Pcsk9 inhibitors and methods of use thereof

Abstract

To provide compounds for treating or preventing cardiovascular diseases.SOLUTION: The invention provides compounds of the formula (I) in the figure. In the formula: A is selected from H, halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR6, and -C(O)NR6R7; X is NR5 or O; and Y is selected from aryl, heteroaryl and heterocyclyl.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Patent Application No. 62 / 794,234, filed January 18, 2019, which is incorporated by reference herein in its entirety. [Background technology]

[0002] PCSK9, also called "proprotein convertase subtilisin / kexin 9," is a member of the secreted proprotein convertase family and plays a key role in cholesterol metabolism. PCSK9 increases the levels of circulating LDL cholesterol through enhancing the degradation of LDL receptors independent 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 the endosomal / lysosomal compartment. The enhanced binding affinity of PCSK9 for the LDL receptor at the acidic pH of late endosomes / lysosomes reduces LDL receptor recycling and instead targets the LDL receptor for lysosomal degradation. Genetic interaction studies have demonstrated that loss-of-function mutations in PCSK9 are associated with lower plasma LDL-C levels and reduced incidence of adverse cardiovascular events.

[0003] Another biological pathway involving the action of PCSK9 on the LDL receptor is the development of septic shock. Septic shock is an often fatal complication of severe microbial infection (sepsis) that induces an uncontrolled systemic inflammatory response and subsequent organ failure. Sepsis is caused by bacterial cell walls that contain pathogenic lipid moieties such as lipopolysaccharide (LPS; gram-negative bacteria). LPS is a potent ligand for mammalian innate immune receptors [Toll-like receptors (TLR)] and therefore plays a prominent role in the septic inflammatory response (septic shock, or sepsis).

[0004] PCSK9 reduces the uptake of LPS by the LDL receptor in the liver, so that free LPS overstimulates the body's immune response to pathogens, causing sepsis.Therefore, inhibition of PCSK9 is beneficial for preserving the LDL receptor in the liver, which provides systemic pathogen clearance and detoxification of the response to sepsis.However, currently, there is no effective treatment for sepsis or septic shock other than antibiotic therapy.

[0005] With regard to cardiovascular disease, there are few options for inhibiting PCSK9. Statins actually upregulate PCSK9 in HepG2 cells and human primary hepatocytes through increasing the expression of SREBP-2, a transcription factor that upregulates both LDLR and PCSK9 genes. Since increasing the level of PCSK9 reduces the abundance of LDL receptors on the cell surface, increasing the dose of statins cannot achieve a proportional LDL-cholesterol lowering effect.

[0006] Alirocumab and evolocumab, two monoclonal antibodies (mAbs) that selectively bind extracellular PCSK9 and prevent its interaction with the LDL receptor, have recently received FDA approval for lowering LDL-C levels. In clinical trials, Alirocumab showed a reduction in LDL levels of about 50% compared to placebo. Non-Patent Document 1. Patients taking evolocumab showed a reduction in LDL levels of about 60-75%. The efficacy of these drugs demonstrates the potential of inhibitors of PCSK9 to be an effective treatment for patients with hypercholesterolemia and other cardiovascular diseases. However, both antibody drugs require intravenous administration and may cause allergic reactions or other adverse immune responses in the body.

[0007] Cardiovascular diseases are not temporary like infectious diseases, but often require management throughout a person's life. Therefore, ease of dosing and administration is an important factor for patient compliance with maintenance drug therapy. There is a need for PCSK9 inhibitors that are highly effective and easier to administer, which can be achieved by small molecule PCSK9 inhibitors. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Elbitar et al.,Expert Opin Therapeutic Patents 2016 26:1377-1392 Summary of the Invention [Means for solving the problem]

[0009] As used herein, a compound of formula (I) [ka] (In the formula, A is H, halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6 , and -C(O)NR 6 R 7 Selected from; B is selected from H, alkyl, and halo; or A and B together with the carbon atom to which they are attached 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 2together with the atom to which they are attached form a 3- to 8-membered cycloalkyl or heterocyclyl ring; or R 1’ and R 2 together with the atom to which they are attached form a 3- to 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’ 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- to 8-membered cycloalkyl or heterocyclyl ring; and R 5 is H or alkyl; or R 1 and R 5 together with the atom to which they are attached form a 6- to 8-membered cycloalkyl or heterocyclyl ring; or R 2 and R 5 together with the atom 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. is disclosed.

[0010] In certain embodiments, the present invention provides a pharmaceutical composition suitable for use in a subject in treating or preventing cardiovascular disease, comprising an effective amount of any of the compounds described herein (e.g., a compound of the present invention, such as a compound of Formula (I)) and one or more pharma- ceutically acceptable excipients. In certain embodiments, the medicament may be for use in treating or preventing a condition or disease described herein.

[0011] Disclosed herein are methods for treating diseases and conditions that would benefit from inhibition of PCSK9, including, but not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipidemia, atherosclerosis, fatty liver, metabolic syndrome, and cardiovascular diseases such as coronary artery disease.

[0012] Other diseases and conditions that can be treated using the methods described herein include, but are not limited to, sepsis and septic shock.

[0013] Provided herein are combination therapies of compounds of formula (I) with monoclonal antibodies, statins and other cardiovascular therapeutics that can enhance cardiovascular therapeutic effects beyond the capabilities of adjunctive therapy alone.Also provided herein are combination therapies of compounds of formula (I) with antibiotic agents that can reduce the incidence and severity of sepsis and septic shock beyond the capabilities of adjunctive therapy alone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein, a compound of formula (I) [ka] (In the formula, A is H, halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6 , and -C(O)NR 6 R 7 Selected from; B is selected from H, alkyl, and halo; or A and B together with the carbon atom to which they are attached 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 atom to which they are attached form a 3- to 8-membered cycloalkyl or heterocyclyl ring; or R 1’ and R 2 together with the atom to which they are attached form a 3- to 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’ 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- to 8-membered cycloalkyl or heterocyclyl ring; and R 5 is H or alkyl; or R 1 and R 5together with the atom to which they are attached form a 6- to 8-membered cycloalkyl or heterocyclyl ring; or R 2 and R 5 together with the atom 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. is disclosed.

[0015] As used herein, a compound of formula (I') [ka] (In the formula, A is H, halo, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR 6 , and -C(O)NR 6 R 7 Selected from; 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- to 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 atom to which they are attached form a 3- to 8-membered cycloalkyl or heterocyclyl ring; or R 1’ and R 2together with the atom to which they are attached form a 3- to 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’ 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- to 8-membered cycloalkyl or heterocyclyl ring; and R 5 is H or alkyl; or R 1 and R 5 together with the atom to which they are attached form a 6- to 8-membered cycloalkyl or heterocyclyl ring; or R 2 and R 5 together with the atom 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. is disclosed.

[0016] It is understood that all of the embodiments below and herein are embodiments of both Formula (I) and Formula (I').

[0017] In certain embodiments, A is H, hydroxy, thioalkyl, alkyl, acyloxy, cyano, cycloalkyl, -C(O)OR 6 , and -C(O)NR 6 R 7The compound of claim 1, wherein A is selected from: In certain embodiments, A is H, while in other embodiments, A is alkyl, such as thioalkyl. In certain embodiments, A is -SCH 3 , -SCHF 2 , and -OCHF 2 In some embodiments, A is alkoxy. In other embodiments, A is cycloalkyl. In certain embodiments, B is H.

[0018] In certain embodiments, A and B, together with the carbon atom to which they are attached, form a pyrrolyl or thienyl ring, which is unsubstituted or substituted with one or more alkyl.

[0019] In certain embodiments, X is preferably NR5. In other embodiments, Y is preferably heteroaryl or heterocyclyl.

[0020] In certain embodiments, R 1 and R 1’ are H. However, when n is 0, R 1 and R 1’ can be taken together with the atoms to which they are attached to form a 4-8 membered cycloalkyl ring. In some embodiments, the cycloalkyl is monocyclic or bicyclic. In other embodiments, R 1 and R 1’ can be taken together with the atoms to which they are attached to form a 4-8 membered cycloalkenyl ring. In some embodiments, the cycloalkyl ring is a cyclopentyl ring, such as S,S-cyclopentyl. In some embodiments, the cycloalkyl ring is substituted with hydroxyl or hydroxyalkyl.

[0021] In certain embodiments, R 2 is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, alkylamino, cyano, and hydroxyl. 2 is C 1~3 It is an alkyl group. 2may be substituted with one or more substituents selected from amino, amido, cyano, hydroxy, and heterocyclyl. In some embodiments, R 2’ is C 1~3 alkyl, but in other embodiments, R 2’ is H.

[0022] In certain embodiments, R 1 and R 2 together with the atoms to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl ring. 1’ and R 2 together with the atoms to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl ring. 2 and R 2’ together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl or heterocyclyl ring.

[0023] In certain embodiments, R 3 is C 1~3 alkyl, but in other embodiments, R 3 is H. In certain embodiments, R 4 is H.

[0024] In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl ring. 1 and R 5 together with the atoms to which they are attached form a 6-8 membered cycloalkyl or heterocyclyl ring. 2 and R 5 together with the atom to which they are attached form a 5-8 membered cycloalkyl or heterocyclyl ring.

[0025] In certain embodiments, Y is a monocyclic heteroaryl, such as, but not limited to, pyridinyl, pyrazinyl, pyrimidinyl, and thiazolyl. In other embodiments, Y is a monocyclic heteroaryl, such as, but not limited to, pyridinyl, pyrazinyl, and pyrimidinyl. In some embodiments, Y is selected from triazenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, and triazolyl. The monocyclic heteroaryl may be unsubstituted or substituted with one or more substituents selected from alkyl, thioalkyl, alkoxy, alkoxycarbonyl, amido, carboxy, cyano, halo, heteroaryl, nitro, sulfonamide, and thioalkyl. In another embodiment, Y is a monocyclic heteroaryl, which may be unsubstituted or substituted with one or more substituents selected from alkyl, thioalkyl, alkoxy, alkoxycarbonyl, amido, carboxy, cyano, halo, aryl, heteroaryl, heterocyclyl, nitro, sulfonamide, and thioalkyl.

[0026] In certain embodiments, 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 certain preferred embodiments, Y is a 6-membered monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is selected from halo, CN, alkyl, alkoxy, hydroxy, carboxy, -CO 2 and heteroaryl or heterocyclyl, which is substituted with one or more substituents selected from alkyl, and tetrazolyl. In certain preferred embodiments, the monocyclic heteroaryl is positioned para to A relative to X.

[0027] In other embodiments, Y is a 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 sulfonamide. In certain embodiments, the bicyclic heteroaryl is unsubstituted or substituted with one or more substituents selected from thioalkyl, alkoxycarbonyl, amido, carboxy, halo, and heteroaryl.

[0028] In certain embodiments, Y is of the formula -C(O)NR 8 R 9 or -NR 9 C(O)R 10 is substituted with an amide substituent of R 8 and R 9 are each independently selected from H, alkyl, heterocyclyl, and heteroaryl; or R 8 and R 9 together with the nitrogen atom to which they are attached, forming a 4-, 5-, 6-, or 7-membered heterocyclic or heteroaryl ring; and R 10 is alkyl.

[0029] In certain embodiments, Y is of the formula -S(O) 2 NR 8 R 9 or -NR 9 S(O) 2 R 10 is substituted with a sulfonamide substituent of R 8 and R 9 are each independently selected from H, alkyl, and heteroaryl; or R 8 and R9 together with the nitrogen atom to which they are attached, forming a 4-, 5-, 6-, or 7-membered heterocyclic ring; and R 10 is alkyl.

[0030] It is understood that all of the above-mentioned embodiments of the variable Y in formula (I) are also embodiments of the variable Het in formula (I').

[0031] In certain embodiments, R 8 and R 9 R is independently selected from H, methyl, ethyl, triazolyl, and pyrazolyl. 8 and R 9 In embodiments where one or both of R 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. 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from azirazine, 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 9together with the nitrogen atom to which they are attached, they are 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-diaza Spiro[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 - forming a heterocycle selected from 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.

[0032] In some embodiments, the heterocycle is unsubstituted or substituted with one or more substituents selected from alkyl, alkoxycarbonyl, halo, hydroxy, cyano, carboxy, and heterocyclyl. In certain embodiments, the heterocycle is unsubstituted or substituted with one or more substituents selected from methyl, ethoxycarbonyl, halo, hydroxy, cyano, carboxy, and oxetanyl.

[0033] In certain embodiments, the present invention provides a medicament suitable for use in a human patient, the medicament comprising any of the compounds set forth above (e.g., a compound of the present invention, such as a compound of formula (I)) and one or more pharma- ceutically acceptable excipients. In certain embodiments, the medicament may be for use in treating or preventing a condition or disease described herein.

[0034] Any of the disclosed compounds can be used in the manufacture of a medicament for the treatment of any disease or condition disclosed herein.

[0035] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of this disclosure. The following references provide those skilled in the art with general definitions of many 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 otherwise specified.

[0036] In this disclosure, "comprises," "comprising," "containing," "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 "consisting essentially of" likewise have the meaning ascribed to them in U.S. Patent Law, and the terms are open-ended, allowing for the presence of more than what is described, but excluding prior art embodiments, so long as the basic or novel characteristics described are not changed by the presence of more than what is described.

[0037] As used herein, unless otherwise stated or clear from the context, the term "or" is understood to be inclusive. Unless otherwise stated or clear from the context, as used herein, the terms "a," "an," and "the" are understood as singular or plural.

[0038] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0039] 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-.

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

[0041] 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.

[0042] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0043] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond, and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl", the latter of which refers to an alkenyl moiety having a substituent replacing hydrogen on one or more carbons of the alkenyl group. Such a substituent may be present on one or more carbons that are included or not included in one or more double bonds. Furthermore, such substituents include all those contemplated for alkyl groups, as described below, so long as stability is not impaired. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0044] An "alkyl" group or "alkane" is a straight or branched chain non-aromatic hydrocarbon that is fully saturated. Typically, a straight or branched chain alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, unless otherwise defined. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. 1 ~C 6 Straight chain or branched chain alkyl groups are also referred to as "lower alkyl" groups.

[0045] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if desired. For example, substituents of substituted alkyl include amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 Exemplary substituted alkyls are described below. Cycloalkyl can include alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF 3 , -CN, and the like.

[0046] "C x~y The term "C" when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, "C x~yThe term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups including straight-chain alkyl and branched-chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. 0 Alkyl represents a hydrogen if the group is terminal and a bond if the group is internal. 2~y Alkenyl" and "C 2~y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0047] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0048] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0049] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter of which refers to an alkynyl moiety having a substituent replacing a hydrogen on one or more carbons of the alkynyl group. Such a substituent may be present on one or more carbons that are included or not included in one or more triple bonds. Furthermore, such substituents include all those contemplated for alkyl groups, as described above, so long as stability is not impaired. For example, substitution of an alkynyl group with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0050] As used herein, the term "amide" refers to the group [ka] In the formula, each R 11 independently represent hydrogen or a hydrocarbyl group, or two R 11together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0051] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] wherein each R 11 independently represent hydrogen or a hydrocarbyl group, or two R 11 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure. As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0052] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0053] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic 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 adjacent rings, at least one of which is aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0054] The term "carbamate" is art-recognized and refers to a group [ka] In the formula, R 11 and R 12 independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R 11and R 12 together with the intervening atoms complete a heterocycle having 4 to 8 atoms in the ring structure.

[0055] As used herein, the terms "carbocycle" and "carbocyclic" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated, and cycloalkene rings that contain at least one double bond.

[0056] The term "carbocycle" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, 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 embodiment, 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 is included in the definition of carbocycle, if valences permit. 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. A "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

[0057] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. 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 can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0058] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocycle group.

[0059] The term "carbonate" is art-recognized and refers to a salt of the group -OCO 2 -R 10 (In the formula, R 10 represents a hydrocarbyl group).

[0060] As used herein, the term "carboxy" refers to a group of the formula -CO 2 H.

[0061] As used herein, the term "ester" refers to the group -C(O)OR 10 (In the formula, R 10 represents a hydrocarbyl group).

[0062] As used herein, the term "ether" refers to a hydrocarbyl group linked to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0063] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0064] As used herein, the terms "hetaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a hetaryl group.

[0065] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where no two heteroatoms are adjacent.

[0066] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, which ring structures include at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 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 adjacent rings, at least one of which is a heteroaromatic ring, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0067] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0068] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3-10 membered rings, more preferably 3-7 membered rings, which ring structures contain at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 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 adjacent rings, at least one of which is heterocyclic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0069] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocycle group.

[0070] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom that does not have =O or =S substituents, typically has at least one carbon-hydrogen bond and a predominantly carbon backbone, but may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, while substituents such as acetyl (having =O substituents on the connecting carbon) and ethoxy (connected through oxygen rather than carbon) are not considered to be hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0071] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0072] The term "lower" when used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer non-hydrogen atoms in the substituent, preferably 6 or fewer. "Lower alkyl" refers, for example, to alkyl groups containing 10 or fewer carbon atoms, preferably 6 or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they appear alone or in combination with other substituents, such as in the recitations of hydroxyalkyl and aralkyl (in which case, for example, atoms in an aryl group are not counted when counting the carbon atoms in an alkyl substituent).

[0073] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms in the ring, preferably 5 to 7.

[0074] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0075] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substitution values ​​of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Substituents include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the substituents can themselves be substituted, if desired. Unless specifically described as "unsubstituted," references to chemical moieties herein are understood to include substituted forms. For example, references to "aryl" groups or moieties implicitly include both substituted and unsubstituted forms.

[0076] The term "sulfate" is art-recognized and refers to the group -OSO 3 H, or a pharma- ceutically acceptable salt thereof.

[0077] The term "sulfonamide" is art-recognized and has the general formula [ka] In the formula, R 11 and R 12 independently represent hydrogen or hydrocarbyl such as alkyl, or R 11 and R 12 together with the intervening atoms complete a heterocycle having 4 to 8 atoms in the ring structure.

[0078] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 10 (In the formula, R 10 represents hydrocarbyl).

[0079] The term "sulfonate" is art-recognized and refers to the group SO 3 H, or a pharma- ceutically acceptable salt thereof.

[0080] The term "sulfone" is art-recognized and refers to the group -S(O) 2 -R 10 (In the formula, R 10 represents hydrocarbyl).

[0081] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0082] As used herein, the term "thioester" refers to the group -C(O)SR 10 Or -SC(O)R 10 (In the formula, R 10 represents hydrocarbyl).

[0083] The term "thioether," as used herein, corresponds to an ether where the oxygen has been replaced with a sulfur.

[0084] The term "urea" is art-recognized and has the general formula [ka] where R 11 and R 12 independently represent hydrogen or hydrocarbyl such as alkyl, or R 11 The presence of any of R 12 and together with the intervening atoms complete a heterocycle having 4 to 8 atoms in the ring structure.

[0085] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed, as needed, during the synthetic process. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd 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 in which the hydroxyl group is 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.

[0086] The present invention includes all pharma- ceutically acceptable isotopically labeled compounds as described herein, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. In certain embodiments, the compounds of the present invention are enriched in such isotopically labeled materials (e.g., compounds in which the distribution of isotopes in the compounds in the composition is different from the natural or typical distribution of isotopes).

[0087] Examples of isotopes suitable for inclusion in the compounds of the invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P, 35 Examples include isotopes of sulfur such as S.

[0088] Certain isotopically labeled compounds as disclosed herein, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e. 14 C are useful for this purpose given their ease of incorporation and ready means of detection.

[0089] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferred in some circumstances as this may afford certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0090] 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0091] In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched in one enantiomer. For example, the compounds of the present invention may have about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, more than about 90% ee, or about 95% or more ee. In certain embodiments, the compounds of the present invention may have two or more stereocenters. In certain such embodiments, the compounds of the present invention may be enriched in one or more diastereomers. For example, the compounds of the present invention may have about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, more than about 90% de, or about 95% or more de.

[0092] In certain embodiments, a therapeutic formulation may be enriched to provide primarily one enantiomer of a compound (e.g., of formula (I)). A mixture enriched in one enantiomer may, for example, contain at least about 60 mole percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or about 99 mole percent. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the material constitutes, for example, 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% relative to the amount of the other enantiomer in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be described as containing about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0093] In certain embodiments, a therapeutic formulation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A mixture enriched in one diastereomer may contain, for example, at least about 60 mole percent of one diastereomer, or more preferably, at least about 75, about 90, about 95, or about 99 mole percent.

[0094] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, toddlers, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or geriatrics)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. A preferred subject is a human.

[0095] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0096] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment includes administration to a subject of one or more of the art-recognized and disclosed compositions. If it is administered prior to clinical manifestation of an undesirable condition (e.g., a disease or other undesirable condition in a subject), the treatment is prophylactic (i.e., it protects the subject against the occurrence of the undesirable condition), whereas if it is administered after the manifestation of an undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0097] The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to the therapeutically active agents of the present invention (e.g., compounds of formula (I)). A common method for making prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of formula (I) in the formulations shown above may be replaced with the corresponding suitable prodrugs, e.g., the hydroxyl in the parent compound is shown as an ester or carbonate or carboxylic acid.

[0098] As used herein, "effective amount" refers to an amount sufficient to achieve a desired biological effect. As used herein, "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount may refer to an amount sufficient to ameliorate at least one sign or symptom of cancer.

[0099] A "response" to a method of treatment may include, inter alia, a decrease or amelioration of negative symptoms, a decrease in progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcome, a reduction in side effects, stabilization of the disease, partial or complete reversal of the disease.

