62 (s, 1H), 2.37 (s, 3H), 2.19 - 2.12 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).458 Reference 12 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 7.90 (s, 1H), 7.52 - 7.44 (m, 2H), 7.00 (s, 1H), 5.90 (s, 1H), 4.75 - 4.68 (m, 1H), 4.51 (dd, J =8.0, 8.0 Hz, 2H), 4.15 - 4.15 (m, 2H), 3.65 - 3.57 (m, 1H), 3.55 - 3.48 (m, 1H), 3.41 - 3.33 (m, 1H), 3.30 - 3.24 (m, 1H), 2.61 (s, 1H), 2.37 (s, 3H), 2.20 - 2.12 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).455 Reference 13 1< H NMR (400 MHz, DMSO) δ 8.33 (s, 2H), 8.22 (dd, J =5.4, 5.4 Hz, 1H), 8.15 (s, 1H), 7.74 (d, J =1.5 Hz, 1H), 7.51 (dd, J =5.8, 5.8 Hz, 1H), 7.36 (d, J =8.3 Hz, 1H), 7.25 (dd, J =1.8, 8.3 Hz, 1H), 4.49 (s, 1H), 3.52 (dd, J =6.0, 6.0 Hz, 5H), 3.47 - 3.40 (m, 2H), 3.29 - 3.19 (m, 4H), 2.48 (d, J =7.5 Hz, 4H), 2.34 (s, 3H), 2.14 - 2.08 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).502 Reference 14 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 8.09 (d, J =1.5 Hz, 1H), 7.66 (dd, J =1.9, 8.5 Hz, 1H), 7.52 (d, J =8.3 Hz, 1H), 6.80 (s, 1H), 6.50 (dd, J =5.2, 5.2 Hz, 1H), 5.69 (dd, J =6.7, 6.7 Hz, 1H), 3.69 - 3.55 (m, 5H), 3.40 (s, 6H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.07 (d, J =6.8 Hz, 3H).447 Reference 15 1< H NMR (400 MHz, DMSO) δ 8.34 (s, 2H), 8.29 (dd, J =5.4, 5.4 Hz, 2H), 8.17 (d, J =1.8 Hz, 1H), 7.74 (dd, J =1.8, 8.5 Hz, 1H), 7.52 (dd, J =6.0, 6.0 Hz, 1H), 7.36 (d, J =8.4 Hz, 1H), 4.71 (dd, J =5.4, 5.4 Hz, 1H), 3.55 - 3.41 (m, 3H), 3.31 - 3.23 (m, 5H), 2.34 (s, 3H), 2.17 - 2.06 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).433 Reference 16 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 8.09 (s, 1H), 8.06 (s, 1H), 7.90 - 7.90 (m, 1H), 7.72 (dd, J =1.9, 8.4 Hz, 1H), 7.52 (d, J =9.0 Hz, 2H), 7.14 (s, 1H), 5.99 (s, 1H), 3.91 (s, 3H), 3.62 (ddd, J =4.4, 6.9, 14.3 Hz, 1H), 3.51 (d, J =13.4 Hz, 1H), 3.41 - 3.33 (m, 1H), 3.29 - 3.22 (m, 1H), 2.37 (s, 3H), 2.21 - 2.13 (m, 1H), 1.08 (d, J =6.9 Hz, 3H).469 Reference 17 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.80 (s, 1H), 7.52 (d, J =8.3 Hz, 1H), 7.46 (d, J =7.9 Hz, 1H), 6.79 - 6.78 (m, 1H), 5.67 (dd, J =6.5, 6.5 Hz, 1H), 3.95 - 3.81 (m, 3H), 3.73 (s, 1H), 3.64 - 3.56 (m, 1H), 3.55 - 3.48 (m, 1H), 3.42 - 3.34 (m, 1H), 3.32 - 3.25 (m, 1H), 3.19 (s, 1H), 2.37 (s, 3H), 2.30 (d, J =6.0 Hz, 2H), 2.20 - 2.10 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).468 Reference 18 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.69 (d, J =1.5 Hz, 1H), 7.52 (d, J =8.3 Hz, 1H), 7.33 (dd, J =1.6, 8.3 Hz, 1H), 6.77 (s, 1H), 5.69 (dd, J =6.5, 6.5 Hz, 1H), 3.96 (d, J =9.9 Hz, 1H), 3.67 (d, J =13.4 Hz, 1H), 3.64 - 3.55 (m, 5H), 3.51 (dd, J =4.5, 13.7 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.29 (dd, J =7.5, 14.2 Hz, 1H), 3.18 (s, 1H), 3.03 (s, 1H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).489 Reference 19 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 7.92 (d, J =1.1 Hz, 1H), 7.52 - 7.50 (m, 2H), 6.87 - 6.87 (m, 1H), 5.73 (dd, J =6.1, 6.1 Hz, 1H), 4.82 (s, 4H), 4.43 - 4.43 (m, 4H), 3.64 - 3.48 (m, 2H), 3.42 - 3.26 (m, 2H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).471 Reference 20 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 8.03 (s, 1H), 7.64 (dd, J =1.9, 8.4 Hz, 1H), 7.49 (d, J =8.4 Hz, 1H), 6.53 - 6.53 (m, 1H), 6.01 - 5.99 (m, 1H), 4.41 (d, J =5.8 Hz, 2H), 3.62 (ddd, J =4.3, 6.7, 14.3 Hz, 1H), 3.51 (dd, J =4.3, 13.8 Hz, 1H), 3.41 - 3.22 (m, 2H), 2.37 (s, 3H), 2.20 - 2.13 (m, 1H), 1.08 (d, J =6.9 Hz, 3H) NH protons not observed.428 Reference 21 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.68 (d, J =1.6 Hz, 1H), 7.51 (d, J =8.3 Hz, 1H), 7.33 (dd, J =1.6, 8.3 Hz, 1H), 6.87 - 6.86 (m, 1H), 5.77 (dd, J =6.2, 6.2 Hz, 1H), 4.70 - 4.60 (m, 4H), 3.70 (s, 3H), 3.63 - 3.47 (m, 3H), 3.42 - 3.25 (m, 2H), 2.37 (s, 6H), 2.20 - 2.12 (m, 2H), 1.06 (d, J =6.9 Hz, 3H) NH protons not observed. 1< H NMR (400 MHz, DMSO) δ 8.33 (s, 2H), 8.23 (dd, J =5.5, 5.5 Hz, 1H), 7.75 (s, 1H), 7.51 (dd, J =5.9, 5.9 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.27 - 7.23 (m, 1H), 4.58 - 4.51 (m, 2H), 4.45 (dd, J =5.7, 5.7 Hz, 2H), 3.53 - 3.53 (m, 4H), 3.47 - 3.39 (m, 2H), 3.29 - 3.22 (m, 3H), 2.34 (s, 3H), 2.29 (s, 4H), 2.17 - 2.06 (m, 1H), 0.95 (d, J =6.7 Hz, 3H). NH protons not observed514 Reference 22 1< H NMR (400 MHz, DMSO) δ 8.34 (s, 2H), 8.22 (dd, J =5.5, 5.5 Hz, 1H), 7.76 (d, J =1.5 Hz, 1H), 7.52 (dd, J =5.9, 5.9 Hz, 1H), 7.36 (d, J =8.2 Hz, 1H), 7.29 (dd, J =1.6, 8.3 Hz, 1H), 4.90 - 4.90 (m, 1H), 3.79 - 3.79 (m, 3H), 3.65 (s, 1H), 3.59 - 3.40 (m, 4H), 3.31 - 3.20 (m, 4H), 2.34 (s, 3H), 2.17 - 2.05 (m, 1H), 0.95 (d, J =6.7 Hz, 3H) NH protons not observed.489 Reference 23 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 8.10 (s, 1H), 8.05 (s, 1H), 7.72 (dd, J =1.9, 8.5 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.18 - 7.17 (m, 1H), 6.04 (d, J =4.9 Hz, 1H), 4.83 (d, J =5.5 Hz, 2H), 3.80 (s, 3H), 3.64 - 3.48 (m, 2H), 3.41 - 3.26 (m, 2H), 2.36 (s, 3H), 2.21 - 2.13 (m, 1H), 1.06 (d, J =6.9 Hz, 3H).484 Reference 24 1< H NMR (400 MHz, DMSO) δ 12.42 - 12.42 (m, 1H), 8.48 (s, 1H), 8.41 (d, J =1.6 Hz, 1H), 8.33 (s, 2H), 8.03 (dd, J =1.6, 8.5 Hz, 1H), 7.51 (dd, J =5.9, 5.9 Hz, 1H), 7.41 (d, J =8.4 Hz, 1H), 3.95 (s, 2H), 3.49 - 3.38 (m, 2H), 3.29 - 3.20 (m, 2H), 2.34 (s, 3H), 2.17 - 2.08 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).488 Reference 25 1< H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.39 (dd, J =5.5, 5.5 Hz, 1H), 8.34 (s, 3H), 8.15 (d, J =1.6 Hz, 1H), 7.72 (dd, J = 1.8, 8.5 Hz, 1H), 7.52 (dd, J =5.3, 5.3 Hz, 1H), 7.36 (d, J =8.4 Hz, 1H), 3.48 - 3.43 (m, 4H), 3.33 - 3.23 (m, 4H), 2.34 (s, 3H), 2.17 - 2.06 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).461 Reference 26 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 2H), 7.95 (s, 1H), 7.52 (s, 2H), 6.93 - 6.93 (m, 1H), 5.65 (dd, J =6.6, 6.6 Hz, 1H), 4.56 (dd, J =12.0, 12.0 Hz, 4H), 3.60 (ddd, J =4.5, 7.2, 14.4 Hz, 1H), 3.51 (s, 1H), 3.42 - 3.26 (m, 2H), 2.38 (s, 3H), 2.20 - 2.11 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).465 Reference 27 1< H NMR (400 MHz, DMSO) δ 8.55 - 8.52 (m, 2H), 8.34 (s, 2H), 8.05 (dd, J =1.8, 8.6 Hz, 1H), 7.65 (s, 3H), 7.51 (dd, J =5.8, 5.8 Hz, 1H), 7.43 (d, J =8.5 Hz, 1H), 3.52 - 3.44 (m, 1H), 3.30 - 3.20 (m, 3H), 2.34 (s, 3H), 2.16 - 2.08 (m, 1H), 0.97 (d, J =6.8 Hz, 3H).456 Reference 28 1< H NMR (400 MHz, DMSO) δ 9.13 (dd, J =5.3, 5.3 Hz, 1H), 8.57 - 8.57 (m, 1H), 8.34 (s, 2H), 8.24 (s, 1H), 7.83 - 7.79 (m, 1H), 7.57 - 7.57 (m, 1H), 7.42 (d, J =8.4 Hz, 1H), 4.76 (d, J =5.6 Hz, 2H), 3.50 - 3.43 (m, 1H), 3.35 - 3.23 (m, 3H), 2.34 (s, 3H), 2.17 - 2.08 (m, 1H), 0.97 (d, J=6.8 Hz, 3H) NH protons not observed.471 Reference 29 1< H NMR (400 MHz, DMSO) δ 8.29 (s, 2H), 8.03 (s, 1H), 7.93 (d, J =1.5 Hz, 1H), 7.49 (dd, J =1.8, 8.4 Hz, 1H), 7.33 (d, J =8.4 Hz, 1H), 7.12 (dd, J =5.8, 5.8 Hz, 1H), 4.82 (dd, J =5.3, 9.4 Hz, 1H), 4.33 - 4.25 (m, 1H), 4.14 - 4.07 (m, 1H), 3.47 - 3.23 (m, 4H), 2.66 - 2.55 (m, 1H), 2.33 (s, 3H), 2.21 - 2.08 (m, 2H), 0.97 (d, J =6.8 Hz, 3H) NH protons not observed, VT @ 85°C.473 Reference 30 1< H NMR (400 MHz, DMSO) δ 8.32 (s, 2H), 7.85 (s, 1H), 7.71 (d, J =1.4 Hz, 1H), 7.37 (d, J =8.3 Hz, 1H), 7.29 (dd, J =1.6, 8.2 Hz, 1H), 7.02 (s, 1H), 3.97 (s, 2H), 3.50 - 3.30 (m, 4H), 3.01 (s, 3H), 2.36 (s, 3H), 2.22 - 2.13 (m, 1H), 1.01 (d, J =6.8 Hz, 3H) NH protons not observed, VT @ 125°C.461 Reference 31 1< H NMR (400 MHz, DMSO) δ 9.03 (dd, J =5.6, 5.6 Hz, 1H), 8.38 (s, 3H), 8.24 (d, J =1.8 Hz, 1H), 7.88 (s, 1H), 7.81 (dd, J =1.9, 8.5 Hz, 1H), 7.57 (dd, J =5.9, 5.9 Hz, 1H), 7.41 (d, J =8.3 Hz, 1H), 4.64 (d, J =5.6 Hz, 2H), 3.94 (s, 3H), 3.53 - 3.44 (m, 1H), 3.35 - 3.27 (m, 3H), 2.38 (s, 3H), 2.21 - 2.10 (m, 1H), 1.00 (d, J =6.8 Hz, 3H).484 Reference 32 1< H NMR (400 MHz, DMSO) δ 9.60 (1H, s), 9.09 (1H, dd, J =5.7, 5.7 Hz), 8.38 (3H, s), 8.24 (1H, d, J =1.8 Hz), 7.81 (1H, dd, J =1.8, 8.3 Hz), 7.58 (1H, dd, J =5.9, 5.9 Hz), 7.43 (1H, d, J =8.3 Hz), 4.67 (2H, d, J =5.8 Hz), 3.54 - 3.45 (2H, m), 3.36 - 3.27 (2H, m), 2.38 (3H, s), 2.21 - 2.10 (1H, m), 1.01 (3H, d, J =6.8 Hz).471 Reference 33 1< H NMR (400 MHz, DMSO) δ 9.16 (dd, J =5.6, 5.6 Hz, 1H), 8.41 (d, J =5.6 Hz, 1H), 8.38 (s, 2H), 8.23 (d, J =1.8 Hz, 1H), 7.80 (dd, J =1.8, 8.6 Hz, 1H), 7.57 (dd, J =5.9, 5.9 Hz, 1H), 7.42 (d, J =8.6 Hz, 1H), 4.80 (d, J =5.6 Hz, 2H), 4.15 (s, 3H), 3.53 - 3.45 (m, 1H), 3.36 - 3.27 (m, 3H), 2.38 (s, 3H), 2.21 - 2.10 (m, 1H), 1.00 (d, J =6.6 Hz, 3H).485 Reference 34 1< H NMR (400 MHz, DMSO) δ 11.30 (2H, s), 8.80 (1H, dd, J =5.3, 5.3 Hz), 8.38 (3H, s), 8.24 (1H, d, J =1.5 Hz), 7.81 (1H, dd, J =1.6, 8.5 Hz), 7.58 (1H, dd, J =5.9, 5.9 Hz), 7.42 (1H, d, J =8.3 Hz), 4.30 (2H, d, J =5.3 Hz), 3.53 - 3.45 (1H, m), 3.35 - 3.27 (3H, m), 2.39 (3H, s), 2.21 - 2.11 (1H, m), 1.00 (3H, d, J =6.6 Hz).486 Reference 35 1< H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.38 (s, 2H), 8.36 (d, J =5.6 Hz, 1H), 8.25 (d, J =1.5 Hz, 1H), 7.83 (dd, J =1.8, 8.3 Hz, 1H), 7.58 (dd, J =5.9, 5.9 Hz, 1H), 7.42 (d, J =8.3 Hz, 1H), 4.59 (d, J =4.8 Hz, 2H), 3.53 - 3.45 (m, 1H), 3.36 - 3.27 (m, 3H), 2.39 (s, 3H), 2.21 - 2.11 (m, 1H), 1.00 (d, J =6.8 Hz, 3H) NH protons not observed.470 Reference 36 1< H NMR (400 MHz, DMSO) δ 9.09 (dd, J =5.8, 5.8 Hz, 1H), 8.38 (s, 3H), 8.23 (d, J =1.5 Hz, 1H), 7.81 (dd, J =1.8, 8.6 Hz, 1H), 7.58 (dd, J =5.9, 5.9 Hz, 1H), 7.42 (d, J =8.3 Hz, 1H), 4.74 (d, J =5.6 Hz, 2H), 4.38 (s, 3H), 3.53 - 3.45 (m, 1H), 3.36 - 3.27 (m, 3H), 2.39 (s, 3H), 2.21 - 2.11 (m, 1H), 1.00 (d, J =6.8 Hz, 3H).485 Reference 37 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 8.14 (d, J =1.6 Hz, 1H), 7.93 - 7.93 (m, 1H), 7.79 (dd, J =1.7, 8.5 Hz, 1H), 7.52 (d, J =8.4 Hz, 1H), 6.92 (s, 1H), 5.82 - 5.81 (m, 1H), 4.94 - 4.87 (m, 1H), 3.88 - 3.82 (m, 2H), 3.61 (ddd, J =4.5, 7.0, 14.4 Hz, 2H), 3.53 - 3.50 (m, 1H), 3.41 - 3.24 (m, 3H), 2.56 (s, 3H), 2.37 (s, 3H), 2.20 - 2.11 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).458 Reference 38 1< H NMR (400 MHz, DMSO) δ 8.41 (s, 2H), 8.38 (d, J =5.5 Hz, 1H), 8.40 - 8.37 (m, 1H), 8.04 (d, J =1.6 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.49 (d, J =6.9 Hz, 5H), 7.43 (d, J =8.3 Hz, 2H), 4.57 - 4.57 (m, 2H), 4.26 - 4.25 (m, 3H), 3.55 - 3.45 (m, 2H), 3.33 (dd, J =6.8, 13.3 Hz, 3H), 2.42 (s, 3H), 2.24 - 2.16 (m, 1H), 1.03 (d, J =6.7 Hz, 3H).560 Reference 39 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (2H, s), 7.94 (1H, d, J =1.4 Hz), 7.56 - 7.53 (1H, m), 7.50 (1H, d, J =8.3 Hz), 6.76 (1H, s), 5.68 (1H, dd, J =6.6, 6.6 Hz), 4.42 (2H, s), 4.04 - 3.92 (2H, m), 3.68 - 3.49 (3H, m), 3.42 - 3.26 (2H, m), 2.40 (6H, d, J =18.1 Hz), 2.25 - 2.11 (1H, m), 1.06 (3H, d, J =6.9 Hz); One NH proton not observed458 Reference 40 1< H NMR (400 MHz, DMSO) δ 8.33 (2H, s), 8.30 (1H, dd, J =5.6, 5.6 Hz), 7.96 (1H, d, J =1.6 Hz), 7.54 - 7.47 (2H, m), 7.34 (1H, d, J =8.3 Hz), 4.45 (1H, s), 4.17 (1H, s), 3.92 (1H, s), 3.76 - 3.69 (2H, m), 3.47 - 3.40 (2H, m), 3.29 - 3.23 (3H, m), 2.34 (3H, s), 2.17 - 2.06 (1H, m), 0.96 (3H, d, J =6.8 Hz); One NH proton not observed444 Reference 41 1< H NMR (400 MHz, MeOD) δ 8.33 (2H, s), 7.97 (1H, d, J =1.6 Hz), 7.60 (1H, dd, J =1.8, 8.4 Hz), 7.48 (1H, d, J =8.5 Hz), 4.59 - 4.10 (4H, m), 3.52 - 3.40 (6H, m), 2.45 (6H, s), 2.34 (3H, s), 2.24 - 2.16 (1H, m), 1.08 (3H, d, J =6.8 Hz); One NH proton not observed472 Reference 42 1< H NMR (400 MHz, DMSO) δ 8.49 - 8.47 (m, 3H), 8.34 (s, 1H), 7.98 (d, J =1.6 Hz, 1H), 7.54 (s, 1H), 7.49 (dd, J =1.8, 8.4 Hz, 1H), 7.37 (d, J =8.4 Hz, 1H), 4.52 - 4.52 (m, 2H), 4.21 (s, 2H), 4.14 - 4.06 (m, 4H), 3.97 (s, 1H), 3.33 - 3.26 (m, 3H), 2.34 (s, 3H), 209 (s, 1H), 0.96 (d, J =6.8 Hz, 3H). Formate salt. One NH not observed.470 Reference 43 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.75 (s, 1H), 7.54 (d, J =8.3 Hz, 1H), 7.39 (dd, J =1.6, 8.3 Hz, 1H), 6.89 - 6.89 (m, 1H), 5.69 - 5.66 (m, 1H), 4.80 (s, 1H), 4.43 (d, J =9.2 Hz, 1H), 4.10 - 4.08 (m, 2H), 3.80 - 3.49 (m, 6H), 3.43 - 3.25 (m, 3H), 2.95 (d, J =12.8 Hz, 2H), 2.38 (s, 3H), 2.20 - 2.10 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).544 Reference 44 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.70 (d, J =1.5 Hz, 1H), 7.53 (d, J =8.4 Hz, 1H), 7.33 (dd, J =1.8, 8.3 Hz, 1H), 6.85 - 6.85 (m, 1H), 5.71 (dd, J =6.6, 6.6 Hz, 1H), 4.72 - 4.12 (m, 3H), 3.98 (d, J =7.8 Hz, 1H), 3.90 - 3.81 (m, 2H), 3.63 - 3.48 (m, 2H), 3.43 - 3.25 (m, 2H), 3.08 - 3.06 (m, 2H), 2.89 - 2.83 (m, 1H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).514 Reference 45 1< H NMR (400 MHz, CDCl 3 ) δ 8.55 - 8.54 (m, 1H), 8.37 (s, 2H), 7.64 (s, 1H), 7.50 (d, J =8.3 Hz, 1H), 6.86 - 6.86 (m, 1H), 5.80 (dd, J =6.5, 6.5 Hz, 1H), 3.74 (s, 4H), 3.63 - 3.46 (m, 6H), 3.42 - 3.24 (m, 2H), 2.37 (s, 3H), 2.20 - 2.09 (m, 1H), 1.83 - 1.86 (m, 4H), 1.06 (d, J =6.9 Hz, 3H), NH proton not observed.498 Reference 46 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.69 (d, J =1.5 Hz, 1H), 7.53 (d, J =8.4 Hz, 1H), 7.32 (dd, J = 1.7, 8.3 Hz, 1H), 6.95 (s, 1H), 5.71 (dd, J =6.6, 6.6 Hz, 1H), 4.18 - 4.18 (m, 2H), 3.91 (d, J =9.7 Hz, 1H), 3.79 - 3.74 (m, 1H), 3.63 - 3.48 (m, 2H), 3.43 - 3.26 (m, 2H), 3.10 (d, J =8.8 Hz, 2H), 2.91 - 2.88 (m, 1H), 2.38 (s, 3H), 2.20 - 2.10 (m, 1H), 1.26 - 1.12 (m, 2H), 1.07 (d, J =6.9 Hz, 3H), 0.78 - 0.75 (m, 2H).540 Reference 47 1< H NMR (400 MHz, CDCl 3 ) δ 8.42 (s, 1H), 8.38 (s, 2H), 7.64 (d, J =1.4 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.30 (dd, J =1.8, 8.3 Hz, 1H), 5.72 (dd, J =6.7, 6.7 Hz, 1H), 3.63 - 3.47 (m, 9H), 3.43 - 3.25 (m, 3H), 2.96 - 2.89 (m, 1H), 2.37 (s, 3H), 2.20 - 2.12 (m, 1H), 1.87 (t, J =6.1 Hz, 4H), 1.20 (d, J =6.4 Hz, 6H), 1.07 (d, J =6.9 Hz, 3H).540 Reference 48 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.67 (s, 1H), 7.51 (d, J =8.3 Hz, 1H), 7.31 (d, J =8.0 Hz, 1H), 6.75 - 6.68 (m, 1H), 5.75 (dd, J =6.7, 6.7 Hz, 1H), 3.63 - 3.46 (m, 4H), 3.42 - 3.26 (m, 2H), 2.92 - 2.91 (m, 2H), 2.39 (d, J =18.2 Hz, 6H), 2.20 - 2.09 (m, 1H), 1.70 (s, 4H), 1.06 (d, J =6.9 Hz, 3H), 0.69 (s, 2H).498 Reference 49 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 7.68 (d, J =1.4 Hz, 1H), 7.52 (d, J =8.3 Hz, 1H), 7.33 (dd, J =1.5, 8.3 Hz, 1H), 5.86 (dd, J =6.6, 6.6 Hz, 1H), 4.78 (d, J =6.8 Hz, 2H), 4.25 (s, 2H), 3.89 - 3.84 (m, 2H), 3.70 - 3.26 (m, 6H), 2.58 (s, 3H), 2.51 (dd, J =4.7, 4.7 Hz, 2H), 2.37 (s, 3H), 2.20 - 2.11 (m, 1H), 1.07 (d, J =6.9 Hz, 3H), NH proton not observed.514 Reference 50 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.68 (d, J =1.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.33 (td, J =1.4, 8.5 Hz, 1H), 6.68 (s, 1H), 5.69 (t, J =6.6 Hz, 1H), 3.62 - 3.47 (m, 2H), 3.42 - 3.26 (m, 2H), 2.37 (s, 3H), 2.20 - 2.08 (m, 1H), 1.06 (d, J =6.9 Hz, 3H), NH not observed.466 General Method 6 2-Chloro-N-(4-methoxybenzyl)benzo[d]thiazole-6-sulfonamide (101B).