[0100] How to use 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 expressed primarily in the liver, intestine, kidney, and nervous system. Without being bound to any particular theory, studies of mutations in the gene have shown that its putative role is in reducing LDL receptors at the cell surface independent of its catalytic activity. (Abifadel, et al. Expert Opin. Ther. Pat. 2010 20:1547-71). Binding of PCSK9 to receptors leads to their lysosomal degradation. This enhanced degradation leads to an increase in the amount of circulating low density lipoprotein LDL (LDL-c). PCSK9 is upregulated by statins, SREBP-1a and SREBP-2, LXR agonists, and insulin, but downregulated by dietary cholesterol, glucagon, ethinyl estradiol, chenodeoxycholic acid, and bile acid-activated farnesoid 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 increasing the level of PCSK9 reduces the abundance of LDL receptors on the cell surface, increasing the dose of statins cannot achieve proportional LDL-cholesterol lowering results. Thus, disclosed herein is a method for treating a wide range of cardiovascular diseases and conditions that benefit from lowering LDL-c by inhibiting PCSK9.

[0101] In certain embodiments, the method of inhibiting PCSK9 is performed in a subject in need thereof, thereby treating a disease or disorder mediated by PCSK9.

[0102] Also disclosed herein is a method for treating or preventing a disease or disorder mediated by PCSK9, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein is a method for treating a disease or disorder mediated by PCSK9, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein is a method for preventing a disease or disorder mediated by PCSK9, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. Prevention of cardiovascular events via inhibition of PCSK9 is described, for example, in Robinson et al.,Artherosclerosis 2015 243:593-597.

[0103] Exemplary cardiovascular diseases and conditions include, but are not limited to, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetic complications, atherosclerosis, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, or congestive heart failure.

[0104] In certain embodiments, exemplary cardiovascular diseases and conditions include, but are not limited to, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipidemia, atherosclerosis, fatty liver, 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.

[0105] In certain embodiments, the disclosed treatment methods can reduce high levels of circulating serum cholesterol, such as LDL-cholesterol and VLDL-cholesterol.In addition, the disclosed methods are useful for reducing circulating serum triglycerides, circulating serum lipoprotein A, circulating serum LDL and atherogenic lipoproteins.In certain embodiments, the disease or condition that is treated with the disclosed compounds and compositions includes atherosclerosis and atherosclerotic plaque formation.Subjects with gain-of-function mutations in PCSK9 gene also benefit from treatment with the disclosed compounds and compositions that suppress the mutations through inhibition of PCSK9.

[0106] Inhibition of PCSK9 has also shown therapeutic benefit in treating sepsis in subjects. Septic shock is an often fatal complication of severe microbial infections (sepsis) that induces uncontrolled systemic inflammatory responses and subsequent organ failure. Sepsis is caused by bacterial cell walls that contain pathogenic lipid moieties, such as lipopolysaccharide (LPS; gram-negative bacteria). LPS is a potent ligand for mammalian innate immune receptors [Toll-like receptors (TLR)] and therefore plays a prominent role in septic inflammatory responses (septic shock, or sepsis). PCSK9 reduces the uptake of LPS by the hepatic LDL receptor, so that free LPS overstimulates the body's immune response to pathogens, causing sepsis. Inhibition of PCSK9 is beneficial for preserving hepatic LDL receptors, which provide systemic pathogen clearance and detoxification in response to sepsis (see, for example, Walley et al Sci.Translat.Med.2014 6:1-10).

[0107] Disclosed herein is a method of treating sepsis or septic shock, comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the disclosed method of treatment is useful for increasing LPS uptake. Certain embodiments provide a method of reducing the inflammatory response induced by sepsis or septic shock.

[0108] Combination Therapy The disclosed compounds and compositions can be administered in conjunction with other therapeutic agents, such as other agents suitable for treating high levels of LDL and triglycerides.In certain embodiments, the administration of one or more additional therapeutic agents in conjunction with the compounds of the present invention produces synergistic effects.In certain embodiments, the administration of one or more additional therapeutic agents in conjunction produces additive effects.

[0109] In some embodiments, the method of treating a disease or disorder mediated by PCSK9 includes administering a PCSK9 inhibitor in combination with one or more other therapeutic agents. In some embodiments, the PCSK9 inhibitor is a compound of formula (I). The other therapeutic agents may include monoclonal antibodies such as alirocumab, evolocumab, bococizumab, RG7652, LY3015014, and mAb316P.Further exemplary antibodies are 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 ... International Publication No. 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 / 1549 No. 99, International Publication No. 2013 / 008185, International Publication No. 2015 / 200438, International Publication No. 2014 / 107739, International Publication No. 2013 / 188855, International Publication No. 2013 / 169886, International Publication No. 2013 / 148284, International Publication No. 2013 / 091103, International Publication No. 2013 / 039958, International Publication No. 2012 / 177741, International Publication No. These include those described in 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 may be used in combination with the disclosed compounds and compositions include plant alkaloids and flavonoids known for their cholesterol-lowering activity, such as berberine and quercetin. In some embodiments, cholesterol-lowering small molecules, such as ezetimibe and policosanol, may be administered as additional therapeutic agents. In certain embodiments, polypeptides, such as BMS-962476 and fibronectin-based scaffolding domain proteins, may be administered in combination with the 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.

[0110] In certain embodiments, the additional therapeutic agent can be a statin, such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, hi other embodiments, the disclosed compounds can be administered in conjunction with HMG-CoA reductase.

[0111] Any HMG-CoA reductase inhibitor may be used in the combination aspect of the present 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.

[0112] The term HMG-CoA reductase inhibitor refers to a compound that inhibits the bioconversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid, which is 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, but other HMG-CoA reductase inhibitors will be known to those skilled in the art. U.S. Pat. No. 4,231,938 (the disclosure of which is incorporated herein by reference) discloses certain compounds isolated after cultivation of microorganisms belonging to the genus Aspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 (the disclosure of which is incorporated herein by reference) discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Also, U.S. Patent No. 4,739,073 (the disclosure of which is incorporated by reference) discloses certain substituted indoles such as fluvastatin. Also, U.S. Patent No. 4,346,227 (the disclosure of which is incorporated by reference) discloses ML-236B derivatives such as pravastatin. Also, European Patent Application Publication No. 491226A (the disclosure of which is incorporated by reference) discloses certain pyridyl dihydroxyheptenoic acids such as cerivastatin. In addition, U.S. Patent No. 5,273,995 (the disclosure of which is incorporated by reference) discloses certain 6-[2-(substituted pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin and any pharma- ceutically acceptable forms thereof (i.e., LIPITOR®). Additional HMG-CoA reductase inhibitors include rosuvastatin and pitavastatin.

[0113] Atorvastatin calcium (ie, atorvastatin hemi-calcium), disclosed in US Pat. No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitor®.

[0114] Statins also include compounds such as rosuvastatin, disclosed in U.S. Reissue Patent No. 37,314E; pitivastatin, disclosed in European Patent No. 304063B1 and U.S. Patent No. 5,011,930; simvastatin, disclosed in U.S. Patent No. 4,444,784, which is incorporated herein by reference; pravastatin, disclosed in U.S. Patent No. 4,346,227, which is incorporated herein by reference; cerivastatin, disclosed in U.S. Patent No. 5,502,199, which is incorporated herein by reference; mevastatin, disclosed in U.S. Patent No. 3,983,140, ​​which is incorporated herein by reference; and statins such as statins disclosed in U.S. Patent No. 5,211,162, both of which are incorporated herein by reference. velostatin, disclosed in U.S. Patent No. 4,448,784 and U.S. Patent No. 4,450,171; fluvastatin, disclosed in U.S. Patent No. 4,739,073, incorporated herein by reference; compactin, disclosed in U.S. Patent No. 4,804,770, incorporated herein by reference; lovastatin, disclosed in U.S. Patent No. 4,231,938, incorporated herein by reference; dalvastatin, disclosed in European Patent Application Publication No. 738510A2; fluindostatin, disclosed in European Patent Application Publication No. 363934A1; and dihydrocompactin, disclosed in U.S. Patent No. 4,450,171, incorporated herein by reference.

[0115] Any HMG-CoA synthase inhibitor can be used in the combination aspect of the present invention. The term HMG-CoA synthase inhibitor refers to a compound that inhibits the bioconversion of acetyl-Coenzyme A and acetoacetyl-Coenzyme A to hydroxymethylglutaryl-Coenzyme A catalyzed by the enzyme HMG-CoA synthase. Such inhibition is easily 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, but other HMG-CoA synthase inhibitors will be known to those skilled in the art. U.S. Patent No. 5,120,729 (the disclosure of which is incorporated herein by reference) discloses certain beta-lactam derivatives. U.S. Patent No. 5,064,856 (the disclosure of which is incorporated herein by reference) discloses certain spiro-lactone derivatives (MF5253) prepared by culturing microorganisms. U.S. Patent No. 4,847,271 (the disclosure of which is incorporated herein by reference) discloses certain oxetane compounds such as 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoic acid derivatives.

[0116] Any compound that reduces HMG-CoA reductase gene expression may be used in the combination aspect of the invention. These agents may be HMG-CoA reductase transcription inhibitors, which block transcription of DNA, or translation inhibitors, which prevent or reduce translation of mRNA encoding HMG-CoA reductase into protein. Such compounds may directly affect transcription or translation, or may be biotransformed by one or more enzymes of the cholesterol biosynthetic cascade into a compound having the aforementioned activity, or may cause the accumulation of isoprene metabolites having the aforementioned activity. Such compounds may cause this effect by reducing the levels of SREBPs (sterol regulatory element binding proteins), by inhibiting the activity of site-1 protease (SIP) or by agonizing oxysterol receptors or antagonizing SCAP. Such modulation is readily determined by those of skill in the art according to standard assays (Meth. Enzymol. 1985;110:9-19). Several compounds are described and referenced below, but other inhibitors of HMG-CoA reductase gene expression will be known to those of skill in the art. US Pat. No. 5,041,432, the disclosure of which is incorporated by reference, discloses certain 15-substituted lanosterol derivatives.

[0117] Other oxygenated sterols that inhibit the synthesis of HMG-CoA reductase are discussed by EI Mercer (Prog. Lip. Res. 1993;32:357-416).

[0118] Any compound that has activity as a CETP inhibitor can function as the second compound in the combination therapy aspect of the present invention.The term CETP inhibitor refers to a compound that inhibits the cholesteryl ester transfer protein (CETP)-mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL.Such CETP inhibitory activity can be easily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343).Various CETP inhibitors will be known to those skilled in the art, for example, those disclosed in U.S. Pat. No. 6,140,343 and U.S. Pat. No. 6,197,786, which are assigned to the assignee of the present invention. CETP inhibitors are also described in U.S. Patent No. 6,723,752 and include some 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.Furthermore, CETP inhibitors included herein are also described in U.S. Patent Application No. 10 / 807,838, filed March 23, 2004. U.S. Pat. No. 5,512,548 discloses certain polypeptide derivatives having activity as CETP inhibitors, while certain CETP-inhibitory rosenonolactone derivatives and phosphate-containing analogs of cholesteryl esters are disclosed in J. Antibiot, 49(8) 815-816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively.

[0119] Any PPAR modulator can be used in the combination aspect of the present invention. The term PPAR modulator refers to a compound that modulates peroxisome proliferator activator receptor (PPAR) activity in mammals, particularly humans. Such modulation is easily determined by those skilled in the art according to standard assays known in the literature. By modulating PPAR receptors, such compounds modulate the transcription of key genes involved in lipid and glucose metabolism, such as those in fatty acid oxidation, and also involved in high density lipoprotein (HDL) association (e.g., apolipoprotein A1 gene transcription), thus reducing total body fat and increasing HDL cholesterol. Due to their activity, these compounds also reduce the plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol, and their associated components, such as apolipoprotein B, in mammals, particularly humans, and increase HDL cholesterol and apolipoprotein A1. Thus, these compounds are useful for treating and correcting various dyslipidemias that are observed to be associated with the development and occurrence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia. A variety of these compounds are described and referenced below, while others will be known to those skilled in the art. International Publication Nos. WO 02 / 064549 and WO 02 / 064130 and U.S. Patent Application Nos. 10 / 720,942, filed November 24, 2003, and 60 / 552,114, filed March 10, 2004, the disclosures of which are incorporated herein by reference, disclose certain compounds that are PPARa activators.

[0120] Any other PPAR regulator can be used in the combination aspect of the present invention.In particular, PPARp and / or PPARy regulator can be useful in combination with the compound of the present invention.An example PPAR inhibitor is described in US Patent Publication No. 2003 / 0225158 as {5-methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid.

[0121] Any MTP / Apo B (microsomal triglyceride transfer protein and / or apolipoprotein B) secretion inhibitor can be used in the combination aspect of the present invention. The term MTP / Apo B secretion inhibitor refers to a compound that inhibits the secretion of triglycerides, cholesteryl esters, and phospholipids. Such inhibition is easily determined by those skilled in the art according to standard assays (e.g., Wetterau, JR 1992; Science 258:999). Various MTP / Apo B secretion inhibitors will be known to those skilled in the art and include implitapide (Bayer) and additional compounds such as those disclosed in WO 96 / 40640 and WO 98 / 23593 (two exemplary publications).

[0122] Any squalene synthase inhibitor can be used in the combination aspect of the present invention. The term squalene synthase inhibitor refers to a compound that inhibits the condensation of two molecules of farnesyl pyrophosphate to form squalene, which is catalyzed by the enzyme squalene synthase. Such inhibition is easily 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 and referenced below, but other squalene synthase inhibitors will be known to those skilled in the art. U.S. Patent No. 5,026,554 (the disclosure of which is incorporated by reference) discloses fermentation products of the microorganism MF5465 (ATCC 74011) that contain zaragozic acid. A summary of other claimed squalene synthase inhibitors has been compiled (Curr. Op. Then Patents (1993) 861-4).

[0123] Any squalene epoxidase synthase inhibitor may be used in the combination aspect of the present invention. The term squalene epoxidase inhibitor refers to a compound that inhibits the bioconversion of squalene and molecular oxygen to squalene-2,3-epoxide, which is catalyzed by the enzyme squalene epoxidase. Such inhibition is easily 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, but other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Patent Nos. 5,011,859 and 5,064,864 (the disclosures of which are incorporated by reference) disclose certain fluoro analogs of squalene. European Patent Application Publication No. 395,768A (the disclosures of which are incorporated by reference) discloses certain substituted arylamine derivatives. WO 9312069A (the disclosure of which is incorporated herein by reference) discloses certain aminoalcohol derivatives. U.S. Patent No. 5,051,534 (the disclosure of which is incorporated herein by reference) discloses certain cyclopropyloxy-squalene derivatives.

[0124] Any squalene cyclase inhibitor can be used as the second component in the combination aspect of the present invention.The term squalene cyclase inhibitor refers to a compound that inhibits the bioconversion of squalene-2,3-epoxide to lanosterol, which is catalyzed by the enzyme squalene cyclase.Such inhibition can be easily 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, but other squalene cyclase inhibitors will also be known to those skilled in the art. WO 09410150 (the disclosure of which is incorporated herein by reference) discloses certain 1,2,3,5,6,7,8,8a-octahydro-5,5,8(beta)-trimethyl-6-isoquinolinamine derivatives, such as N-trifluoroacetyl-1,2,3,5,6,7,8,8a-octahydro-2-allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolinamine. FR 2697250 (the disclosure of which is incorporated herein by reference) discloses certain beta,beta-dimethyl-4-piperidineethanol derivatives, such as 1-(1,5,9-trimethyldecyl)-beta,beta-dimethyl-4-piperidineethanol.

[0125] Any combined squalene epoxidase / squalene cyclase inhibitor may be used as the second component in the combination aspect of the present invention. The term combined squalene epoxidase / squalene cyclase inhibitor refers to a compound that inhibits the bioconversion of squalene to lanosterol via a squalene-2,3-epoxide intermediate. Although in some assays squalene epoxidase inhibitors and squalene cyclase inhibitors cannot be distinguished; these assays are recognized by those skilled in the art. Thus, inhibition by combined squalene epoxidase / squalene cyclase inhibitors is easily determined by those skilled in the art according to the aforementioned standard assays for squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referenced below, but other squalene epoxidase / squalene cyclase inhibitors will be known to those skilled in the art. U.S. Patent Nos. 5,084,461 and 5,278,171, the disclosures of which are incorporated by reference, disclose certain azadecalin derivatives. EP 468,434 (the disclosure of which is incorporated by reference) discloses certain piperidyl ether and thio-ether derivatives such as 2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethyl sulfide. WO 9401404 (the disclosure of which is incorporated by reference) discloses certain acyl-piperidines such as 1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)-ethyl)piperidine. U.S. Patent No. 5,102,915 (the disclosure of which is incorporated by reference) discloses certain cyclopropyloxy-squalene derivatives.

[0126] 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 generally called functional foods, and include, for example, garlic extract and niacin. A sustained release form of niacin is available and is known as Niaspan. Niacin can 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 (trademark) (Kos Pharmaceuticals Inc.).

[0127] Any cholesterol absorption inhibitor can be used as the additional compound in the combination aspect of the present invention.The term cholesterol absorption inhibitor refers to the ability of a compound to inhibit cholesterol contained in the intestinal lumen from entering enterocytes and / or from entering enterocytes into lymphatic system and / or bloodstream.Such cholesterol absorption inhibitory activity can be easily 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 WO 94 / 00480.An example of a cholesterol absorption inhibitor is ZETIA™ (ezetimibe) (Schering-Plough / Merck).

[0128] Any ACAT inhibitor can be used in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl-CoA:cholesterol acyltransferase. Such inhibition can be easily determined by those skilled 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 carboxysulfonate salts, while WO 96 / 26948 and WO 96 / 10559 both disclose urea derivatives with ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as avasimibe (Pfizer), CS-505 (Sankyo) and eflutimibe (Eli Lilly and Pierre Fabre).

[0129] Lipase inhibitors can be used in the combination therapy aspect of the present invention. Lipase inhibitors are compounds that inhibit the metabolic cleavage of dietary triglycerides or plasma phospholipids into free fatty acids and corresponding glycerides (e.g., EL, HL, etc.). Under normal physiological conditions, lipolysis occurs via a two-step process involving the acylation of the activated serine moiety of lipase enzymes. This results in the production of fatty acid-lipase hemiacetal intermediates, which are subsequently cleaved to release diglycerides. After further deacylation, the lipase-fatty acid intermediates are cleaved to produce free lipase, glycerides, and fatty acids. In the intestinal tract, the resulting 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 ultimately enter the peripheral circulation as chylomicrons. Such lipase inhibitory activity is easily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol 286:190-231).

[0130] Pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the 1- and 3-carbon positions. The main site of metabolism of ingested fat is in the duodenum and proximal jejunum by pancreatic lipase, which is normally secreted in large excess over the amount required for fat degradation in the upper small intestine. Since pancreatic lipase is the main enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and other related conditions. Such pancreatic lipase inhibitory activity is easily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol 286:190-231).

[0131] Gastric lipase is an immunologically distinct lipase involved in approximately 10-40% of dietary fat digestion. Gastric lipase is secreted in response to mechanical stimuli, food ingestion, the presence of a fatty meal, or sympathomimetics. Lipolysis of ingested fat in the stomach is physiologically important in providing the fatty acids necessary to induce pancreatic lipase activity in the intestinal tract, and is also important for fat absorption in various physiological and pathological conditions associated with pancreatic insufficiency. See, for example, C.K.Abrams, et al., Gastroenterology, 92, 125 (1987). Such gastric lipase inhibitory activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol 286:190-231).

[0132] Various gastric and / or pancreatic lipase inhibitors are known to those skilled in the art.Preferred lipase inhibitors are selected from lipstatin, tetrahydrolipstatin (orlistat), valilactone, estellatin, ebelactone A, and ebelactone B.The compound tetrahydrolipstatin is particularly preferred.The lipase inhibitor N-3-trifluoromethylphenyl-N'-3-chloro-4'-trifluoromethylphenylurea and various urea derivatives related thereto are disclosed in U.S. Pat. No. 4,405,644.The lipase inhibitor estellatin is disclosed in U.S. Pat. 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, can be prepared as described in Petersen et al., Liebig's Annalen, 562, 205-229 (1949).

[0133] Various 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 acid 1,3 acid lactone, as well as variously substituted N-formylleucine derivatives and their stereoisomers are disclosed in U.S. Pat. No. 4,598,089. For example, tetrahydrolipstatin is prepared as described, for example, in 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 related variously substituted sulfonic acid derivatives are disclosed in U.S. Patent No. 4,452,813. The pancreatic lipase inhibitor, WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and various carbamates and pharma- ceutically acceptable salts related thereto, are disclosed in U.S. Patents 5,512,565; 5,391,571 and 5,602,151. The pancreatic lipase inhibitor, valilactone, and a process for its preparation by microbial culture 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 their preparation by microbial culture 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 inhibiting monoglyceride formation is disclosed in JP 8-143457, published Jun. 4, 1996.

[0134] Other compounds marketed for hyperlipidemia, including hypercholesterolemia, and 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®.

[0135] Considering the link between diabetes and atherosclerosis (e.g., metabolic syndrome), the compound of formula I may be administered with an antidiabetic compound. Diabetes may be treated by administering a therapeutically effective amount of the compound of the present invention to a patient with either diabetes (especially type II), insulin resistance, glucose intolerance, metabolic syndrome, etc., or diabetic complications such as neuropathy, nephropathy, retinopathy, or cataract, in combination with other drugs that may be used to treat diabetes (e.g., insulin). This includes the classes of antidiabetic agents (and specific agents) described herein.

[0136] Any glycogen phosphorylase inhibitor can be used as the second drug in combination with the compound of the present invention.The term glycogen phosphorylase inhibitor refers to a compound that inhibits the bioconversion of glycogen to glucose-1-phosphate, which is catalyzed by the enzyme glycogen phosphorylase.Such glycogen phosphorylase inhibitory activity can be easily determined by those skilled in the art according to standard assays (e.g., J.MedChem.41(1998)2934-2938).A variety of glycogen phosphorylase inhibitors are known to those skilled in the art, and include those described in WO 96 / 39384 and WO 96 / 39385.

[0137] Any aldose reductase inhibitor can be used in combination with the compound of the present invention.The term aldose reductase inhibitor refers to a compound that inhibits the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase.Aldose reductase inhibition can be easily 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, including 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.

[0138] Any sorbitol dehydrogenase inhibitor can be used in combination with the compound of the present invention.The term sorbitol dehydrogenase inhibitor refers to a compound that inhibits the bioconversion of sorbitol to fructose, which is catalyzed by the enzyme sorbitol dehydrogenase.Such sorbitol dehydrogenase inhibitor activity can be easily determined by those skilled in the art according to standard assays (e.g., Analyt.Biochem (2000) 280:329-331).Various sorbitol dehydrogenase inhibitors are known, and for example, U.S. Patent Nos. 5,728,704 and 5,866,578 disclose compounds and methods for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase.

[0139] Any glucosidase inhibitor can be used in combination with the compounds of the present invention. Glucosidase inhibitors inhibit the enzymatic hydrolysis of complex carbohydrates into bioavailable simple sugars, such as glucose, by glycoside hydrolases, such as amylase or maltase. In particular, the rapid metabolic action of glucosidase after the ingestion of high levels of carbohydrates leads to a state of dietary hyperglycemia, which leads to enhanced insulin secretion, increased fat synthesis and decreased lipolysis in obese or diabetic subjects. After such hyperglycemia, hypoglycemia often occurs due to the increased levels of insulin present. In addition, chyme remaining in the stomach promotes the production of gastric juice, which is known to cause or favor the development of gastritis or duodenal ulcers. Thus, glucosidase inhibitors are known to have utility in promoting the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. Moreover, carbohydrates are converted to lipids in adipose tissue, and the incorporation of dietary fat into adipose tissue deposits is then correspondingly reduced or retarded, with the attendant benefit of reducing or preventing the deleterious disorders that result therefrom. Such glucosidase inhibitory activity is readily determined by those skilled in the art according to standard assays (e.g., Biochemistry (1969) 8:4214).

[0140] Generally preferred glucosidase inhibitors include amylase inhibitors. Amylase inhibitors are glucosidase inhibitors that inhibit the enzymatic degradation of starch or glycogen to maltose. Such amylase inhibitory activity is easily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol (1955) 1:149). Inhibition of such enzymatic degradation is beneficial in reducing the amount of bioavailable sugars, including glucose and maltose, and the associated harmful conditions that result therefrom.

[0141] Various glucosidase inhibitors are known to those skilled in the art, and examples are provided below.Preferred glucosidase inhibitors are selected from acarbose, adipocin, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin.The glucosidase inhibitor, acarbose, and various amino sugar derivatives related thereto are disclosed in U.S. Patent Nos. 4,062,950 and 4,174,439, respectively.The glucosidase inhibitor, adipocin, 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 various N-substituted pseudoamino sugars related thereto, are disclosed in U.S. Pat. No. 4,701,559. The glucosidase inhibitor miglitol, (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, and various 3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S. Pat. No. 4,639,436. The glucosidase inhibitor emiglitate, ethyl p-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]-benzoate, various derivatives related thereto and pharma- ceutically 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-|3-D-glucopyranosyl-2,6-imino-D-glycero-L-gluco-heptitol, various homodisaccharides related thereto and pharma- ceutically acceptable acid addition salts thereof are disclosed in U.S. Patent No. 4,634,765.The glucosidase inhibitor camiglibose, 6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-aD-glucopyranoside methyl sesquihydrate, related deoxy-nojirimycin derivatives, various pharma- ceutically acceptable salts thereof and synthetic methods for their preparation are disclosed in U.S. Patents 5,157,116 and 5,504,078.The glycosidase inhibitor salbostatin and various related pseudosugars are disclosed in U.S. Patent 5,091,524.

[0142] Various amylase inhibitors are known to those skilled in the art. The amylase inhibitor tendamistat and various cyclic peptides related thereto are disclosed in U.S. Patent No. 4,451,455. The amylase inhibitor AI-3688 and 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 various trehalose-containing amino sugars related thereto are disclosed in U.S. Patent No. 4,273,765.

[0143] Additional antidiabetic compounds that can be used as a second agent in combination with the compound of the present invention include, for example: 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 decomposers.

[0144] The compounds of the present invention can also be used in combination with cardiovascular drugs such as antihypertensive drugs.Any antihypertensive drug can be used as the second drug in such combination, and examples are provided herein.Such antihypertensive activity can be easily determined by those skilled in the art according to standard assays (e.g., blood pressure measurement).

[0145] Amlodipine and related dihydropyridine compounds are disclosed in U.S. Pat. No. 4,572,909, incorporated herein by reference, as potent anti-ischemic and antihypertensive agents. U.S. Pat. No. 4,879,303, incorporated herein by reference, discloses amlodipine benzenesulfonate (also called amlodipine besylate). Amlodipine and amlodipine besylate are potent and long-lasting calcium channel blockers. Thus, amlodipine, amlodipine besylate, amlodipine maleate and other pharma- ceutically acceptable acid addition salts of amlodipine have utility as antihypertensive and anti-ischemic agents. Amlodipine besylate is currently sold as Norvasc®.

[0146] Calcium channel blockers within the scope of the present invention include bepridil, which may be prepared as disclosed in U.S. Pat. No. 3,962,238 or U.S. Reissue Pat. No. 30,577; clentiazem, which may be prepared as disclosed in U.S. Pat. No. 4,567,175; diltiazem, which may be prepared as disclosed in U.S. Pat. No. 3,562; fendiline, which may be prepared as disclosed in U.S. Pat. No. 3,262,977; gallopamil, which may be prepared as disclosed in U.S. Pat. No. 4,808,605; mibefradil, which may be prepared as disclosed in U.S. Pat. No. 3,152,173; prenylamine, which may be prepared as disclosed in U.S. Pat. No. 4,786,635; terodiline, which may be prepared as disclosed in U.S. Pat. No. 3,371,014; verapamil, which may be prepared as disclosed in U.S. Pat. No. 3,261,859; alanipine, which may be prepared as disclosed in U.S. Pat. No. 4,572,909; barnidipine, which may be prepared as disclosed in U.S. Pat. No. 4,220,649; benidipine, which may be prepared as disclosed in European Patent Publication No. 106,275; cilnidipine, which may be prepared as disclosed in U.S. Pat. No. 4,672,068; efonidipine, which may be prepared as disclosed in U.S. Pat. No. 4,885,284; efonidipine, which may be prepared as disclosed in U.S. Pat. No. 4,952,592 ergodipine, which may be prepared as disclosed; felodipine, which may be prepared as disclosed in U.S. Pat. No. 4,264,611; isradipine, which may be prepared as disclosed in U.S. Pat. No. 4,466,972; lacidipine, which may be prepared as disclosed in U.S. Pat. No. 4,801,599; lercanidipine, which may be prepared as disclosed in U.S. Pat. No. 4,705,797; manidipine, which may be prepared as disclosed in U.S. Pat. No. 4,892,875;Nicardipine, which may be prepared as disclosed in U.S. Pat. No. 3,985,758; Nifedipine, which may be prepared as disclosed in U.S. Pat. No. 3,485,847; Nilvadipine, which may be prepared as disclosed in U.S. Pat. No. 4,338,322; Nimodipine, which may be prepared as disclosed in U.S. Pat. No. 3,799,934; Nisoldipine, which may be prepared as disclosed in U.S. Pat. No. 4,154,839; Nitrendipine, which may be prepared as disclosed in U.S. Pat. No. 3,799,934; Including but not limited to, cinnarizine, which can be prepared as disclosed in United States Patent No. 3,773,939; flunarizine, which can be prepared as disclosed in United States Patent No. 3,267,104; lomerizine, which can be prepared as disclosed in United States Patent No. 4,663,325; bencyclane, which can be prepared as disclosed in Hong Kong Patent No. 151,865; etafenone, which can be prepared as disclosed in German Patent No. 1,265,758; and perhexiline, which can be prepared as disclosed in British Patent No. 1,025,578.The disclosures of all such United States patents are incorporated herein by reference. Examples of products containing antihypertensive drugs currently on the market 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®;

[0147] Angiotensin-converting enzyme inhibitors (ACE inhibitors) within the scope of the present invention include alacepril, which may be prepared as disclosed in U.S. Pat. No. 4,248,883; benazepril, which may be prepared as disclosed in U.S. Pat. No. 4,410,520; captopril, which may be prepared as disclosed in U.S. Pat. Nos. 4,046,889 and 4,105,776; ceronapril, which may be prepared as disclosed in U.S. Pat. No. 4,452,790; delapril, which may be prepared as disclosed in U.S. Pat. No. 4,385,051; enalapril, which may be prepared as disclosed in U.S. Pat. No. 4,374,829; fosinopril, which may be prepared as disclosed in U.S. Pat. No. 4,337,201; and cephalosporin, which may be prepared as disclosed in U.S. Pat. No. 4,508,727. The imadapril can be prepared as disclosed in US Patent 4,555,502; lisinopril can be prepared as disclosed in US Patent 893,553; perindopril can be prepared as disclosed in US Patent 4,508,729; quinapril can be prepared as disclosed in US Patent 4,344,949; ramipril can be prepared as disclosed in US Patent 4,587,258; spirapril can be prepared as disclosed in US Patent 4,470,972; temocapril can be prepared as disclosed in US Patent 4,699,905; and trandolapril can be prepared as disclosed in US Patent 4,933,361.The disclosures of all such US patents are incorporated herein by reference.

[0148] The angiotensin-II receptor antagonist (A-II antagonist) within the scope of the present invention includes, but is not limited to, candesartan, which can be prepared as disclosed in US Patent No. 5,196,444; eprosartan, which can be prepared as disclosed in US Patent No. 5,185,351; irbesartan, which can be prepared as disclosed in US Patent No. 5,270,317; losartan, which can be prepared as disclosed in US Patent No. 5,138,069; and valsartan, which can be prepared as disclosed in US Patent No. 5,399,578.The disclosures of all such US patents are incorporated herein by reference.

[0149] Beta adrenergic receptor blockers (beta or β-blockers) within the scope of the present invention include acebutolol, which may be prepared as disclosed in U.S. Pat. No. 3,857,952; alprenolol, which may be prepared as disclosed in Dutch Patent No. 6,605,692; amosulalol, which may be prepared as disclosed in U.S. Pat. No. 4,217,305; arotinolol, which may be prepared as disclosed in U.S. Pat. No. 3,932,400; Atenolol, which may be prepared as disclosed in U.S. Pat. No. 3,836,671; Befunolol, which may be prepared as disclosed in U.S. Pat. No. 3,853,923; Betaxolol, which may be prepared as disclosed in U.S. Pat. No. 4,252,984; Bevantolol, which may be prepared as disclosed in U.S. Pat. No. 3,857,981; Bisoprolol, which may be prepared as disclosed in U.S. Pat. No. 4,171,370; bopindolol, which may be prepared as disclosed in U.S. Pat. No. 3,663,570; bucumolol, which may be prepared as disclosed in U.S. Pat. No. 3,723,476; bufetolol, which may be prepared as disclosed in U.S. Pat. No. 3,929,836; bunitrolol, which may be prepared as disclosed in U.S. Pat. Nos. 3,940,489 and 3,961,071; buprandolol, which may be prepared as disclosed in U.S. Pat. No. 4,503,067; butofilolol, which may be prepared as disclosed in U.S. Pat. No. 4,252,825; carazolol, which may be prepared as disclosed in U.S. Pat. No. 2,240,599; carteolol, which may be prepared as disclosed in U.S. Pat. No. 3,910,924; carvedilol, which may be prepared as disclosed in U.S. Pat. No. 4,503,067;Celiprolol, which may be prepared as disclosed in U.S. Pat. No. 4,034,009; Cetamolol, which may be prepared as disclosed in U.S. Pat. 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 No. 41,491; Indenolol, which may be prepared as disclosed in U.S. Pat. No. 4,045,482; Labetalol, which may be prepared as disclosed in U.S. Pat. No. 4,012,444; Levobunolol, which may be prepared as disclosed in U.S. Pat. No. 4,463,176; Seeman et al. Mepindolol, which may be prepared as disclosed in U.S. Pat. No. 3,873,600; Moprolol, which may be prepared as disclosed in U.S. Pat. No. 3,501,7691; Nadolol, which may be prepared as disclosed in U.S. Pat. No. 3,935,267; Nadoxolo, which may be prepared as disclosed in U.S. Pat. No. 3,819,702; Metipranolol, which may be prepared as disclosed in Czechoslovak Patent Application No. 128,471; Metoprolol, which may be prepared as disclosed in U.S. Pat. No. 3,873,600; Moprolol, which may be prepared as disclosed in U.S. Pat. No. 3,501,7691; Nadolol, which may be prepared as disclosed in U.S. Pat. No. 3,935,267; Nadoxolo, which may be prepared as disclosed in U.S. Pat. No. 3,819,702. nebivarol, which may be prepared as disclosed in U.S. Pat. No. 4,654,362; nipradilol, which may be prepared as disclosed in U.S. Pat. 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. Pat. 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. Pat. 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. Pat. Nos. 3,337,628 and 3,520,919; Uloth et al., Journal of Medicinal Chemistry, 1966,9,88, sotalol, which can be prepared as disclosed; German Patent No. 2,728,641, sufinalol, which can be prepared as disclosed; U.S. Patent No. 3,935,259 and No. 4,038,313, talindol, which can be prepared as disclosed; U.S. Patent No. 3,960,891, tertatolol, which can be prepared as disclosed; U.S. Patent No. 4,129,565, tilisolol, which can be prepared as disclosed; U.S. Patent No. 3,655,663, timolol, which can be prepared as disclosed; U.S. Patent No. 3,432,545, triprolol, which can be prepared as disclosed; and U.S. Patent No. 4,018,824, xibenolol. The disclosures of all such U.S. patents are incorporated herein by reference.

[0150] Alpha adrenergic receptor blockers (alpha or a-blockers) within the scope of the present invention include amosulalol, which may be prepared as disclosed in U.S. Pat. No. 4,217,307; arotinolol, which may be prepared as disclosed in U.S. Pat. No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S. Pat. No. 4,252,721; doxazosin, which may be prepared as disclosed in U.S. Pat. No. 4,188,390; fenspiride, which may be prepared as disclosed in U.S. Pat. No. 3,399,192; indoramin, which may be prepared as disclosed in U.S. Pat. No. 3,527,761; The following are included: labetolol, which can be prepared as disclosed in US Patent 3,997,666; naftopidil, which can be prepared as disclosed in US Patent 3,228,943; prazosin, which can be prepared as disclosed in US Patent 3,511,836; tamsulosin, which can be prepared as disclosed in US Patent 4,703,063; tolazoline, which can be prepared as disclosed in US Patent 2,161,938; trimazosin, which can be prepared as disclosed in US Patent 3,669,968; and yohimbine, which can be isolated from natural sources according to the method well known to those skilled in the art.The disclosures of all such US patents are incorporated herein by reference.

[0151] As used herein, the term "vasodilator" includes cerebral vasodilators, coronary vasodilators and peripheral vasodilators.Cerebral vasodilators within the scope of the present invention include bencyclane, which can be prepared as disclosed above; cinnarizine, which can be prepared as disclosed above; citicoline, which can 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 can be prepared as disclosed in U.S. Pat. No. 3,663,597; cyclonicate, which can be prepared as disclosed in German Patent No. 1,910,481; diisopropylamine dichloroacetate, which can be prepared as disclosed in British Patent No. 862,248; Hermann et al., Journal of the American Chemical Society, 1955, 77, 250; citicoline, which can be isolated from natural sources as disclosed in Kennedy, Journal of Biological Chemistry, 1956, 222, 185; cyclandelate, which can be prepared as disclosed in U.S. Pat. No. 3,663,597; cyclonicate, which can be prepared as disclosed in German Patent No. 1,910,481; diisopropylamine dichloroacetate, which can be prepared as disclosed in British Patent No. 862,248; Society, 1979,101,1540; fasudil, which may be prepared as disclosed in U.S. Pat. No. 4,678,783; fenoxedil, which may be prepared as disclosed in U.S. Pat. No. 3,818,021; flunarizine, which may be prepared as disclosed in U.S. Pat. No. 3,773,939; ibudilast, which may be prepared as disclosed in U.S. Pat. No. 3,850,941; ifenprodil, which may be prepared as disclosed in U.S. Pat. No. 3,509,164; lomerizine, which may be prepared as disclosed in U.S. Pat. No. 4,663,325; nafronil, which may be prepared as disclosed in U.S. Pat. No. 3,334,096; 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. Pat. No. 3,799,934; papaverine, which may be prepared as outlined in Goldberg, Chem. Prod. Chem. News, 1954, 17,371; pentifylline, which may be prepared as disclosed in German Patent No. 860,217; tinofedrine, which may be prepared as disclosed in U.S. Pat. No. 3,563,997; vincamine, which may be prepared as disclosed in U.S. Pat. No. 3,770,724; vinpocetine, which may be prepared as disclosed in U.S. Pat. No. 4,035,750; and biquidil, which may be prepared as disclosed in U.S. Pat. No. 2,500,444. The disclosures of all such U.S. patents are incorporated herein by reference.

[0152] Coronary vasodilators within the scope of the present invention include amotrifen, which may be prepared as disclosed in U.S. Pat. No. 3,010,965; J. Chem. Soc.bendazole, which may be prepared as disclosed in U.S. Pat. No. 1958,2426; benfurozil hemisuccinate, which may be prepared as disclosed in U.S. Pat. No. 3,355,463; benziodarone, which may be prepared as disclosed in U.S. Pat. No. 3,012,042; chloracidin, which may be prepared as disclosed in British Patent No. 740,932; chromonal, which may be prepared as disclosed in U.S. Pat. No. 3,282,938; British Patent No. 1,160,925; clobenfural, which may be prepared as disclosed in the specification; clonitrate, which may be prepared from propanediol according to methods well known to those skilled in the art (see, for example, Annalen, 1870, 155, 165); chloricromene, which may be prepared as disclosed in U.S. Pat. No. 4,452,811; dilazep, which may be prepared as disclosed in U.S. Pat. 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 U.S. 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; phenanthrene, which may be prepared as disclosed in U.S. Patent No. 3,262,977; Zirin; Floresil, which may be prepared as disclosed in German Patent No. 2,020,464; Gangrefene, which may be prepared as disclosed in Soviet Patent No. 115,905; Hexestrol, which may be prepared as disclosed in U.S. Pat. No. 2,357,985; Hexobendine, which may be prepared as disclosed in U.S. Pat. No. 3,267,103; Itramin Tosylate, which may be prepared as disclosed in Chinese Patent No. 168,308; Baxter et al.,Kellin, which may be prepared as disclosed in Journal of the Chemical Society, 1949, S 30;Lidoflazine, which may be prepared as disclosed in U.S. Pat. No. 3,267,104;Mannitol hexanitrate, which may be prepared by nitration of mannitol according to methods well known to those skilled in the art;Medibazine, which may be prepared as disclosed in U.S. Pat. No. 3,119,826;Nitroglycerin;Pentaerythritol tetranitrate, which may be prepared by 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;Perhexiline, which may be prepared as disclosed above;Pimefilline, which may be prepared as disclosed in U.S. Pat. No. 3,350,400;U.S. Pat. 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; Trinitrate 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. The disclosures of all such U.S. patents are incorporated herein by reference.

[0153] Peripheral vasodilators within the scope of the present invention include aluminum nicotinate, which may be prepared as disclosed in U.S. Pat. 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; al., Arch. Biochem. Biophys., 1958, 76, 252; brovincamine, which may be prepared as disclosed in U.S. Pat. No. 4,146,643; bufeniod, which may be prepared as disclosed in U.S. Pat. No. 3,542,870; buflomedil, which may be prepared as disclosed in U.S. Pat. No. 3,895,030; butalamine, which may be prepared as disclosed in U.S. Pat. No. 3,338,899; cetiedil, which may be prepared as disclosed in French Patent No. 1,460,571; cyclonicate, which may be prepared as disclosed in German Patent No. 1,910,481; cinepazide, which may be prepared as disclosed in U.S. Pat. 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 U.S. Pat. No. 984,810; phenoxedil, 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. Pat. No. 3,384,642; ifenprodil, which may be prepared as disclosed above; iloprost, which may be prepared as disclosed in U.S. Pat. No. 4,692,464; Badgett et al.inositol niacinate, which may be prepared as disclosed in US Pat. No. 3,056,836; isoxsuprine, 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; nafronil, which may be prepared as disclosed above; nicametate, which may be prepared as disclosed in; 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. Patents 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; Merck Prostaglandins Ei, which may be prepared by any of the methods referenced in the 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 nicotinate, which may be prepared as disclosed in German Patent No. 1,102,750 or Korbonits et al., Acta.Pharm.Hung., 1968, 38, 98. The disclosures of all such U.S. patents are incorporated herein by reference.

[0154] The term "diuretic" within the scope of the present invention includes diuretic benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracil as well as amanodine, which may be prepared as disclosed in Australian Patent No. 168,063; amiloride, which may be prepared as disclosed in Chinese 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 U.S. Pat. No. 168,063; ethacrynic acid, which may be prepared as disclosed in U.S. Pat. No. 3,255,241; etozolin, which may be prepared as disclosed in U.S. Pat. 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. Pat. No. 3,160,641; mannitol; Freudenberg Metochalcone, which may be prepared as disclosed in U.S. Pat. No. 4,018,890; muzolimine, which may be prepared as disclosed in U.S. Pat. No. 4,018,890; perhexiline, which may be prepared as disclosed above; ticrynafen, which may be prepared as disclosed in U.S. Pat. No. 3,758,506; triamterene, which may be prepared as disclosed in U.S. Pat. No. 3,081,230; and other diuretics such as urea. The disclosures of all these U.S. patents are incorporated herein by reference.