[0224] (4-Methoxyphenyl)methanamine (134 mg, 0.97 mmol, 1.05 eq) was added dropwise to an ice cooled solution of 2-chlorobenzothiazole-6-sulfonyl chloride (101A) (250 mg, 0.932 mmol, 1.0 eq), triethylamine (0.39 mL, 2.79 mmol, 3.0 eq) in tetrahydrofuran (10 mL), and the mixture stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a solid which was washed with ice cold water (10 mL), ice cold tetrahydrofuran (10 mL) and then dried under vacuum to give the desired 2-chloro-N-(4-methoxybenzyl)benzo[d]thiazole-6-sulfonamide as a white solid (101B).

[0225] Yield: 295 mg (85%). 1< H NMR (400 MHz, DMSO) δ 8.56 (d, J =1.6 Hz, 1H), 8.24 (s, 1H), 8.11 (d, J =8.7 Hz, 1H), 7.90 (dd, J =1.9, 8.7 Hz, 1H), 7.10 (d, J =8.8 Hz, 2H), 6.76 (d, J =8.8 Hz, 2H), 3.98 (s, 2H), 3.67 (s, 3H); MS (ESI+) m / z 369 (M+H) +< .

[0226] The intermediates in Table 2 were synthesized using conditions analogous to those described for intermediate 101B: Table 2 Structure Compound No. 1< H NMR LC-MS (M+H) +< Intermediate 1< H NMR (400 MHz, CDCl 3 ) δ 8.33 (1H, d, J = 1.6 Hz), 8.12 (1H, d, J =8.5 Hz), 7.95 (1H, dd, J =1.8, 8.6 Hz), 4.55 (1H, d, J =3.9 Hz), 4.08 (2H, dd, J =6.5, 9.3 Hz), 3.64 (2H, dd, J =5.3, 9.2 Hz), 2.13 - 2.13 (1H, m).305 IntermediateNot acquired263 IntermediateNot acquired418 Intermediate 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J =1.8 Hz, 1H), 8.07 (d, J =8.7 Hz, 1H), 7.96 (dd, J =1.8, 8.6 Hz, 1H), 5.13 (dd, J =5.3, 5.3 Hz, 1H), 4.07 (q, J =7.2 Hz, 2H), 3.82 (d, J =5.5 Hz, 2H), 1.17 (dd, J =7.2, 7.2 Hz, 3H).335 Intermediate 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J = 1.8 Hz, 1H), 8.07 (d, J =8.5 Hz, 1H), 7.97 (dd, J =1.8, 8.6 Hz, 1H), 5.18 (s, 1H), 3.73 (dd, J =4.3, 4.3 Hz, 2H), 3.15 (dd, J =5.8, 10.4 Hz, 2H), 2.01 - 2.01 (m, 1H).293 IntermediateNot acquired430 (S)-N-(4-Methoxybenzyl)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)benzo[d]thiazole-6-sulfonamide (101C)

[0227] Methodology applied was analogous to that described in General method 3.

[0228] Yield: 298 mg, (69%). 1< H NMR (400 MHz, DMSO) δ 8.56 (1H, d, J =1.6 Hz), 8.24 (1H, s), 8.11 (1H, d, J =8.7 Hz), 7.90 (1H, dd, J =1.9, 8.7 Hz), 7.10 (2H, d, J =8.8 Hz), 6.76 (2H, d, J =8.8 Hz), 3.98 (2H, s), 3.67 (3H, s); MS (ESI+) m / z 545 (M+H) +< .(S)-2-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d] thiazole-6-sulfonamide (Reference Example 87)

[0229] Trifluoroacetic acid (5 mL) was added dropwise to an ice cooled solution of N-(4-methoxybenzyl)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)benzo [d]thiazole-6-sulfonamide (101C) (250 mg, 0.459 mmol, 1.0 eq) in anhydrous dichloromethane (5 mL). The mixture was stirred on ice for 30 minutes and then allowed to warm to ambient temperature over 18 h. The reaction mixture was diluted with dichloromethane (15 mL) and saturated sodium hydrogen carbonate (15 mL) was added slowly. The organic phase was separated, washed with brine (5 mL), dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The crude residue obtained was purified by flash chromatography (eluting DCM to methanol, 0-10%) give the desired (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d] thiazole-6-sulfonamide (Reference Example 87) as a white solid.

[0230] Yield: 190 mg (97%). 1< H NMR (400 MHz, DMSO) δ 8.40 (dd, J =5.5, 5.5 Hz, 1H), 8.34 (s, 2H), 8.12 (d, J =1.6 Hz, 1H), 7.66 (dd, J =2.0, 8.4 Hz, 1H), 7.51 (dd, J =6.0, 6.0 Hz, 1H), 7.44 (d, J =8.5 Hz, 1H), 7.21 (s, 2H), 3.49 - 3.42 (m, 1H), 3.31 - 3.23 (m, 3H), 2.34 (s, 3H), 2.17 - 2.07 (m, 1H), 0.96 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 425 (M+H) +< .

[0231] Using the procedures described in Scheme 2, following General Method 3, the following examples were prepared: Table 3 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 88 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 8.05 (d, J =1.5 Hz, 1H), 7.74 (dd, J =1.9, 8.5 Hz, 1H), 7.60 (d, J =8.5 Hz, 1H), 7.16 (s, 1H), 5.70 (dd, J =6.8, 6.8 Hz, 1H), 4.50 - 4.45 (m, 1H), 4.05 - 4.01 (m, 2H), 3.62 - 3.57 (m, 3H), 3.54 (dd, J =4.1, 13.6 Hz, 1H), 3.43 - 3.26 (m, 2H), 2.38 (s, 3H), 2.21 - 2.05 (m, 1H), 1.08 (d, J =6.9 Hz, 3H).481 Reference 89 1< H NMR (400 MHz, DMSO) δ 8.45 (dd, J =5.4, 5.4 Hz, 1H), 8.33 (s, 2H), 8.11 (d, J =1.9 Hz, 1H), 7.60 (dd, J =1.9, 8.5 Hz, 1H), 7.51 (dd, J =5.7, 5.7 Hz, 1H), 7.47 (d, J =8.5 Hz, 1H), 7.26 (q, J =5.1 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.31 - 3.20 (m, 3H), 2.41 - 2.34 (m, 6H), 2.29 - 2.07 (m, 1H), 0.96 (d, J =6.8 Hz, 3H).439 Reference 90 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.96 (d, J =1.6 Hz, 1H), 7.64 (dd, J =1.8, 8.5 Hz, 1H), 7.57 (d, J =8.5 Hz, 1H), 5.86 (t, J = 13.1 Hz, 1H), 3.64 - 3.26 (m, 6H), 3.08 - 2.95 (m, 8H), 2.38 (s, 3H), 2.21 - 2.11 (m, 1H), 1.08 (d, J =6.9 Hz, 3H).494 Reference 91 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (2H, s), 7.97 (1H, d, J =1.8 Hz), 7.65 (1H, dd, J =1.8, 8.5 Hz), 7.59 (1H, d, J =8.5 Hz), 7.11 (1H, s), 5.63 (1H, t, J =10.5 Hz), 3.77 - 3.73 (4H, m), 3.65 - 3.52 (2H, m), 3.43 - 3.26 (2H, m), 3.04 - 2.95 (4H, m), 2.38 (3H, s), 2.21 - 2.10 (1H, m), 1.08 (3H, d, J =6.9 Hz);495 Reference 92 1< H NMR (400 MHz, MeOD) δ 8.33 (2H, s), 8.11 (1H, d, J =1.6 Hz), 7.74 (1H, dd, J =2.0, 8.5 Hz), 7.52 (1H, d, J =8.5 Hz), 4.00 (2H, q, J =7.2 Hz), 3.77 (2H, s), 3.49 (2H, d, J =6.1 Hz), 3.42 - 3.40 (2H, m), 2.35 (3H, s), 2.25 - 2.16 (1H, m), 1.15 - 1.06 (6H, m); N-CH 3 obscured by MeOH peak511 Reference 93 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 8.07 (d, J =1.6 Hz, 1H), 7.74 (dd, J =1.9, 8.5 Hz, 1H), 7.54 (d, J =8.5 Hz, 1H), 7.18 (s, 1H), 5.80 (dd, J =6.5, 6.5 Hz, 1H), 5.02 (dd, J =6.1, 6.1 Hz, 1H), 3.73 - 3.70 (m, 2H), 3.64 - 3.50 (m, 2H), 3.43 - 3.25 (m, 2H), 3.13 (dd, J =5.9, 10.4 Hz, 2H), 2.38 (s, 3H), 2.21 - 2.10 (m, 1H), 1.07 (d, J =7.0 Hz, 3H).469 Reference 94 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (2H, s), 8.05 (1H, d, J =1.6 Hz), 7.74 (1H, dd, J =1.9, 8.5 Hz), 7.61 (1H, d, J =8.5 Hz), 5.68 (1H, dd, J =6.7, 6.7 Hz), 3.81 (2H, dd, J =7.6, 7.6 Hz), 3.64 - 3.53 (4H, m), 3.43 - 3.26 (2H, m), 3.06 - 2.98 (1H, m), 2.38 (3H, s), 2.21 - 2.11 (1 H, m), 2.02 (6H, s), 1.33 - 1.24 (1H, m), 1.08 (3H, d, J =6.9 Hz).508 Reference 95 1< H NMR (400 MHz, DMSO) δ 8.44 (dd, J =5.5, 5.5 Hz, 1H), 8.34 (s, 2H), 8.07 (d, J =1.9 Hz, 1H), 7.88 (dd, J =6.0, 6.0 Hz, 1H), 7.62 (dd, J =2.0, 8.5 Hz, 1H), 7.52 (dd, J =6.0, 6.0 Hz, 1H), 7.43 (d, J =8.5 Hz, 1H), 7.14 (d, J =8.8 Hz, 2H), 6.81 (d, J =8.8 Hz, 2H), 3.89 (d, J =5.8 Hz, 2H), 3.70 (s, 3H), 3.52 - 3.42 (m, 1H), 3.32 - 3.23 (m, 3H), 2.34 (s, 3H), 2.17 - 2.07 (m, 1H), 0.97 (d, J =6.7 Hz, 3H).545 Reference 96 1< H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.55 - 8.46 (m, 2H), 8.35 (s, 2H), 8.20 (d, J =1.9 Hz, 1H), 7.61 (dd, J =1.9, 8.5 Hz, 1H), 7.52 (d, J =8.4 Hz, 1H), 3.94 - 3.85 (m, 9H), 3.38 - 3.21 (m, 3H), 2.35 (s, 3H), 2.18 - 2.08 (m, 1H), 0.97 (d, J =6.8 Hz, 3H).505 2-Methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A)

[0232] Methodology applied was analogous to General Method 2.

[0233] A solution of hydrogen chloride (54 mL, 4M in 1,4-dioxane) was added to tert-butyl (2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (100C) (4.25 g, 13.60 mmol) and the mixture stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford the desired 2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) as a pale yellow semi-solid. The semi-crude sample was taken on into the next reaction without further purification.N 1< -(6-Bromobenzo[d]thiazol-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B)

[0234] Methodology applied was analogous to General Method 3.

[0235] 6-Bromo-2-chlorobenzothiazole (828 mg, 3.33 mmol, 0.95 eq) was added to a stirred suspension of 2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) (1.00 g, 3.51 mmol, 1.0 eq) and cesium carbonate (3.43 g, 10.52 mmol, 3.0 eq) in anhydrous dimethylformamide (25 mL) under nitrogen. The mixture was stirred at room temperature for 72 h and was then concentrated under vacuum to ~3 mL. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (25 mL) then dried over magnesium sulfate. The solvents were removed under vacuum to give a crude yellow oil which was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-100%) to give the desired N 1< -(6-bromobenzo[d]thiazol-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B) as a sticky yellow solid.

[0236] Yield: 266 mg (18%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 7.66 (d, J =0.6 Hz, 1H), 7.37 (d, J =1.9 Hz, 2H), 6.58 (s, 1H), 5.69 (dd, J =6.3, 6.3 Hz, 1H), 3.67 - 3.23 (m, 4H), 2.37 (s, 3H), 2.17 - 2.09 (m, 1H), 1.06 (d, J =6.9 Hz, 3H).General Method 7 tert-Butyl 4-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol-6-yl)-1H-pyrazole-1-carboxylate (102C)

[0237] A solution of N 1< -(6-bromobenzo[d]thiazol-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B) (50 mg, 0.12 mmol, 1.0 eq) was added to a solution of (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (27.8 mg, 0.13 mmol, 1.0 eq), cesium carbonate (58 mg, 0.18 mmol, 1.5 eq) and tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.01 mmol, 0.05 eq) in water (0.20 mL) and N,N-dimethylformamide (0.80 mL) under nitrogen. The reaction mixture was heated to 90°C for 16 h. An additional aliquot of (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (27.8 mg, 0.13 mmol, 1.0 eq) and tetrakis(triphenylphosphine) palladium (0) (7 mg, 0.01 mmol, 0.05 eq) was added to the reaction and the mixture was heated to 90°C under nitrogen for a further 16 h. The solvents were removed under reduced pressure; water (2 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with water (2 mL) and brine (2 mL), dried by passing through a phase separator and then concentrated under vacuum. The crude residue obtained was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-75%) to give the desired tert-butyl 4-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol -6-yl)-1H-pyrazole-1-carboxylate (102C) as an off-white solid. The semi-crude product was taken through to the next reaction without further purification.N 1< -(6-(1H-Pyrazol-4-yl)benzo[d]thiazol-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 97)

[0238] A solution of hydrogen chloride (2 mL, 4M in 1,4-dioxane) was added to tert-butyl 4-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol-6-yl)-1H-pyrazole-1-carboxylate (102C) (100 mg, 0.12 mmol) and the mixture stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford the desired N 1< -(6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin -2-yl)propane-1,3-diamine (Reference Example 97) as an off-white solid.

[0239] Using the procedures described in Scheme 3, according to General Method 7, the following examples were prepared: Table 4 Structure Ex. # 1H NMR LC-MS (M+H) +< Reference 97 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 7.84 (s, 2H), 7.69 (d, J =1.6 Hz, 1H), 7.53 (d, J =8.3 Hz, 1H), 7.43 (dd, J =1.8, 8.4 Hz, 1H), 6.00 - 5.91 (m, 1H), 3.63 - 3.26 (m, 4H), 2.36 (s, 3H), 2.21 - 2.11 (m, 1H), 1.07 (d, J =6.9 Hz, 3H) NH exchangeable proton not observed.412 Reference 98 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.74 (s, 1H), 7.66 (d, J =1.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J =8.4 Hz, 1H), 7.39 (dd, J =1.7, 8.3 Hz, 1H), 6.61 - 6.61 (m, 1H), 5.76 (dd, J =6.3, 6.3 Hz, 1H), 3.95 (s, 3H), 3.63 - 3.47 (m, 2H), 3.43 - 3.26 (m, 2H), 2.36 (s, 3H), 2.19 - 2.11 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).426 Reference 99 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 2H), 7.59 (d, J =8.3 Hz, 1H), 7.43 (d, J =1.6 Hz, 1H), 7.16 (dd, J =1.8, 8.3 Hz, 1H), 6.64 - 6.64 (m, 1H), 5.74 (dd, J =6.2, 6.2 Hz, 1H), 3.64 - 3.49 (m, 2H), 3.43 - 3.27 (m, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.27 (s, 3H), 2.18 - 2.14 (m, 1H), 1.08 (d, J =6.8 Hz, 3H).441 Reference 100 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 2H), 8.14 (dd, J =1.8, 5.0 Hz, 1H), 7.79 (d, J =1.8 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.47 (dd, J =1.7, 8.3 Hz, 1H), 6.97 (dd, J =5.0, 7.3 Hz, 1H), 6.61 - 6.61 (m, 1H), 5.74 (dd, J =6.3, 6.3 Hz, 1H), 3.98 (s, 3H), 3.63 - 3.50 (m, 2H), 3.43 - 3.27 (m, 2H), 2.37 (s, 3H), 2.20 - 2.11 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).453 General Method 8 2-Methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)-N 3< -(6-(oxazol-2-yl)benzo[d]thiazol-2-yl)propane-1,3-diamine (Reference Example 101)

[0240] N 1< -(6-Bromobenzo[d]thiazol-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B) (90 mg, 0.21 mmol, 1.0 eq) was added to a solution of 2-(tri-n-butylstannyl)oxazole (0.044 mL, 0.21 mmol, 1.0 eq) and tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.1 eq) in N,N-dimethylformamide (0.80 mL) under nitrogen. The reaction mixture was heated to 90°C for 16 h. A further aliquot of 2-(tri-n-butylstannyl)oxazole (0.044 mL, 0.21 mmol, 1.0 eq) and tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.1 eq) were added to the reaction mixture, heating to 110°C for 18 h. The reaction was cooled to room temperature, diluted with water (2 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with water (2 mL) and brine (2 mL), filtered through a celite pad, and dried by passing through a phase separator before concentrating to dryness under vacuum. The crude residue obtained was twice purified by flash chromatography (first eluting isohexane to ethyl acetate, 0-100%, then ethyl acetate to methanol, 0-10%) to give a semi-crude residue which was further purified by reverse phase preparative HPLC to give the desired 2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)-N 3< -(6-(oxazol-2-yl)benzo[d]thiazol-2-yl)propane-1,3-diamine (101) as an off-white solid. Using the procedures described in Scheme 3, according to General Method 8, the following examples were prepared: Table 5 Structure Ex. # 1H NMR LC-MS (M+H) +< Reference 101 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 2H), 8.26 (d, J =1.6 Hz, 1H), 7.98 (dd, J =1.8, 8.5 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J =8.4 Hz, 1H), 7.21 (s, 1H), 6.75 - 6.75 (m, 1H), 5.68 (dd, J =6.3, 6.3 Hz, 1H), 3.65 - 3.57 (m, 1H), 3.56 - 3.50 (m, 1H), 3.43 - 3.28 (m, 2H), 2.37 (s, 3H), 2.17 (s, 1H), 1.07 (d, J =6.9 Hz, 3H).413 Reference 102 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 7.80 (s, 1H), 7.53 (s, 2H), 7.13 (s, 1H), 6.76 (s, 1H), 5.84 (t, J =6.9 Hz, 1H), 3.64 - 3.48 (m, 2H), 3.43 - 3.25 (m, 2H), 2.52 (s, 3H), 2.36 (s, 3H), 2.19 - 2.10 (m, 1H), 1.07 (d, J =6.9 Hz, 3H).427

[0241] Using the procedures described in Scheme 4, according to General Method 3, the following examples were prepared: Table 6 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 103 1< H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 8.34 (s, 2H), 7.79 (d, J =7.8 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.59 (s, 1H), 7.46 (d, J =8.4 Hz, 2H), 7.22 (dd, J =7.4, 7.4 Hz, 1H), 3.43 - 3.35 (m, 2H), 3.31 - 3.25 (m, 2H), 2.34 (s, 3H), 2.12 - 2.08 (m, 1H), 0.94 (d, J =6.8 Hz, 3H).341 Reference 104 1< H NMR (400 MHz, DMSO) δ 8.33 (s, 3H), 7.75 (d, J =7.9 Hz, 1H), 7.64 (dd, J =5.6, 5.6 Hz, 1H), 7.59 (dd, J =6.1, 6.1 Hz, 1H), 7.53 (d, J =3.8 Hz, 2H), 7.34 - 7.28 (m, 1H), 3.45 - 3.35 (m, 2H), 3.28 (t, J =6.2 Hz, 2H), 2.34 (s, 3H), 2.16 - 2.08 (m, 1H), 0.98 (d, J =6.8 Hz, 3H).341 Reference 105 1< H NMR (400 MHz, DMSO) δ 8.32 (s, 2H), 7.92 (dd, J =5.8, 5.8 Hz, 1H), 7.48 (dd, J =5.7, 5.7 Hz, 1H), 7.32 (d, J =7.7 Hz, 1H), 7.22 (d, J =7.4 Hz, 1H), 7.10 (dd, J =7.4, 7.4 Hz, 1H), 6.99 - 6.94 (m, 1H), 3.30 - 3.16 (m, 4H), 2.34 (s, 3H), 2.13 - 2.05 (m, 1H), 0.94 (d, J =6.7 Hz, 3H).330 Reference 106 1< H NMR (400 MHz, DMSO) δ 8.26 (s, 2H), 7.96 (dd, J =5.6, 5.6 Hz, 1H), 7.57 (d, J =7.1 Hz, 1H), 7.46 (dd, J =5.9, 5.9 Hz, 1H), 7.28 (d, J =7.3 Hz, 1H), 7.16 - 7.11 (m, 1H), 6.95 - 6.90 (m, 1H), 3.37 - 3.30 (m, 1H), 3.23 - 3.14 (m, 3H), 2.26 (s, 3H), 2.09 - 1.97 (m, 1H), 0.87 (d, J =6.8 Hz, 3H).346 Reference 107 1< H NMR (400 MHz, DMSO) δ 8.33 (s, 2H), 7.93 (s, 1H), 7.89 (d, J =2.6 Hz, 1H), 7.61 (d, J =2.8 Hz, 1H), 7.44 (dd, J =5.8, 5.8 Hz, 1H), 7.05 (dd, J =5.7, 5.7 Hz, 1H), 3.31 - 3.14 (m, 4H), 2.35 (s, 3H), 2.09 - 1.99 (m, 1H), 0.92 (d, J =6.8 Hz, 3H).291 tert-Butyl (2,2-dimethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (105A)

[0242] Methodology applied was analogous to those described in General Method 1 except additional heating was required.