[0155] Diuretic benzothiadiazine derivatives within the scope of the present invention include althiazide, which may be prepared as disclosed in British Patent No. 902,658; bendroflumethiazide, which may be prepared as disclosed in U.S. Pat. No. 3,265,573; benzthiazide, McManus et al., 136th Am. Soc. Meeting (Atlantic City, September 1959), Abstract of papers, pp13-0; benzylhydrochlorothiazide, which may be prepared as disclosed in U.S. Pat. No. 3,108,097; buthiazide, which may be prepared as disclosed in British Patents Nos. 861,367 and 885,078; chlorothiazide, which may be prepared as disclosed in U.S. Pat. Nos. 2,809,194 and 2,937,169; chlorthalidone, which may be prepared as disclosed in U.S. Pat. No. 3,055,904; cyclopenthiazide, which may be prepared as disclosed in White Patent No. 587,225; Whitehead et al., Journal of Organic cyclothiazide, which may be prepared as disclosed in U.S. Pat. No. 3,009,911; epithiazide, which may be prepared as disclosed in U.S. Pat. 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. Pat. No. 3,870,720; indapamide, which may be prepared as disclosed in U.S. Pat. No. 3,565,911; hydrochlorothiazide, which may be prepared as disclosed in U.S. Pat. No. 3,164,588; hydroflumethiazide, which may be prepared as disclosed in U.S. Pat. No. 3,254,076; Close et al.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 Patents M2790 and 1,365,504; metolazone, which may be prepared as disclosed in U.S. Pat. No. 3,360,518; paraflutizide, which may be prepared as disclosed in French Patent No. 620,829; polythiazide, which may be prepared as disclosed in U.S. Pat. No. 3,009,911; quinethazone, which may be prepared as disclosed in U.S. Pat. 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 deStevens et al. Examples of suitable antibacterial agents include, but are not limited to, trichlormethiazide, which may be prepared as disclosed in U.S. Pat. No. 6,313, 1960, 16, 113, the disclosures of which are incorporated herein by reference.

[0156] Diuretic sulfonamide derivatives within the scope of the present invention include acetazolamide, which may be prepared as disclosed in U.S. Pat. No. 2,980,679; ambuside, which may be prepared as disclosed in U.S. Pat. No. 3,188,329; azosemide, which may be prepared as disclosed in U.S. Pat. No. 3,665,002; bumetanide, which may be prepared as disclosed in U.S. Pat. No. 3,634,583; butazolamide, which may be prepared as disclosed in U.S. Pat. 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. Pat. No. 3,459,756; chlorexolone, which may be prepared as disclosed in British Patent No. 243; disulfamide, which may be prepared as disclosed in British Patent No. 851,287; etoxolamide, which may be prepared as disclosed in British Patent No. 795,174; furosemide, which may be prepared as disclosed in U.S. Pat. No. 3,058,882; mefruside, which may be prepared as disclosed in U.S. Pat. No. 3,356,692; U.S. Pat. No. 2,783,241 The present invention includes, but is not limited to, methazolamide, which can be prepared as disclosed in U.S. Patent No. 4,010,273; piretanide, which can be prepared as disclosed in U.S. Patent No. 4,018,929; tripamide, which can be prepared as disclosed in Japanese Patent No. 7305,585; and xipamide, which can be prepared as disclosed in U.S. Patent No. 3,567,777. The disclosures of all such U.S. patents are incorporated herein by reference.Other additional agents for combination with the compounds disclosed herein include PCSK9 translation inhibitors as described in WO 2016 / 055901, which is incorporated herein by reference.

[0157] In some embodiments, the additional therapeutic agents include HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, HMG-CoA synthase gene expression inhibitors, MTP / Apo B secretion inhibitors, CETP inhibitors, bile acid absorption inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, squalene cyclase inhibitors, combined squalene epoxidase / squalene cyclase inhibitors, fibrates, niacin, combinations of niacin and lovastatin, ion exchange resins, antioxidants, ACAT inhibitors, bile acid sequestrants, and PCSK9 translation inhibitors.

[0158] With regard to the treatment of sepsis or septic shock, the disclosed methods may include additional therapeutic agents such as antibiotics. In certain embodiments, the antibiotics are aminoglycosides, such as, but not limited to, kanamycin, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, streptomycin, and neomycin B, C, and E. Other antibiotics include carbapenems, such as, but not limited to, imipenam, meropenam, ertapenam, doripenam, panipenam, biapenem, razupenem, tebipenam, ranapenam, tomopenam, and thienpenam.

[0159] Additional antibiotics include, but are not limited to, ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, cinoxacin, nalidixic acid, moxifloxacin, oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, oncolytic acid, nafloxacin ... quinolones such as floxacin, pefloxacin, rufloxacin, balofloxacin, grepafloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, sitafloxacin, trovafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, nemonoxacin, and zavofloxacin.

[0160] Additional antibiotics include tetracyclines such as, but not limited to, doxycycline, tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, and tigecycline.

[0161] Additional antibiotics useful in the methods disclosed herein include, but are not limited to, ampicillin, amoxicillin, augmentin, piperacillin, tazobactam, chloramphenicol, and ticarcillin.

[0162] Pharmaceutical Compositions 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 a subject, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising the compound of the present 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 buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic acid esters. In a preferred embodiment, when such pharmaceutical compositions are for administration to humans, particularly for invasive routes of administration (i.e., routes such as injection or infusion that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient may be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized for reconstitution, powders, liquids, syrups, suppositories, injections, etc. The compositions may also be present in transdermal delivery systems, such as skin patches. The compositions may also be present in liquids suitable for topical administration, such as eye drops.

[0163] A pharma- ceutically acceptable carrier may contain a physiologically acceptable agent that functions, for example, to stabilize, increase the solubility, or increase the absorption of a compound, such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix, which may, for example, incorporate a compound of the present invention therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers that are relatively easy to prepare and administer.

[0164] The phrase "physiologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable risk-benefit ratio.

[0165] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically 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 harmful to the subject. Some examples of materials that can function as pharma-ceutically 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (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) buffers, 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 buffers; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0166] Pharmaceutical compositions (formulations) may be administered to a subject by any of several routes of administration, including, for example, orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, etc., in aqueous or non-aqueous solutions or suspensions); absorption through the oral mucosa (e.g., sublingually); anally, rectally, or intravaginally (e.g., as a pessary, cream, or foam); parenterally (e.g., as a sterile solution or suspension, including intramuscular, intravenous, subcutaneous, or intrathecal); intranasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in 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, and the patents cited therein.

[0167] The formulations may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated, the particular method of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0168] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carriers 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.

[0169] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and acacia or tragacanth), lyophilized, powders, granules, or as a solution or 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 a troche (with an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0170] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dibasic calcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as glycerol; agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarders such as paraffin;(6) absorption enhancers such as quaternary ammonium compounds;(7) wetting agents such as cetyl alcohol and glycerol monostearate;(8) absorbents such as kaolin and bentonite clay;(9) lubricants such as 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 include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0171] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0172] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially in a certain part 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 excipients described above.

[0173] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilized for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0174] 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.

[0175] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0176] Formulations of pharmaceutical compositions for rectal, intravaginal, or urethral administration may be provided as suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound.

[0177] Formulations of the pharmaceutical composition for administration to the mouth may be provided as a mouthwash, or an oral spray, or an oral ointment.

[0178] Additionally or alternatively, the compositions may be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0179] 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.

[0180] Dosage forms for 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 pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0181] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0182] Powders and sprays can contain, in addition to the 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.

[0183] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing active compound in suitable medium.Absorption enhancers can also be used to increase the flux of compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0184] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated within the scope of the present invention. Exemplary ophthalmic formulations are described in US Patent Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and US Patent No. 6,583,124, the contents of which are incorporated herein by reference. Optionally, the liquid ophthalmic formulation has similar properties to tears, aqueous humor or vitreous humor, or is compatible with such fluids. The preferred route of administration is topical administration (e.g., topical administration such as eye drops, or administration via implant).

[0185] The phrases "parenteral administration" and "administered parenterally" as used herein refer to methods of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, spinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharma- ceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0186] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical composition of the present invention include water, ethanol, polyol (glycerol, propylene glycol, polyethylene glycol, etc.) 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 using coating materials such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.

[0187] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial action may be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the composition. In addition, prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0188] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of the drug.This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0189] Injectable depot forms are prepared by forming microencapsulated matrices of the compounds of the present invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, 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 tissues.

[0190] For use in the methods of the present invention, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0191] Methods of introduction can also be provided by rechargeable or biodegradable devices. A variety of sustained release polymeric devices have been developed and tested in vivo recently for the controlled delivery of drugs, including proteinaceous biologics. A variety of biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0192] Actual dosage levels of the active ingredients in pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without being toxic to the patient.

[0193] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound used, the age, sex, weight, condition, general health and previous medical history of the subject being treated, and similar factors well known in the medical arts.

[0194] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level lower than that required 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 the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the drug. Methods for determining 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, incorporated herein by reference).

[0195] In general, a suitable daily dose of an active compound used in the compositions and methods of the present 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 on the factors described above.

[0196] If necessary, the effective daily dose of the active compound may be administered as 1, 2, 3, 4, 5, 6 or more separate doses administered at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0197] In certain embodiments, the compounds of the present invention can be used alone or in conjunction with another type of therapeutic agent. As used herein, the phrase "co-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 effective in the subject at the same time, which may include the synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered simultaneously or sequentially, either in the same formulation or in separate formulations. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, subjects receiving such treatment can benefit from the combined effect of the different therapeutic compounds.

[0198] In certain embodiments, the combined administration of a compound of the invention with one or more additional therapeutic agents provides improved efficacy compared to the separate administration of either the compound of the invention (e.g., a compound of Formula I or Ia) or the one or more additional therapeutic agents. In certain such embodiments, the combined administration provides an additive effect, where additive effect refers to the sum of the effects of the separate administration of the compound of the invention and the one or more additional therapeutic agents.

[0199] The present invention includes the use of pharma- ceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present 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 present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0200] Pharmaceutically acceptable acid addition salts may also exist in a variety of solvents, such as water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0201] Wetting agents, emulsifying agents and lubricating agents, 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 composition.

[0202] Examples of pharma- ceutically 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, α-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. EXAMPLES

[0203] Examples of compounds of formula (I), or pharma- ceutically acceptable salts thereof, that have 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, a 5 mm 1H / nX broadband probehead for reverse detection, a deuterium digital lock channel unit, and a quadrature digital detection unit with transmitter offset frequency shift. Chemical shifts 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 abbreviations (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, nd=undetermined).

[0204] A. Analysis method Method 1 (Acid FA) UPLC settings Solvents:- A Water containing 0.1% formic acid (high purity via PureLab optional unit) B Acetonitrile containing 0.1% (V / V) formic acid (Far UV grade) Column:-Acquity UPLC HSS C18 1.8um 100×2.1mm.(Plus guard cartridge) Flow rate: -0.5mL / min gradient:

[0205] [Table 1]

[0206] Injection 0.5~2uL UV detection via Waters DAD Starting range (nm) 210 Ending range (nm) 400 Resolution (nm) 1.2 MS detection: Waters SQD2, single quadrupole UPLC-MS Scan range for MS data (m / z) Start (m / z) 100 End (m / z) 700 or 1500 (as appropriate) With +ve / -ve switching Ionization is by ESI. The ESI voltage and temperature are Power supply is 150C 3.5KV Capillary 25V Cone.

[0207] Method 2 (basic FA) UPLC settings Solvent:- Acetonitrile (Far UV grade) Water containing 10 mM ammonium bicarbonate (high purity via PureLab optional unit) Column: -Acquity UPLC BEH Shield RP18 1.7um 100×2.1mm. (Plus Guard Cartridge) Flow rate: -0.5mL / min Gradient: -A: water / basic BMeCN / basic

[0208] [Table 2]

[0209] Typical injection: 0.5-2uL (concentration approximately 0.2-1mg / mL). UV detection via Waters DAD Start range (nm) 210 End range (nm) 400 Resolution (nm) 1.2 Other wavelength signatures are extracted from the DAD data. MS detection: Waters SQD2, single quadrupole UPLC-MS A flow splitter delivers approximately 300 ul / min to mass spectrometry. Scan range for MS data (m / z) Start (m / z)100 End (m / z) 700 or 1500 (as appropriate) With +ve / -ve switching

[0210] Preparative reversed-phase HPLC conditions Preparative HPLC Waters Micromass ZQ / Sample Manager 2767 Photodiode array detector 2996; Column: XTerra Prep MS C18 column (5 μm, 19 × 150 mm, Waters) Flow rate: 20 mL / min with MS detection UV wavelength: 254nm. Mobile phase: Solvent A (water:MeCN:HCO2H 95:5:0.05); Solvent B (water:MeCN:HCO2H 5:95:0.05) gradient:

[0211] [Table 3]

[0212] Flash chromatography is performed using an Isolera MPLC system (manufactured by Biotage) using pre-packed silica gel or reverse phase cartridges (provided by Biotage or Interchim).

[0213] B. Chemical synthesis The general procedures used in the methods of preparing the compounds of this invention are described below. Scheme 1 [ka]

[0214] 2-Chloro-5-(methylthio)pyrimidine (100B) Dimethyl disulfide (13.96 mL, 155.4 mmol, 1.0 equiv) was added to a solution of 5-bromo-2-chloropyrimidine (100A) (30 g, 155.4 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (700 mL) cooled to -75 °C under nitrogen. To this mixture was added a solution of n-butyllithium (2.5 M, 68.4 mL, 170.9 mmol, 1.0 equiv) dropwise over 1.5 h, maintaining the internal temperature at -70 °C to -75 °C throughout the addition. After the addition was complete, the mixture was stirred at -75 °C for 4.5 h and subsequently quenched by the slow addition of a saturated solution of ammonium chloride (100 mL). The cold bath was removed and the reaction was allowed to warm to room temperature under nitrogen for 18 h. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (50 mL) followed by saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting crude pale yellow oil was purified by flash chromatography (eluting with isohexane-ethyl acetate, 0-50%) to give the desired product 2-chloro-5-(methylthio)pyrimidine as a waxy pale yellow solid (100B). Yield: 7.39g (29%). 1 H NMR (CDCl 3 )δ 8.48(2H,s),2.54(3H,s);MS(ESI+)m / z 161(M+H) + .

[0215] Common method 1 tert-Butyl (2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (100C) tert-Butyl (3-amino-2-methylpropyl)carbamate (4.79 g, 25.52 mmol, 1.05 equiv) was added to a stirred solution of 2-chloro-5-(methylthio)pyrimidine (100B) (3.89 g, 24.31 mmol, 1.0 equiv) and cesium carbonate (11.85 g, 36.46 mmol, 1.4 equiv) in anhydrous dimethylformamide (50 mL). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to approximately 20 mL. The solution was diluted with ethyl acetate (100 mL), washed with water (75 mL) and brine (50 mL), and then dried over magnesium sulfate. The solvent was removed in vacuo to give a crude residue which was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0 to 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: 6.59g (86%) MS(ESI+)m / z 313(M+H) + .

[0216] (S)-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate tert-butyl (100D) 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 , 100mL / min, 120bar, 40℃, GLS 40psi, System 3900psi, drop 140bar, Stacker, DAD 245nm.

[0217] First eluting isomer, 1.3 min. (R)-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate tert-Butyl Yield: 2.05g. 1 H NMR (400 MHz, CDCl 3)δ 8.34(s,2H),5.79(dd,J=6.7,6.7Hz,1H),5.18(dd,J=5.8,5.8Hz,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=6.9Hz,3H).MS(ESI+)m / z 313(M+H) + .

[0218] Second eluting isomer, 1.7 min. (S)-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl) tert-butyl carbamate (100D) Yield: 2.48g. 1 H NMR (400 MHz, CDCl 3 )δ 8.34(s,2H),5.77-5.69(m,1H),5.15(dd,J=6.5,6.5Hz,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=6.9Hz,3H);MS(ESI+)m / z 313(M+H) + .

[0219] Common method 2 (R)-2-Methyl-N 1 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) A solution of hydrogen chloride (15 mL, 4 M in 1,4-dioxane) was added to (S)-(2-ethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)tert-butylcarbamate (100D) (600 mg, 2.48 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the desired product (R)-2-methyl-N,N-dimethylformamide (100D) as a pale yellow semi-solid. 1 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) was obtained. Yield: 548 mg (100%) HCl salt. 1H NMR(400MHz,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=6.8Hz,3H);MS(ESI+)m / z 213(M+H) + .

[0220] Common Method 3 (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxylate ethyl (100F) Ethyl 2-chlorobenzothiazole-6-carboxylate (600 mg, 2.48 mmol, 1.0 equiv.) was dissolved in anhydrous dimethylformamide (20 mL) in (R)-2-methyl-N 1 To a stirred solution of -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (100E) (548 mg, 2.48 mmol, 1.0 equiv) and triethylamine (1.73 mL, 12.44 mmol, 5.0 equiv) under nitrogen was added. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo to approximately 5 mL. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with water (20 mL) and brine (25 mL) and then dried over magnesium sulfate. The solvent was removed under vacuum to give a crude yellow oil which was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0 to 100%) to give the desired (S)-ethyl 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=1.5Hz,1H),7.99(dd,J=1.8,8.5Hz,1H),7.51(d, J=8.4Hz,1H),7.02-6.98(m,1H),5.83(dd,J=6.7,6.7Hz,1H),4.38(q,J= 7.2Hz,2H),3.67-3.47(m,2H),3.42-3.24(m,2H),2.37(s,3H),2.20-2.1 1(m,1H),1.40(dd,J=7.2,7.2Hz,3H),1.07(d,J=7.0Hz,3H);MS(ESI+)m / z 418(M+H) + .

[0221] Common Method 4 (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxylic acid (Example 1) Lithium hydroxide monohydrate (318 mg, 7.75 mmol, 5.0 equiv.) was added to a stirred solution of (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxylic acid (100F) (647 mg, 1.55 mmol, 1.0 equiv.) in ethanol (7 mL) and water (5 mL). The mixture was stirred at ambient temperature for 18 hours and then concentrated under reduced pressure. Water (5 mL) was added to the residue and the mixture was acidified to pH approx. 3 with aqueous hydrochloric acid (2 M). The 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 (Example 1) as a pale yellow solid.

[0222] Common Method 5 (S)-2-Methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxamido)propanoate methyl (100G) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 146 mg, 0.385 mmol, 1.5 equiv.) 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 equiv.), triethylamine (0.36 mL, 2.57 mmol, 10.0 equiv.) and methyl-2-amino-2-methylpropanoate hydrochloride (196 mg, 1.28 mmol, 4.9 equiv.) in dimethylformamide (5 mL) and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the crude residue obtained was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0 to 75%) to give the desired (S)-2-methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxamido)methyl 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). No NH exchangeable protons observed; MS (ESI+) m / z 489 (M+H). + .

[0223] (S)-2-Methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxamido)propanoic acid (Example 2) A method similar to general method 4 Lithium hydroxide monohydrate (50 mg, 1.22 mmol, 5.0 equiv) was added to a stirred solution of (S)-2-methyl-2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxamido)methylpropanoate (100G) (120 mg, 0.245 mmol, 1.0 equiv) in ethanol (5 mL) and water (5 mL) and the mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was diluted with water (3 mL) and acidified to pH approx. 3 with an aqueous solution of hydrochloric acid (2 M). The 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.

[0224] Using the above procedures, the following examples were synthesized.

[0225] [Table 4]

[0226] [Table 5]

[0227] [Table 6]

[0228] [Table 7]

[0229] [Table 8]

[0230] [Table 9]

[0231] [Table 10]

[0232] [Table 11]

[0233] [Table 12]

[0234] [Table 13]

[0235] [Table 14]

[0236] Scheme 2 [ka]

[0237] Common Method 6 2-Chloro-N-(4-methoxybenzyl)benzo[d]thiazole-6-sulfonamide (101B) (4-Methoxyphenyl)methanamine (134 mg, 0.97 mmol, 1.05 equiv) was added dropwise to an ice-cold solution of 2-chlorobenzothiazole-6-sulfonyl chloride (101A) (250 mg, 0.932 mmol, 1.0 equiv), triethylamine (0.39 mL, 2.79 mmol, 3.0 equiv) in tetrahydrofuran (10 mL) and the mixture was stirred for 1 h at 0° C. 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 subsequently dried under vacuum to give the desired 2-chloro-N-(4-methoxybenzyl)benzo[d]thiazole-6-sulfonamide (101B) as a white solid. Yield: 295 mg (85%). 1H NMR(400MHz,DMSO)δ 8.56(d,J=1.6Hz,1H),8.24(s,1H),8.11(d,J=8.7Hz,1H),7.90(dd,J=1.9,8.7Hz,1H) ,7.10(d,J=8.8Hz,2H),6.76(d,J=8.8Hz,2H),3.98(s,2H),3.67(s,3H);MS(ESI+)m / z 369(M+H) + .

[0238] The intermediates in Table 2 were synthesized using conditions similar to those described for intermediate 101B.

[0239] [Table 15]

[0240] [Table 16]

[0241] (S)-N-(4-Methoxybenzyl)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-sulfonamide (101C) The methodology applied was similar to that described in general method 3. Yield: 298 mg, (69%). 1 H NMR(400MHz,DMSO)δ 8.56(1H,d,J=1.6Hz),8.24(1H,s),8.11(1H,d,J=8.7Hz),7.90(1H,dd,J=1.9,8.7Hz) ,7.10(2H,d,J=8.8Hz),6.76(2H,d,J=8.8Hz),3.98(2H,s),3.67(3H,s);MS(ESI+)m / z 545(M+H) + .

[0242] (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-sulfonamide (Example 87) Trifluoroacetic acid (5 mL) was added dropwise to an ice-cold 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 equiv) in anhydrous dichloromethane (5 mL). The mixture was stirred on ice for 30 min and then allowed to warm to ambient temperature over 18 h. The reaction mixture was diluted with dichloromethane (15 mL) and saturated sodium bicarbonate (15 mL) was added slowly. The organic phase was separated, washed with brine (5 mL), dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The crude residue obtained was purified by flash chromatography (eluting with DCM to methanol, 0-10%) to afford the desired (S)-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-sulfonamide (Example 87) as a white solid. Yield: 190mg (97%). 1 H NMR(400MHz,DMSO)δ 8.40(dd,J=5.5,5.5Hz,1H),8.34(s,2H),8.12(d,J=1.6Hz,1H),7.66(dd,J=2.0,8.4Hz,1H),7.51(dd,J=6.0,6.0Hz,1H),7.44(d,J =8.5Hz,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=6.8Hz,3H);MS(ESI+)m / z 425(M+H) + .

[0243] The following examples were prepared according to general method 3 using the procedures described in Scheme 2.

[0244] [Table 17]

[0245] [Table 18]

[0246] Scheme 3 [ka]

[0247] 2-Methyl-N 1 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) The methodology applied was similar to general method 2. A solution of hydrogen chloride (54 mL, 4 M 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 was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the desired 2-methyl-N-(2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate as a pale yellow semi-solid. 1 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) was obtained. The semi-crude sample was carried on to the next reaction without further purification.

[0248] N 1 -(6-Bromobenzo[d]thiazol-2-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B) The methodology applied was similar to general method 3. 6-Bromo-2-chlorobenzenethiazole (828 mg, 3.33 mmol, 0.95 equiv.) was dissolved in 2-methyl-N 1To a stirred suspension of -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) (1.00 g, 3.51 mmol, 1.0 equiv) and cesium carbonate (3.43 g, 10.52 mmol, 3.0 equiv) under nitrogen. The mixture was stirred at room temperature for 72 h and then concentrated in vacuo to approximately 3 mL. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water (20 mL) and brine (25 mL) and then dried over magnesium sulfate. The solvent was removed in vacuo to give a crude yellow oil which was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0-100%) to give the desired N-(4-methyl-5-pyrimidin-2-yl)propane-1,3-diamine hydrochloride as a sticky yellow solid. 1 -(6-Bromobenzo[d]thiazol-2-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B) was obtained. Yield: 266 mg (18%). 1 H NMR (400 MHz, CDCl 3 )δ 8.37(s,2H),7.66(d,J=0.6Hz,1H),7.37(d,J=1.9Hz,2H),6.58(s,1H),5.69(dd,J=6.3 ,6.3Hz,1H),3.67-3.23(m,4H),2.37(s,3H),2.17-2.09(m,1H),1.06(d,J=6.9Hz,3H).

[0249] Common Method 7 4-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol-6-yl)-1H-pyrazole-1-carboxylate tert-butyl (102C) N 1 -(6-Bromobenzo[d]thiazol-2-yl)-2-methyl-N 3A solution of -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (102B) (50 mg, 0.12 mmol, 1.0 equiv) was added to a solution of (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (27.8 mg, 0.13 mmol, 1.0 equiv), cesium carbonate (58 mg, 0.18 mmol, 1.5 equiv) and tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.01 mmol, 0.05 equiv) 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 equiv) and tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.01 mmol, 0.05 equiv) was added to the reaction and the mixture was heated to 90° C. under nitrogen for a further 16 h. The solvent was removed under reduced pressure; water (2 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with water (2 mL) and brine (2 mL), dried through a phase separator and subsequently concentrated in vacuo. The resulting crude residue was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0 to 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 carried on to the next reaction without further purification.

[0250] 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 (Example 97) A solution of hydrogen chloride (2 mL, 4 M 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 was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the desired N- ... as an off-white solid. 1 -(6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Example 97) was obtained.

[0251] The following examples were prepared according to general method 7 using the procedures described in Scheme 3.

[0252] [Table 19]

[0253] Common 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 (Example 101) 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 equiv) was added to a solution of 2-(tri-n-butylstannyl)oxazole (0.044 mL, 0.21 mmol, 1.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol, 0.1 equiv) in N,N-dimethylformamide (0.80 mL) under nitrogen. The reaction mixture was heated to 90° C. for 16 h. An additional aliquot of 2-(tri-n-butylstannyl)oxazole (0.044 mL, 0.21 mmol, 1.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol, 0.1 equiv) was added to the reaction mixture and heated 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 pad of Celite, dried by passing through a phase separator and then concentrated to dryness under vacuum. The resulting crude residue was purified twice by flash chromatography (eluting first with isohexane-ethyl acetate, 0-100%, followed by ethyl acetate-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-(2-methyl-3-phenylpropanediol) as an off-white solid. 1 -(5-(methylthio)pyrimidin-2-yl)-N 3 -(6-(oxazol-2-yl)benzo[d]thiazol-2-yl)propane-1,3-diamine (101) was obtained.

[0254] The following examples were prepared according to general method 8 using the procedures described in Scheme 3.

[0255] [Table 20]

[0256] Scheme 4 [ka] The following examples were prepared according to general method 3 using the procedures described in Scheme 4.

[0257] [Table 21]

[0258] Scheme 7 [ka]

[0259] tert-Butyl (2,2-dimethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (105A) The methodology applied was similar to that described in general method 1 except that additional heating was required. tert-Butyl (3-amino-2,2-dimethylpropyl)carbamate (0.13 g, 0.65 mmol, 1.05 equiv.) was added to a stirred suspension of 2-chloro-5-(methylthio)pyrimidine (100B) (0.10 g, 0.62 mmol, 1.0 equiv.) and cesium carbonate (0.24 g, 0.75 mmol, 1.2 equiv.) in anhydrous N,N-dimethylformamide (1.5 mL) and the mixture was stirred at 80° C. for 4 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (20 mL), washed with water (7.5 mL) and brine (5.0 mL), and then dried through a phase separator. The solvent was removed in vacuo to give the desired tert-butyl (2,2-dimethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate (105A) as a pale yellow oil. Yield: 0.163g (81%). 1 H NMR(400MHz,DMSO)δ 8.37(s,2H),7.24(dd,J=6.6,6.6Hz,1H),6.93(dd,J=6.3,6.3Hz,1H),3.20(d,J=6 .8Hz,2H),2.85(d,J=8.7Hz,2H),2.40(s,3H),1.43(d,J=3.3Hz,9H),0.83(s,6H).

[0260] 2,2-Dimethyl-N 1 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (105B) The methodology applied was similar to that described in general method 2. A solution of hydrogen chloride (5 mL, 4 M 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 h. The solvent was removed in vacuo to give the desired 2,2-dimethyl-N,N-dimethyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)carbamate as a pale yellow semi-solid. 1 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (105B) was obtained. Yield: 0.13 g (100%) HCl salt. 1 H NMR(400MHz,DMSO)δ 8.39(s,2H),7.95(s,3H),7.70(s,1H),3.25(d,J=5.5Hz,2H),2.68-2.61(m,2H),2.38(s,3H),0.96(s,6H).

[0261] N1-(benzo[d]oxazol-2-yl)-2,2-dimethyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Example 164) The methodology applied was similar to that described in general method 3, except that cesium carbonate was used as the common base. 2-Chlorobenzoxazole (0.06 mL, 0.54 mmol, 0.1 equiv.) was dissolved in 2,2-dimethyl-N,N-dimethylformamide (2.0 mL) 1To a stirred solution of -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (105B) (0.13 g, 0.49 mmol, 1.0 equiv) and cesium carbonate (0.48 g, 1.48 mmol, 3.0 equiv) under nitrogen was added. The mixture was stirred at either 80° C. or room temperature for 16 h and then concentrated in vacuo. Water (2.5 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with water (2 mL) and brine (2 mL) and dried through a phase separator. The solvent was removed in vacuo to give a crude yellow oil which was purified by preparative HPLC to give the desired N-(4-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride as an off-white solid. 1 -(benzo[d]oxazol-2-yl)-2,2-dimethyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Example 164) was obtained.

[0262] The following examples were prepared according to general method 3 using the procedures described in Scheme 7.

[0263] [Table 22]

[0264] [Table 23]

[0265] [Table 24]

[0266] Scheme 8 [ka]

[0267] 3-Chloro-N-(2-chlorobenzo[d]thiazol-6-yl)propane-1-sulfonamide (106B) Sodium hydride (60% dispersion in mineral oil) (326 mg, 8.15 mmol, 3.0 equiv) was added portionwise to an ice-cold solution of 2-chlorobenzothiazol-6-amine (500 mg, 2.71 mmol, 1.0 equiv) in N,N-dimethylformamide (25 mL) and the mixture was stirred under ice-cooling for 1 h. A solution of 3-chloropropane-1-sulfonyl chloride (673 mg, 3.80 mmol, 1.4 equiv) 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 (2×25 mL). The combined organic fractions were combined and concentrated under reduced pressure to give a pale yellow oil which was purified by flash chromatography (eluting with iso-hexanes to ethyl acetate, 0 to 100%) to give the desired product 3-chloro-N-(2-chlorobenzo[d]thiazol-6-yl)propane-1-sulfonamide 106B as an off-white gum. Yield: 427 mg (48%). 1 H NMR (400MHz, MeOD) δ 7.87-7.84 (m, 2H), 7.38 (dd, J = 2.3, 8.8Hz, 1H), 3.67 (dd, J = 6.3, 6.3Hz, 2H), 2.27-2.19 (m, 2H). CH obscured by MeOD 2 Note the protons.

[0268] 2-(2-chlorobenzo[d]thiazol-6-yl)isothiazolidine 1,1-dioxide (106C) Sodium hydride (60% dispersion in mineral oil) (98 mg, 2.46 mmol, 2.0 equiv) was added to an ice-cold solution of 3-chloro-N-(2-chlorobenzo[d]thiazol-6-yl)propane-1-sulfonamide (106B) (400 mg, 1.23 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred under ice-cooling for 1 h and then quenched by careful addition of a saturated solution of ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (3x20 mL) and the combined organic phases were washed with water (20 mL), brine (20 mL) and concentrated in vacuo to give a gum. The crude product was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0-100%) to give the desired product (106C) as an off-white gum. Yield: 220 mg (62%). 1 H NMR (400 MHz, CDCl 3 )δ 7.92(d,J=8.9Hz,1H),7.72(d,J=2.1Hz,1H),7.38(dd,J=2.4,8.9Hz,1H),3 .84(dd,J=6.5,6.5Hz,2H),3.43(dd,J=7.5,7.5Hz,2H),2.63-2.55(m,2H).

[0269] 2-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol-6-yl)isothiazolidine 1,1-dioxide (Example 175) The methodology applied was similar to that described in general method 3. Yield: 25 mg (15%). 1H NMR(400MHz,DMSO)δ 8.34(s,2H),8.03(dd,J=5.6,5.6Hz,1H),7.57(d,J=2.3Hz,1H),7.51(dd,J=5.9, 5.9Hz,1H),7.35(d,J=8.8Hz,1H),7.14(dd,J=2.4,8.7Hz,1H),3.72(dd,J=6.5,6. 5Hz,2H),3.47(dd,J=7.5,7.5Hz,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=6.8Hz,3H);MS(ESI+)m / z 465(M+H) + .

[0270] Scheme 9 [ka]

[0271] N-(2-chlorobenzo[d]thiazol-6-yl)methanesulfonamide (107B) Methanesulfonyl chloride (0.055 mL, 0.706 mmol, 1.3 equiv) was added dropwise to an ice-cold solution of 2-chlorobenzothiazol-6-amine (100 mg, 0.54 mmol, 1.0 equiv) and pyridine (0.066 mL, 0.815 mmol, 1.5 equiv) in anhydrous dichloromethane (5 mL). The mixture was stirred at 0° C. for 15 min and then warmed to ambient temperature over 1 h. 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 with iso-hexane to ethyl acetate, 0 to 100%) to give the desired N-(2-chlorobenzo[d]thiazol-6-yl)methanesulfonamide (107B) as a pale yellow gum. Yield: 135mg (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 protons are CDCl 3The NH exchangeable protons are not observed.

[0272] N-(2-chlorobenzo[d]thiazol-6-yl)-N-methylmethanesulfonamide (107C) Sodium hydride (60% dispersion in mineral oil) (31 mg, 0.772 mmol, 1.5 equiv) was added in small portions to an ice-cold solution of N-(2-chlorobenzo[d]thiazol-6-yl)methanesulfonamide (107B) (135 mg, 0.515 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (2 mL). The mixture was stirred at room temperature for 2 h. Iodomethane (0.048 mL, 0.772 mmol, 1.5 equiv) was added and the mixture was stirred at room temperature for an additional 2 h. Water (1 mL) was added followed by removal of the solvent under high vacuum to give a pale yellow gum which was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0-100%) to give the desired N-(2-chlorobenzo[d]thiazol-6-yl)-N-methylmethanesulfonamide (107C) as a pale yellow gum. Yield: 100mg (70%) 1 H NMR (400 MHz, CDCl 3 )δ 7.95(d,J=8.8Hz,1H),7.86(d,J=2.1Hz,1H),7.48(dd,J=2.3,8.8Hz,1H),3.39(s,3H),2.88(s,3H).

[0273] N-Methyl-N-(2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazol-6-yl)methanesulfonamide (Example 176) The methodology applied was similar to that described in general method 3. Yield: 89mg (60%) 1 H NMR (400 MHz, CDCl 3) δ 8.38(s,2H), 7.62(d,J=2.0Hz,1H), 7.51(d,J=8.7Hz,1H), 7.24(d,J=3.2Hz,1H), 5.74(dd,J=6.5,6.5Hz,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=6.9Hz,3H). Not all NH exchangeable protons were observed; MS(ESI+) m / z 453(M+H). + .

[0274] Scheme 10 [ka]

[0275] 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)pyrrolidin-2-one (108B) The methodology applied was similar to that described in general method 1. 5-Aminomethyl-pyrrolidin-2-one (108A) (1.0 g, 8.76 mmol, 1.0 equiv.) was added to a stirred solution of 2-chloro-5-(methylthio)pyrimidine (100B) (1.4 g, 8.76 mmol, 1.0 equiv.) and cesium carbonate (8.56 g, 26.28 mmol, 3.0 equiv.) in anhydrous dimethylformamide (10 mL). The mixture was heated to 50° C. for 18 h and then concentrated under reduced pressure. The resulting solution was diluted with ethyl acetate (50 mL), washed with water (10 mL) and brine (10 mL), then passed through a phase separator and dried. The solvent was removed under reduced pressure to give a crude residue which 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 and combined with the filtrate and purified by flash chromatography (eluting with 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. Yield: 0.74g (36%). 1 H NMR (400 MHz, CDCl 3 )δ 8.35(s,2H),5.79-5.76(m,1H),5.48(dd,J=5.5,5.5Hz,1H),3.57-3.50(m,3H),3.20(dd,J=5. 3,9.5Hz,1H),2.89-2.84(m,1H),2.53-2.46(m,1H),2.37(s,3H),2.16(dd,J=6.4,17.1Hz,1H).

[0276] 4-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-2-oxopyrrolidine-1-carboxylate tert-butyl (108C) 4-Dimethylaminopyridine (5 mg, 0.04 mmol, 0.1 equiv) 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 equiv), di-tert-butyl dicarbonate (229 mg, 1.0 mmol, 2.5 equiv) and triethylamine (0.146 mL, 1.00 mmol, 2.5 equiv) in dichloromethane (4.2 mL). The mixture was stirred at room temperature for 72 h, followed by the addition of water (3.0 mL). The mixture was extracted with ethyl acetate (3×5.0 mL) and the combined organic phase was washed with brine (2.5 mL) and passed through a phase separator to dryness. The solvent was removed under reduced pressure to give a crude residue which was purified by reverse phase chromatography (eluting with 0.1% formic acid solution to acetonitrile, 5 to 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(400MHz,DMSO)δ 8.35(s,2H),7.62(t,J=6.1Hz,1H),3.73(dd,J=7.8,10.4Hz,1H),3.50-3.44(m,1H),3.29( d,J=6.4Hz,2H),2.60-2.55(m,2H),2.36(s,3H),2.28(dd,J=9.6,20.9Hz,1H),1.44(s,9H).

[0277] tert-Butyl (4-amino-2-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-4-oxobutyl)carbamate (108D) 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 and then extracted with dichloromethane (3×5 mL). The organic solvent was passed through a phase separator to dryness and then removed under reduced pressure to give the desired product (tert-butyl 4-amino-2-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)-4-oxobutyl)carbamate (108D). Yield: 61 mg (86%). 1 H NMR(400MHz,DMSO)δ 8.33(s,2H),7.32(s,1H),7.25(dd,J=6.0,6.0Hz,1H),6.81(s,2H),3.24(dd,J=6.2,6.2Hz,2H), 2.97(dd,J=6.0,6.0Hz,2H),2.36(s,3H),2.18-2.08(m,1H),2.04(d,J=6.4Hz,2H),1.38(s,9H).

[0278] 4-Amino-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide dihydrochloride (108E) The methodology applied was similar to that described in general method 2. A solution of hydrogen chloride (0.7 mL, 4 M 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 solvent was removed under reduced pressure to give the desired product 4-amino-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide dihydrochloride (108E) as a pale yellow solid. Yield: 56 mg (100%) HCl salt.

[0279] 4-((6-(N-(4-methoxybenzyl)sulfamoyl)benzo[d]thiazol-2-yl)amino)-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide (177) The methodology applied was similar to that described in general method 3. 2-Chloro-N-(4-methoxybenzyl)benzo[d]thiazole-6-sulfonamide (101B) (70 mg, 0.19 mmol, 1.10 equiv.) was added to a stirred solution of 4-amino-3-(((5-(methylthio)pyrimidin-2-yl)amino)methyl)butanamide dihydrochloride (108E) (56 mg, 0.17 mmol, 1.0 equiv.) and triethylamine (0.072 mL, 0.51 mmol, 3.0 equiv.) 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 followed by washing with methanol. The organic filtrate was concentrated under reduced pressure to give a crude residue which was purified by flash chromatography (eluting with dichloromethane to methanol, 0 to 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 (Example 177) as an off-white solid. Yield: 25 mg (25%). 1 H NMR(400MHz,DMSO)δ 8.45(dd,J=5.6,5.6Hz,1H),8.33(s,2H),8.08(d,J=1.8Hz,1H),7.88(dd,J=6.1,6.1Hz,1H ),7.62(dd,J=1.9,8.5Hz,1H),7.49-7.42(m,2H),7.39-7.37(m,1H),7.14(d,J=8.7Hz,2H) ,6.87-6.87(m,1H),6.81(d,J=8.7Hz,2H),3.89(d,J=6.0Hz,2H),3.70(s,3H),3.48(d,J=1 .1Hz,2H),3.37(dd,J=6.1,6.1Hz,2H),2.43-2.37(m,1H),2.34(s,3H),2.22-2.17(m,2H).

[0280] 4-((5-(methylthio)pyrimidin-2-yl)amino)-3-(((6-sulfamoylbenzo[d]thiazol-2-yl)amino)methyl)butanamide (178) 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 equiv) in anhydrous dichloromethane (0.3 mL). The mixture was stirred for 30 min 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 and then carefully basified by the addition of a saturated aqueous solution of sodium bicarbonate (3 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crude residue obtained was purified by flash chromatography (eluting with dichloromethane to methanol, 0 to 20%) to give the desired product 4-((5-(methylthio)pyrimidin-2-yl)amino)-3-(((6-sulfamoylbenzo[d]thiazol-2-yl)amino)methyl)butanamide (Example 178) as a white solid. Yield: 12 mg (75%). 1 H NMR(400MHz,DMSO)δ 8.41(dd,J=5.5,5.5Hz,1H),8.33(s,2H),8.13(d,J=1.8Hz,1H),7.67(dd,J=1.9,8.5Hz,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=6.2,6.2Hz,2H),2.39-2.38(m,1H),2.34(s,3H),2.21-2.17(m,2H).

[0281] The following examples were synthesized using the procedure described in Scheme 10.

[0282] [Table 25]

[0283] Scheme 11 [ka]

[0284] 4-((2-chlorobenzo[d]thiazol-6-yl)sulfonyl)morpholine (109B) The methodology applied was similar to that described in general method 6, using dichloromethane instead of tetrahydrofuran as solvent. Yield: 686mg. 1 H NMR(400MHz,CDCl3)δ 8.25(d,J=1.8Hz,1H),8.10(d,J=8.6Hz,1H),7.85(dd,J=1.3,8.6Hz,1H),3.75(dd,J=4.7,4.7Hz,4H),3.04(dd,J=4.7,4.7Hz,4H);MS(ESI+)m / z 319(M+H)+.

[0285] tert-Butyl (3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)-2-methylpropyl)carbamate (109D) The methodology applied was similar to that described in general method 1. Yield: 433mg. 1 H NMR(400MHz,CDCl3)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)+.

[0286] N1-(5-(difluoromethoxy)pyrimidin-2-yl)-2-methylpropane-1,3-diamine hydrochloride (109E) A solution of hydrogen chloride (2.7 mL, 4 M 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 min. The solvent was removed under vacuum to give the crude title compound N1-(5-(difluoromethoxy)pyrimidin-2-yl)-2-methylpropane-1,3-diamine hydrochloride (109E), which was carried on to the next step without further purification. Yield: 225 mg (quantitative). MS(ESI+)m / z 233(M+H)+.