[0243] tert-Butyl (3-amino-2,2-dimethylpropyl)carbamate (0.13 g, 0.65 mmol, 1.05 eq) was added to a stirred suspension of 2-chloro-5-(methylthio)pyrimidine (100B) (0.10 g, 0.62 mmol, 1.0 eq) and cesium carbonate (0.24 g, 0.75 mmol, 1.2 eq) in anhydrous N,N-dimethylformamide (1.5 mL) and the mixture stirred at 80°C for 4 h. The reaction mixture was concentrated under vacuum, diluted with ethyl acetate (20 mL), washed with water (7.5 mL) and brine (5.0 mL) then dried through a phase separator. The solvents were removed under vacuum to give the desired tert-butyl (2,2-dimethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (105A) as a pale yellow oil.

[0244] Yield: 0.163 g (81%). 1< H NMR (400 MHz, DMSO) δ 8.37 (s, 2H), 7.24 (dd, J =6.6, 6.6 Hz, 1H), 6.93 (dd, J =6.3, 6.3 Hz, 1H), 3.20 (d, J =6.8 Hz, 2H), 2.85 (d, J =8.7 Hz, 2H), 2.40 (s, 3H), 1.43 (d, J =3.3 Hz, 9H), 0.83 (s, 6H).2,2-Dimethyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (105B)

[0245] Methodology applied was analogous to those described in General Method 2.

[0246] A solution of hydrogen chloride (5 mL, 4M in 1,4-dioxane) was added to tert-butyl (2,2-dimethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (105A) (0.16 g, 0.50 mmol) and the mixture was stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford the desired 2,2-dimethyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (105B) as a pale yellow semi solid.

[0247] Yield: 0.13 g (100%) HCl salt. 1< H NMR (400 MHz, DMSO) δ 8.39 (s, 2H), 7.95 (s, 3H), 7.70 (s, 1H), 3.25 (d, J =5.5 Hz, 2H), 2.68 - 2.61 (m, 2H), 2.38 (s, 3H), 0.96 (s, 6H).N1-(Benzo[d]oxazol-2-yl)-2,2-dimethyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 164)

[0248] Methodology applied was analogous to those described in General Method 3 except cesium carbonate was used as a general base.

[0249] 2-Chlorobenzoxazole (0.06 mL, 0.54 mmol, 0.1 eq) was added to a stirred solution of 2,2-dimethyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (105B) (0.13 g, 0.49 mmol, 1.0 eq) and cesium carbonate (0.48 g, 1.48 mmol, 3.0 eq) in anhydrous N,N-dimethylformamide (2.0 mL) under nitrogen. The mixture was stirred at either 80°C or room temperature for 16 h and was then concentrated under vacuum. Water (2.5 mL) was added and the mixture extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with water (2 mL) and brine (2 mL) then dried through a phase separator. The solvents were removed under vacuum to give a crude yellow oil which was purified by preparative HPLC to give the desired N 1< -(benzo[d]oxazol-2-yl)-2,2-dimethyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 164) as an off-white solid.

[0250] Using the procedures described in Scheme 7, according to General Method 3, the following examples were prepared: Table 9 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 164 1< H NMR (400 MHz, DMSO) δ 8.33 (s, 2H), 8.21 (s, 1H), 7.53 - 7.51 (m, 1H), 7.37 (d, J =7.8 Hz, 1H), 7.24 (d, J =7.4 Hz, 1H), 7.14 (dd, J =7.4, 7.4 Hz, 1H), 7.02 (dd, J =7.3, 7.3 Hz, 1H), 3.30 - 3.23 (m, 4H), 2.34 (s, 3H), 0.93 (s, 6H).344 Reference 165 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 7.34 (d, J =7.5 Hz, 1H), 7.23 (d, J =7.8 Hz, 1H), 7.15 (dd, J =7.2, 7.2 Hz, 1H), 7.01 (dd, J =7.3, 7.3 Hz, 1H), 6.28 - 6.27 (m, 1H), 5.73 (dd, J=6.3, 6.3 Hz, 1H), 3.47 - 3.38 (m, 4H), 2.36 (s, 3H), 0.69 - 0.65 (m, 2H), 0.58 - 0.54 (m, 2H).342 Reference 166 1< H NMR (400 MHz, DMSO) δ 8.36 (s, 2H), 8.35 - 8.29 (m, 1H), 7.84 (d, J =6.7 Hz, 1H), 7.35 (d, J =7.8 Hz, 1H), 7.25 (d, J =7.4 Hz, 1H), 7.12 (dd, J =7.4, 7.4 Hz, 1H), 6.99 (dd, J =7.3, 7.3 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.29 (dd, J =6.5, 12.9 Hz, 1H), 2.38 (d, J =14.1 Hz, 6H) NH proton not observed.328 Reference 167 1< H NMR (400 MHz, DMSO) δ 8.30 (s, 2H), 7.84 (d, J =8.2 Hz, 1H), 7.41 (dd, J =5.4, 5.4 Hz, 1H), 7.31 (d, J =7.7 Hz, 1H), 7.21 (d, J =7.4 Hz, 1H), 7.10 (dd, J =7.4, 7.4 Hz, 1H), 6.96 (dd, J =7.2, 7.2 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.38 - 3.34 (m, 2H), 2.32 (s, 3H), 1.85 - 1.77 (m, 2H), 1.24 (d, J =6.5 Hz, 3H).330 Reference 168 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (2H, s), 7.37 (1H, d, J =7.8 Hz), 7.24 (1H, s), 7.17 (1H, dd, J =7.6, 7.6 Hz), 7.04 (1H, dd, J =7.7, 7.7 Hz), 6.23 - 6.23 (1H, m), 5.95 (1H, dd, J =6.5, 6.5 Hz), 3.96 - 3.74 (2H, m), 3.69 - 3.58 (2H, m), 2.37 (3H, s), 1.47 (3H, d, J =21.8 Hz);348 Reference 169 1< H NMR (400 MHz, DMSO) δ 8.32 (s, 2H), 7.86 (dd, J =5.3, 5.3 Hz, 1H), 7.44 (dd, J =6.0, 6.0 Hz, 1H), 7.32 (d, J =7.5 Hz, 1H), 7.22 (d, J =7.3 Hz, 1H), 7.10 (dd, J =7.3, 7.3 Hz, 1H), 6.99 - 6.94 (m, 1H), 2.34 (s, 3H), 1.94 - 1.84 (m, 1H), 1.42 - 1.23 (m, 3H), 0.93 (dd, J =7.5, 7.5 Hz, 4H). 2H not observed, under water peak.344 Reference 170 1< H NMR (400 MHz, DMSO) δ 8.86 (d, J =6.4 Hz, 1H), 8.36 (s, 2H), 8.32 (d, J =1.8 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.44 (d, J =8.4 Hz, 1H), 4.49 - 4.40 (m, 2H), 4.30 (q, J =7.1 Hz, 2H), 2.44 - 2.32 (m, 7H), 1.33 (dd, J =7.1, 7.1 Hz, 3H).416 Reference 171 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 7.38 (d, J =7.8 Hz, 1H), 7.25 - 7.24 (m, 1H), 7.17 (dd, J =7.5, 7.5 Hz, 1H), 7.04 (dd, J =7.7, 7.7 Hz, 1H), 5.37 (d, J =7.0 Hz, 1H), 5.10 (d, J =7.3 Hz, 1H), 4.26 - 4.14 (m, 2H), 3.11 - 3.04 (m, 2H), 2.37 (s, 3H), 2.06 - 1.98 (m, 2H).328 Reference 172 1< H NMR (400 MHz, DMSO) δ 8.77 (d, J =5.9 Hz, 1H), 8.36 (s, 2H), 8.27 (d, J =1.5 Hz, 1H), 7.86 (d, J =6.7 Hz, 1H), 7.81 (dd, J =1.8, 8.4 Hz, 1H), 7.40 (d, J =8.4 Hz, 1H), 4.47 - 4.38 (m, 2H), 2.47 - 2.34 (m, 6H).388 Reference 173 1< H NMR (400 MHz, CDCl 3 ) δ 8.79 (1H, s), 8.36 (2H, s), 7.89 (1H, s), 5.46 (1H, d, J =5.9 Hz), 5.38 (1H, d, J =4.9 Hz), 4.61 - 4.48 (2H, m), 3.96 (3H, s), 2.49 (3H, dd, J =6.6, 6.6 Hz), 2.37 (3H, s).347 Reference 174 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 7.37 (d, J =7.7 Hz, 1H), 7.17 (dd, J =7.4, 7.4 Hz, 1H), 7.07 - 7.02 (m, 1H), 5.80 (dd, J =5.7, 5.7 Hz, 1H), 5.63 (s, 1H), 4.82 - 4.81 (m, 1H), 4.12 - 4.06 (m, 1H), 3.74 - 3.49 (m, 4H), 2.38 (s, 3H).332 3-Chloro-N-(2-chlorobenzo[d]thiazol-6-yl)propane-1-sulfonamide (106B)

[0251] Sodium hydride (60% dispersion in mineral oil) (326 mg, 8.15 mmol, 3.0 eq) was added portion-wise to an ice cooled solution of 2-chlorobenzothiazole-6-amine (500 mg, 2.71 mmol, 1.0 eq) in N,N-dimethylformamide (25 mL) and the mixture stirred for 1 hour under ice cooling. A solution of 3-chloropropane-1-sulfonyl chloride (673 mg, 3.80 mmol, 1.4 eq) in N,N-dimethylformamide (3 mL) was added dropwise and the reaction mixture was then allowed to warm to ambient temperature over 3 h. The reaction mixture was diluted with brine (20 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic fractions were combined and concentrated under reduced pressure to give a pale yellow oil that was purified by flash chromatography (eluting iso-hexanes to ethyl acetate, 0-100%) to give the desired product 3-chloro-N-(2-chlorobenzo[d]thiazol-6-yl)propane-1-sulfonamide 106B as an off-white gum.

[0252] Yield: 427 mg (48%). 1< H NMR (400 MHz, MeOD) δ 7.87 - 7.84 (m, 2H), 7.38 (dd, J =2.3, 8.8 Hz, 1H), 3.67 (dd, J =6.3, 6.3 Hz, 2H), 2.27 - 2.19 (m, 2H). Note CH 2 protons obscured by MeOD.2-(2-Chlorobenzo[d]thiazol-6-yl)isothiazolidine 1,1-dioxide (106C)

[0253] Sodium hydride (60% dispersion in mineral oil) (98 mg, 2.46 mmol, 2.0 eq) was added to an ice cooled solution of 3-chloro-N-(2-chlorobenzo[d]thiazol-6-yl)propane-1-sulfonamide (106B) (400 mg, 1.23 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred for 1 hour under ice cooling and then quenched by the careful addition of a saturated solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL) and the combined organic phases were washed with water (20 mL), brine (20 mL) and then concentrated under vacuum to give a gum. The crude product was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-100%) to give the desired product (106C) as an off-white gum.

[0254] Yield: 220 mg (62%). 1< H NMR (400 MHz, CDCl 3 ) δ 7.92 (d, J =8.9 Hz, 1H), 7.72 (d, J =2.1 Hz, 1H), 7.38 (dd, J =2.4, 8.9 Hz, 1H), 3.84 (dd, J =6.5, 6.5 Hz, 2H), 3.43 (dd, J =7.5, 7.5 Hz, 2H), 2.63 - 2.55 (m, 2H).2-(2-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo [d]thiazol-6-yl)isothiazolidine 1,1-dioxide (Reference Example 175)

[0255] Methodology applied was analogous to those described in General Method 3.

[0256] Yield: 25 mg (15%). 1< H NMR (400 MHz, DMSO) δ 8.34 (s, 2H), 8.03 (dd, J =5.6, 5.6 Hz, 1H), 7.57 (d, J =2.3 Hz, 1H), 7.51 (dd, J =5.9, 5.9 Hz, 1H), 7.35 (d, J =8.8 Hz, 1H), 7.14 (dd, J =2.4, 8.7 Hz, 1H), 3.72 (dd, J =6.5, 6.5 Hz, 2H), 3.47 (dd, J =7.5, 7.5 Hz, 2H), 3.45 - 3.38 (m, 1H), 3.30 - 3.22 (m, 3H), 2.44 - 2.36 (m, 2H), 2.35 (s, 3H), 2.13 - 2.06 (m, 1H), 0.95 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 465 (M+H) +< . N-(2-Chlorobenzo[d]thiazol-6-yl)methanesulfonamide (107B)

[0257] Methanesulfonyl chloride (0.055 mL, 0.706 mmol, 1.3 eq) was added dropwise into an ice cooled solution of 2-chlorobenzothiazole-6-amine (100 mg, 0.54 mmol, 1.0 eq) and pyridine (0.066 mL, 0.815 mmol, 1.5 eq) in anhydrous dichloromethane (5 mL). The mixture was stirred at 0°C for 15 minutes and was then allowed to warm to ambient temperature over 1 hour. The reaction mixture was quenched with water (1 mL). The organic phase was removed and concentrated under reduced pressure to give a pale yellow oil which was purified by flash chromatography (eluting iso-hexanes to ethyl acetate, 0-100%) to give the desired N-(2-chlorobenzo[d]thiazol-6-yl)methanesulfonamide (107B) as a pale yellow gum. Yield: 135 mg (94.8%) 1< H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J =8.8 Hz, 1H), 7.79 (d, J =2.1 Hz, 1H), 3.00 (s, 3H). Aromatic H proton obscured by CDCl 3 , NH exchangeable proton not observed.N-(2-Chlorobenzo[d]thiazol-6-yl)-N-methylmethanesulfonamide (107C)

[0258] Sodium hydride (60% dispersion in mineral oil) (31 mg, 0.772 mmol, 1.5 eq) was added portion-wise to an ice cooled solution of N-(2-chlorobenzo[d]thiazol-6-yl)methanesulfonamide (107B) (135 mg, 0.515 mmol, 1.0 eq) in anhydrous tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 2 h. Iodomethane (0.048 mL, 0.772 mmol, 1.5 eq) was added and the mixture was stirred at room temperature for a further 2 h. Water (1 mL) was added and the solvents were then removed under high vacuum to give a pale yellow gum that was purified by flash chromatography (eluting iso-hexanes to ethyl acetate, 0-100%) to give the desired N-(2-chlorobenzo[d]thiazol-6-yl)-N-methylmethanesulfonamide (107C) as a pale yellow gum.

[0259] Yield: 100 mg (70%) 1< H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J =8.8 Hz, 1H), 7.86 (d, J =2.1 Hz, 1H), 7.48 (dd, J =2.3, 8.8 Hz, 1H), 3.39 (s, 3H), 2.88 (s, 3H).N-Methyl-N-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d]thiazol-6-yl)methanesulfonamide (Reference Example 176)

[0260] Methodology applied was analogous to those described in General Method 3.

[0261] Yield: 89 mg (60%) 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.62 (d, J =2.0 Hz, 1H), 7.51 (d, J =8.7 Hz, 1H), 7.24 (d, J =3.2 Hz, 1H), 5.74 (dd, J =6.5, 6.5 Hz, 1H), 3.34 - 3.33 (m, 6H), 2.86 (s, 3H), 2.37 (s, 3H), 2.20 - 2.10 (m, 1H), 1.06 (d, J =6.9 Hz, 3H). Not all NH exchangeable protons observed; MS (ESI+) m / z 453 (M+H) +< . 4-(((5-(Methylthio)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (108B)

[0262] Methodology applied was analogous to those described in General Method 1. 5-Aminomethyl-pyrrolidin-2-one (108A) (1.0 g, 8.76 mmol, 1.0 eq) was added to a stirred suspension of 2-chloro-5-(methylthio)pyrimidine (100B) (1.4 g, 8.76 mmol, 1.0 eq) and cesium carbonate (8.56 g, 26.28 mmol, 3.0 eq) in anhydrous dimethylformamide (10 mL). The mixture was heated to 50°C for 18 h and then concentrated under reduced pressure. The liquor obtained was diluted with ethyl acetate (50 mL), washed with water (10 mL) and brine (10 mL) and then dried through a phase separator. The solvents were removed under reduced pressure to afford a crude residue that was purified by trituration in methanol to give the desired product 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (108B) as a yellow solid. The aqueous phase was concentrated under reduced pressure, combined with the filtrate and purified by flash chromatography (eluting dichloromethane to methanol, 0-10%) to give the desired product 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (108B) as a yellow solid. Both crops were combined and used in the next step.

[0263] Yield: 0.74 g (36%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 5.79 - 5.76 (m, 1H), 5.48 (dd, J =5.5, 5.5 Hz, 1H), 3.57 - 3.50 (m, 3H), 3.20 (dd, J =5.3, 9.5 Hz, 1H), 2.89 - 2.84 (m, 1H), 2.53 - 2.46 (m, 1H), 2.37 (s, 3H), 2.16 (dd, J =6.4, 17.1 Hz, 1H).tert-Butyl 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-2-oxopyrrolidine-1-carboxylate (108C)

[0264] 4-Dimethylaminopyridine (5 mg, 0.04 mmol, 0.1 eq) was added to a stirred suspension of 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (108B) (100 mg, 0.4 mmol, 1.0 eq), di-tert-butyl dicarbonate (229 mg, 1.0 mmol, 2.5 eq) and triethylamine (0.146 mL, 1.00 mmol, 2.5 eq) in dichloromethane (4.2 mL). The mixture was stirred at room temperature for 72 h and then water (3.0 mL) was added. The mixture was extracted with ethyl acetate (3 x 5.0 mL) and the combined organic phases were washed with brine (2.5 mL) then dried passing through a phase separator. The solvents were removed under reduced pressure to afford a crude residue which was purified by reverse phase chromatography (eluting 0.1% formic solution to acetonitrile, 5-100%) to give the desired product tert-butyl 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-2-oxopyrrolidine-1-carboxylate (108C). Yield: 72 mg (53%). 1< H NMR (400 MHz, DMSO) δ 8.35 (s, 2H), 7.62 (t, J =6.1 Hz, 1H), 3.73 (dd, J =7.8, 10.4 Hz, 1H), 3.50 - 3.44 (m, 1H), 3.29 (d, J =6.4 Hz, 2H), 2.60 - 2.55 (m, 2H), 2.36 (s, 3H), 2.28 (dd, J =9.6, 20.9 Hz, 1H), 1.44 (s, 9H).tert-Butyl (4-amino-2-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-4-oxobutyl)carbamate (108D)

[0265] A solution of ammonium hydroxide (2.2 mL) was added to tert-butyl 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-2-oxopyrrolidine-1-carboxylate (108C) (72 mg, 0.21 mmol) and the mixture was heated at 80°C for 1.5 h. The mixture was cooled to room temperature then extracted with dichloromethane (3 x 5 mL). The organic solvents were dried passing through a phase separator then removed under reduced pressure to afford the desired product tert-butyl (4-amino-2-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-4-oxobutyl)carbamate (108D).

[0266] Yield: 61 mg (86%). 1< H NMR (400 MHz, DMSO) δ 8.33 (s, 2H), 7.32 (s, 1H), 7.25 (dd, J =6.0, 6.0 Hz, 1H), 6.81 (s, 2H), 3.24 (dd, J =6.2, 6.2 Hz, 2H), 2.97 (dd, J =6.0, 6.0 Hz, 2H), 2.36 (s, 3H), 2.18 - 2.08 (m, 1H), 2.04 (d, J =6.4 Hz, 2H), 1.38 (s, 9H).4-Amino-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide dihydrochloride salt (108E)

[0267] Methodology applied was analogous to those described in General Method 2.

[0268] A solution of hydrogen chloride (0.7 mL, 4M in 1,4-dioxane) was added to tert-butyl (4-amino-2-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-4-oxobutyl)carbamate (108D) (61 mg, 0.17 mmol) and the mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure to afford the desired product 4-amino-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide dihydrochloride salt (108E) as a pale yellow solid.

[0269] Yield: 56 mg (100%) HCl salt.4-((6-(N-(4-Methoxybenzyl)sulfamoyl)benzo[d]thiazol-2-yl)amino)-3-(((5-(methylthio) pyrimidin-2-yl)amino)methyl)butanamide (Reference Example 177)

[0270] Methodology applied was analogous to those described in General Method 3. 2-Chloro-N-(4-methoxybenzyl)benzo[d]thiazole-6-sulfonamide (101B) (70 mg, 0.19 mmol, 1.10 eq) was added to a stirred solution of 4-amino-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide dihydrochloride salt (108E) (56 mg, 0.17 mmol, 1.0 eq) and triethylamine (0.072 mL, 0.51 mmol, 3.0 eq) in anhydrous dimethylformamide (2.0 mL) under nitrogen. The mixture was stirred at room temperature for 72 h and then concentrated under reduced pressure. Water (2.5 mL) was added and the resulting precipitate was collected by filtration, then washed with methanol. The organic filtrate was concentrated under reduced pressure to give a crude residue which was purified by flash chromatography (eluting dichloromethane to methanol, 0-25%) to give the desired product 4-((6-(N-(4-methoxybenzyl)sulfamoyl)benzo[d]thiazol-2-yl)amino)-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide (Reference Example 177) as an off white solid.

[0271] Yield: 25 mg (25%). 1< H NMR (400 MHz, DMSO) δ 8.45 (dd, J =5.6, 5.6 Hz, 1H), 8.33 (s, 2H), 8.08 (d, J =1.8 Hz, 1H), 7.88 (dd, J =6.1, 6.1 Hz, 1H), 7.62 (dd, J =1.9, 8.5 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.39 - 7.37 (m, 1H), 7.14 (d, J =8.7 Hz, 2H), 6.87 - 6.87 (m, 1H), 6.81 (d, J =8.7 Hz, 2H), 3.89 (d, J =6.0 Hz, 2H), 3.70 (s, 3H), 3.48 (d, J =1.1 Hz, 2H), 3.37 (dd, J =6.1, 6.1 Hz, 2H), 2.43 - 2.37 (m, 1H), 2.34 (s, 3H), 2.22 - 2.17 (m, 2H).4-((5-(Methylthio)pyrimidin-2-yl)amino)-3-(((6-sulfamoylbenzo[d]thiazol-2-yl)amino)methyl)butanamide (Reference Example 178)

[0272] Trifluoroacetic acid (0.3 mL) was added dropwise to a 0°C cooled solution of 4-((6-(N-(4-methoxybenzyl)sulfamoyl)benzo[d]thiazol-2-yl)amino)-3-(((5-(methylthio) pyrimidin-2-yl)amino)methyl)butanamide (177) (20 mg, 0.03 mmol, 1.0 eq) in anhydrous dichloromethane (0.3 mL). The mixture was stirred for 30 minutes and then allowed to warm to room temperature over 8 h. A further aliquot of trifluoroacetic acid (1 mL) was added and the mixture was stirred for 16 h. The reaction mixture was concentrated under pressure then carefully made basic with the addition of a saturated aqueous solution of sodium hydrogen carbonate (3 mL). The mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with brine (3 mL), dried over anhydrous magnesium sulphate and then concentrated under reduced pressure. The crude residue obtained was purified by flash chromatography (eluting dichloromethane to methanol, 0-20%) to give the desired product 4-((5-(methylthio)pyrimidin-2-yl)amino)-3-(((6-sulfamoylbenzo[d] thiazol-2-yl)amino) methyl)butanamide (Reference Example 178) as a white solid.