[0287] N1-(5-(difluoromethoxy)pyrimidin-2-yl)-2-methyl-N3-(6-(morpholinosulfonyl)benzo[d]thiazol-2-yl)propane-1,3-diamine (180) The methodology applied was similar to that described in general method 3. Yield: 225mg. 1 H NMR(400MHz,CDCl3)δ 8.21(s,2H),7.97(d,J=1.5Hz,1H),7.65(dd,J=1.8,8.5Hz,1H),7.59(d, J=8.5Hz,1H),6.91(s,1H),6.43(t,J=71.6Hz,1H),5.72(dd,J=6.6,6.6H z,1H),3.77-3.73(m,4H),3.62-3.51(m,2H),3.43-3.29(m,2H),3.01(dd ,J=4.6,4.6Hz,4H),2.21-2.12(m,1H),1.08(d,J=6.9Hz,3H);(ESI+)m / z 515(M+H)+.

[0288] The following examples were synthesized according to the procedure described in Scheme 11.

[0289] [Table 26]

[0290] [Table 27]

[0291] Scheme 12 [ka]

[0292] tert-Butyl (2-methyl-3-(pyridin-2-ylamino)propyl)carbamate (110B) A solution of tert-butyl 3-amino-2-methylpropylcarbamate (110A) (150 mg, 0.80 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) was added to a solution of 2-bromopyridine (0.076 mL, 0.80 mmol, 1.0 equiv), sodium tert-butoxide (383 mg, 3.98 mmol, 5.0 equiv), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (38 mg, 0.08 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (73 mg, 0.08 mmol, 0.1 equiv) in 1,4-dioxane (10 mL) under nitrogen. The reaction mixture was heated to 70° C. for 72 h. The solvent was removed under reduced pressure and the resulting residue was partitioned between water (2 mL) and ethyl acetate (5 mL). The mixture was filtered through Celite, followed by removal of the aqueous phase and extraction with ethyl acetate (3×5 mL). The combined organic phases were washed with water (2 mL) and brine (2 mL), followed by drying by passing through a phase separator, and then concentrated to dryness under vacuum. The resulting crude residue was purified by reverse phase chromatography (eluting with 10 mM aqueous ammonium bicarbonate-acetonitrile, 5-95%) to afford the somewhat pure desired tert-butyl (2-methyl-3-(pyridin-2-ylamino)propyl)carbamate (110B) as an off-white solid, which was used in the next step without further purification. Yield: 27 mg (12%). MS(ESI+)m / z 266(M+H) + .

[0293] 2-Methyl-N 1 -(Pyridin-2-yl)propane-1,3-diamine hydrochloride (110C) The methodology applied was similar to that described in general method 2. A solution of hydrogen chloride (0.4 mL, 4 M 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 h. The solvent was removed in vacuo to give 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 carried on to the next reaction without further purification. Yield: 25 mg (assumed to be quantitative %).

[0294] 2-Methyl-N 1 -(5-(methylthio)pyrimidin-2-yl)-N 3 -(Pyridin-2-yl)propane-1,3-diamine (Example 187) The methodology applied was similar to that described in general method 3. 2-Chloro-5-methylsulfanyl-pyrimidine (100B) (17 mg, 0.11 mmol, 1.05 equiv.) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) to give 2-methyl-N 1 To a stirred solution of 2-(pyridin-2-yl)propane-1,3-diamine hydrochloride (110C) (24 mg, 0.10 mmol, 1.0 equiv) and cesium carbonate (99 mg, 0.30 mmol, 3.0 equiv) was added under nitrogen. The mixture was heated to 50° C. for 16 h and then concentrated under vacuum. Water (2 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with water (2 mL) and brine (2 mL) and dried by passing through a phase separator. The solvent was removed under vacuum to give a crude yellow oil which was purified by reverse phase chromatography (eluting with 10 mM aqueous ammonium bicarbonate to acetonitrile, 5-95%) to give the desired 2-methyl-N-(pyridin-2-yl)propane-1,3-diamine hydrochloride as a sticky yellow solid.1 -(5-(methylthio)pyrimidin-2-yl)-N 3 -(pyridin-2-yl)propane-1,3-diamine (Example 187) was obtained. Yield: 1.5 mg (5%). 1 H NMR (400 MHz, CDCl 3 )δ 8.35(s,2H),8.10(dd,J=0.6,3.6Hz,1H),7.41-7.35(m,1H),6.54(dd,J=5.3,6.8Hz,1H),6.38(d,J=8.4Hz,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=6.9Hz,3H);MS(ESI+)m / z 290(M+H) + .

[0295] Scheme 13 [ka]

[0296] Methyl 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylate (188) The methodology applied was similar to that described in general method 3. Methyl 5-bromopyrazine-2-carboxylate (114 mg, 0.53 mmol, 1.0 equiv.) was dissolved in anhydrous N,N-dimethylformamide (2.0 mL) to give 2-methyl-N 1To a stirred solution of -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine hydrochloride (102A) (150 mg, 0.53 mmol, 1.0 equiv) and cesium carbonate (514 mg, 1.58 mmol, 3.0 equiv) 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 (3×5 mL). The combined organic phases were washed with water (2 mL) and brine (2.5 mL) and then dried through a phase separator. The solvent was removed under vacuum to give a brown oil which was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0-100%). The resulting semi-crude product was further purified by flash chromatography (eluting with dichloromethane to methanol, 0 to 10%) to afford the desired methyl 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylate (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=1.4Hz,1H),6.36-6.36(m,1H),5.56(dd,J=6.0,6.0Hz,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=6.9Hz,3H).MS(ESI+)m / z 349(M+H) + .

[0297] 5-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylic acid (189) The methodology applied was similar to that described in general method 4. Lithium hydroxide monohydrate (23 mg, 55 mmol, 5.0 equiv) 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 equiv) 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 the mixture was acidified to pH approx. 3 with aqueous hydrochloric acid (2 M). The sticky precipitate was collected under filtration, then extracted with ethyl acetate (3×3 mL), washed with water (1 mL), and then dried by passing through a phase separator. The solvent was removed in vacuo to give the desired 5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazine-2-carboxylic acid (Example 189) as a pale yellow solid. 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). + .

[0298] (4-Hydroxypiperidin-1-yl)(5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazin-2-yl)methanone (Example 190) The methodology applied was similar to that described in general method 5. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 58 mg, 0.15 mmol, 1.5 equiv) 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 equiv) and 4-hydroxypiperidine (103 mg, 1.02 mmol, 10 equiv) in N,N-dimethylformamide (1 mL) and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the resulting crude residue was purified by reverse phase preparative HPLC to afford the desired (4-hydroxypiperidin-1-yl)(5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazin-2-yl)methanone (Example 190) as an off-white solid. 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),3.4 2-3.25(m,4H),2.37(s,3H),2.08(ddd,J=11.5,11.5,5.1Hz,1H),2.00-1.94(m,2H),1.62-1.60(m,3H),1.04(d,J=6.8Hz,3H);MS(ESI+)m / z 418(M+H) + .

[0299] Scheme 16 [ka]

[0300] 5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine (111B) The methodology applied was similar to that described in general method 7. 2-Bromo-5-methyl-1,3,4-oxadiazole (0.58 g, 3.58 mmol, 1.05 equiv) 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 equiv), cesium carbonate (3.33 g, 10.22 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.39 g, 0.34 mmol, 0.10 equiv) 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 solvent was removed under vacuum, water (20 mL) was added and the mixture was extracted with ethyl acetate (6×50 mL). The combined organic phase was washed with water (10 mL) and brine (10 mL), dried through a phase separator, and then concentrated in vacuo. The crude residue obtained was purified by reverse phase chromatography (eluting with 10 mM ammonium bicarbonate solution-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. Yield: 153 mg (25%). 1 H NMR(400MHz,DMSO)δ 8.49(d,J=2.0Hz,1H),7.87(dd,J=2.4,8.8Hz,1H),6.75(s,2H),6.57(d,J=8.8Hz,1H),2.53(s,3H).

[0301] (2-methyl-3-((5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)propyl)carbamate tert-butyl (111C) tert-Butyl N-(2-methyl-3-oxopropyl)carbamate (111B) (225 mg, 1.21 mmol, 1.2 equiv) 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 equiv), acetic acid (0.230 mL, 4.02 mmol, 4.0 equiv) and molecular sieves (4 Å type, 250 mg) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 5 min, followed by the addition of sodium triacetoxyborohydride (532 mg, 2.51 mmol, 2.5 equiv) 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 equiv) was added and the reaction mixture was stirred at room temperature for a further 72 h. The reaction was quenched by careful addition of a saturated aqueous solution of sodium bicarbonate (30 mL). The mixture was stirred vigorously for 30 min, then the dichloromethane layer was isolated and concentrated under reduced pressure to give a gum. The crude product was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0 to 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 carried on to the next reaction without further purification. Yield: 101 mg (29%).

[0302] 2-Methyl-N 1 -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride (111D) The methodology applied was similar to that described in general method 2. A solution of hydrogen chloride (1.2 mL, 4 M 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 was stirred at room temperature for 1 h. The solvent was removed in vacuo to give the desired 2-methyl-N-(2-methyl-N-propyl)-2-propanediol (110C) as an off-white solid. 1 -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride (111D) was obtained. The crude sample was carried on to the next reaction without further purification. Yield: 93 mg (assumed to be quantitative %).

[0303] 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 (Example 203) The methodology applied was similar to that described in general method 3. 2-Chloro-5-methylsulfanyl-pyrimidine (100B, 51 mg, 0.32 mmol, 1.1 equiv.) was dissolved in anhydrous N,N-dimethylformamide (2.9 mL) and diluted with 2-methyl-N 1To a stirred suspension of 2-methyl-N-(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 equiv) and cesium carbonate (283 mg, 0.87 mmol, 3.0 equiv) under nitrogen was added. 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 (3×50 mL). The combined organic phases were washed with water (10 mL) and brine (10 mL), then passed through a phase separator and dried. The solvent was removed under vacuum to give a yellow oil, which was purified by flash chromatography (eluting with isohexane to ethyl acetate, 0-100%) to give the crude residue, which was further purified by reverse phase preparative HPLC to give the desired 2-methyl-N-(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 equiv) as a yellow solid. 1 -(5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-yl)-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (Example 203) was obtained. Yield: 3.5 mg (3%). 1 H NMR (400 MHz, CDCl 3 )δ 8.70(d,J=1.8Hz,1H),8.37(s,2H),8.00(dd,J=2.3,8.8Hz,1H),6.47(d,J=8.1Hz,1H),5.79-5.69(m,2 MS(ESI+)m / z 372(M+H) + .

[0304] Scheme 17 [ka]

[0305] Ethyl 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropane-1-carboxylate (112B) In a reaction tube, add (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) were added and the mixture was flushed 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 pad of celite and the filtrate was 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 (2×30 mL). The combined organics were washed with water (2×40 mL) and brine (2×50 mL), dried over magnesium sulfate, and then concentrated in vacuo 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 light brown oil. (Note that purification via normal phase chromatography failed to resolve some close impurities). Yield: 284mg. 1 H NMR (400 MHz, CDCl 3)d 8.36(s,2H),8.21(dd,J=2.1,6.2Hz,1H),7.95(s,1H),7.26-7.19(m,1H),7.12(d,J=8.1Hz,1H ),6.33(d,J=8.6Hz,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=11.8,11.8,11.8Hz,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=6.8Hz,3H);MS(ESI+)m / z 402(M+H) + .

[0306] 2-(6-(((R)-2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyridin-3-yl)cyclopropane-1-carboxylic acid (112C) 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 h. The mixture was concentrated in vacuo and the resulting residue was diluted with water (8 mL). The solution was adjusted to pH approx. 2 with 2 M aqueous hydrochloric acid and subsequently extracted with dichloromethane / methanol (20% methanol in dichloromethane, 2×10 mL). The combined organic layers were passed through a phase separator cartridge and concentrated in vacuo 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. Yield: 280mg. MS(ESI+)m / z 374(M+H) + .

[0307] 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 tert-butyl (112D) 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]pyridinium 3-oxide 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 hours. Upon completion, the reaction mixture was concentrated under vacuum and the resulting residue 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 with 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. Yield: 69mg. 1 H NMR (400 MHz, CDCl 3)δ 8.35(s,2H),7.92(d,J=1.5Hz,1H),7.15(dd,J=2.1,8.5Hz,1H),6.34(d,J=8.6Hz,1H),5.96 (dd,J=6.2,6.2Hz,1H),5.00(s,1H),3.73-3.63(m,5H),3.49(s,4H),3.38-3.29(m,2H),3.2 6-3.18(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=6.8Hz,3H);MS(ESI+)m / z(M+H) + .

[0308] (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 (Example 204) 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 min. The solvent was removed under vacuum followed by azeotroping with dichloromethane (3×5 mL). The resulting crude residue was dissolved in dimethylsulfoxide (1.5 mL) and purified by preparative HPLC. The resulting liquid was dried under vacuum and then lyophilized from an acetonitrile / water mixture to give 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 (204) as a fluffy white solid. Yield: 15mg. 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=2.0,8.6Hz,1H),6.36(d,J=8.6 Hz,1H),5.98(dd,J=6.9,6.9Hz,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=6.6,13.4Hz,2H),2.38-2.31(m,4H),2.11-2.01(m,1H),1.8 9-1.79(m,5H),1.59-1.52(m,1H),1.27-1.14(m,1H),1.03(d,J=6.8Hz,3H);MS(ESI+)m / z 482(M+H) + .

[0309] The following examples were synthesized according to the procedure described in Scheme 17.

[0310] [Table 28]

[0311] Scheme 18 [ka]

[0312] N 1 -(5-bromopyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (113B) 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 equiv) in dimethylformamide (8 mL) was added to a suspension of 2,5-dibromopyrazine (457 mg, 1.92 mmol, 1.2 equiv) and cesium carbonate (1.56 g, 4.80 mmol, 3.0 equiv) in dimethylformamide (2 mL). The reaction mixture was heated to 90° C. for 18 h. The solvent was removed under reduced pressure and the resulting residue 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 phase was washed with brine (25 mL), dried by passing through a phase separator, and subsequently concentrated to dryness under vacuum. The crude residue was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0 to 100%) to give the title compound N as a pale yellow gum. 1 -(5-bromopyrazin-2-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (113B) was obtained. Yield: 230 mg (38%). 1 H NMR (400 MHz, CDCl 3 )δ 8.36(s,2H),8.06(d,J=1.3Hz,1H),7.67(d,J=1.4Hz,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=6.9Hz,3H).

[0313] N 1 -(5-(2-methoxypyridin-3-yl)pyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (209) The methodology applied was similar to that described in general method 7 (note 1,4-dioxane was used instead of dimethylformamide). N 1A solution of -(5-bromopyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (113B) (50 mg, 0.135 mmol, 1.0 equiv.) was added to a solution of 2-methoxy-3-phenylboronic acid (23 mg, 0.149 mmol, 1.1 equiv.), cesium carbonate (132 mg, 0.406 mmol, 3 equiv.) and tetrakis(triphenylphosphine)palladium(0) (15.6 mg, 0.0135 mmol, 0.1 equiv.) 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 h. The solvent was removed under reduced pressure, water (2 mL) was added and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic phase was washed with brine (10 mL) and concentrated in vacuo. The crude residue obtained was purified by preparative HPLC to give the desired N-(2-methyl-3-phenyl-2-propanediol) as an off-white solid. 1 -(5-(2-methoxypyridin-3-yl)pyrazin-2-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (154) was obtained. Yield: 24 mg (44%). 1 H NMR (400 MHz, CDCl 3 )δ 8.77(d,J=1.4Hz,1H),8.37(s,2H),8.18-8.13(m,2H),7.99(d,J=1.5Hz,1H),7.01(dd,J=4.9,7.4Hz,1H),5.69(dd,J=6.5,6.5Hz,1H),5.55( dd,J=6.1,6.1Hz,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=6.9Hz,3H);MS(ESI+)m / z 398(M+H) + .

[0314] Scheme 19 [ka]

[0315] tert-Butyl (2-methyl-3-oxopropyl)carbamate (114B) CAUTION - exothermic reaction; Dess-Martin periodinane (2.94 g, 6.94 mmol, 1.3 equiv) was added in portions over 20 min to a solution of tert-butyl (3-hydroxy-2-methylpropyl)carbamate (1.0 g, 5.34 mmol, 1.0 equiv) 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 1 M aqueous sodium dithionite (2 x 10 mL) and saturated aqueous sodium bicarbonate (2 x 10 mL). The organic phase was passed through a phase separator to dryness 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.

[0316] tert-Butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (114C) The methodology applied was similar to that described in Scheme 13 (for the production of 109D). The crude product was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0 to 100%) to give the desired tert-butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (114C) as a pale yellow gum. Yield: 875 mg (47%). (MS(ESI+)m / z 345(M+H) + .

[0317] (3-((2'-methoxy-[3,3'-bipyridin]-6-yl)amino)-2-methylpropyl) tert-butyl carbamate (114D) The methodology applied was similar to that described in general method 7. The 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. Yield: 110mg, MS(ESI+)m / z 373(M+H) + .

[0318] N1-(2'-methoxy-[3,3'-bipyridin]-6-yl)-2-methylpropane-1,3-diamine (114E) The methodology applied was similar to that described in general method 2. Crude N 1 -(2'-Methoxy-[3,3'-bipyridin]-6-yl)-2-methylpropane-1,3-diamine (114E) was immediately carried onto the next step without further purification. Crude yield: 75mg MS(ESI+)m / z 273(M+H) + .

[0319] N 1 -(2'-Methoxy-[3,3'-bipyridin]-6-yl)-2-methyl-N3-(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (210) The methodology applied was similar to that described in general method 1. The resulting crude residue 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 (155). Yield: 8 mg (7%). 1 H NMR (400 MHz, CDCl 3)δ 8.36(s,2H),8.30(d,J=2.1Hz,1H),8.11(dd,J=1.9,5.0Hz,1H),7.67(dd,J=2.4,8 .7Hz,1H),7.57(dd,J=1.9,7.3Hz,1H),6.95(dd,J=5.0,7.3Hz,1H),6.45(d,J=8.4 Hz,1H),5.90(dd,J=6.3,6.3Hz,1H),5.11(dd,J=6.0,6.0Hz,1H),3.97(s,3H),3.5 6-3.23(m,4H),2.36(s,3H),2.13-2.04(m,1H),1.05(d,J=6.9Hz,3H);MS(ESI+)m / z 397(M+H) + .

[0320] Scheme 20 [ka]

[0321] (3-([3,3'-bipyridin]-6-ylamino)-2-methylpropyl) tert-butyl carbamate (115A) The methodology applied was similar to that in Scheme 19 (Example 115B) to generate aldehyde (114B), followed by similar methodology to general method 7. Crude N 1 -([3,3'-bipyridin]-6-yl)-2-methylpropane-1,3-diamine (115A) was immediately carried on to the next step. Yield: 253mg (63%) 1 H NMR(400MHz,DMSO)δ 8.82(d,J=1.8Hz,1H),8.48(dd,J=1.6,4.8Hz,1H),8.36(d,J=2.1Hz,1H), 8.00-7.96(m,1H),7.76(dd,J=2.6,8.7Hz,1H),7.44-7.40(m,1H),6.90-6 .76(m,2H),6.62-6.59(m,1H),4.10(q,J=5.3Hz,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).

[0322] N 1 -([3,3'-bipyridin]-6-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (211) The methodology applied was similar to that described in Scheme 13 (for the production of 109D). The resulting crude residue was purified by reverse phase chromatography (eluting with 10 mM aqueous ammonium bicarbonate-acetonitrile, 5-95%) to give the desired product, N, as an off-white solid. 1 -([3,3'-bipyridin]-6-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (211) was obtained. Yield: 32 mg (14%). 1 H NMR (400 MHz, CDCl 3 )δ 8.77(1H,d,J=2.1Hz),8.53(1H,dd,J=1.6,4.8Hz),8.37-8.35(3H,m),7.81-7 .77(1H,m),7.63(1H,dd,J=2.5,8.7Hz),7.33(1H,dd,J=4.6,7.8Hz),6.50(1H, d,J=8.7Hz),5.93(1H,dd,J=6.1,6.1Hz),5.25(1H,dd,J=6.1,6.1Hz),3.56-3. 25(4H,m),2.36(3H,s),2.18-2.00(1H,m),1.06(3H,d,J=6.9Hz);MS(ESI+)m / z 367(M+H) + .

[0323] Scheme 21 [ka]

[0324] 2-Bromo-5-((trimethylsilyl)ethynyl)pyridine (116B) Triethylamine (49 mL, 352.25 mmol, 25 equiv) was added to 2-bromo-5-iodopyridine (4.0 g, 14.09 mmol, 1.0 equiv), followed by ethynyltrimethylsilane (2.9 mL, 21.13 mmol, 1.5 equiv), copper(I) iodide (270 mg, 1.41 mmol, 0.1 equiv), bis(triphenylphosphine)palladium(II) dichloride (99 mg, 0.14 mmol, 0.01 equiv) and the mixture was stirred at room temperature for 17 h. The mixture was concentrated in vacuo to give a crude gum which was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0 to 40%) to give the intermediate 2-bromo-5-((trimethylsilyl)ethynyl)pyridine (116B) as a white solid. Yield: 2.5g (69%). MS(ESI+)m / z 254 / 256(M+H) + .

[0325] 2-Bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116C) To a solution of 2-bromo-5-((trimethylsilyl)ethynyl)pyridine (116B) (250 mg, 0.983 mmol, 1.0 equiv) in ethanol (20 mL) was added 1-(azidomethyl)-4-methoxybenzene (177 mg, 1.08 mmol, 1.1 equiv) and the mixture was stirred at room temperature for 1 h. A solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (0.54 mL, 1.08 mmol, 1.1 equiv) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum and subsequently purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0 to 100%) to give 2-bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116C) as an off-white solid. Yield: 0.21g (61%). MS(ESI+)m / z 347(M+H) + .

[0326] (3-((5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-methylpropyl)carbamate tert-butyl (116D) To a degassed solution of 2-bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116C) (135 mg, 0.391, 1.0 equiv.) in dimethylsulfoxide (5 mL) was added tert-butyl (3-amino-2-methylpropyl)carbamate (96 mg, 0.508 mmol, 1.3 equiv.), L-proline (18 mg, 0.156 mmol, 0.4 equiv.), potassium phosphate (1.6.5 mg, 0.078 mmol, 0.2 equiv.) and copper(I) iodide (15 mg, 0.782 mmol, 0.2 equiv.). 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 in vacuo and the crude residue was purified by flash chromatography (eluting with iso-hexane to ethyl acetate, 0 to 100%) to give 2-bromo-5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridine (116D) as a light brown solid. Yield: 0.080g (45%). MS(ESI+)m / z 453(M+H) + .

[0327] (3-((5-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-methylpropyl)carbamate tert-butyl (116E) The methodology applied was similar to that described in general method 2. 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).

[0328] N 1 -(5-(1H-1,2,3-triazol-5-yl)pyridin-2-yl)-2-methyl-N3-(4-(methylthio)phenyl)propane-1,3-diamine (212) The methodology applied was similar to that described in general method 3. Yield: 18 mg (96%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.53(d,J=2.1Hz,1H), 8.38(s,2H), 7.84(s,1H), 7.82(dd,J=2.3,8.7Hz,1H), 6.45(d,J=8.4Hz,1H), 6.17(dd,J=6.3,6.3Hz,1H), 5.31(dd,J=6.0,6.0Hz,1H), 3.57-3.26(m,4H), 2.36(s,3H), 2.19-2.06(m,1H), 1.06(d,J=6.8Hz,3H), (NH not observed); MS(ESI+) m / z 457(M+H) + .

[0329] Scheme 22 [ka]

[0330] tert-Butyl (2-methyl-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)propyl)carbamate (117B) To a solution of 5-(pyridin-2-yl)pyrazin-2-amine (200 mg, 1.16 mmol, 1.0 equiv.) in dichloromethane (10 mL) was added tert-butyl (2-methyl-3-oxopropyl)carbamate (117B) (221 mg, 1.17 mmol, 1.0 equiv.), 3 Å 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) and subsequently passed through a phase separator cartridge. The solvent was removed in vacuo to give 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. Yield: 310 mg (78%).

[0331] 2-Methyl-N 1 -(5-(pyridin-2-yl)pyrazin-2-yl)propane-1,3-diamine (117C) The methodology applied was similar to that described in general method 2. Yield: 200mg (100%).

[0332] 2-Methyl-N 1 -(5-(methylthio)pyrimidin-2-yl)-N3-(5-(pyridin-2-yl)pyrazin-2-yl)propane-1,3-diamine (213) The methodology applied was similar to that described in general method 1. Yield: 20 mg (10%). 1 H NMR (400 MHz, CDCl 3)δ 9.04(d,J=1.4Hz,1H),8.62-8.61(m,1H),8.37(s,2H),8.10(d,J=8.0Hz,1H),7.94(d,J=1.4Hz,1H),7.77-7.72(m,1H),7.20(dd,J=4.8, MS(ESI+)m / z 368(M+H) + .

[0333] The following examples were synthesized according to the procedure described in Scheme 22.

[0334] [Table 29]

[0335] Scheme 23 [ka]

[0336] 5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-amine (118B) The methodology applied was similar to that described in general method 7 (note 1,4-dioxane / water was used as solvent instead of dimethylformamide). Yield: 158mg(73%)m / z 176(M+H) + .

[0337] tert-Butyl (2-methyl-3-((5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)amino)propyl)carbamate (118C) The methodology applied was similar to that described in Scheme 13 (for the production of 109D). The crude tert-butyl (2-methyl-3-((5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)amino)propyl)carbamate (118C) was immediately carried on to the next step. Yield: 101mg(34%)MS(ESI+)m / z 347(M+H) + .

[0338] 2-Methyl-N1-(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)propane-1,3-diamine (118D) The methodology applied was similar to that described in general method 2. Crude 2-Methyl-N 1 -(5-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazin-2-yl)propane-1,3-diamine (106D) was immediately carried on to the next step. Yield: 71 mg (expected) MS (ESI+) m / z 367 (M+H) + .

[0339] 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 (218) The methodology applied was similar to that described in general method 1. Yield: 25 mg (23%). 1 H NMR (400 MHz, CDCl 3 )δ 8.35(s,3H),8.30(s,1H),8.05(dd,J=2.3,8.9Hz,1H),7.67(s,1H),6.56(d,J=9.2Hz,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=6.8Hz,3H);MS(ESI+)m / z 371(M+H) + .

[0340] Scheme 24 [ka]

[0341] N 1 -(5-bromopyrazin-2-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (119a) The methodology applied was similar to that described in general method 3. Yield: 230 mg (38%). 1 H NMR (400 MHz, CDCl 3 )δ 8.36(s,2H),8.06(d,J=1.3Hz,1H),7.67(d,J=1.4Hz,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=6.9Hz,3H).

[0342] 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 (219) The methodology applied was similar to that described in general method 7 (note 1,4-dioxane / water was used and no additional aliquots of reagents were added). Yield: 18 mg (31%). 1 H NMR(400MHz,DMSO)δ 13.70(s,1H),8.35-8.34(m,2H),8.26(d,J=1.0Hz,1H),8.13-8.12(m,1H),8.00(d,J=1.5Hz,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=6.8Hz,3H);MS(ESI+)m / z 426(M+H) + .

[0343] Scheme 25 [ka]

[0344] tert-Butyl (2-methyl-3-(pyrazolo[1,5-a]pyrimidin-5-ylamino)propyl)carbamate (120A) A microwave vial containing 5-chloropyrazolo[1,5-c]pyrimidine (500 mg, 3.26 mmol, 1 equiv.) and tert-butyl (3-amino-2-methylpropyl)carbamate (100E) (6.13 g, 32.56 mmol, 10 equiv.) was heated under microwave irradiation to 140° C. for 30 min. The crude reaction mixture was purified by flash chromatography (eluting with iso-hexanes to ethyl acetate, 0-100%) to give tert-butyl (2-methyl-3-(pyrazolo[1,5-a]pyrimidin-5-ylamino)propyl)carbamate (120A). Yield: 700 mg (70%). MS(ESI+)m / z 306(M+H) + .

[0345] 2-Methyl-N 1 -(Pyrazolo[1,5-a]pyrimidin-5-yl)propane-1,3-diamine (120B) The methodology applied was similar to that described in general method 2. MS(ESI+)m / z 229(M+H) + .

[0346] tert-Butyl (2-methyl-3-(pyrazolo[1,5-a]pyrimidin-5-ylamino)propyl)carbamate (220) The methodology applied was similar to that described in general method 3. Yield: 20 mg (14%). 1H 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), (2xNH not observed); MS (ESI+) m / z 330 (M+H). + .

[0347] Scheme 26 [ka]

[0348] Methyl 6-bromonicotinimidate (121B) Sodium methoxide (0.71 g, 13.22 mmol, 1.1 equiv) was added to an ice-cold solution of 6-bromonicotininonitrile (121A) (2.2 g, 12.02 mmol, 1.0 equiv) in dioxane / water (20 mL / 20 mL). The mixture was stirred under ice-cooling for 30 min and then allowed to warm to room temperature. After 1 h, 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 solvent removed in vacuo to give crude methyl 6-bromonicotinimidate (121B), which was used in the next step without further purification. Yield: 2.5g (96%).

[0349] 6-Bromo-N'-methylnicotinimide hydrazide (121C) Methylhydrazine (0.73 mL, 13.96 mmol, 1.2 equiv.) was added to a solution of 6-bromonicotinimidate (121B) (2.5 g, 11.63 mmol, 1.0 equiv.) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give 6-bromo-N'-methylnicotinimide hydrazide (121C), which was Used in the next step without further purification. Yield: 2g (75%).

[0350] 2-Bromo-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (121D) Formic acid (10 mL, 265 mmol, 30.4 equiv.) was added to 6-bromo-N'-methylnicotinimide hydrazide (121C) (2.0 g, 8.73 mmol, 1.0 equiv.) and the mixture was heated to reflux for 1 h. The reaction mixture was diluted with water (100 mL) followed by extraction with ethyl acetate (3 x 50 mL). The combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate (50 mL), dried over sodium sulfate, and filtered. The solvent was removed under vacuum to give a crude brown residue which was purified by flash chromatography (eluting with dichloromethane / 0-10% methanol in dichloromethane) to give 2-bromo-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (121D) as an off-white solid. Yield: 500 mg (23%). MS(ESI+)m / z 240(M+H) + .

[0351] (2-methyl-3-((5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)propyl)carbamate tert-butyl (121E) The methodology applied was similar to that described in general method 7 (note 1,4-dioxane / water was used and no additional aliquots of reagents were added). Yield: 125mg

[0352] 2-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 (221) The methodology applied was similar to that described in general method 2 followed by general method 1 for deprotection. Yield: 25 mg (18%). 1H NMR(400MHz,DMSO)δ 8.42(d,J=2.0Hz,1H),8.34(s,2H),8.04(s,1H),7.76(dd,J=2.4,8.8Hz,1H),7.48(dd,J=6.0,6.0Hz,1H),6.82(dd,J=5.8,5.8Hz ,1H),6.57(d,J=8.4Hz,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=6.7Hz,3H);MS(ESI+)m / z 371(M+H) + .

[0353] Scheme 27 [ka]

[0354] tert-Butyl (3-((5-bromopyridin-2-yl)amino)-2-methylpropyl)carbamate (122B) tert-Butyl N-(2-methyl-3-oxopropyl)carbamate (100E) (1.0 g, 5.34 mmol, 1.0 equiv.) was added to a solution of 5-bromopyridin-2-amine (122A) (920 mg, 5.34 mmol, 1.0 equiv.), acetic acid (1.2 mL, 21.36 mmol, 4.0 equiv.) and molecular sieves (4 Å type, 1.0 g) in anhydrous dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 5 min, followed by the addition of sodium triacetoxyborohydride (2.83 g, 13.35 mmol, 2.5 equiv.) in one portion. The mixture was stirred at room temperature for 5 h. The reaction was quenched by careful addition of a saturated aqueous solution of sodium bicarbonate (30 mL). The mixture was stirred vigorously for 30 min, then the dichloromethane layer was separated and washed with an aqueous solution of sodium thiosulfate (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 light brown gum, which was used in the next reaction without further purification. Yield: 875 mg (47%).

[0355] (3-((2'-methoxy-[3,3'-bipyridin]-6-yl)amino)-2-methylpropyl)carbamate tert-butyl (122C) The methodology applied was similar to that described in general method 7. Yield: 138mg.

[0356] N 1 -(2'-Methoxy-[3,3'-bipyridin]-6-yl)-2-methyl-N 3 -(5-(methylthio)pyrimidin-2-yl)propane-1,3-diamine (222) The methodology applied was similar to that described for general method 2 followed by general method 1 for deprotection. Yield: 57mg. 1 H NMR (400 MHz, CDCl 3 )δ 8.36(s,2H),8.23(d,J=2.0Hz,1H),7.68(dd,J=2.3,8.7Hz,1H),7.32-7. 27(m,2H),7.03-6.95(m,2H),6.48(d,J=8.7Hz,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=6.6,13.4Hz ,1H),2.35(s,3H),2.18-2.07(m,1H),1.06(d,J=6.9Hz,3H);MS(ESI+)m / z 396(M+H) + .

[0357] Scheme 28 [ka]

[0358] 6'-Chloro-2H-[1,3'-bipyridin]-2-one (123B) 2-Amino-5-iodopyridine (123A) (1.12 g, 5.00 mmol, 1.0 equiv) was combined with 2-hydroxypyridine (582 mg, 6.00 mmol, 1.2 equiv), potassium carbonate (760 mg, 5.50 mmol, 1.1 equiv), copper(I) iodide (143 mg, 0.75 mmol, 0.15 equiv) and 8-hydroxyquinoline (110 mg, 0.75 mmol, 0.15 equiv) in anhydrous dimethylsulfonamide (5 mL). The mixture was degassed under a stream of nitrogen and heated at 130° C. for 21 h. The reaction mixture was allowed to cool to room temperature and then poured into a mixture of 10% aqueous ammonium hydroxide (100 mL) and ethyl acetate (50 mL). Activated charcoal (1 g) was added and the mixture was filtered through a pad of celite and washed 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 with dichloromethane to methanol, 0-10%) to give the desired product 6′-chloro-2H-[1,3′-bipyridin]-2-one (123B) as an off-white solid. Yield: 245mg, (26%). 1 H NMR(400MHz,DMSO)δ 7.88(1H,d,J=2.5Hz),7.60(1H,ddd,J=0.7,2.1,6.8Hz),7.49(1H,ddd,J=2.2,6.7,9.1Hz),7.41(1H,dd,J=2.7,8.7Hz),6 .52(1H,dd,J=0.4,8.8Hz),6.45(1H,ddd,J=0.7,1.3,9.2Hz),6.28(1H,ddd,J=6.7,6.7,1.3Hz),6.23(2H,s);MS(ESI+)m / z 188(M+H) + .

[0359] (2-methyl-3-((2-oxo-2H-[1,3'-bipyridin]-6'-yl)amino)propyl)carbamate tert-butyl (123C) The methodology applied was similar to that described in Scheme 19. 6'-Chloro-2H-[1,3'-bipyridin]-2-one (123B) was used in excess (245 mg, 1.31 mmol, 1.1 equiv). 4 Å molecular sieves were used in the reaction. The crude product was purified by flash chromatography (eluting with 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 light brown solid. Yield: 249mg, (58%). MS(ESI+)m / z 359(M+H) + .

[0360] 6'-((2-Methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)-2H-[1,3'-bipyridin]-2-one (223) The methodology applied was similar to that described in General Method 2 using a (4:1) ratio of 4 M HCl in 1,4 dioxane-water, followed by General Method 3 using cesium carbonate (3.0 equiv.) in combination with triethylamine (2.0 equiv.). Yield: 152 mg (57% over two steps). 1 H NMR(400MHz,DMSO)δ 8.35(2H,s),7.91(1H,d,J=2.6Hz),7.61(1H,ddd,J=0.6,2.1,6.8Hz),7.52-7.45( 2H,m),7.40(1H,dd,J=2.7,8.9Hz),6.90(1H,dd,J=5.8,5.8Hz),6.57(1H,dd,J=0.5 ,8.9Hz),6.45(1H,ddd,J=0.7,1.2,9.2Hz),6.28(1H,ddd,J=6.7,6.7,1.4Hz),3.3 3-3.14(4H,m),2.35(3H,s),2.10-2.00(1H,m),0.94(3H,d,J=6.8Hz);MS(ESI+)m / z 383(M+H) + .

[0361] The following examples were synthesized using the procedure described in Scheme 28.

[0362] [Table 30]

[0363] [Table 31]

[0364] [Table 32]

[0365] Scheme 29 [ka]

[0366] tert-Butyl (2-methyl-3-((5-(2-oxopyrrolidin-1-yl)pyrazin-2-yl)amino)propyl)carbamate (124B) A solution of tert-butyl N-(3-amino-2-methylpropyl)carbamate (100E) (436 mg, 2.20 mmol, 1.1 equiv.) in anhydrous dimethylsulfonamide (10 mL) was added to 2-bromo-5-(pyrrolidinon-1-yl)pyrazine (124A) (510 mg, 2.00 mmol, 1.0 equiv.), tripotassium phosphate (866 mg, 4.00 mmol, 2 equiv.), L-proline (94 mg, 0.80 mmol, 0.4 equiv.) and copper(I) iodide (76 mg, 0.40 mmol, 0.2 equiv.). The mixture was degassed and maintained under a stream of nitrogen and heated at 90° C. with stirring for 20 hours. The reaction mixture was allowed to cool to room temperature and was 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 with 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. Yield: 375mg, (54%). MS(ESI+)m / z 350(M+H) + .

[0367] 1-(5-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)pyrazin-2-yl)pyrrolidin-2-one (233) The methodology applied was similar to that described in general method 2 using a [4:1] ratio of 4M HCl in 1,4 dioxane-water, followed by general method 3. Yield: 71 mg (18% over two steps). 1 H NMR (400 MHz, CDCl 3)δ 9.02(1H,d,J=1.5Hz),8.35(2H,s),7.64(1H,d,J=1.5Hz),5.63(1H,dd,J=6.2,6.2Hz),5.24(1H,dd,J=5.7,5.7Hz),3.97(2H,t,J=7.1Hz),3.55 -3.46(1H,m),3.45-3.32(2H,m),3.28-3.19(1H,m),2.62(2H,t,J=8.1Hz),2.36(3H,s),2.20-2.02(3H,m),1.03(3H,d,J=6.8Hz);MS(ESI+)m / z 374(M+H) + .

[0368] Scheme 30 [ka]

[0369] 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester (125B) 1,1-Difluoro-2-iodo-ethane (128 mg, 0.67 mmol, 1.2 equiv.) was added to a suspension of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (125A) (126 mg, 0.56 mmol, 1.0 equiv.), potassium carbonate (231 mg, 1.67 mmol, 3.0 equiv.) 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 subsequently concentrated under reduced pressure to give the desired tert-butyl 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (125B) as a pale yellow oil. 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).

[0370] 2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane (125C) 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 equiv.) in dichloromethane (1.3 mL). The mixture was stirred for 30 minutes and then concentrated to dryness under reduced pressure to give 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.

[0371] The intermediates in Table 17 were synthesized using conditions similar to those described for intermediate 125C.

[0372] [Table 33]

[0373] Scheme 31 [ka]

[0374] 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-butyl ester (126B) 2,2,2-Trifluoroethyl trifluoromethanesulfonate (153 mL, 1.06 mmol, 1.2 equiv) was added to a suspension of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (126A) (200 mg, 0.88 mmol, 1.0 equiv), cesium carbonate (862 mg, 2.65 mmol, 3.0 equiv) 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 phases were washed with brine, passed through a phase separator to dryness and then concentrated under reduced pressure to give 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. Yield: 341 mg (quantitative). 1 H NMR (400 MHz, CDCl 3 )δ 3.38-3.30(m,4H),3.19(s,4H),3.01(q,J=9.4Hz,2H),1.73-1.69(m,4H),1.45(s,9H).

[0375] 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane (126C) 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 equiv) in dichloromethane (1.0 mL). The mixture was stirred for 30 min and then concentrated to dryness under reduced pressure to give 2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonane (126C) as a light brown oil, which was used directly in the next step without further purification and assumed to be in 100% yield.

[0376] Scheme 32 [ka]

[0377] 2-Methyl-5-oxa-2,8-diazaspiro[3.5]nonane (127B) Lithium aluminum hydride (1M solution in tetrahydrofuran, 1.97 mL, 1.97 mmol, 3.0 equiv) was added dropwise 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 equiv) in tetrahydrofuran (4.0 mL) under nitrogen. The reaction was stirred at 0° C. for 5 min, the cold 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 (15%, 0.075 mL), followed by water (0.22 mL). The cold bath was removed, the reaction mixture was stirred for 15 min, magnesium sulfate was added, and stirred for an additional 40 min. The mixture was dried by passing through a phase separator, washed with tetrahydrofuran and diethyl ether, and then concentrated to dryness under reduced pressure to give 2-methyl-5-oxa-2,8-diazaspiro[3.5]nonane (127B) as a light brown oil. The sample was carried on to the next reaction without further purification. Yield: assumed to be 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.

[0378] The intermediates in Table 18 were synthesized using conditions similar to those described for intermediate 127B.

[0379] [Table 34]

[0380] Scheme 33 [ka]

[0381] 6-(Dimethylcarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl (128B) The method used was similar to that described in general method 5, using 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid to give the desired product tert-butyl 6-(dimethylcarbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (128B). Yield: 111 mg (quantitative). 1 H NMR(400MHz,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).

[0382] N,N-Dimethyl-2-azaspiro[3.3]heptane-6-carboxamide (128C) 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 equiv) in dichloromethane (2.1 mL). The mixture was stirred for 30 min and then concentrated to dryness under reduced pressure to give the desired product N,N-dimethyl-2-azaspiro[3.3]heptane-6-carboxamide (128C) as a brown oil. The sample was carried on to the next reaction without further purification and was assumed to be in 100% yield.

[0383] Scheme 34 [ka]

[0384] (S)-Methyl 5-fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxylate (129A) The methodology applied was similar to that described in general method 3. Yield: 134 mg (20%). 1 H NMR (400 MHz, CDCl 3 )δ 8.38(s,2H),8.13(d,J=6.9Hz,1H),7.21(d,J=12.2Hz,1H),7.12(s,1H),5.62(t,J=6.7Hz,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=6.9Hz,3H);MS(ESI+)m / z 422(M+H) + .

[0385] (S)-5-Fluoro-2-((2-methyl-3-((5-(methylthio)pyrimidin-2-yl)amino)propyl)amino)benzo[d]thiazole-6-carboxylic acid (129B) The methodology applied was similar to that described in general method 4. Yield: 98 mg (quantitative). 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). No NH exchangeable protons observed; MS (ESI+) m / z 408 (M+H). + .

[0386] (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 tert-butyl (129C) The methodology applied was similar to that described in general method 5. Yield: 20 mg (54%). 1H NMR (400 MHz, CDCl 3 )δ 8.27(d,J=1.8Hz,1H),8.14(s,1H),7.99(dd,J=1.7,8.5Hz,1H),7.51(d, J=8.5Hz,1H),7.00-6.97(m,1H),5.47(dd,J=6.7,6.7Hz,1H),4.37(q,J= 7.2Hz,2H),3.63-3.49(m,2H),3.40-3.23(m,2H),2.47(s,3H),2.17-2.0 9(m,1H),1.40(dd,J=7.2,7.2Hz,3H),1.06(d,J=6.9Hz,3H);MS(ESI+)m / z 489(M+H) + .