[0273] Yield: 12 mg (75%). 1< H NMR (400 MHz, DMSO) δ 8.41 (dd, J =5.5, 5.5 Hz, 1H), 8.33 (s, 2H), 8.13 (d, J =1.8 Hz, 1H), 7.67 (dd, J =1.9, 8.5 Hz, 1H), 7.47 - 7.43 (m, 2H), 7.38 (s, 1H), 7.21 (s, 2H), 6.86 (s, 1H), 3.46 - 3.46 (m, 2H), 3.36 (dd, J =6.2, 6.2 Hz, 2H), 2.39 - 2.38 (m, 1H), 2.34 (s, 3H), 2.21 - 2.17 (m, 2H).

[0274] Using the procedures described in Scheme 10, the following example was synthesized: Table 10 Structure Ex. # 1H NMR LC-MS (M+H) +< Reference 179 1< H NMR (400 MHz, DMSO) δ 8.45 (dd, J =5.4, 5.4 Hz, 1H), 8.33 (s, 2H), 8.08 (d, J =1.9 Hz, 1H), 7.88 (dd, J =6.0, 6.0 Hz, 1H), 7.81 (q, J =4.5 Hz, 1H), 7.62 (dd, J =1.9, 8.5 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.14 (d, J =8.8 Hz, 2H), 6.81 (d, J =8.8 Hz, 2H), 3.89 (d, J =4.8 Hz, 2H), 3.70 (s, 3H), 3.52 - 3.42 (m, 2H), 3.38 - 3.31 (m, 2H), 2.59 (d, J =4.5 Hz, 3H), 2.48 - 2.35 (m, 1H), 2.34 (s, 3H), 2.22 - 2.17 (m, 2H).602 4-((2-Chlorobenzo[d]thiazol-6-yl)sulfonyl)morpholine (109B)

[0275] Methodology applied was analogous to those described in General Method 6 using dichloromethane as solvent instead of tetrahydrofuran.

[0276] Yield: 686 mg. 1< H NMR (400 MHz, CDCl 3 ) δ 8.25 (d, J =1.8 Hz, 1H), 8.10 (d, J =8.6 Hz, 1H), 7.85 (dd, J =1.3, 8.6 Hz, 1H), 3.75 (dd, J =4.7, 4.7 Hz, 4H), 3.04 (dd, J =4.7, 4.7 Hz, 4H); MS (ESI+) m / z 319 (M+H)+.tert-Butyl (3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-methylpropyl)carbamate (109D)

[0277] Methodology applied was analogous to those described in General Method 1.

[0278] Yield: 433 mg. 1< H NMR (400 MHz, CDCl 3 ) □δ 8.16 - 8.15 (m, 2H), 5.05 - 5.05 (m, 1H), 3.47 - 3.38 (m, 1H), 3.31 - 3.17 (m, 2H), 3.04 - 2.95 (m, 1H), 1.96 - 1.86 (m, 1H), 1.60 - 1.58 (m, 1H), 0.96 - 0.94 (m, 3H); MS (ESI+) m / z 333 (M+H)+.N1-(5-(Difluoromethoxy)pyrimidin-2-yl)-2-methylpropane-1,3-diamine hydrochloride (109E)

[0279] A solution of hydrogen chloride (2.7 mL, 4M in 1,4-dioxane) was added to tert-butyl (3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-methylpropyl)carbamate (109D) (300 mg, 0.903 mmol) and stirred at room temperature for 15 minutes. The solvents were removed under vacuum to give the crude title compound N1-(5-(difluoromethoxy)pyrimidin-2-yl)-2-methylpropane-1,3-diamine hydrochloride (109E) was taken on to next step without further purification.

[0280] Yield: 225 mg (Quant.). MS (ESI+) m / z 233 (M+H)+.N1-(5-(Difluoromethoxy)pyrimidin-2-yl)-2-methyl-N3-(6-(morpholinosulfonyl) benzo[d]thiazol-2-yl)propane-1,3-diamine (Reference Example 180)

[0281] Methodology applied was analogous to those described in General Method 3.

[0282] Yield: 225 mg. 1< H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 2H), 7.97 (d, J =1.5 Hz, 1H), 7.65 (dd, J =1.8, 8.5 Hz, 1H), 7.59 (d, J =8.5 Hz, 1H), 6.91 (s, 1H), 6.43 (t, J =71.6 Hz, 1H), 5.72 (dd, J =6.6, 6.6 Hz, 1H), 3.77 - 3.73 (m, 4H), 3.62 - 3.51 (m, 2H), 3.43 - 3.29 (m, 2H), 3.01 (dd, J =4.6, 4.6 Hz, 4H), 2.21 - 2.12 (m, 1H), 1.08 (d, J =6.9 Hz, 3H); (ESI+) m / z 515 (M+H)+.

[0283] Following the procedures described in Scheme 11, the following examples were synthesized: Table 11 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 181 1< H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 2H), 7.94 (d, J =1.5 Hz, 1H), 7.64 - 7.60 (m, 2H), 6.93 (s, 1H), 6.44 (t, J =72.8 Hz, 1H), 5.66 (dd, J =6.1, 6.1 Hz, 1H), 4.44 - 4.39 (m, 1H), 3.88 (tt, J =7.5, 7.8 Hz, 3H), 3.80 - 3.74 (m, 1H), 3.62 - 3.51 (m, 2H), 3.42 - 3.17 (m, 3H), 2.37 - 2.29 (m, 1H), 2.23 - 2.14 (m, 2H), 1.08 (d, J =6.9 Hz, 3H).570 Reference 182 1< H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 2H), 7.96 - 7.95 (m, 1H), 7.65 - 7.57 (m, 2H), 6.88 - 6.83 (m, 1H), 5.68 - 5.62 (m, 1H), 4.31 (s, 4H), 3.62 - 3.49 (m, 2H), 3.42 - 3.28 (m, 2H), 2.97 - 2.92 (m, 4H), 2.19 - 2.10 (m, 1H), 1.98 - 1.93 (m, 4H), 1.08 (d, J =6.9 Hz, 3H).555 Reference 183 1< H NMR (400 MHz, CDCl 3 ) δ 8.21 - 8.20 (2H, m), 7.68 (1H, d, J =1.5 Hz), 7.54 - 7.51 (1H, m), 7.33 (1H, dd, J =1.5, 8.3 Hz), 6.42 - 6.42 (1H, m), 5.69 (1H, t, J =6.4 Hz), 3.69 - 3.48 (6H, m), 3.42 - 3.28 (2H, m), 2.63 - 2.56 (6H, m), 2.18 - 2.09 (1H, m), 1.08 - 1.05 (3H, m);522 Reference 184 1< H NMR (400 MHz, DMSO) δ 8.16 - 8.15 (m, 3H), 7.65 - 7.64 (m, 1H), 7.42 (t, J =5.9 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.17 - 7.13 (m, 1H), 4.72 - 4.65 (m, 1H), 3.71 - 3.63 (m, 2H), 2.45 - 2.42 (m, 12H), 2.08 - 1.98 (m, 1H), 1.67 - 1.25 (m, 4H), 0.88 (d, J =6.8 Hz, 3H).493 Reference 185 1< H NMR (400 MHz, DMSO) δ 8.44 (t, J =5.5 Hz, 1H), 8.30 - 8.23 (m, 3H), 7.82 (dd, J =1.9, 8.4 Hz, 1H), 7.50 (t, J =5.9 Hz, 1H), 7.41 - 7.38 (m, 1H), 4.30 (q, J =7.1 Hz, 2H), 2.17 - 2.07 (m, 1H), 1.35 - 1.30 (m, 3H), 0.98 - 0.95 (m, 3H).438 Reference 186 1< H NMR (400 MHz, DMSO) δ 8.43 - 8.39 (m, 1H), 8.25 - 8.24 (m, 2H), 8.12 (d, J =1.9 Hz, 1H), 7.66 (dd, J =1.9, 8.5 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.21 (d, J =4.8 Hz, 2H), 2.16 - 2.07 (m, 1H), 0.98 - 0.95 (m, 3H).445 tert-Butyl (2-methyl-3-(pyridin-2-ylamino)propyl)carbamate (110B)

[0284] A solution of tert-butyl 3-amino-2-methylpropylcarbamate (110A) (150 mg, 0.80 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added to a solution of 2-bromopyridine (0.076 mL, 0.80 mmol, 1.0 eq), sodium tert-butoxide (383 mg, 3.98 mmol, 5.0 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (38 mg, 0.08 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (0) (73 mg, 0.08 mmol, 0.1 eq) in 1,4-dioxane (10 mL) under nitrogen. The reaction mixture was heated to 70°C for 72 h. The solvents were removed under reduced pressure and the residue obtained was partitioned between water (2 mL) and ethyl acetate (5 mL). The mixture was filtered through celite and the aqueous phase was then removed and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with water (2 mL) and brine (2 mL) then dried by passing through a phase separator before concentrating to dryness under vacuum. The crude residue obtained was purified by reverse phase chromatography (eluting 10 mM ammonium bicarbonate aqueous solution to acetonitrile, 5-95%) to give the semi-pure desired tert-butyl (2-methyl-3-(pyridin-2-ylamino)propyl)carbamate (110B) as an off-white solid that was used in the next step without further purification.

[0285] Yield: 27 mg (12%). MS (ESI+) m / z 266 (M+H) +< .2-Methyl-N 1< -(pyridin-2-yl)propane-1,3-diamine hydrochloride (110C)

[0286] Methodology applied was analogous to those described in General Method 2.

[0287] A solution of hydrogen chloride (0.4 mL, 4M in 1,4-dioxane) was added to tert-butyl (2-methyl-3-(pyridin-2-ylamino)propyl)carbamate (108B) (27 mg, 0.10 mmol) and the mixture was stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford the desired product 2-methyl-N1-(pyridin-2-yl)propane-1,3-diamine hydrochloride (110C) as a pale yellow semi-solid. The semi-crude sample was taken on into the next reaction without further purification.

[0288] Yield: 25 mg (assumed quant. %).2-Methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)-N 3< -(pyridin-2-yl)propane-1,3-diamine (Reference Example 187)

[0289] Methodology applied was analogous to those described in General Method 3. 2-Chloro-5-methylsulfanyl-pyrimidine (100B) (17 mg, 0.11 mmol, 1.05 eq) was added to a stirred solution of 2-methyl-N 1< -(pyridin-2-yl)propane-1,3-diamine hydrochloride (110C) (24 mg, 0.10 mmol, 1.0 eq) and cesium carbonate (99 mg, 0.30 mmol, 3.0 eq) in anhydrous N,N-dimethylformamide (0.5 mL) under nitrogen. The mixture was heated to 50°C for 16 h and was then concentrated under vacuum. Water (2 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with water (2 mL) and brine (2 mL) then dried by passing through a phase separator. The solvents were removed under vacuum to give a crude yellow oil which was purified by reverse phase chromatography (eluting 10 mM ammonium bicarbonate aqueous solution to acetonitrile, 5-95%) to give the desired 2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)-N 3< -(pyridin-2-yl)propane-1,3-diamine (Reference Example 187) as a sticky yellow solid.

[0290] Yield: 1.5 mg (5%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 8.10 (dd, J =0.6, 3.6 Hz, 1H), 7.41 - 7.35 (m, 1H), 6.54 (dd, J =5.3, 6.8 Hz, 1H), 6.38 (d, J =8.4 Hz, 1H), 5.93 - 5.93 (m, 1H), 4.96 - 4.96 (m, 1H), 3.53 - 3.21 (m, 4H), 2.35 (s, 3H), 2.10 - 2.01 (m, 1H), 1.03 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 290 (M+H) +< . Methyl 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)pyrazine-2-carboxylate (Reference Example 188)

[0291] Methodology applied was analogous to those described in General Method 3.

[0292] Methyl 5-bromopyrazine-2-carboxylate (114 mg, 0.53 mmol, 1.0 eq) was added to a stirred solution of 2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) (150 mg, 0.53 mmol, 1.0 eq) and cesium carbonate (514 mg, 1.58 mmol, 3.0 eq) in anhydrous N,N-dimethylformamide (2.0 mL) under nitrogen. The mixture was stirred at room temperature for 16 h and then concentrated under vacuum. Water (2.5 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with water (2 mL) and brine (2.5 mL) then dried passing through a phase separator. The solvents were removed under vacuum to give a brown oil which was purified by flash chromatography (eluting iso-hexanes to ethyl acetate, 0-100%). The semi-crude product obtained was further purified by flash chromatography (eluting dichloromethane to methanol, 0-10%) to give the desired methyl 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) pyrazine-2-carboxylate (Reference Example 188) as a white solid. Yield: 60 mg (32%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.37 (s, 2H), 7.91 (d, J =1.4 Hz, 1H), 6.36 - 6.36 (m, 1H), 5.56 (dd, J =6.0, 6.0 Hz, 1H), 3.95 (s, 3H), 3.60 - 3.51 (m, 2H), 3.40 - 3.26 (m, 2H), 2.38 (s, 3H), 2.10 - 2.03 (m, 1H), 1.04 (d, J =6.9 Hz, 3H). MS (ESI+) m / z 349 (M+H) +< .5-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylic acid (Reference Example 189)

[0293] Methodology applied was analogous to those described in General Method 4.

[0294] Lithium hydroxide monohydrate (23 mg, 55 mmol, 5.0 eq) was added to a stirred solution of methyl 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) pyrazine-2-carboxylate (188) (38 mg, 0.11 mmol, 1.0 eq) in ethanol (0.4 mL) and water (0.4 mL). The mixture was stirred at ambient temperature for 72 h and then concentrated under reduced pressure. Water (0.5 mL) was added to the residue and this mixture was acidified to pH ~3 with a solution of aqueous hydrochloric acid (2M). A sticky precipitate was collected under filtration and then extracted with ethyl acetate (3 x 3 mL), washed with water (1 mL) and then dried by passing through a phase separator. The solvents were removed under vacuum to give the desired 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylic acid (Reference Example 189) as a pale yellow solid.

[0295] Yield: 34 mg (94%); 1< H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.36 (s, 2H), 7.99 (s, 2H), 7.65 - 7.64 (m, 1H), 3.39 - 3.20 (m, 4H), 2.36 (s, 3H), 2.12 - 2.03 (m, 1H), 0.94 (d, J =6.8 Hz, 3H), One NH proton not observed; MS (ESI+) m / z 335 (M+H) +< .(4-Hydroxypiperidin-1-yl)(5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino) pyrazin-2-yl)methanone (Reference Example 190)

[0296] Methodology applied was analogous to those described in General Method 5. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate (HATU, 58 mg, 0.15 mmol, 1.5 eq) was added to a solution of 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylic acid (189) (34 mg, 0.10 mmol, 1.0 eq) and 4-hydroxypiperidine (103 mg, 1.02 mmol, 10 eq) in N,N-dimethylformamide (1 mL) and the reaction mixture was stirred at room temperature for 18 h. The solvents were removed under reduced pressure and the crude residue obtained was purified by reverse phase preparative HPLC to give the desired (4-hydroxypiperidin-1-yl)(5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)pyrazin-2-yl)methanone (Reference Example 190) as an off-white solid.

[0297] Yield: 22 mg (53%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.37 (s, 2H), 7.79 (s, 1H), 5.97 - 5.97 (m, 1H), 5.71 - 5.71 (m, 1H), 4.15 - 4.15 (m, 2H), 4.01 - 3.94 (m, 1H), 3.58 - 3.47 (m, 2H), 3.42 - 3.25 (m, 4H), 2.37 (s, 3H), 2.08 (ddd, J =11.5, 11.5, 5.1 Hz, 1H), 2.00 - 1.94 (m, 2H), 1.62 - 1.60 (m, 3H), 1.04 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 418 (M+H) +< . 5-(5-Methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (111B)

[0298] Methodology applied was analogous to those described in General Method 7.

[0299] 2-Bromo-5-methyl-1,3,4-oxadiazole (0.58 g, 3.58 mmol, 1.05 eq) was added to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (111A) (0.75 g, 3.41 mmol, 1.0 eq), cesium carbonate (3.33 g, 10.22 mmol, 3.0 eq) and tetrakis(triphenylphosphine)palladium (0) (0.39 g, 0.34 mmol, 0.10 eq) in water (5.5 mL) and 1,4-dioxane (22.5 mL) under nitrogen. The reaction mixture was heated to 100°C for 16 h. The solvents were removed under vacuum, water (20 mL) was added and the mixture extracted with ethyl acetate (6 x 50 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried by passing through a phase separator and then concentrated under vacuum. The crude residue obtained was purified by reverse phase chromatography (eluting 10 mM ammonium bicarbonate solution to acetonitrile, 5-30%) to give the desired 5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (111B) as an off-white solid.

[0300] Yield: 153 mg (25%). 1< H NMR (400 MHz, DMSO) δ 8.49 (d, J =2.0 Hz, 1H), 7.87 (dd, J =2.4, 8.8 Hz, 1H), 6.75 (s, 2H), 6.57 (d, J =8.8 Hz, 1H), 2.53 (s, 3H).tert-Butyl (2-methyl-3-((5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)propyl) carbamate (111C)

[0301] tert-Butyl N-(2-methyl-3-oxopropyl)carbamate (111B) (225 mg, 1.21 mmol, 1.2 eq) was added to a solution of 5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (114B) (153 mg, 1.00 mmol, 1.0 eq), acetic acid (0.230 mL, 4.02 mmol, 4.0 eq) and molecular sieves (type 4Å, 250 mg) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 5 minutes and then sodium triacetoxyborohydride (532 mg, 2.51 mmol, 2.5 eq) was added in one portion. The mixture was stirred at room temperature for 40 h. tert-Butyl N-(2-methyl-3-oxopropyl)carbamate (225 mg, 1.21 mmol, 1.2 eq) was added and the reaction mixture stirred at room temperature for a further 72 h. The reaction was quenched by the careful addition of a saturated aqueous solution of sodium hydrogen carbonate (30 mL). The mixture was stirred vigorously for 30 minutes and the dichloromethane layer was then isolated and concentrated under reduced pressure to give a gum. The crude product was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-100%) to give the desired tert-butyl (2-methyl-3-((5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)propyl) carbamate (111C) as an off-white gum. The crude sample was taken on into the next reaction without further purification.

[0302] Yield: 101 mg (29%).2-Methyl-N 1< -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride (111D)

[0303] Methodology applied was analogous to those described in General Method 2.

[0304] A solution of hydrogen chloride (1.2 mL, 4M in 1,4-dioxane) was added to tert-butyl (2-methyl-3-((5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)propyl)carbamate (110C) (101 mg, 0.29 mmol) and the mixture stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford the desired 2-methyl-N 1< -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride (111D) as an off-white solid. The crude sample was taken on into the next reaction without further purification.

[0305] Yield: 93 mg (assumed quant. %).2-Methyl-N 1< -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-N 1< -(5-(methylthio) pyrimidin-2-yl)propane-1,3-diamine (Reference Example 203)

[0306] Methodology applied was analogous to those described in General Method 3. 2-Chloro-5-methylsulfanyl-pyrimidine (100B, 51 mg, 0.32 mmol, 1.1 eq) was added to a stirred suspension of 2-methyl-N 1< -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride (111D) (93 mg, 0.29 mmol, 1.0 eq) and cesium carbonate (283 mg, 0.87 mmol, 3.0 eq) in anhydrous N,N-dimethylformamide (2.9 mL) under nitrogen. The mixture was stirred at room temperature for 16 h, heated to 40°C for a further 16 h and then concentrated under vacuum. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL) then dried passing through a phase separator. The solvents were removed under vacuum to give a yellow oil which was purified by flash chromatography (eluting isohexane to ethyl acetate, 0-100%) to give a crude residue which was further purified by reverse phase preparative HPLC to give the desired 2-methyl-N 1< -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 203) as a yellow solid.

[0307] Yield: 3.5 mg (3%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J =1.8 Hz, 1H), 8.37 (s, 2H), 8.00 (dd, J =2.3, 8.8 Hz, 1H), 6.47 (d, J =8.1 Hz, 1H), 5.79 - 5.69 (m, 2H), 3.55 - 3.25 (m, 4H), 2.59 (s, 3H), 2.37 (s, 3H), 2.12 - 2.04 (m, 1H), 1.05 (d, J =6.8 Hz, 3H) ; MS (ESI+) m / z 372 (M+H) +< . Ethyl 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) pyridin -3-yl)cyclopropane-1-carboxylate (112B)

[0308] To a reaction tube was added (R)-2-methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) (544 mg, 2.19 mmol), ethyl 2-(6-bromopyridin-3-yl)cyclopropane-1-carboxylate (650 mg, 2.41 mmol), L-Proline (101 mg, 0.875 mmol) potassium phosphate (928 mg, 4.37 mmol) and dimethylsulfoxide (5 mL) and the mixture was sparged with nitrogen for 2 minutes before copper (I) iodide (83 mg, 0.437 mmol) was added. The tube was sealed under nitrogen and heated at 90°C overnight. The reaction was cooled, diluted with ethyl acetate (20 mL), passed through a celite pad and the filtrate concentrated under vacuum. The resulting residue was diluted with ethyl acetate (30 mL) and water (20 mL) and the aqueous phase was separated and extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with water (2 x 40 mL) and then brine (2 x 50 mL), dried over magnesium sulfate and then concentrated under vacuum to give the crude title compound ethyl 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropane-1-carboxylate (112B) as a pale brown oil. (N.B. Purification via normal phase chromatography could not resolve several close running impurities).

[0309] Yield: 284 mg. 1< H NMR (400 MHz, CDCl 3 ) d 8.36 (s, 2H), 8.21 (dd, J =2.1, 6.2 Hz, 1H), 7.95 (s, 1H), 7.26 - 7.19 (m, 1H), 7.12 (d, J =8.1 Hz, 1H), 6.33 (d, J =8.6 Hz, 1H), 4.22 - 4.15 (m, 2H), 3.53 - 3.46 (m, 1H), 3.39 - 3.31 (m, 2H), 3.23 - 3.17 (m, 1H), 2.49 (ddd, J =11.8, 11.8, 11.8 Hz, 1H), 2.33 (s, 3H), 2.12 - 2.02 (m, 1H), 1.79 - 1.74 (m, 1H), 1.55 - 1.48 (m, 1H), 1.32 - 1.24 (m, 3H), 1.24 - 1.17 (m, 1H), 1.02 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 402 (M+H) +< .2-(6-(((R)-2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropane-1-carboxylic acid (112C)

[0310] To a solution of ethyl 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)pyridin-3-yl)cyclopropane-1-carboxylate (112B, 274 mg, 0.682 mmol) in ethanol (6 mL) and water (4 mL) was added lithium hydroxide monohydrate (143 mg, 3.41 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue obtained was diluted with water (8 mL). The solution was adjusted to pH ~ 2 with a 2M aqueous solution of hydrochloric acid and was then extracted with dichloromethane / methanol (20% methanol in dichloromethane, 2 x 10 mL). The combined organic layers were passed through a phase separator cartridge and then concentrated under vacuum to give the crude title compound 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) pyridin-3-yl)cyclopropane-1-carboxylic acid (112C) as a brown oil which was used directly without further purification.

[0311] Yield: 280 mg. MS (ESI+) m / z 374 (M+H) +< .tert-Butyl 7-(2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) amino)pyridin-3-yl)cyclopropane-1-carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (112D)

[0312] tert-Butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (65 mg, 0.281 mmol) was added to a solution of 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) pyridin-3-yl)cyclopropane-1-carboxylic acid (112C, 70 mg, 0.187 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU, 86 mg, 0.225 mmol) and triethylamine (0.26 mL, 1.87 mmol) in dimethylformamide (2 mL) and the resulting mixture was stirred at room temperature for 18 h. Once complete the reaction mixture was concentrated under vacuum and the residue obtained was diluted with ethyl acetate (5 mL) and water (3 mL). The aqueous phase was separated and extracted with ethyl acetate (2 × 5 mL). The combined organics were washed with water (5 mL), brine (2 × 10 mL), dried over magnesium sulfate and then concentrated under vacuum. The crude residue obtained was purified using column chromatography (eluting 0-10% methanol in dichloromethane) to give the title compound tert-butyl 7-(2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropane-1-carbonyl)-2,7-diazaspiro[3.5] nonane-2-carboxylate (112D) as an off white solid.

[0313] Yield: 69 mg. 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.92 (d, J =1.5 Hz, 1H), 7.15 (dd, J =2.1, 8.5 Hz, 1H), 6.34 (d, J =8.6 Hz, 1H), 5.96 (dd, J =6.2, 6.2 Hz, 1H), 5.00 (s, 1H), 3.73 - 3.63 (m, 5H), 3.49 (s, 4H), 3.38 - 3.29 (m, 2H), 3.26 - 3.18 (m, 2H), 2.37 - 2.30 (m, 4H), 2.10 - 1.98 (m, 1H), 1.89 - 1.82 (m, 1H), 1.61 - 1.53 (m, 2H), 1.44 (s, 9H), 1.29 - 1.23 (m, 2H), 1.21 - 1.14 (m, 1H), 1.02 (d, J =6.8 Hz, 3H); MS (ESI+) m / z (M+H) +< .(2-(6-(((R)-2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropyl)(2,7-diazaspiro[3.5]nonan-7-yl)methanone (Reference Example 204)

[0314] Trifluoroacetic acid (0.2 mL) was added to a stirred solution of tert-butyl 7-(2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropane-1-carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (112D, 69 mg, 0.119 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 30 minutes. The solvents were removed under vacuum and then azeotroped with dichloromethane (3 × 5 mL). The crude residue obtained was dissolved in dimethylsulfoxide (1.5 mL) and purified by preparative HPLC. The liquors obtained were dried under vacuum then freeze-dried from an acetonitrile / water mix to afford the title compound (2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropyl)(2,7-diazaspiro[3.5]nonan-7-yl) methanone (Reference Example 204) as a fluffy white solid. Yield: 15 mg. 1< H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 1H), 8.35 (s, 2H), 7.89 - 7.86 (m, 1H), 7.16 (dd, J =2.0, 8.6 Hz, 1H), 6.36 (d, J =8.6 Hz, 1H), 5.98 (dd, J =6.9, 6.9 Hz, 1H), 5.49 - 5.49 (m, 1H), 3.76 (s, 4H), 3.51 - 3.43 (m, 2H), 3.39 - 3.30 (m, 3H), 3.22 (dd, J =6.6, 13.4 Hz, 2H), 2.38 - 2.31 (m, 4H), 2.11 - 2.01 (m, 1H), 1.89 - 1.79 (m, 5H), 1.59 - 1.52 (m, 1H), 1.27 - 1.14 (m, 1H), 1.03 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 482 (M+H) +< .

[0315] Following the procedures described in Scheme 17 , the following examples were synthesized: Table 14 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 205 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.93 (d, J =2.0 Hz, 1H), 7.14 (dd, J =2.3, 8.6 Hz, 1H), 6.33 (d, J =8.6 Hz, 1H), 5.97 - 5.90 (m, 1H), 4.90 (dd, J =6.1, 6.1 Hz, 1H), 3.57 - 3.11 (m, 10H), 3.06 (d, J =6.1 Hz, 2H), 2.36 (d, J =7.1 Hz, 7H), 2.09 - 1.99 (m, 1H), 1.89 - 1.82 (m, 2H), 1.82 - 1.76 (m, 3H), 1.59 - 1.48 (m, 1H), 1.19 - 1.12 (m, 1H), 1.02 (d, J =6.8 Hz, 3H).496 Reference 206 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.91 (d, J =1.8 Hz, 1H), 7.16 (dd, J =2.3, 8.6 Hz, 1H), 6.35 (d, J =8.6 Hz, 1H), 5.94 - 5.91 (m, 1H), 5.14 (s, 1H), 4.46 (d, J =2.8 Hz, 4H), 3.53 - 3.44 (m, 6H), 3.39 - 3.30 (m, 2H), 3.25 - 3.19 (m, 1H), 2.35 (s, 4H), 2.09 - 2.01 (m, 1H), 1.90 - 1.85 (m, 5H), 1.20 - 1.14 (m, 1H), 1.03 (d, J =6.8 Hz, 3H).483 Reference 207 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.91 (s, 1H), 7.20 (s, 1H), 6.38 (d, J =7.3 Hz, 1H), 5.91 - 5.91 (m, 1H), 5.44 - 5.18 (m, 1H), 4.72 (dd, J =20.0, 62.4 Hz, 1H), 4.49 - 4.43 (m, 1H), 4.13 - 4.13 (m, 1H), 4.03 - 3.97 (m, 1H), 3.87 - 3.87 (m, 2H), 3.53 - 3.45 (m, 1H), 3.38-3.31 (m, 2H), 3.22 (dd, J =6.4, 6.4 Hz, 2H), 3.10-3.00 (m, 2H), 2.64 (tt, J =22.1, 20.6 Hz, 2H), 2.42 - 2.38 (m, 1H), 2.36 (s, 4H), 2.09 - 2.01 (m, 1H), 1.87 - 1.82 (m, 1H), 1.28 - 1.22 (m, 1H), 1.03 (d, J =6.8 Hz, 3H).498 Reference 208 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.95 (d, J =2.4 Hz, 1H), 7.16 (dd, J =2.4, 8.6 Hz, 1H), 6.33 (d, J =8.5 Hz, 1H), 5.95 - 5.92 (m, 1H), 4.88 (dd, J =6.1, 6.1 Hz, 1H), 3.52 - 3.17 (m, 4H), 3.14 (s, 3H), 2.99 (s, 3H), 2.36 (s, 4H), 2.06 - 2.00 (m, 1H), 1.90 - 1.85 (m, 1H), 1.59 - 1.53 (m, 1H), 1.17 (ddd, J =4.5, 6.2, 8.3 Hz, 1H), 1.02 (d, J =6.8 Hz, 3H).401 N 1< -(5-Bromopyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (113B)

[0316] A solution of crude 2-methyl-N-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) (340 mg, 1.60 mmol, 1.0 eq) in dimethylformamide (8 mL) was added to a suspension of 2,5-dibromopyrazine (457 mg, 1.92 mmol, 1.2 eq) and cesium carbonate (1.56 g, 4.80 mmol, 3.0 eq) in dimethylformamide (2 mL). The reaction mixture was heated to 90°C for 18 h. The solvents were removed under reduced pressure and the residue obtained was partitioned between water (20 mL) and dichloromethane (50 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (3 × 25 mL). The combined organic phases were washed with brine (25 mL), dried by passing through a phase separator and then concentrated to dryness under vacuum. The crude residue was purified by flash chromatography (eluting with iso-hexanes to ethyl acetate, 0-100%) to give the title compound N 1< -(5-bromopyrazin-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (113B) as a pale yellow gum.

[0317] Yield: 230 mg (38%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 8.06 (d, J =1.3 Hz, 1H), 7.67 (d, J =1.4 Hz, 1H), 5.67 - 5.51 (m, 2H), 3.55 - 3.31 (m, 3H), 3.25 - 3.12 (m, 1H), 2.37 (s, 3H), 2.04 (s, 1H), 1.03 (d, J =6.9 Hz, 3H).N 1< -(5-(2-Methoxypyridin-3-yl)pyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 209)

[0318] Methodology applied was analogous to those described in General Method 7 , (N.B. used 1,4-dioxane instead of dimethylformamide).

[0319] A solution of N 1< -(5-bromopyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (113B) (50 mg, 0.135 mmol, 1.0 eq) was added to a solution of 2-methoxy-3-phenylboronic acid (23 mg, 0.149 mmol, 1.1 eq), cesium carbonate (132 mg, 0.406 mmol, 3 eq) and tetrakis(triphenylphosphine)palladium (0) (15.6 mg, 0.0135 mmol, 0.1 eq) in water (1 mL) and 1,4-dioxane (2 mL) under an atmosphere of nitrogen. The reaction mixture was heated to 80°C for 1 hour. The solvents were removed under reduced pressure, water (2 mL) was added and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with brine (10 mL) and concentrated under vacuum. The crude residue obtained was purified by preparative HPLC to give the desired N 1< -(5-(2-methoxypyridin-3-yl)pyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (154) as an off white solid.

[0320] Yield: 24 mg (44%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.77 (d, J =1.4 Hz, 1H), 8.37 (s, 2H), 8.18 - 8.13 (m, 2H), 7.99 (d, J =1.5 Hz, 1H), 7.01 (dd, J =4.9, 7.4 Hz, 1H), 5.69 (dd, J =6.5, 6.5 Hz, 1H), 5.55 (dd, J =6.1, 6.1 Hz, 1H), 4.04 (s, 3H), 3.59 - 3.48 (m, 2H), 3.42 - 3.25 (m, 2H), 2.37 (s, 3H), 2.19 - 2.06 (m, 1H), 1.06 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 398 (M+H) +< . tert-Butyl (2-methyl-3-oxopropyl)carbamate (114B)

[0321] Caution - exothermic reaction; Dess-Martin periodinane (2.94 g, 6.94 mmol, 1.3 eq) was added portion-wise over 20 minutes to a solution of tert-butyl (3-hydroxy-2-methylpropyl)carbamate (1.0 g, 5.34 mmol, 1.0 eq) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane (25 mL) and washed with 1M aqueous sodium dithionite solution (2 × 10 mL) and saturated aqueous sodium bicarbonate solution (2 × 10 mL). The organic phase dried passing through a phase separator and then concentrated under vacuum to give crude tert-butyl (2-methyl-3-oxopropyl)carbamate (114B) which was used immediately in the next step without further purification.tert-Butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (114C)

[0322] Methodology applied was analogous to method described in Scheme 13 (for the generation of 109D).

[0323] The crude product was purified by flash chromatography (eluting iso-hexanes to ethyl acetate, 0-100%) to give the desired tert-butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (114C) as a pale yellow gum

[0324] Yield: 875 mg (47%) (MS (ESI+) m / z 345 (M+H) +< .tert-Butyl(3-((2'-methoxy-[3,3'-bipyridin]-6-yl)amino)-2-methylpropyl)carbamate (114D)

[0325] Methodology applied was analogous to those described in General Method 7.

[0326] Crude tert-butyl(3-((2'-methoxy-[3,3'-bipyridin]-6-yl)amino)-2-methylpropyl)carbamate (114D) was used immediately in the next step without further purification.

[0327] Yield: 110 mg, MS (ESI+) m / z 373 (M+H) +< .N1-(2'-Methoxy-[3,3'-bipyridin]-6-yl)-2-methylpropane-1,3-diamine (114E)

[0328] Methodology applied was analogous to those described in General Method 2.

[0329] Crude N 1< -(2'-methoxy-[3,3'-bipyridin]-6-yl)-2-methylpropane-1,3-diamine (114E) was taken on immediately to the next step without further purification.

[0330] Crude yield: 75 mg MS (ESI+) m / z 273 (M+H) +< .N1-(2'-Methoxy-[3,3'-bipyridin]-6-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 210)

[0331] Methodology applied was analogous to those described in General Method 1.

[0332] The crude residue obtained was purified by preparative HPLC to give the desired product, N 1< -(2'-methoxy-[3,3'-bipyridin]-6-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine as an off white solid (155)

[0333] Yield: 8 mg (7%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 8.30 (d, J =2.1 Hz, 1H), 8.11 (dd, J =1.9, 5.0 Hz, 1H), 7.67 (dd, J =2.4, 8.7 Hz, 1H), 7.57 (dd, J =1.9, 7.3 Hz, 1H), 6.95 (dd, J =5.0, 7.3 Hz, 1H), 6.45 (d, J =8.4 Hz, 1H), 5.90 (dd, J =6.3, 6.3 Hz, 1H), 5.11 (dd, J =6.0, 6.0 Hz, 1H), 3.97 (s, 3H), 3.56 - 3.23 (m, 4H), 2.36 (s, 3H), 2.13 - 2.04 (m, 1H), 1.05 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 397 (M+H) +< . tert-Butyl (3-([3,3'-bipyridin]-6-ylamino)-2-methylpropyl)carbamate (115A)

[0334] Methodology applied was analogous to scheme 19 (example 115B) to generate the aldehyde (114B), and then using methodology analogous to general method 7.

[0335] The crude N 1< -([3,3'-bipyridin]-6-yl)-2-methylpropane-1,3-diamine (115A) was immediately taken on the next step.

[0336] Yield: 253 mg (63%) 1< H NMR (400 MHz, DMSO) δ 8.82 (d, J =1.8 Hz, 1H), 8.48 (dd, J =1.6, 4.8 Hz, 1H), 8.36 (d, J =2.1 Hz, 1H), 8.00 - 7.96 (m, 1H), 7.76 (dd, J =2.6, 8.7 Hz, 1H), 7.44 - 7.40 (m, 1H), 6.90 - 6.76 (m, 2H), 6.62 - 6.59 (m, 1H), 4.10 (q, J =5.3 Hz, 1H), 3.19 - 3.18 (m, 4H), 3.03 - 2.94 (m, 1H), 2.88 - 2.80 (m, 1H), 1.93 - 1.82 (m, 1H), 1.40 - 1.38 (m, 9H).N 1< -([3,3'-bipyridin]-6-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 211)

[0337] Methodology applied was analogous to method described in Scheme 13 (for the generation of 109D).

[0338] The crude residue obtained was purified by reverse phase chromatography (eluting 10 mM ammonium bicarbonate aqueous solution to acetonitrile, 5-95%) to give the desired product, N 1< -([3,3'-bipyridin]-6-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 211) as an off white solid.

[0339] Yield: 32 mg (14%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.77 (1H, d, J =2.1 Hz), 8.53 (1H, dd, J =1.6, 4.8 Hz), 8.37 - 8.35 (3H, m), 7.81 - 7.77 (1H, m), 7.63 (1H, dd, J =2.5, 8.7 Hz), 7.33 (1H, dd, J =4.6, 7.8 Hz), 6.50 (1H, d, J =8.7 Hz), 5.93 (1H, dd, J =6.1, 6.1 Hz), 5.25 (1H, dd, J =6.1, 6.1 Hz), 3.56 - 3.25 (4H, m), 2.36 (3H, s), 2.18 - 2.00 (1H, m), 1.06 (3H, d, J =6.9 Hz); MS (ESI+) m / z 367 (M+H) +< . 2-Bromo-5-((trimethylsilyl)ethynyl)pyridine (116B)

[0340] Triethylamine (49 mL, 352.25 mmol, 25 eq) was added to 2-bromo-5-iodopyridine (4.0 g, 14.09 mmol, 1.0 eq) followed by ethynyltrimethylsilane (2.9 mL, 21.13 mmol, 1.5 eq), copper (I) iodide (270 mg, 1.41 mmol, 0.1 eq), bis(triphenylphosphine)palladium (II) dichloride (99 mg, 0.14 mmol, 0.01 eq) and the mixture was stirred at room temperature for 17 h. The mixture was concentrated under vacuum to give a crude gum which was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0-40%) to give the intermediate 2-bromo-5-((trimethylsilyl)ethynyl)pyridine (116B) as a white solid.

[0341] Yield: 2.5 g (69%). MS (ESI+) m / z 254 / 256 (M+H) +< .2-Bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116C)

[0342] To a solution of 2-bromo-5-((trimethylsilyl)ethynyl)pyridine (116B) (250 mg, 0.983 mmol, 1.0 eq) in ethanol (20 mL) was added 1-(azidomethyl)-4-methoxybenzene (177 mg, 1.08 mmol, 1.1 eq) and the mixture was stirred at room temperature for 1 hour. A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (0.54 mL, 1.08 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum and then purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0-100%) to give 2-bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116C) as an off white solid.

[0343] Yield: 0.21 g (61%). MS (ESI+) m / z 347 (M+H) +< .Tert-Butyl(3-((5-(1-(4-methoaybenzyl)-1H1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-methylpropyl)carbamate (116D)

[0344] To a de-gassed solution of 2-bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116C) (135 mg, 0.391, 1.0 eq) in dimethyl sulfoxide (5 mL) was added tert-butyl(3-amino-2-methylpropyl)carbamate (96 mg, 0.508 mmol, 1.3 eq), L-proline (18 mg, 0.156 mmol, 0.4 eq), potassium phosphate (1.6.5 mg, 0.078 mmol, 0.2 eq) and copper (I) iodide (15 mg, 0.782 mmol, 0.2 eq). The mixture was stirred at 90°C for 28 h, diluted with water (20 mL) and extracted with dichloromethane (3 × 20 mL). The organic phases were combined and concentrated under vacuum and the crude residue was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0-100%) to give 2-bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116D) as a pale brown solid.

[0345] Yield: 0.080 g (45%). MS (ESI+) m / z 453 (M+H) +< .Tert-Butyl (3-((5-(1-(4-methoaybenzyl)-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-methylpropyl)carbamate (116E)

[0346] Methodology applied was analogous to those described in General Method 2.

[0347] Yield: 25 mg (29%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.42 (d, J =2.0 Hz, 1H), 8.35 (s, 2H), 7.90 (dd, J =2.4, 8.7 Hz, 1H), 7.52 (s, 1H), 6.94 - 6.90 (m, 2H), 6.44 (d, J =9.0 Hz, 1H), 5.94 (dd, J =6.1, 6.1 Hz, 1H), 5.49 (s, 2H), 5.09 (dd, J =6.3, 6.3 Hz, 1H), 3.81 (s, 4H), 3.53 - 3.22 (m, 4H), 2.35 (s, 3H), 2.10 - 2.01 (m, 1H), 1.03 (d, J =6.9 Hz, 3H), (NH not observed).N 1< -(5-(1H-1,2,3-Triazol-5-yl)pyridin-2-yl)-2-methyl-N3-(4-(methylthio)phenyl)propane-1,3-diamine (Reference Example 212)

[0348] Methodology applied was analogous to those described in General Method 3.

[0349] Yield: 18 mg (96%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.53 (d, J =2.1 Hz, 1H), 8.38 (s, 2H), 7.84 (s, 1H), 7.82 (dd, J =2.3, 8.7 Hz, 1H), 6.45 (d, J =8.4 Hz, 1H), 6.17 (dd, J =6.3, 6.3 Hz, 1H), 5.31 (dd, J =6.0, 6.0 Hz, 1H), 3.57 - 3.26 (m, 4H), 2.36 (s, 3H), 2.19 - 2.06 (m, 1H), 1.06 (d, J =6.8 Hz, 3H), (NH not observed); MS (ESI+) m / z 457 (M+H) +< . tert-Butyl (2-methyl-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)propyl)carbamate (117B)

[0350] To a solution of 5-(pyridin-2-yl)pyrazin-2-amine (200 mg, 1.16 mmol, 1.0 eq) in dichloromethane (10 mL) was added tert-butyl (2-methyl-3-oxopropyl)carbamate (117B) (221 mg, 1.17 mmol, 1.0 eq), 3Å molecular sieves (750 mg), acetic acid (0.266 mL, 4.65 mmol) and sodium triacetoxyborohydride (616 mg , 2.9 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane (25 mL) and filtered. The organic phase was washed with water (25 mL) and brine (25 mL) then passed through a phase separator cartridge. The solvents were removed under vacuum to afford crude tert-butyl (2-methyl-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)propyl)carbamate (117B) which was used in the next step without further purification.

[0351] Yield: 310 mg (78%).2-Methyl-N 1< -(5-(pyridin-2-yl)pyrazin-2-yl)propane-1,3-diamine (117C)

[0352] Methodology applied was analogous to those described in General Method 2.

[0353] Yield: 200 mg (100%).2-Methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)-N3-(5-(pyridin-2-yl)pyrazin-2-yl)propane-1,3-diamine (Reference Example 213)

[0354] Methodology applied was analogous to those described in General Method 1.

[0355] Yield: 20 mg (10%). 1< H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J =1.4 Hz, 1H), 8.62 - 8.61 (m, 1H), 8.37 (s, 2H), 8.10 (d, J =8.0 Hz, 1H), 7.94 (d, J =1.4 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.20 (dd, J =4.8, 6.5 Hz, 1H), 5.75 - 5.63 (m, 2H), 3.58 - 3.50 (m, 2H), 3.42 - 3.28 (m, 2H), 2.37 (s, 3H), 2.19 - 2.06 (m, 1H), 1.06 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 368 (M+H) +< .

[0356] Following the procedures described in Scheme 22, the following examples were synthesized: Table 15 Structure Ex. # 1H NMR LC-MS (M+H) +< Reference 214 1< H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J =1.4 Hz, 1H), 8.37 (s, 2H), 8.27 (d, J =2.3 Hz, 1H), 7.69 (dd, J =1.4, 7.0 Hz, 2H), 6.45 - 6.43 (m, 1H), 5.65 (dd, J =6.3, 6.3 Hz, 1H), 5.53 (dd, J =6.1, 6.1 Hz, 1H), 3.57 - 3.24 (m, 4H), 2.36 (s, 3H), 2.14 - 2.04 (m, 1H), 1.06 (d, J =6.9 Hz, 3H).357 Reference 215 1< H NMR (400 MHz, CDCl 3 ) δ 9.20 (d, J =2.0 Hz, 1H), 8.71 (d, J =4.9 Hz, 2H), 8.40 (dd, J =2.3, 8.8 Hz, 1H), 8.37 (s, 2H), 7.08 (dd, J =4.8, 4.8 Hz, 1H), 6.47 (d, J =8.5 Hz, 1H), 5.88 (dd, J =6.0, 6.0 Hz, 1H), 5.43 (dd, J =6.1, 6.1 Hz, 1H), 3.56 - 3.27 (m, 4H), 2.36 (s, 3H), 2.14 - 2.00 (m, 1H), 1.06 (d, J =6.9 Hz, 3H).368 Reference 216 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 - 8.36 (m, 3H), 8.16 (s, 1H), 7.78 (dd, J =2.4, 8.7 Hz, 1H), 6.51 (d, J =8.4 Hz, 1H), 5.83 - 5.78 (m, 1H), 5.57 (dd, J =5.8, 5.8 Hz, 1H), 3.76 (s, 3H), 3.57 - 3.24 (m, 4H), 2.36 (s, 3H), 2.14 - 1.99 (m, 1H).371 Reference 217 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.99 (d, J =2.1 Hz, 1H), 7.36 (dd, J =2.4, 8.5 Hz, 1H), 6.37 (d, J =8.5 Hz, 1H), 5.94 (dd, J =6.0, 6.0 Hz, 1H), 4.96 (dd, J =5.8, 5.8 Hz, 1H), 4.14 (q, J =7.2 Hz, 2H), 3.52 - 3.45 (m, 3H), 3.42 - 3.31 (m, 2H), 3.26 - 3.20 (m, 1H), 2.35 (s, 3H), 2.09 - 2.00 (m, 1H), 1.25 (dd, J =7.2, 7.2 Hz, 3H), 1.03 (d, J =6.9 Hz, 3H).376 5-(1-Methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-amine (118B)

[0357] Methodology applied was analogous to those described in General Method 7, (N.B. used 1,4-dioxane / water used as solvent instead of dimethylformamide)

[0358] Yield: 158 mg (73%) m / z 176 (M+H) +< .Tert-Butyl (2-methyl-3-((5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)amino) propyl)carbamate (118C)

[0359] Methodology applied was analogous to the method described in Scheme 13 (for the generation of 109D).

[0360] Crude tert-butyl (2-methyl-3-((5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)amino) propyl)carbamate (118C) was taken on immediately to the next step.

[0361] Yield: 101 mg (34%) MS (ESI+) m / z 347 (M+H) +< .2-Methyl-N1-(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)propane-1,3-diamine (118D)

[0362] Methodology applied was analogous to those described in General Method 2.

[0363] Crude 2-methyl-N 1< -(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)propane-1,3-diamine (106D) was taken on immediately to the next step.

[0364] Yield: 71 mg (assumed) MS (ESI+) m / z 367 (M+H) +< .2-Methyl-N1-(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 218)

[0365] Methodology applied was analogous to those described in General Method 1.

[0366] Yield: 25 mg (23%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 3H), 8.30 (s, 1H), 8.05 (dd, J =2.3, 8.9 Hz, 1H), 7.67 (s, 1H), 6.56 (d, J =9.2 Hz, 1H), 6.11 - 6.06 (m, 1H), 4.14 (s, 3H), 2.63 (s, 4H), 2.35 (s, 3H), 2.19 - 2.10 (m, 1H), 1.07 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 371(M+H) +< . N 1< -(5-Bromopyrazin-2-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (119a)

[0367] Methodology applied was analogous to those described in General Method 3.

[0368] Yield: 230 mg (38%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 8.06 (d, J =1.3 Hz, 1H), 7.67 (d, J =1.4 Hz, 1H), 5.67 - 5.51 (m, 2H), 5.30 (s, 2H), 3.55 - 3.31 (m, 3H), 3.25 - 3.12 (m, 1H), 2.37 (s, 3H), 2.04 (s, 1H), 1.03 (d, J =6.9 Hz, 3H).2-Methyl-N 1< -(5-(methylthio)pyrimidin-2-yl)-N 3< -(5-(5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)propane-1,3-diamine (Reference Example 219)

[0369] Methodology applied was analogous to those described in General Method 7, (N.B. used 1,4-dioxane / water and no additional aliquots of reagents were added)

[0370] Yield: 18 mg (31%). 1< H NMR (400 MHz, DMSO) δ 13.70 (s, 1H), 8.35 - 8.34 (m, 2H), 8.26 (d, J =1.0 Hz, 1H), 8.13 - 8.12 (m, 1H), 8.00 (d, J =1.5 Hz, 1H), 7.55 - 7.44 (m, 1H), 7.23 - 7.18 (m, 1H), 3.35 - 3.18 (m, 4H), 2.35 (s, 3H), 2.11 - 2.02 (m, 1H), 0.95 (d, J =6.8 Hz, 3H); MS (ESI+) m / z 426 (M+H) +< . tert-Butyl (2-methyl-3-(pyrazolo[1,5-α]pyrimidin-5-ylamino)propyl)carbamate (120A).

[0371] A microwave vial containing 5-chloropyrazolo[1,5-c]pyrimidine (500 mg, 3.26 mmol, 1 eq) and tert-butyl (3-amino-2-methylpropyl)carbamate (100E) (6.13 g, 32.56 mmol, 10 eq) was heated to 140°C for 30 minutes under microwave irradiation. The crude reaction mixture was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0-100%) to give tert-butyl (2-methyl-3-(pyrazolo[1,5-α]pyrimidin-5-ylamino)propyl)carbamate (120A) Yield: 700 mg (70%). MS (ESI+) m / z 306 (M+H) +< .2-Methyl-N 1< -(pyrazolo[1,5-a]pyrimidin-5-yl)propane-1,3-diamine (120B)

[0372] Methodology applied was analogous to those described in General Method 2.

[0373] MS (ESI+) m / z 229 (M+H) +< .Tert-Butyl (2-methyl-3-(pyrazolo[1,5-α]pyrimidin-5-ylamino)propyl)carbamate (Reference Example 220)

[0374] Methodology applied was analogous to those described in General Method 3.

[0375] Yield: 20 mg (14%). 1< H NMR (400 MHz, DMSO) δ 7.34 (s, 2H), 7.27 (d, J =7.6 Hz, 1H), 6.79 (d, J =1.8 Hz, 1H), 5.29 (d, J =7.6 Hz, 1H), 5.08 (d, J =1.5 Hz, 1H), 2.44 - 2.37 (m, 4H), 1.36 (s, 3H), 1.20 - 1.11 (m, 1H), (2 × NH not observed); MS (ESI+) m / z 330 (M+H) +< . Methyl 6-bromonicotinimidate (121B)

[0376] Sodium methoxide (0.71 g, 13.22 mmol, 1.1 eq) was added to an ice cooled solution of 6-bromonicotinonitrile (121A) (2.2 g, 12.02 mmol, 1.0 eq) in dioxane / water (20 mL / 20 mL). The mixture was stirred under ice cooling for 30 minutes and then allowed to warm to room temperature. After 1 hour the mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (50 mL). The organics were combined and the solvents were removed under vacuum to afford crude methyl 6-bromonicotinimidate (121B) which was used in the next step without further purification.

[0377] Yield: 2.5 g (96%).6-Bromo-N'-methylnicotinimidohydrazide (121C)

[0378] Methyl hydrazine (0.73 mL, 13.96 mmol, 1.2 eq) was added to a solution of 6-bromonicotinimidate (121B) (2.5 g, 11.63 mmol, 1.0 eq) and the mixture was stirred at room temperature for 1 hour. The solvents were removed under vacuum to afford crude 6-bromo-N'-methylnicotinimidohydrazide (121C) which was used in the next step without further purification.

[0379] Yield: 2 g (75%).2-Bromo-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (121D)

[0380] Formic acid (10 mL, 265 mmol, 30.4 eq) was added to 6-bromo-N'-methylnicotinimidohydrazide (121C) (2.0 g, 8.73 mmol, 1.0 eq) and the mixture was heated to reflux for 1 hour. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL), dried over sodium sulphate and filtered. The solvents were removed under vacuum to afford crude a brown residue which was purified by flash chromatography (eluting with 0-10% methanol in dichloromethane / dichloromethane to give 2-bromo-5-(1-methyl-1H-1,2,4-triazol-3-yl) pyridine (121D) as an off white solid.

[0381] Yield: 500 mg (23%). MS (ESI+) m / z 240 (M+H) +< .Tert-Butyl (2-methyl-3-((5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino) propyl)carbamate (121E)

[0382] Methodology applied was analogous to those described in General Method 7, (N.B. used 1,4-dioxane / water and no additional aliquots of reagents were added) Yield: 125 mg2-Methyl-N 1< -(5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 221)

[0383] Methodology applied was analogous to those described in General Method 2 for the deprotection and then General Method 1.

[0384] Yield: 25 mg (18%). 1< H NMR (400 MHz, DMSO) δ 8.42 (d, J =2.0 Hz, 1H), 8.34 (s, 2H), 8.04 (s, 1H), 7.76 (dd, J =2.4, 8.8 Hz, 1H), 7.48 (dd, J =6.0, 6.0 Hz, 1H), 6.82 (dd, J =5.8, 5.8 Hz, 1H), 6.57 (d, J =8.4 Hz, 1H), 4.16 (s, 3H), 3.32 - 3.17 (m, 4H), 2.35 (s, 3H), 2.09 - 1.99 (m, 1H), 0.93 (d, J =6.7 Hz, 3H); MS (ESI+) m / z 371 (M+H) +< . tert-Butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (122B)

[0385] tert-Butyl N-(2-methyl-3-oxopropyl)carbamate (100E) (1.0 g, 5.34 mmol, 1.0 eq) was added to a solution of 5-bromopyridin-2-amine (122A) (920 mg, 5,34 mmol, 1.0 eq), acetic acid (1.2 mL, 21.36 mmol, 4.0 eq) and molecular sieves (type 4Å, 1.0 g) in anhydrous dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 5 minutes and then sodium triacetoxyborohydride (2.83 g, 13.35 mmol, 2.5 eq) was added in one portion. The mixture was stirred at room temperature for 5 h. The reaction was quenched by the careful addition of a saturated aqueous solution of sodium hydrogen carbonate (30 mL). The mixture was stirred vigorously for 30 minutes and the dichloromethane layer was then separated and washed with an aqueous solution of sodium thiosulphate (1M, 15 mL). The organic phase was isolated and concentrated under reduced pressure to give semi-crude tert-butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (122B) as a pale brown gum which was used in the next reaction without further purification.

[0386] Yield: 875 mg (47%).Tert-Butyl (3-((2'-methoxy-[3,3'-bipyridin]-6-yl)amino)-2-methylpropyl)carbamate (122C)

[0387] Methodology applied was analogous to those described in General Method 7.

[0388] Yield: 138 mg.N 1< -(2'-Methoxy-[3,3'-bipyridin]-6-yl)-2-methyl-N 3< -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Reference Example 222)

[0389] Methodology applied was analogous to those described for General Method 2 for the deprotection and then General Method 1.

[0390] Yield: 57 mg. 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 8.23 (d, J =2.0 Hz, 1H), 7.68 (dd, J =2.3, 8.7 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.03 - 6.95 (m, 2H), 6.48 (d, J =8.7 Hz, 1H), 5.94 - 5.90 (m, 2H), 3.82 (s, 3H), 3.56 - 3.47 (m, 1H), 3.44 - 3.35 (m, 2H), 3.28 (dd, J =6.6, 13.4 Hz, 1H), 2.35 (s, 3H), 2.18 - 2.07 (m, 1H), 1.06 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 396 (M+H) +< . 6'-Chloro-2H-[1,3'-bipyridin]-2-one (123B)

[0391] 2-Amino-5-iodopyridine (123A) (1.12 g, 5.00 mmol, 1.0 eq) was combined with 2-hydroxypyridine (582 mg, 6.00 mmol, 1.2 eq), potassium carbonate (760 mg, 5.50 mmol, 1.1 eq), copper (I) iodide (143 mg, 0.75 mmol, 0.15 eq) and 8-hydroxyquinoline (110 mg, 0.75 mmol, 0.15 eq) in anhydrous dimethylsulfonamide (5 mL). The mixture was degassed under a stream of nitrogen and then heated at 130°C for 21 h. The reaction mixture was allowed to cool to room temperature then poured into a mixture of 10% aqueous ammonium hydroxide solution (100 mL) and ethyl acetate (50 mL). Activated charcoal (1 g) was added and the mixture was filtered through a pad of celite, washing with ethyl acetate (2 × 50 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude pale yellow solid was purified by flash chromatography (eluting dichloromethane to methanol, 0-10%) to give the desired product 6'-chloro-2H-[1,3'-bipyridin]-2-one as an off white solid (123B).

[0392] Yield: 245 mg, (26%). 1< H NMR (400 MHz, DMSO) δ 7.88 (1H, d, J =2.5 Hz), 7.60 (1H, ddd, J =0.7, 2.1, 6.8 Hz), 7.49 (1H, ddd, J =2.2, 6.7, 9.1 Hz), 7.41 (1H, dd, J =2.7, 8.7 Hz), 6.52 (1H, dd, J =0.4, 8.8 Hz), 6.45 (1H, ddd, J =0.7, 1.3, 9.2 Hz), 6.28 (1H, ddd, J =6.7, 6.7, 1.3 Hz), 6.23 (2H, s); MS (ESI+) m / z 188 (M+H) +< .tert-Butyl (2-methyl-3-((2-oxo-2H [1,3'-bipyridin]-6'-yl)amino)propyl)carbamate (123C)

[0393] Methodology applied was analogous to those described in Scheme 19.

[0394] 6'-Chloro-2H-[1,3'-bipyridin]-2-one (123B) was used in excess (245 mg, 1.31 mmol, 1.1 eq). 4Å Molecular sieves were used in the reaction. The crude product was purified by flash chromatography (eluting dichloromethane to methanol, 0-7%) to give the desired product tert-butyl (2-methyl-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino) propyl)carbamate (123C) as a pale brown solid.

[0395] Yield: 249 mg, (58%). MS (ESI+) m / z 359 (M+H) +< .6'-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)-2H [1,3'-bipyridin]-2-one (Reference Example 223)

[0396] Methodology applied was analogous to those described in General Method 2 using a (4:1) ratio of 4M HCl in 1,4-dioxane-water, followed by General Method 3 using cesium carbonate (3.0 eq) in combination with triethylamine (2.0 eq).

[0397] Yield: 152 mg (57% over 2 steps).

[0398] 1< H NMR (400 MHz, DMSO) δ 8.35 (2H, s), 7.91 (1H, d, J =2.6 Hz), 7.61 (1H, ddd, J =0.6, 2.1, 6.8 Hz), 7.52 - 7.45 (2H, m), 7.40 (1H, dd, J =2.7, 8.9 Hz), 6.90 (1H, dd, J =5.8, 5.8 Hz), 6.57 (1H, dd, J =0.5, 8.9 Hz), 6.45 (1H, ddd, J =0.7, 1.2, 9.2 Hz), 6.28 (1H, ddd, J =6.7, 6.7, 1.4 Hz), 3.33 - 3.14 (4H, m), 2.35 (3H, s), 2.10 - 2.00 (1H, m), 0.94 (3H, d, J =6.8 Hz); MS (ESI+) m / z 383 (M+H) +< .

[0399] Using the procedures described in Scheme 28, the following examples were synthesized: Table 16 Structure Ex. # 1< H NMR LC-MS (M+H) +< Reference 224 1< H NMR (400 MHz, DMSO) δ 8.34 (2H, s), 8.18 (0.5H, s), 8.10 (1H, dd, J =0.4, 2.6 Hz), 8.03 (1H, dd, J =1.6, 3.9 Hz), 7.52 (1H, dd, J =2.7, 9.0 Hz), 7.50-7.45 (2H, m), 7.04 (1H, dd, J =1.6, 9.4 Hz), 6.91 (1H, dd, J =5.8, 5.8 Hz), 6.57 (1H, dd, J =0.5, 9.0 Hz), 3.35 - 3.15 (4H, m), 2.35 (3H, s), 2.10 - 2.00 (1H, m), 0.94 (3H, d, J =6.8 Hz). Partial formate salt.384 Reference 225 1< H NMR (400 MHz, DMSO) δ 8.34 (2H, s), 8.16 (1H, s), 7.64 (1H, d, J =2.8 Hz), 7.47 (1H, dd, J =6.0, 6.0 Hz), 7.19 (1H, dd, J =2.9, 9.0 Hz), 6.46 (1H, d, J =8.9 Hz), 6.11 (1H, dd, J =5.1, 5.1 Hz), 3.75 - 3.68 (4H, m), 3.30 - 3.05 (4H, m), 2.94 - 2.87 (4H, m), 2.35 (3H, s), 2.05 - 1.92 (1H, m), 0.91 (3H, d, J =6.8 Hz). Formate salt.375 Reference 226 1< H NMR (400 MHz, CDCl 3 ) δ 8.40 - 8.31 (4H, m), 8.09 (1H, s), 7.65 (1H, dd, J =2.5, 8.8 Hz), 6.49 (1H, d, J =8.8 Hz), 5.77 (1H, dd, J =6.2, 6.2 Hz), 5.44 (1H, dd, J =5.7, 5.7 Hz), 3.57 - 3.23 (4H, m), 2.36 (3H, s), 2.13 - 2.02 (1H, m), 1.05 (3H, d, J =6.8 Hz).357 Reference 227 1< H NMR (400 MHz, DMSO) δ 9.04 (1H, s), 8.41 - 8.33 (3H, m), 8.10 (1H, dd, J =2.0, 9.3 Hz), 7.59 (4H, br s), 7.03 (1H, d, J =9.3 Hz), 3.44 - 3.23 (4H, m), 2.41 (3H, s), 2.39 (3H, s), 2.20 - 209 (1H, m), 101 (3H, d, J =6.6 Hz). Bis(trifluoroacetate) salt.371 Reference 228 1< H NMR (400 MHz, DMSO) δ 8.39 (2H, s), 8.23 (1H, d, J =2.3 Hz), 8.10 (1H, s), 7.78 (1H, dd, J =2.0, 9.1 Hz), 7.57 (1H, br s), 6.91 (1H, d, J =9.1 Hz), 5.11 (3H, br s), 3.43 - 3.24 (4H, m), 2.46 (3H, s), 2.40 (3H, s), 2.19 - 2.09 (1H, m), 1.01 (3H, d, J =6.8 Hz). Bis(trifluoroacetate) salt.371 Reference 229 1< H NMR (400 MHz, DMSO) δ 8.34 (2H, s), 8.16 (1H, s), 7.98 (1H, d, J =2.4 Hz), 7.47 (1H, dd, J =6.0, 6.0 Hz), 7.43 (1H, dd, J =2.7, 8.9 Hz), 7.16 (1H, d, J =1.4 Hz), 6.92 (1H, dd, J =5.8, 5.8 Hz), 6.87 (1H, d, J =1.1 Hz), 6.60 (1H, dd, J =0.6, 8.9 Hz), 3.35 - 3.26 (3H, m), 3.26 - 3.14 (2H, m), 2.35 (2H, s), 2.21 (3H, s), 2.10 - 2.00 (1H, m), 0.94 (3H, d, J =6.8 Hz). Formate salt.370 Reference 230 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (2H, s), 8.05 (1H, d, J =2.4 Hz), 7.92 (1H, dd, J =2.8, 9.0 Hz), 6.43 (1H, dd, J =0.5, 9.1 Hz), 5.96 (1H, dd, J =5.8, 5.8 Hz), 3.80 (2H, ddt, J =3.5, 3.5, 3.5 Hz), 3.53 - 3.44 (1H, m), 3.39 - 3.30 (2H, m), 3.22 (1H, dd, J =6.8, 13.6 Hz), 2.63 - 2.53 (3H, m), 2.36 (3H, s), 2.22 - 2.01 (3H, m), 1.03 (3H, d, J =6.9 Hz).373 Reference 231 1< H NMR (400 MHz, CDCl 3 ) δ 8.39 - 8.34 (3H, m), 7.77 - 7.74 (1H, m), 7.73 (1H, d, J =2.7 Hz), 7.70 (1H, d, J =1.5 Hz), 6.47 (1H, dd, J =0.5, 9.0 Hz), 6.44 (1H, dd, J =2.1, 2.1 Hz), 5.84 (1H, dd, J =6.1, 6.1 Hz), 5.19 (1H, dd, J =6.1, 6.1 Hz), 3.56 - 3.33 (3H, m), 3.31 - 3.23 (1H, m), 2.36 (3H, s), 2.12 - 2.03 (1H, m), 1.05 (3H, d, J =6.9 Hz).356 Reference 232 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (2H, s), 8.16 (1H, d, J =2.5 Hz), 7.87 - 7.76 (1H, m), 7.41 (1H, dd, J =2.6, 8.9 Hz), 7.22 - 7.11 (1H, m), 6.48 (1H, d, J =8.8 Hz), 5.81 (1H, br s), 5.52 (1H, br s), 3.57 - 3.48 (1H, m), 3.47 - 3.34 (2H, m), 3.27 (1H, dd, J =7.2, 13.7 Hz), 2.36 (3H, s), 2.15 - 2.04 (2H, m), 1.06 (3H, d, J =6.9 Hz).356 tert-Butyl (2-methyl-3-((5-(2-oxopyrrolidin-1-yl)pyrazin-2-yl)amino)propyl) carbamate (124B)

[0400] A solution of tert-butyl N-(3-amino-2-methylpropyl)carbamate (100E) (436 mg, 2.20 mmol, 1.1 eq) in anhydrous dimethylsulfonamide (10 mL) was added to 2-bromo-5-(pyrrolidinon-1-yl)pyrazine (124A) (510 mg, 2.00 mmol, 1.0 eq), potassium phosphate tribasic (866 mg, 4.00 mmol, 2 eq), L-proline (94 mg, 0.80 mmol, 0.4 eq) and copper (I) iodide (76 mg, 0.40 mmol, 0.2 eq). The mixture was degassed and kept under a stream of nitrogen, then heated at 90 °C with stirring for 20 h. The reaction mixture was allowed to cool to room temperature then poured into a mixture of water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting dichloromethane to methanol, 0-6%) to give the desired product tert-butyl (2-methyl-3-((5-(2-oxopyrrolidin-1-yl)pyrazin-2-yl)amino)propyl)carbamate (124B) as a yellow solid.

[0401] Yield: 375 mg, (54%). MS (ESI+) m / z 350 (M+H) +< .1-(5-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazin-2-yl)pyrrolidin-2-one (Reference Example 233)

[0402] Methodology applied was analogous to those described in General Method 2 using a [4:1] ratio of 4M HCl in 1,4-dioxane-water, followed by General Method 3.

[0403] Yield: 71 mg (18% over 2 steps).

[0404] 1< H NMR (400 MHz, CDCl 3 ) δ 9.02 (1H, d, J =1.5 Hz), 8.35 (2H, s), 7.64 (1H, d, J =1.5 Hz), 5.63 (1H, dd, J =6.2, 6.2 Hz), 5.24 (1H, dd, J =5.7, 5.7 Hz), 3.97 (2H, t, J =7.1 Hz), 3.55 - 3.46 (1H, m), 3.45 - 3.32 (2H, m), 3.28 - 3.19 (1H, m), 2.62 (2H, t, J =8.1 Hz), 2.36 (3H, s), 2.20 - 2.02 (3H, m), 1.03 (3H, d, J =6.8 Hz); MS (ESI+) m / z 374 (M+H) +< . tert-Butyl 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (125B).

[0405] 1,1-Difluoro-2-iodo-ethane (128 mg, 0.67 mmol, 1.2 eq) was added to a suspension of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (125A) (126 mg, 0.56 mmol, 1.0 eq), potassium carbonate (231 mg, 1.67 mmol, 3.0 eq) in dimethylformamide (1.0 mL) and the mixture was stirred at 60°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried by passing through a phase separator and then concentrated under reduced pressure to afford the desired tert-butyl 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (125B) as a pale yellow oil.

[0406] Yield: 73 mg (45%). 1< H NMR (400 MHz, CDCl 3 ) δ 5.87 - 5.57 (m, 1H), 3.41 - 3.30 (m, 4H), 3.14 (s, 4H), 2.89 - 2.77 (m, 2H), 1.76 - 1.67 (m, 4H), 1.46 (s, 9H).2-(2,2-Difluoroethyl)-2,7-diazaspiro[3.5]nonane (125C)

[0407] Trifluoroacetic acid (1.3 mL) was added dropwise to a solution of tert-butyl 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (125B) (73 mg, 0.25 mmol, 1.0 eq) in dichloromethane (1.3 mL). The mixture was stirred for 30 minutes and then concentrated to dryness under reduced pressure to afford the desired product 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane (125C) as a pale yellow oil which was used in the next reaction without further purification.

[0408] The intermediates in Table 17 were synthesized using conditions analogous to those described for intermediate 125C: Table 17 Structure Compound No. 1< H NMR LC-MS (M+H) +< Intermediate 1< H NMR (400 MHz, CDCl 3 ) δ 4.67 - 4.24 (m, 4H), 3.74 (s, 2H), 3.35 - 3.08 (m, 6H), 1.76 - 1.66 (m, 4H). NH not observed.N / A Intermediate 1< H NMR (400 MHz, CDCl 3 ) δ 5.87 - 5.57 (m, 1H), 3.41 - 3.30 (m, 4H), 3.14 (s, 4H), 2.89 - 2.77 (m, 2H), 1.76 - 1.67 (m, 4H), 1.46 (s, 9H).N / A tert-Butyl 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (126B).

[0409] 2,2,2-Trifluoroethyl trifluoromethanesulfonate (153 mL, 1.06 mmol, 1.2 eq) was added to a suspension of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (126A) (200 mg, 0.88 mmol, 1.0 eq), cesium carbonate (862 mg, 2.65 mmol, 3.0 eq) in acetonitrile (2.0 mL) and the mixture was stirred at 80°C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried passing though a phase separator and then concentrated under reduced pressure to afford tert-butyl 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (126B) as a sticky white solid. The sample was used in the next step without further purification.

[0410] Yield: 341 mg (Quant.). 1< H NMR (400 MHz, CDCl 3 ) δ 3.38 - 3.30 (m, 4H), 3.19 (s, 4H), 3.01 (q, J =9.4 Hz, 2H), 1.73 - 1.69 (m, 4H), 1.45 (s, 9H).2-(2,2,2-Trifluoroethyl)-2,7-diazaspiro[3.5]nonane (126C)

[0411] Trifluoroacetic acid (1.3 mL) was added dropwise to a solution of tert-butyl 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (126B) (110 mg, 0.357 mmol, 1.0 eq) in dichloromethane (1.0 mL). The mixture was stirred for 30 minutes and then concentrated to dryness under reduced pressure to afford 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane (126C) as a pale brown oil, which was used directly in the next step without further purification, assumed 100% yield. 2-Methyl-5-oxa-2,8-diazaspiro[3.5]nonane (127B)

[0412] Lithium aluminium hydride (1M solution in tetrahydrofuran, 1.97 mL, 1.97 mmol, 3.0 eq) was added dropwise under nitrogen to a 0°C cooled solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (127A) (150 mg, 0.657 mmol, 1.0 eq) in tetrahydrofuran (4.0 mL). The reaction was stirred at 0°C for 5 minutes, the cooling bath was removed and the reaction was then heated to 70°C for 16 h (effervescence was observed at 0°C and 35°C). The reaction mixture was cooled to 0°C and quenched by the slow addition of water (0.075 mL), aqueous sodium hydroxide solution (15%, 0.075 mL) and then water (0.22 mL). The cooling bath was removed and the reaction mixture was stirred for 15 minutes, magnesium sulfate was added and stirred for a further 40 minutes. The mixture was dried passing through a phase separator, washed with tetrahydrofuran and diethyl ether and then concentrated to dryness under reduced pressure to afford 2-methyl-5-oxa-2,8-diazaspiro[3.5]nonane (127B) as a pale brown oil. The sample was taken on into the next reaction without further purification.

[0413] Yield: assumed 100%. 1< H NMR (400 MHz, CDCl 3 ) δ 3.63 - 3.56 (m, 2H), 3.47 - 3.43 (m, 2H), 3.00 (s, 2H), 2.94 - 2.86 (m, 2H), 2.83 - 2.79 (m, 2H), 2.40 (s, 3H), NH not observed.

[0414] The intermediate in Table 18 were synthesized using conditions analogous to those described for intermediate 127B: Table 18 Structure Compound No. 1< H NMR LC-MS (M+H) +< Intermediate 1< H NMR (400 MHz, CDCl 3 ) δ 3.63 - 3.56 (m, 2H), 3.47 - 3.43 (m, 2H), 3.00 (s, 2H), 2.94 - 2.86 (m, 2H), 2.83 - 2.79 (m, 2H), 2.40 (s, 3H), NH not observed.- tert-Butyl 6-(dimethylcarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (128B)

[0415] Method used was analogous to those described in General Method 5 using 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid to afford the desired product tert-butyl 6-(dimethylcarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (128B).

[0416] Yield: 111 mg (Quant.). 1< H NMR (400 MHz, DMSO) δ 3.87 (s, 2H), 3.70 (s, 2H), 3.23 - 3.14 (m, 1H), 2.86 (s, 3H), 2.79 (s, 3H), 2.32 - 2.24 (m, 4H), 1.37 - 1.36 (m, 9H).N,N-Dimethyl-2-azaspiro[3.3]heptane-6-carboxamide (128C)

[0417] Trifluoroacetic acid (2.1 mL) was added dropwise to a solution of tert-butyl 6-(dimethylcarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (128B) (110 mg, 0.357 mmol, 1.0 eq) in dichloromethane (2.1 mL). The mixture was stirred for 30 minutes and then concentrated to dryness under reduced pressure to afford the desired product N,N-dimethyl-2-azaspiro[3.3]heptane-6-carboxamide (128C) as a pale brown oil. The sample was taken on into the next reaction without further purification, assumed 100% yield. Methyl (S)-5-fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d|thiazole-6-carboxylate (129A)

[0418] Methodology applied was analogous to those described in General Method 3.

[0419] Yield: 134 mg (20%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 8.13 (d, J =6.9 Hz, 1H), 7.21 (d, J =12.2 Hz, 1H), 7.12 (s, 1H), 5.62 (t, J =6.7 Hz, 1H), 3.93 (s, 3H), 3.64 - 3.46 (m, 2H), 3.42 - 3.22 (m, 2H), 2.38 - 2.38 (m, 3H), 2.18 - 2.09 (m, 1H), 1.07 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 422 (M+H) +< .(S)-5-Fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)aniino)propyl)amino) benzo[d]thiazole-6-carboxylic acid (129B)

[0420] Methodology applied was analogous to those described in General Method 4.

[0421] Yield: 98 mg (quant.). 1< H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 8.57 - 8.54 (m, 1H), 8.33 - 8.32 (m, 2H), 8.18 (d, J =7.4 Hz, 1H), 7.50 (t, J =6.1 Hz, 1H), 7.16 (d, J =12.5 Hz, 1H), 2.34 (s, 3H), 2.16 - 2.06 (m, 1H), 0.97 - 0.94 (m, 3H). NH exchangeable protons not observed; MS (ESI+) m / z 408 (M+H) +< .Tert-Butyl (S)-6-(5-fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (129C)

[0422] Methodology applied was analogous to those described in General Method 5.

[0423] Yield: 20 mg (54%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J =1.8 Hz, 1H), 8.14 (s, 1H), 7.99 (dd, J =1.7, 8.5 Hz, 1H), 7.51 (d, J =8.5 Hz, 1H), 7.00 - 6.97 (m, 1H), 5.47 (dd, J =6.7, 6.7 Hz, 1H), 4.37 (q, J =7.2 Hz, 2H), 3.63 - 3.49 (m, 2H), 3.40 - 3.23 (m, 2H), 2.47 (s, 3H), 2.17 - 2.09 (m, 1H), 1.40 (dd, J =7.2, 7.2 Hz, 3H), 1.06 (d, J =6.9 Hz, 3H); MS (ESI+) m / z 489 (M+H) +< .(S)-(5-Fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol-6-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone formate salt (Reference Example 240)

[0424] Trifluoroacetic acid (1 mL) was added dropwise to a 0°C cooled solution of tert-butyl (S)-6-(5-fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d] thiazole-6-carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (149) (17 mg, 0.0166 mmol, 1.0 eq) in anhydrous dichloromethane (1 mL). The mixture was stirred for 30 minutes and then concentrated under reduced pressure. The crude residue obtained was purified preparative HPLC (formic additive) to give the desired product (S)-(5-fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d] thiazol-6-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone formate salt (Reference Example 189) as an off white solid.

[0425] Yield: 9 mg (100%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 - 8.36 (m, 3H), 7.60 - 7.52 (m, 1H), 5.84 - 5.72 (m, 1H), 3.98 (d, J =9.0 Hz, 1H), 3.84 -- 3.57 (m, 6H), 3.50 - 3.24 (m, 4H), 2.86 (s, 12H), 2.38 - 2.37 (m, 3H), 2.29 - 2.13 (m, 3H), 1.09 - 1.04 (m, 3H). NH exchangeable protons not observed; MS (ESI+) m / z 502 (M+H) +< .

[0426] Using the procedures described in Scheme 34, the following examples were prepared: Table 19 Structure Ex. # 1H NMR LC-MS (M+H) +< Reference 241 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 - 8.37 (m, 2H), 8.24 (d, J =7.4 Hz, 1H), 8.10 (s, 1H), 7.52 - 7.44 (m, 1H), 5.72 - 5.69 (m, 1H), 4.91 - 4.87 (m, 2H), 3.80 - 3.78 (m, 3H), 3.64 - 3.56 (m, 1H), 3.54 - 3.48 (m, 1H), 3.42 - 3.24 (m, 2H), 2.38 (s, 3H), 2.20-2.10 (m, 1H), 1.09 - 1.05 (m, 3H).502 Reference 242 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 8.28 - 8.26 (m, 1H), 5.71 (t, J -6.5 Hz, 1H), 3.86 (t, J =5.0 Hz, 2H), 3.70 - 3.57 (m, 3H), 3.53 - 3.48 (m, 1H), 3.41 - 3.22 (m, 2H), 2.78 (s, 1H), 2.38 (s, 3H), 2.20 - 2.11 (m, 1H), 1.08 - 1.06 (m, 3H).451 Reference 243 1< H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 2H), 7.56 (d, J =6.3 Hz, 1H), 6.85 (t, J =6.0 Hz, 1H), 5.63 (t, J =6.7 Hz, 1H), 3.78 (s, 2H), 3.63 - 3.45 (m, 2H), 3.42 - 3.22 (m, 4H), 2.95 - 2.80 (m, 4H), 2.38 (s, 3H), 2.20-2.08 (m, 1H), 1.06 (d, J =6.9 Hz, 3H).478 2-((3-((5-Mercaptopyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N dimethylbenzo [d]thiazole-6-carboxamide (130A)

[0427] N,7V-dimethyl-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino) benzo[d] thiazole-6-carboxamide (Compound 10, 75 mg, 0.18 mmol), sodium methanethiolate (126 mg, 1.80 mmol, 10.0 eq and N-methylpyrolidine (1.5 mL) were added to a microwave vessel under nitrogen, sealed and then heated to 160°C for 1 hour. LCMS analysis indicated complete conversion to the desired thiol 2-((3-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)-2-methylpropyl) amino)-N,N-dimethyl benzo[d]thiazole-6-carboxamide (130A), which was used directly in the next step without purification.2-((3-((5-((Difluoromethyl)thio)pytimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide (Reference Example 244)

[0428] Potassium hydroxide (201 mg, 3.58 mmol, 20.0 eq) and water (0.5 mL) were added to the crude thiol solution of 2-((3-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide in N-methyl pyrolidine (1.5 mL) and the mixture was cooled to -70°C, freezing to a solid. Bromodifluoromethyldiethylphosphonate (40 uL, 0.215 mmol, 1.2 eq) was added in one portion and the reaction was allowed to warm to ambient temperature over 1 hour then recooled to -70°C. A further aliquot of bromodifluoromethyldiethylphosphonate (40 uL, 0.215 mmol, 1.2 eq) was added, and the mixture was allowed to warm to ambient temperature over 1 hour. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with water (20 mL) and brine (25 mL) then dried over magnesium sulfate. The solvents were removed under vacuum to give a crude brown oil which was purified by flash chromatography (eluting dichloromethane to methanol, 0-10%) and then by preparative HPLC to give the desired 2-((3-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide (Reference Example 244) as an off white solid. Yield: 15 mg (19%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.42 - 8.39 (m, 2H), 7.69 (d, J =1.4 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.36 (dd, J =1.8, 8.3 Hz, 1H), 6.33 (s, 1H), 6.15 (t, J =6.7 Hz, 1H), 3.65 - 3.51 (m, 2H), 3.43 - 3.29 (m, 2H), 3.08 (s, 6H), 2.20 - 2.10 (m, 1H), 1.09 - 1.06 (m, 3H); MS (ESI+) m / z 453 (M+H) +< .

[0429] Following methodology described in Scheme 35 , the following examples were prepared: Table 20 Structure Ex. # 1H NMR LC-MS (M+H) +< Reference 245 1< H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 2H), 7.65 (d, J =1.4 Hz, 1H), 7.53 (d, J =7.9 Hz, 1H), 7.31 (dd, J =1.8, 8.3 Hz, 1H), 6.68 (t, J =56.8 Hz, 1H), 6.38 (s, 1H), 6.16 (dd, J =6.5, 6.5 Hz, 1H), 4.48 (s, 4H), 3.64 - 3.53 (m, 6H), 3.44 - 3.31 (m, 2H), 2.20 - 2.12 (m, 1H), 1.91 (s, 4H), 1.07 (d, J =6.9 Hz, 3H).535 Reference 246 1< H NMR (400 MHz, CDCl 3 ) δ 8.42 - 8.38 (m, 2H), 7.66 - 7.65 (m, 1H), 7.54 - 7.52 (m, 1H), 7.33 - 7.30 (m, 1H), 6.32 (s, 1H), 6.14 (t, J =6.6 Hz, 1H), 3.64 - 3.52 (m, 6H), 3.46 - 3.32 (m, 6H), 2.20 - 2.12 (m, 1H), 1.83 - 1.82 (m, 4H), 1.09 - 1.06 (m, 3H).534 Reference 247 1< H NMR (400 MHz, CDCl 3 ) δ 8.44 - 8.39 (m, 2H), 7.66 (d, J =1.3 Hz, 1H), 7.54 - 7.51 (m, 1H), 6.12 (t, J =6.5 Hz, 1H), 3.64 - 3.51 (m, 6H), 3.44 - 3.30 (m, 3H), 3.25 - 3.23 (m, 4H), 3.02 (q, J =9.4 Hz, 2H), 2.20 - 2.10 (m, 1H), 1.80 - 1.77 (m, 4H), 1.07 (d, J =6.9 Hz, 3H).616 Reference 248 1< H NMR (400 MHz, CDCl 3 ) δ 8.44 - 8.38 (m, 4H), 7.70 (d, J =1.5 Hz, 2H), 7.57 - 7.54 (m, 2H), 7.36 - 7.32 (m, 2H), 6.69 (s, 1H), 6.54 (s, 1H), 6.09 (t, J =6.6 Hz, 2H), 4.45 (t, J =8.4 Hz, 3H), 4.00 - 3.82 (m, 6H), 3.65 - 3.52 (m, 4H), 3.45 - 3.30 (m, 4H), 3.07 (s, 6H), 2.89 - 2.83 (m, 2H), 2.62 (s, 1H), 2.20 - 2.12 (m, 2H), 1.08 (d, J =6.9 Hz, 6H).550 Reference 249 1< H NMR (400 MHz, DMSO) δ 8.41 - 8.35 (m, 3H), 8.25 (d, J =1.5 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.81 (dd, J =1.8, 8.4 Hz, 1H), 7.44 - 7.35 (m, 1H), 3.51 - 3.42 (m, 2H), 2.17 - 2.09 (m, 1H), 0.99 - 0.96 (m, 3H).426 rac-tert-Butyl ((1R,3R)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)carbamate (131B)

[0430] Methodology applied was analogous to those described in General Method 1.

[0431] Yield: 220 mg (44%). 1< H NMR (400 MHz, CDCl 3 ) δ δ 8.35 - 8.34 (m, 4H), 5.35 (s, 1H), 5.18 - 5.15 (m, 1H), 4.84 - 4.82 (m, 1H), 4.56 - 4.53 (m, 1H), 4.36 (dd, J =6.9, 13.8 Hz, 1H), 4.26 - 4.18 (m, 1H), 4.02 - 3.94 (m, 2H), 2.55 - 2.47 (m, 1H), 2.36 (d, J =1.0 Hz, 6H), 2.30 - 2.16 (m, 2H), 2.10 - 1.89 (m, 4H), 1.46 - 1.43 (m, 24H).; MS (ESI+) m / z 325 (M+H) +< .rac-(1R,3R)-N 1< -(5-(Methylthio)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (131C)

[0432] Methodology applied was analogous to those described in General Method 2.

[0433] Yield: 250 mg (quant.%). MS (ESI+) m / z 225 (M+H) +< .

[0434] Used in next step without further purification.rac-N,N-Bis(4-methoxybenzyl)-2-(((trans)-3-((5-(methylthio)pyrimidin-2- yl)amino)cyclopentyl)amino)benzo[d]thiazole-6-sulfonamide (131D)

[0435] Methodology applied was analogous to those described in General Method 3.

[0436] Yield: 52 mg (23%). 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 8.00 (d, J =1.6 Hz, 1H), 7.74 (dd, J =1.9, 8.5 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.01 - 6.96 (m, 4H), 6.76 - 6.73 (m, 4H), 5.59 - 5.54 (m, 1H), 5.22 (d, J =6.9 Hz, 1H), 4.50 - 4.44 (m, 1H), 4.35 - 4.30 (m, 1H), 4.25 (s, 4H), 3.77 - 3.76 (m, 6H), 2.37 - 2.37 (m, 6H), 2.23 - 2.07 (m, 2H); MS (ESI+) m / z 677 (M+H) +< .rac-2-(((trans)-3-((5-(Methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)benzo[d] thiazole-6-sulfonamide (Reference Example 250)

[0437] Trifluoroacetic acid (1 mL) was added dropwise to an ice cooled solution of rac-N,N-bis(4-methoxybenzyl)-2-(((trans)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl) amino)benzo[d]thiazole-6-sulfonamide (131D) (45 mg, 66.48 mmol, 1.0 eq) in anhydrous dichloromethane (1 mL). The mixture was allowed to warm to ambient temperature over 18 h and was then concentrated to dryness under reduced pressure. The crude residue obtained was purified by preparative HPLC and the clean fractions obtained were freeze dried to give the desired 2-(((trans)-3-((5-(methylthio)pyrirnidin-2-yl)arnino)cyclopentyl)arnino) benzo[d] thiazole-6-sulfonamide (Reference Example 250) as a white powder.

[0438] Yield: 23 mg (79%). 1< H NMR (CDCl 3 ) δ 8.36 (s, 2H), 8.17 (d, J =1.8 Hz, 1H), 7.84 (dd, J =2.0, 8.5 Hz, 1H), 7.59 - 7.52 (m, 1H), 5.34 (d, J =6.5 Hz, 1H), 4.79 (s, 2H), 4.50 - 4.43 (m, 1H), 4.34 - 4.27 (m, 1H), 2.37 - 2.37 (m, 6H), 2.22 - 2.07 (m, 2H).; MS (ESI+) m / z 437 (M+H) +< . Step 1: Example 301C

[0439] To a solution of Example 301A (1 g, 3.14 mmol) in DMF (30 mL) was added Cs 2 CO 3 (2.05 g, 6.28 mmol) and Example 301B (5.6 g, 62.8 mmol). The mixture was heated to 25 °C for 1 h. TLC detected the starting material was consumed. The reaction was filtered and the filtrate (crude Example 301C) was used to next step without any purification.Step 2: Example 301D

[0440] A solution of Example 301C was treated with Boc 2 O (1.03 g, 4.72 mmol )and stirred at r.t for 2 h. Water (100 mL) was added, then extracted with EA (50 mL × 2), washed with water and brine, dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure, then purified by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 5∼1 / 1) to give the desired product (Example 301D , 1.2 g, yield 81%) as a yellow solid. LCMS [M+H] +< = 573Step 3: Example 301E

[0441] To a solution of Example 301D (1.2 g, 2.54 mmol) in DCM (3 mL) was added TFA (1 mL) at r.t. After addition, the reaction mixture was stirred at r.t. for 1 h. TLC detected the starting material was consumed, the mixture was concentrated to give the desired product (Example 301E 945 mg, yield: 100%) as a yellow oil, which used to next step without further purification.Step 4: Reference Example 301

[0442] To a solution of Example 301E (945mg, 2.54 mmol) in ACN(10 mL) was added TEA (514 mg, 5.08 mmol) and Example 301F (408 mg, 2.54 mmol) at r.t. then to 70 °C for 18 h. TLC detected the starting material was consumed. The reaction was concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=3 / 1∼5 / 3) to give the desired product Reference Example 301 (780 mg, yield: 61%) as a white solid. LCMS [M+H] +< = 497. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.34 (s, 2H), 8.12 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.5, 1.8 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 3.94-3.86 (m, 1H), 3.59 (dd, J = 16.6, 11.9 Hz, 6H), 3.39 (dd, J = 19.4, 5.9 Hz, 4H), 2.85-2.81 (m, 4H), 2.33 (s, 3H). Step 1: Example 302B

[0443] A solution of Example 302A (6.77g, 21 mmol) in THF (200 mL) under N 2 atmosphere was cooled to -65 °C. MeMgBr (21 mL, 63.1 mmol, 3M in THF) was added dropwise, then stirred at -65 °C for 0.5 h. The reaction was warmed to r.t. for 2 h, quenched by addition of water (200 mL). After extraction with EtOAc (200 mL × 2), the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc=3 / 1) to give the desired product Example 302B (4 g, yield 56%) as a yellow oil. LCMS [M+H] +< = 339Step 2: Example 302C

[0444] To a solution of Example 302B (4g, 0.012 mmol) in MeOH (40 mL) a suspension of Pd / C (400 mg) catalyst was introduced into the reactor. The vessel was purged with nitrogen and then with hydrogen, and the reaction mixture was stirred at r.t. for 18 h. TLC and LCMS detected the starting material was consumed. Example 302C (4 g, yield: 100%) was obtained by filtration and concentrated and used in the next step without any purification. LCMS [M+H] +< = 205Step 3: Example 302D

[0445] To a solution of Example 301A (154 mg, 0.48 mmol) in DMF (30 mL) was added Cs 2 CO 3 (313 mg, 0.96 mmol) and Example 302C (982 mg, 4.8 mmol), the mixture was heated to 25 °C for 2h. TLC detected the starting material was consumed. The reaction was filtered and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 1∼1 / 4) to give the desired product Example 302D (500mg, yield: 100%) as a white solid. LCMS [M+H] +< = 487Step 4: Example 302E

[0446] To a solution of Example 302D (486 mg, 2 mmol) in DCM (2 mL) was added TFA (1 mL) at r.t. After addition, the reaction mixture was stirred at r.t. for 1 h. TLC detected the starting material was consumed, the mixture was concentrated to give the desired product Example 302E (532 mg, yield: 100%) as a yellow oil which used to next step without further purification.Step 5: Reference Example 302

[0447] Example 302E (193 mg, 0.5mmol), TEA (101 mg, 1 mmol) and Example 301F (81 mg, 0.5 mmol) were dissolved in ACN (5 mL), the mixture was heated to 60 °C for 18 h. LCMS detected TM was formed. Purified by Pre-HPLC to give the desired product Reference Example 302 (15 mg, yield: 6%) as a white solid. LCMS [M+H] +< = 511

[0448] 1< H NMR (400MHz, CDCl 3 ) δ 8.41 (s, 2H), 7.98 (s, 1H), 7.65 (s, 2H), 6.10 (s, 1H), 3.77-3.72 (m, 4H), 3.67-3.52 (m, 4H), 3.04-2.98 (m, 4H), 2.38 (s, 3H), 1.33 (s, 3H). Step 1: Example 303B

[0449] To a solution of Example 303A (33 g, 500 mmol) and methyl carbonochloridate (49.5 g, 520 mmol) in THF (75 mL) was added KOH (56.1 g, 1000 mmol) in H 2 O (50 mL) over a period of 30 min (maintaining internal temperature below 40 °C). After addition, the suspension was stirred at room temperature for 16 h. The suspension was filtered and the filter cake was washed with EtOH (50 mL × 3) and dried in vacuum to afford the desired product Example 303B (67 g, yield 82.7%) as a white solid. LCMS [M+H] +< = 163Step 2: Example 303C

[0450] To a solution of Example 303B (4 g, 24.52 mmol) in MeOH (300 mL) and HCl (5 mL, 4.0 M in MeOH) was added Pd / C (8 g) at room temperature. The suspension was stirred under 15 psi of H 2 at room temperature for 44 h. LCMS showed the starting material was consumed completely and the desired product was detected. The mixture was filtered and the filter cake was washed with MeOH (30 mL × 3). The filtrates were concentrated under reduced pressure to afford the product Example 303C (3.7 g, yield: 54.4%) as a yellow solid. LCMS [M+H] +< = 133.2Step 3: Example 303D

[0451] A solution of Example 303C (2.18 g, 7.84 mmol), Example 301A (0.5 g, 1.57 mmol) and DIEA (13.35 g, 103.5 mmol) in MeCN (100 mL) was heated to 80 °C and stirred for 4 h. LCMS showed the starting material was consumed completely and the desired product was detected. The reaction mixture Example 303D was used for the next step without further purification. LCMS [M+H] +< = 415.5Step 4: Example 303E

[0452] Boc 2 O (5 g, 22.9 mmol) was added to a solution of Example 303D at room temperature and stirred for 1 h. LCMS showed the starting material was consumed. The reaction was diluted with DCM (200 mL) and washed with water (150 mL × 2), brine (200 mL × 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure, which was purified by silica gel chromatography (eluted with petroleum ether / EtOAc=2 / 1~1 / 9) to afford the product Example 303E (680 mg, yield: 76.7% over two steps ) as a white solid. LCMS [M+H] +< = 515.5Step 5: Example 303F

[0453] To a solution of Example 303E (840 mg, 1.63 mmol) in THF (20 mL) was added CaCl 2 (363 mg, 3.27 mmol) and NaBH 4 (124 mg, 3.27 mmol) at room temperature and the reaction was stirred for 16 h. The reaction was poured into sat. aq. NH 4 Cl (100 mL) and diluted with EtOAc (30 mL) and separated. The aqueous layer was extracted with EtOAc (30 mL × 2) and the combined organic layers were concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=3 / 1∼1 / 9) to afford the product Example 303F (383 mg, yield: 48.3%) as a white solid. LCMS [M+H] +< = 487.6Step 6: Example 303G

[0454] To a solution of Example 303F (553 mg, 1.14 mmol) dissolved in DCM (10 mL) was added HCl / Dioxane (4.0 M, 10 mL) at room temperature and the reaction was stirred for 0.5 h. TLC showed the starting material was consumed. The reaction mixture was concentrated under reduced pressure to afford the product Example 303G (563 mg, yield: 100%) as a white solid. LCMS [M+H] +< = 387.5Step 7: Reference Example 303

[0455] To a solution of Example 303G (563 mg, 1.14 mmol) and K 2 CO 3 (940 mg, 6.82 mmol) in DMF (10 mL) was added Example 301A (183 mg, 1.14 mmol) at room temperature. The reaction was then heated to 60 °C and stirred for 16 h. TLC showed the starting material was consumed. The mixture was cooled to room temperature and diluted with EtOAc (30 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL × 4) and the combined organic layers were washed with brine (20 mL × 2), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc=3 / 1~1 / 9) to afford the crude product, which was purified by prep-HPLC to afford the product Reference Example 303 (75.2 mg, yield: 12.93%), as a light yellow solid. LCMS [M+H] +< = 511 1< H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 2H), 7.96 (s, 1H), 7.66-7.58 (m, 2H), 6.82 (s, 1H), 5.87 (s, 1H), 3.83-3.73 (m, 5H), 3.59-3.44 (m, 5H), 3.01 (s, 4H), 2.38 (s, 3H), 2.14-2.08 (m, 1H). Step 1: Example 304B

[0456] Example 304A (23.6 g, 0.12 mol), NaN 3 (15.1g, 0.23 mol) and NH 4 Cl (7.5 g, 0.14 mol) were suspended in DMF (250 mL), and the resulting mixture was heated to 80 °C for 1 h. After TLC detected the reaction was complete, EtOAc(1 L) was added, and the organic extract was washed with water (200 mL × 5), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc=5 / 1) to give the desired product Example 304B (29 g, yield 100%) as a white solid. LCMS [M+H] +< = 247Step 2: Example 304C

[0457] To a solution of Example 304B (29 g, 0.12 mol) in EtOH (400 mL) was added HCl (22 mL) and Pd / C (1 g), and the heterogeneous mixture was stirred at r.t. for 18 h under H 2 . TLC detected the starting material was mostly consumed. The mixture was filtered and the filtrate was concentrated to give the desired product Example 304C (21 g, yield: 100 %) as a white solid. LCMS [M+H] +< = 221Step 3: Example 304D

[0458] To a solution of Example 304C (6.6g, 3 mol) in DMF (50 mL) was added 2-chloro-5-(methylthio)pyrimidine (2.4 g, 15 mmol) and TEA (7.6 g, 75 mmol). The resulting mixture was stirred at 100 °C for 1 h. TLC detected the starting material was consumed. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 1∼1 / 4) to give the desired product Example 304D (450 mg, yield: 8 %) as a white solid. LCMS [M+H] +< = 345Step 4: Example 304E

[0459] To a solution of Example 304D (450 mg, 1.3 mmol) in EtOH (5 mL) was added hydrazine hydrate (131 mg, 2.6 mmol) at r.t. TLC after 3 h detected the starting material was consumed, at which point the reaction was concentrated and purified by silica gel chromatography (eluted with DCM / MeOH =10 / 1) to give the desired product Example 304E (120 mg, yield: 43 %) as a white solid.Step 5: Reference Example 304

[0460] To solution of Example 304E (43 mg, 0.20 mmol) and 2-chloro-N,N-dimethylbenzo[d]thiazole-6-sulfonamide (37 mg, 0.13 mmol) in DMF (1 mL) was added DBU (40 mg, 0.26 mmol). The resulting mixture was stirred at 50 °C for 1 h. TLC detected the starting material was consumed, and the reaction mixture was concentrated and purified by Pre-TLC to give the desired product Reference Example 304 (30 mg, yield: 51 %) as a white solid. LCMS [M+H] +< = 454.9. 1< H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 2H), 7.99 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 8.5, 1.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 5.97 (s, 1H), 4.11 (dd, J = 9.3, 4.8 Hz, 1H), 3.74 (dd, J = 13.7, 4.3 Hz, 1H), 3.66 (s, 1H), 3.58 (dd, J = 13.6, 6.3 Hz, 2H), 2.70 (s, 6H), 2.37 (s, 3H). Step 1: Reference Example 305

[0461] To solution of Example 304E (30 mg, 0.14 mmol) and 2-chloro-N-methylbenzo[d]thiazole-6-sulfonamide (24.5 mg, 0.09 mmol) in DMF (2 mL) was added DBU (47 mg, 0.18 mmol). After addition, the mixture was stirred at 50 °C for 1 h. LCMS determined that starting material was consumed. The mixture was cooled to room temperature, diluted with EtOAc (5 mL) and washed with brine (5 mL). The organic layer was concentrated and purified by Pre-TLC to give the desired product Reference Example 305 (23.8 mg, yield: 60 %) as a white solid. LCMS [M+H] +< = 440.9 1< H NMR (400 MHz, MeOD-d 4 ) δ 8.35 (s, 2H), 8.07 (s, 1H), 7.69 (dd, J = 8.0, 1H), 7.50 (d, J = 8.0 Hz, 1H), 4.06 (m, 0.46H), 3.57 (m, 4H), 2.51 (s, 3H), 2.32 (s, 3H).

[0462] Reference Example 306 (30 mg, yield: 50%) was prepared in analogous fashion as a white solid starting from Example 306A: LCMS [M+H] +< = 454.9. 1< H NMR (400 MHz, CDCl3) δ 8.35 (s, 2H), 7.98 (d, J = 1.5 Hz, 1H), 7.66 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 6.04 (t, J = 5.6 Hz, 1H), 4.11 (dd, J = 9.3, 5.1 Hz, 1H), 3.74-3.64 (m, 2H), 3.61-3.54 (m, 2H), 2.70 (s, 6H), 2.36 (s, 3H). Step 1: Example 307A

[0463] To a solution of Example 306E (100 mg, 0.47 mmol) in DMF (0.5 mL) was added DBU (89 mg, 0.58 mmol) and methyl 2-chlorobenzo[d]thiazole-6-carboxylate (89 mg, 0.39 mmol). The mixture was heated to 50 °C for 1 h. After TLC determined the starting material was consumed, the mixture was concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 1∼1 / 4) to give the desired product Example 307A (50 mg, yield: 26 %) as a white solid. LCMS [M+H] +< = 406Step 2: Example 307B

[0464] To a solution of Example 307A (50 mg, 0.12 mmol) in THF (1 mL) was added LiOH (0.4 mL, 1M in water) and the resulting mixture was stirred at r.t. for 18 h. After TLC determined the starting material was consumed, the mixture was concentrated and purified by silica gel chromatography (eluted with DCM / MeOH =10 / 1) to give the desired product Example 307B (5 mg, yield: 11 %) as a white solid. LCMS [M+H] +< = 392Step 3: Reference Example 307

[0465] A solution of Example 307B (10 mg, 0.025 mmol) was charged with dimethylamine hydrochloride (2.5 mg, 0.031 mmol), TEA (8 mg, 0.075 mmol) and HBTU (14 mg, 0.038 mmol). The resulting mixture was stirred at r.t. for 1 h. After TLC detected the starting material was consumed, the mixture was concentrated and purified by Pre-TLC (eluted with EtOAc) to give the desired product Reference Example 307 (2 mg, yield: 19 %) as a white solid. LCMS [M+H] +< = 419. 1< H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 2H), 7.67 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 8.3, 1.5 Hz, 1H), 5.91 (s, 1H), 4.14-4.00 (m, 1H), 3.72-3.64 (m, 2H), 3.53 (dd, J = 13.8, 6.3 Hz, 2H), 3.07 (s, 6H), 2.37 (s, 3H). Step 2: Example 308A

[0466] A Schlenk tube equipped with magnetic stir bar was charged with TBAI (5 g, 13.6 mmol), cyclopentene (9.25 g, 136 mmol), and O-Phthalimide (10 g, 68 mmol) in 250 mL of benzene. A solution of 65% TBHP (18.8 g, 136 mmol) was added before the vial was sealed and the reaction mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted in ethyl acetate and washed with brine. The aqueous phase was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / ethyl acetate=5 / 1) to afford the desired compound Example 308A (6.5 g) as a white solid. LCMS [M+H] +< = 214.

[0467] 1< H NMR (400 MHz, CDCl 3 ) δ 2.08-2.17 (m, 1H), 2.32-2.47 (m, 1H), 2.41-2.53 (m, 1H), 2.80-2.88 (m, 1H), 5.33-5.46 (m, 1H), 5.61- 5.70 (m, 1H), 6.07-6.16 (m, 1H), 7.67-7.75 (m, 2H), 7.80-7.87 (m, 2H).Step 2: Example 308B

[0468] To a solution of Example 308A (5 g, 23.5 mmol) in THF (25 mL) was added 50% hydrazine hydrate in H 2 O (3.52 g, 35.2 mmol). The mixture was stirred at 70 °C for 2 h. The mixture was then filtered and concentrated under reduced pressure. Di-tert-butyl dicarbonate (10.2 g, 47 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with PE / ethyl acetate=5 / 1) to afford the desired compound Example 308B (550 mg) as a white solid. LCMS [M+H] +< = 184.Step 3: Example 308C

[0469] To a solution of Example 308B (700 mg, 3.825 mmol) in DCM (5 mL) was added m-CPBA (790 mg, 4.59 mmol) portion-wise at 0 °C. Following addition, the mixture was stirred at room temperature overnight. The resulting mixture was cooled to 0 °C and the m-chlorobenzoic acid filtered off and washed with additional cold DCM. The combined filtrate and wash were stirred with 20% NaHSO 3 for 30 min. The DCM layers were separated and extracted with 3 N NaOH (3 × 30 mL), saturated NaCl (30 mL), and then dried over Na 2 SO 4 . Evaporation left a white solid, which was purified by silica gel column chromatography (eluting with PE / ethyl acetate=5 / 1) to afford the desired compound Example 308C (455 mg) as a white solid. LCMS [M+H] +< = 144. 1< H NMR (400 MHz, CDCl 3 ) δ 1.07-1.17 (m, 1H), 1.48 (s, 9H), 1.66-1.76 (m, 1H), 1.89-1.96 (m, 1H), 2.05-2.16 (m, 1H), 3.41-3.50 (m, 1H), 3.53 (br s, 1H), 4.07-4.26 (m, 1H), 4.63-4.77 (m, 1H).Step 4: Example 308D

[0470] A mixture of Example 308C (445 mg, 2.28 mmol), NaN 3 (297 mg, 4.57 mmol), NH 4 Cl (61 mg, 1.14 mmol), 2-methoxyethanol (5 mL) and H 2 O (1 mL) was stirred in a bath maintained at 80 °C for 16 hr. The resulting solution was evaporated to dryness, and the residue was dissolved in H 2 O (5 mL). This solution was saturated with NaCl and then extracted with DCM (4 × 5 mL). The DCM solution was evaporated, the residue was purified by silica gel column chromatography (eluting with MeOH / DCM=3%-5%) to afford the desired compound Example 308D (420 mg) as a colorless oil. LCMS [M+H] +< = 188.Step 5: Example 308E

[0471] A suspension of Example 308D (420 mg, 1.74 mmol), Pd / C (cat.) in EtOH (5 mL) was stirred at r.t. for 16h under H 2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was dried and used directly in the next step without further purification Example 308E (320 mg). LCMS [M+H] +< = 217.Step 6: Example 308F

[0472] A mixture of Example 308E (150 mg, 0.694 mmol), 2-chloro-5-(methylthio)pyrimidine (111 mg, 0.694 mmol), DIPEA (180 mg, 1.4 mmol) in DMSO (5 mL) was stirred at 130 °C for 3 hr. The resulting solution was cooled to room temperature, poured into water, and extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EA=2 / 1) to afford the desired compound Example 308F (100 mg) as a colorless oil. LCMS [M+H] +< = 341.

[0473] 1< H NMR (400 MHz, CDCl 3 ) δ 1.45 (s, 9H), 1.75-1.85 (m, 1H), 2.13-2.21 (m, 1H), 2.23-2.30 (m, 1H), 2.38 (s, 3H), 3.83-4.05 (m, 3H), 5.33 (br s, 1H), 5.57 (br s, 1H), 8.35 (s, 2H).Step 7: Example 308G

[0474] To a solution of Example 308F (100 mg, 0.294 mmol) in DCM (3 mL) was added 4 M HCl in dioxane (3 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, dried and used directly in the next step without further purification Example 308G (70.6 mg). LCMS [M+H] +< = 241.Step 8: Example 308H

[0475] A mixture of Example 308G (70.6 mg, 0.256 mmol), tert-butyl 6-((2-chlorobenzo[d]thiazol-6-yl)sulfonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (130 mg, 0.294 mmol), DIPEA (99 mg, 0.768 mmol) in DMF (4 mL) was stirred at 40 °C for 2 days. The resulting solution was cooled to room temperature, poured into water, and extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM=5%) to afford the desired compound Example 308H (70 mg) as a white solid. LCMS [M+H] +< = 648.Step 9: Reference Example 308

[0476] To a solution of Example 308H (70 mg, 0.108 mmol) in DCM (3 mL) was added 4 M HCl in dioxane (3 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by prep-HPLC to afford the title compound Reference Example 308 (20 mg) as a white solid. LCMS [M+H] +< = 548.

[0477] 1< H NMR (400 MHz, DMSO-d 6 ) δ 1.47 - 1.56 (m, 1 H), 1.63 - 1.73 (m, 1 H), 1.97 (t, J=6.98 Hz, 2 H), 2.06 - 2.23 (m, 2 H), 2.31 - 2.41 (m, 3 H), 3.19 (t, J=6.98 Hz, 2 H), 3.35 (s, 2 H), 3.68 (t, J=6.04 Hz, 4 H), 3.95 - 4.02 (m, 1 H), 4.15 (br. s., 1 H), 4.38 (br. s., 1 H), 7.48 (d, J=8.33 Hz, 1 H), 7.59 (dd, J=8.33, 1.88 Hz, 2 H), 8.16 (d, J=1.88 Hz, 1 H), 8.37 (s, 2 H), 8.49 (d, J=7.79 Hz, 2 H), 8.66 (br. s., 1 H). Step 1: Example 309A

[0478] Sodium cyclopentadienylide (2 M solution in THF, 50 mL, 100 mmol, 1 equiv) was added dropwise to a solution of benzylchloromethyl ether (90%, 23 g, 130 mmol, 1.3 equiv) in DMF (200 mL) at -40 °C. After 20 min of vigorous stirring at -40 °C, the reaction mixture was poured into a 2:1 mixture of pentane / ice-cold water (900 mL). After shaking and allowing the phases to separate, the organic layer was washed twice with 150 mL of cold water and dried over Na 2 SO 4 with stirring, maintaining the temperature below 0 °C to avoid isomerization of the double bonds. After removal of the drying agent by filtration, the pentane was removed in vacuo at 0 °C to afford (benzyloxymethyl)cyclopent-2,4-ene 1 as a pale orange oil. The resulting crude material was kept at 0 °C under argon and diluted with THF (160 mL), cooled to -78 °C, and added dropwise via a cannula to a suspension of (-)-Ipc2BH (1 M solution in THF, 100 mL, 100 mmol, 1 equiv) in THF (400 mL) at -78 °C. The mixture was allowed to warm slowly to -10 °C and stirred for 3 days at that temperature. The reaction was then quenched by addition of MeOH (40 mL), followed by a 3 M aqueous solution of NaOH (40 mL) and 30% H 2 O 2 (40 mL). After 24 h of vigorous stirring at room temperature, the THF was removed under reduced pressure and the remaining aqueous suspension was partitioned between EtOAc (400 mL) and brine (200 mL). After extraction, the organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude orange oil was purified by column chromatography (eluent: 9:1 ∼ 8:2 heptane:EtOAc) to give Example 309A (4.8 g, 23.53 mmol, 23%) as a pale yellow oil. Rf = 0.29 (eluent: 7:3 heptane:EtOAc); 1H NMR (400 MHz, CDCl 3 ) δ 2.23-2.32 (m, 1H), 2.35 (s, 1H), 2.63-2.73 (m, 1H), 2.81-2.88 (m, 1H), 3.28 (t, J = 8.9 Hz, 1H), 3.53 (dd, J = 5.4, 9.1 Hz, 1H), 4.29 (td, J = 4.1, 7.0 Hz, 1H), 4.52 (s, 2H), 5.53-5.58 (m, 1H), 5.70-5.74 (m, 1H), 7.24-7.37 (m, 5H).Step 2: Example 309B

[0479] To a solution of Example 309A (4.8 g, 23.53 mmol, 1 equiv) in anhydrous THF (100 mL) was added NaH (50% in mineral oil, 1.13 g, 28.2 mmol, 1.2 equiv) at 0 °C and the mixture was stirred for 20 min at temperature. Benzyl bromide (BnBr, 3.6 mL, 30.5 mmol, 1.3 equiv) and tetrabutylammonium iodide (TBAI, 100 mg, 0.3 mmol, 0.01 equiv) were then added at 0 °C and the reaction mixture was stirred at room temperature. After 15 h, crushed ice was added carefully and the mixture was stirred for 30 min. After extraction with EtOAc (150 mL), the organic layer was washed with H2O (150 mL), brine (150 mL), dried over Na 2 SO 4 and concentrated in vacuo. Purification by column chromatography (eluent: 98:2 ∼ 95:5 heptane:EtOAc) gave Example 309B (6.3 g, 21.4 mmol, 80%) as a colorless syrup. Rf = 0.41 (eluent: 9:1 heptane:EtOAc). LCMS [M+H] +< =295.1H NMR (500 MHz, CDCl 3 ) δ 2.42 (d, J = 17.4 Hz, 1H), 2.65-2.70 (m, 1H), 3.07 (brs, 1H), 3.33 and 3.44 (ABX, JAB = 9.2 Hz, JAX = 5.7 Hz, JBX = 7.3 Hz, 2H), 4.08 (ddd, J = 3.0, 3.3, 7.0 Hz, 1H), 4.51 (d, J = 3.4 Hz, 2H), 4.54 (s, 2H), 5.64-5.66 (m, 1H), 5.74-5.7...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, which is 2. A compound of claim 1, which is 3. A compound of claim 1, which is a pharmaceutically acceptable salt of 4. A pharmaceutical composition comprising a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

5. The compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3, for use as a medicament.

6. The compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3, for use in the treatment of cardiovascular disease.

7. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to claim 6, wherein the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome and coronary artery disease.

8. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to claims 6 or 7, wherein the cardiovascular disease is - a. familial hypercholesterolemia; b. autosomal dominant hypercholesterolemia; or c. atherosclerosis.

9. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to any one of claims 6-8, wherein - a. the level of circulating serum cholesterol is decreased in a subject; b. the level of circulating serum LDL-cholesterol is decreased in a subject; c. the level of circulating serum VLDL-cholesterol is decreased in a subject; d. the level of circulating serum triglycerides is decreased in a subject; or e. the level of circulating serum lipoprotein A is decreased in a subject.

10. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to any one of claims 6-9, further comprising conjointly administering one or more additional therapeutic agents.

11. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to claim 10, wherein the one or more additional therapeutic agents are selected from alirocumab, evolocumab, bococizumab, RG7652, LY3015014, mAb316P, berberine, quercetin, ezetimbe, policosanol, BMS-962476, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

12. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to claim 10, wherein the one or more additional therapeutic agents are selected from an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP / Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase / squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, a bile acid sequestrant, and a PCSK9 translation inhibitor.

13. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to claim 10, wherein the one or more additional therapeutic agents is a statin.

14. The compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease according to claim 10, wherein the one or more additional therapeutic agents are selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.