[0387] (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 (Example 240) Trifluoroacetic acid (1 mL) was added dropwise to a 0° C. cooled solution of (S)-tert-butyl 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 equiv) in anhydrous dichloromethane (1 mL). The mixture was stirred for 30 min and then concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC (formic acid 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 (Example 189) as an off-white solid. 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=9.0Hz,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). No NH exchangeable protons observed; MS(ESI+) m / z 502(M+H) + .

[0388] The following examples were prepared using the procedures described in Scheme 34.

[0389] [Table 35]

[0390] Scheme 35 [ka]

[0391] 2-((3-((5-mercaptopyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide (130A) N,N-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 equiv.) and N-methylpyrrolidine (1.5 mL) were added to a microwave vessel under nitrogen, sealed, and subsequently heated to 160° C. for 1 h. LCMS analysis showed complete conversion to the desired thiol 2-((3-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide (130A), which was used directly in the next step without purification.

[0392] 2-((3-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide (244) Potassium hydroxide (201 mg, 3.58 mmol, 20.0 equiv) and water (0.5 mL) were added to a solution of the crude thiol 2-((3-((5-((difluoromethyl)thio)pyrimidin-2-yl)amino)-2-methylpropyl)amino)-N,N-dimethylbenzo[d]thiazole-6-carboxamide in N-methylpyrrolidine (1.5 mL) and the mixture was cooled to -70°C and frozen to a solid. Bromodifluoromethyl diethylphosphonate (40 uL, 0.215 mmol, 1.2 equiv) was added in one portion and the reaction was allowed to warm to ambient temperature over 1 hour, then cooled back to -70°C. An additional aliquot of bromodifluoromethyl diethylphosphonate (40 uL, 0.215 mmol, 1.2 equiv) 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 phase was washed with water (20 mL) and brine (25 mL) and then dried over magnesium sulfate. The solvent was removed under reduced pressure to give a crude brown oil, which was purified by flash chromatography (eluting with dichloromethane to methanol, 0-10%) followed 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 (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=1.4Hz,1H),7.55-7.52(m,1H),7.36(dd,J=1.8,8.3Hz,1H),6.33(s,1H),6.15(t,J= MS(ESI+)m / z 453(M+H)+ .

[0393] The following examples were prepared according to the methodology described in Scheme 35.

[0394] [Table 36]

[0395] [Table 37]

[0396] Scheme 36 [ka]

[0397] ((1R,3R)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)carbamate rac-tert-butyl (131B) The methodology applied was similar to that described in general method 1. Yield: 220 mg (44%). 1 H NMR (400 MHz, CDCl 3 )δδ 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=6.9,13.8Hz,1H),4.26-4.18(m,1H) ),4.02-3.94(m,2H),2.55-2.47(m,1H),2.36(d,J=1.0Hz,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) + .

[0398] rac-(1R,3R)-N 1 -(5-(methylthio)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (131C) The methodology applied was similar to that described in general method 2. Yield: 250 mg (quantitative %). MS(ESI+)m / z 225(M+H) + . Used in the next step without further purification.

[0399] rac-N,N-bis(4-methoxybenzyl)-2-(((trans)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)benzo[d]thiazole-6-sulfonamide (131D) The methodology applied was similar to that described in general method 3. Yield: 52 mg (23%). 1 H NMR (400 MHz, CDCl 3 )δ 8.36(s,2H),8.00(d,J=1.6Hz,1H),7.74(dd,J=1.9,8.5Hz,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=6.9Hz,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) + .

[0400] rac-2-(((trans)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)benzo[d]thiazole-6-sulfonamide (250) Trifluoroacetic acid (1 mL) was added dropwise to an ice-cold 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 equiv) in anhydrous dichloromethane (1 mL). The mixture was allowed to warm to ambient temperature over 18 h and then concentrated to dryness under reduced pressure. The resulting crude residue was purified by preparative HPLC and the resulting clean fractions were lyophilized to afford the desired 2-(((trans)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)benzo[d]thiazole-6-sulfonamide (Example 250) as a white powder. Yield: 23 mg (79%). 1 H NMR (CDCl 3 )δ 8.36(s,2H),8.17(d,J=1.8Hz,1H),7.84(dd,J=2.0,8.5Hz,1H),7.59-7.52(m,1H),5.34(d,J=6.5Hz,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) + .

[0401] Scheme 41 [ka]

[0402] Step 1: Example 301C 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) were added. The mixture was heated to 25° C. for 1 h. TLC detected that the starting material was consumed. The reaction was filtered and the filtrate (crude Example 301C) was used in the next step without any purification.

[0403] Step 2: Example 301D The solution of Example 301C was dissolved in Boc 2 The mixture was treated with 2H2O (1.03 g, 4.72 mmol) and stirred at room temperature for 2 h. Water (100 mL) was added, followed by extraction with EA (50 mL x 2), washing with water and brine, and addition of Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure, followed by purification by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 5 to 1 / 1) to give the desired product (Example 301D, 1.2 g, 81% yield) as a yellow solid. LCMS [M+H] + =573

[0404] Step 3: Example 301E To a solution of Example 301D (1.2 g, 2.54 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 1 h. TLC detected that the starting material was consumed, and the mixture was concentrated to give the desired product (Example 301E, 945 mg, yield: 100%) as a yellow oil, which was used in the next step without further purification.

[0405] Step 4: Example 301 To a solution of Example 301E (945 mg, 2.54 mmol) in ACN (10 mL), TEA (514 mg, 5.08 mmol) and Example 301F (408 mg, 2.54 mmol) were added at room temperature, followed by 70° C. for 18 h. TLC detected that the starting material was consumed. The reaction was concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=3 / 1 to 5 / 3) to give the desired product Example 301 (780 mg, yield: 61%) as a white solid. LCMS [M+H] + =497. 1 H NMR (400MHz, DMSO-d 6)δ 8.78(s,1H),8.34(s,2H),8.12(d,J=1.6Hz,1H),7.54(dd,J=8.5,1.8Hz,1H),7.48(d,J=8.5Hz,1H),3.94- 3.86(m,1H),3.59(dd,J=16.6,11.9Hz,6H),3.39(dd,J=19.4,5.9Hz,4H),2.85-2.81(m,4H),2.33(s,3H).

[0406] Scheme 42 [ka]

[0407] Step 1: Example 302B N 2 A solution of Example 302A (6.77 g, 21 mmol) in THF (200 mL) under atmospheric pressure was cooled to -65°C. MeMgBr (21 mL, 63.1 mmol, 3M in THF) was added dropwise followed by stirring at -65°C for 0.5 h. The reaction was allowed to warm to room temperature for 2 h and quenched by the addition of water (200 mL). After extraction with EtOAc (200 mL x 2), the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether / EtOAc = 3 / 1) to give the desired product Example 302B (4 g, 56% yield) as a yellow oil. LCMS [M+H] + =339

[0408] Step 2: Example 302C To a solution of Example 302B (4 g, 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, followed by hydrogen, and the reaction mixture was stirred at room temperature for 18 h. TLC and LCMS detected that the starting material was consumed. Example 302C (4 g, yield: 100%) was obtained by filtration, concentrated, and used in the next step without any purification. LCMS [M+H] + =205

[0409] Step 3: Example 302D 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) were added and the mixture was stirred to 25° C. for 2 hours. TLC detected that 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 to 1 / 4) to give the desired product Example 302D (500 mg, yield: 100%) as a white solid. LCMS [M+H] + =487

[0410] Step 4: Example 302E To a solution of Example 302D (486 mg, 2 mmol) in DCM (2 mL) was added TFA (1 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 1 h. TLC detected that the starting material was consumed, and the mixture was concentrated to give the desired product Example 302E (532 mg, yield: 100%) as a yellow oil, which was used in the next step without further purification.

[0411] Step 5: Example 302 Example 302E (193 mg, 0.5 mmol), TEA (101 mg, 1 mmol) and Example 301F (81 mg, 0.5 mmol) were dissolved in ACN (5 mL) and the mixture was heated to 60° C. for 18 h. LCMS detected that TM was formed. Purification by preparative HPLC gave the desired product Example 302 (15 mg, yield: 6%) as a white solid. LCMS [M+H] + =511 1 H NMR(400MHz,CDCl3)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).

[0412] Scheme 43 [ka]

[0413] Step 1: Example 303B To a solution of Example 303A (33 g, 500 mmol) and methyl carbonochloridate (49.5 g, 520 mmol) in THF (75 mL) was added H 2 KOH (56.1 g, 1000 mmol) in 0 (50 mL) was added over 30 min (maintaining the internal temperature below 40° C.). After the addition, the suspension was stirred at room temperature for 16 h. The suspension was filtered and the cake was washed with EtOH (50 mL×3) and dried in vacuum to give the desired product Example 303B (67 g, 82.7% yield) as a white solid. LCMS [M+H] + =163

[0414] Step 2: Example 303C 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 heated under 15 psi of H 2 The mixture was stirred at room temperature under reduced pressure for 44 hours. LCMS showed that the starting material was completely consumed and the desired product was detected. The mixture was filtered and the filter cake was washed with MeOH (30 mL x 3). The filtrate was concentrated under reduced pressure to give the product Example 303C (3.7 g, yield: 54.4%) as a yellow solid. LCMS [M+H] + =133.2

[0415] Step 3: Example 303D 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 that the starting material was completely consumed and the desired product was detected. The reaction mixture Example 303D was used for the next step without further purification. LCMS [M+H] + =415.5

[0416] Step 4: Example 303E Boc 2 2H2O (5 g, 22.9 mmol) was added to the solution of Example 303D at room temperature and stirred for 1 h. LCMS showed that the starting material was consumed. The reaction was diluted with DCM (200 mL) and washed with water (150 mL x 2), brine (200 mL x 3) and added with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=2 / 1 to 1 / 9) to give the product Example 303E (680 mg, 76.7% yield over two steps) as a white solid. LCMS [M+H] + =515.5

[0417] Step 5: Example 303F 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) was added at room temperature and the reaction was stirred for 16 h. The reaction was diluted with NH 4 Poured into saturated aqueous Cl (100 mL), diluted with EtOAc (30 mL) and separated. The aqueous layer was extracted with EtOAc (30 mL x 2), and the combined organic layers were concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc = 3 / 1 to 1 / 9) to give the product Example 303F (383 mg, yield: 48.3%) as a white solid. LCMS [M+H] + =487.6

[0418] Step 6: Example 303G 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 that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to give the product Example 303G (563 mg, yield: 100%) as a white solid. LCMS [M+H] + =387.5

[0419] Step 7: Example 303 Example 303G (563 mg, 1.14 mmol) and K in DMF (10 mL) 2 CO 3 To a solution of (940 mg, 6.82 mmol) 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 that the starting material was consumed. The mixture was cooled to room temperature, 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) and diluted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc=3 / 1 to 1 / 9) to give the crude product, which was purified by preparative HPLC to give the product Example 303 (75.2 mg, yield: 12.93%) as a pale yellow solid. LCMS [M+H] + =511 1 H NMR(400MHz,CDCl3)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).

[0420] Scheme 44 [ka]

[0421] Step 1: Example 304B Example 304A (23.6 g, 0.12 mol), NaN 3 (15.1 g, 0.23 mol) and NH 4Cl (7.5 g, 0.14 mol) was suspended in DMF (250 mL) and the resulting mixture was heated to 80° C. for 1 h. After the reaction was completed by TLC, 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, 100% yield) as a white solid. LCMS [M+H] + =247

[0422] Step 2: Example 304C 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 for 2 h. 2 The mixture was stirred at room temperature for 18 hours under reduced pressure. TLC detected that 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] + =221

[0423] Step 3: Example 304D To a solution of Example 304C (6.6 g, 3 mol) in DMF (50 mL), 2-chloro-5-(methylthio)pyrimidine (2.4 g, 15 mmol) and TEA (7.6 g, 75 mmol) were added. The resulting mixture was stirred at 100° C. for 1 h. TLC detected that the starting material was consumed. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 1 to 1 / 4) to give the desired product Example 304D (450 mg, yield: 8%) as a white solid. LCMS [M+H] + =345

[0424] Step 4: Example 304E 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 room temperature. After 3 hours, TLC detected that 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.

[0425] Step 5: Example 304 To a 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 that the starting material was consumed, and the reaction mixture was concentrated and purified by preparative TLC to give the desired product Example 304 (30 mg, yield: 51%) as a white solid. LCMS [M+H] + =454.9. 1 H NMR(400MHz,CDCl3)δ 8.35(s,2H),7.99(d,J=1.5Hz,1H),7.67(dd,J=8.5,1.7Hz,1H),7.59(d,J=8.5Hz,1H),5.97(s,1H),4.11(dd,J=9 .3,4.8Hz,1H),3.74(dd,J=13.7,4.3Hz,1H),3.66(s,1H),3.58(dd,J=13.6,6.3Hz,2H),2.70(s,6H),2.37(s,3H).

[0426] Scheme 45 [ka]

[0427] Step 1: Example 305 To a 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 the addition, the mixture was stirred at 50° C. for 1 h. LCMS determined that the 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 preparative TLC to give the desired product Example 305 (23.8 mg, yield: 60%) as a white solid. LCMS [M+H] + =440.9 1 H NMR (400MHz, MeOD-d 4 )δ 8.35(s,2H),8.07(s,1H),7.69(dd,J=8.0,1H),7.50(d,J=8.0Hz,1H),4.06(m,0.46H),3.57(m,4H),2.51(s,3H),2.32(s,3H).

[0428] Scheme 46 [ka] Example 306 (30 mg, yield: 50%) was prepared in a similar manner starting from Example 306A as a white solid. LCMS [M+H] + =454.9. 1 H NMR(400MHz,CDCl3)δ 8.35(s,2H),7.98(d,J=1.5Hz,1H),7.66(dd,J=8.5,1.7Hz,1H),7.58(d,J=8.5Hz,1H),6.04(t,J=5.6 Hz,1H),4.11(dd,J=9.3,5.1Hz,1H),3.74-3.64(m,2H),3.61-3.54(m,2H),2.70(s,6H),2.36(s,3H).

[0429] Scheme 47 [ka]

[0430] Step 1: Example 307A To a solution of Example 306E (100 mg, 0.47 mmol) in DMF (0.5 mL), DBU (89 mg, 0.58 mmol) and methyl 2-chlorobenzo[d]thiazole-6-carboxylate (89 mg, 0.39 mmol) were added. The mixture was heated to 50° C. for 1 h. After TLC determined that the starting material was consumed, the mixture was concentrated and purified by silica gel chromatography (eluted with petroleum ether / EtOAc=1 / 1 to 1 / 4) to give the desired product Example 307A (50 mg, yield: 26%) as a white solid. LCMS [M+H] + =406

[0431] Step 2: Example 307B 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 room temperature for 18 h. After TLC determined that 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] + =392

[0432] Step 3: Example 307 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 room temperature for 1 h. After TLC detected the starting material was consumed, the mixture was concentrated and purified by preparative TLC to obtain the desired product Example 307 (2 mg, yield: 19%) as a white solid. LCMS [M+H] + =419. 1H NMR(400MHz,CDCl3)δ 8.36(s,2H),7.67(s,1H),7.53(d,J=8.2Hz,1H),7.35(dd,J=8.3,1.5Hz,1H),5.91(s,1H),4 .14-4.00(m,1H),3.72-3.64(m,2H),3.53(dd,J=13.8,6.3Hz,2H),3.07(s,6H),2.37(s,3H).

[0433] Scheme 48 [ka]

[0434] Step 2: Example 308A A Schlenk tube equipped with a 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. After adding a solution of 65% TBHP (18.8 g, 136 mmol), 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 give the desired compound Example 308A (6.5 g) as a white solid. LCMS [M+H] + =214. 1 H NMR(400MHz,CDCl3)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),5.33-5.4 6(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).

[0435] Step 2: Example 308B To a solution of Example 308A (5 g, 23.5 mmol) in THF (25 mL) was added H 250% Hydrazine hydrate in O (3.52 g, 35.2 mmol) was added. The mixture was stirred at 70° C. for 2 h. Then the mixture was 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 give the desired compound Example 308B (550 mg) as a white solid. LCMS [M+H] + =184.

[0436] Step 3: Example 308C To a solution of Example 308B (700 mg, 3.825 mmol) in DCM (5 mL) was added m-CPBA (790 mg, 4.59 mmol) in small portions at 0° C. After the addition, the mixture was stirred at room temperature overnight. The resulting mixture was cooled to 0° C. and m-chlorobenzoic acid was filtered off and washed with additional cold DCM. The combined filtrate and washings were diluted with 20% NaHSO 3 The DCM layer was separated and extracted with 3N NaOH (3×30 mL), saturated NaCl (30 mL), and Na 2 SO 4 Drying at 40° C. Evaporation left a white solid, which was purified by silica gel column chromatography (eluting with PE / ethyl acetate=5 / 1) to give the desired compound Example 308C (455 mg) as a white solid. LCMS [M+H] + =144. 1 H NMR(400MHz,CDCl3)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).

[0437] Step 4: Example 308D Example 308C (445 mg, 2.28 mmol), NaN 3 (297 mg, 4.57 mmol), NH 4Cl (61 mg, 1.14 mmol), 2-methoxyethanol (5 mL) and H 2 A mixture of 200 mL of HO (1 mL) was stirred for 16 h in a bath maintained at 80° C. The resulting solution was evaporated to dryness and the residue was diluted with H 2 The mixture was dissolved in 200 mL of 1H2O (5 mL). The solution was saturated with NaCl, followed by extraction with DCM (4 x 5 mL). The DCM solution was evaporated and the residue was purified by silica gel column chromatography (eluting with MeOH / DCM = 3% to 5%) to give the desired compound Example 308D (420 mg) as a colorless oil. LCMS [M+H] + =188.

[0438] Step 5: Example 308E A suspension of Example 308D (420 mg, 1.74 mmol), Pd / C (catalytic amount) in EtOH (5 mL) was added to H 2 Stirred at room temperature under atmosphere for 16 hours. The mixture was filtered and concentrated in vacuum. The residue was dried and used directly in the next step without further purification. Example 308E (320 mg). LCMS [M+H] + =217.

[0439] Step 6: Example 308F 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 h. 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 give the desired compound Example 308F (100 mg) as a colorless oil. LCMS [M+H] + =341. 1H NMR(400MHz,CDCl3)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).

[0440] Step 7: Example 308G To a solution of Example 308F (100 mg, 0.294 mmol) in DCM (3 mL) was added 4M 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.

[0441] Step 8: Example 308H 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 give the desired compound Example 308H (70 mg) as a white solid. LCMS [M+H] + =648.

[0442] Step 9: Example 308 To a solution of Example 308H (70 mg, 0.108 mmol) in DCM (3 mL) was added 4M HCl in dioxane (3 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound Example 308 (20 mg) as a white solid. LCMS [M+H] + =548. 1H NMR (400MHz, DMSO-d 6 )δ 1.47-1.56(m,1H),1.63-1.73(m,1H),1.97(t,J=6.98Hz,2H),2.06-2.23(m,2H),2.31- 2.41(m,3H),3.19(t,J=6.98Hz,2H),3.35(s,2H),3.68(t,J=6.04Hz,4H),3.95-4.02(m ,1H),4.15(br.s.,1H),4.38(br.s.,1H),7.48(d,J=8.33Hz,1H),7.59(dd,J=8.33,1.8 8Hz,2H),8.16(d,J=1.88Hz,1H),8.37(s,2H),8.49(d,J=7.79Hz,2H),8.66(br.s.,1H).

[0443] Scheme 49 [ka]

[0444] Step 1: Example 309A Cyclopentadienylsodium (2M in THF, 50 mL, 100 mmol, 1 equiv.) was added dropwise to a solution of benzyl chloromethyl 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 phase separation, the organic layer was washed twice with 150 mL of cold water and added with stirring to the Na 2 SO 4The mixture was dried at 40° C. and the temperature was kept below 0° C. to avoid isomerization of the double bond. After removal of the drying agent by filtration, the pentane was removed in vacuo at 0° C. to give (benzyloxymethyl)cyclopent-2,4-ene 1 as a pale orange oil. The resulting crude material was kept under argon at 0° C., diluted with THF (160 mL), cooled to −78° C., and added dropwise via 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 at that temperature for 3 days. The reaction was then quenched by the addition of MeOH (40 mL), followed by 3 M aqueous NaOH (40 mL) and 30% H 2 O 2 (40 mL) was added. 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 washed with Na 2 SO 4 The crude orange oil was purified by column chromatography (eluent: 9:1 to 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 (400MHz, CDCl3)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=8.9Hz,1H),3.53(dd,J=5.4, 9.1Hz,1H),4.29(td,J=4.1,7.0Hz,1H),4.52(s,2H),5.53-5.58(m,1H),5.70-5.74(m,1H),7.24-7.37(m,5H).

[0445] Step 2: Example 309B 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 at room temperature for 20 min. Then, 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 added at 0° C. and the reaction mixture was stirred at room temperature. After 15 h, crushed ice was carefully added and the mixture was stirred for 30 min. After extraction with EtOAc (150 mL), the organic layer was washed with HO (150 mL), brine (150 mL) and Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. Purification by column chromatography (eluent: 98:2 to 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(500MHz,CDCl3)δ 2.42(d,J=17.4Hz,1H),2.65-2.70(m,1H),3.07(brs,1H),3.33 and 3.44(ABX,JAB=9.2Hz,JAX=5.7Hz,JBX=7.3Hz,2H),4.08(ddd,J=3.0,3.3,7.0Hz,1H),4.5 1(d,J=3.4Hz,2H),4.54(s,2H),5.64-5.66(m,1H),5.74-5.75(m,1H),7.22-7.34(m,10H).

[0446] Step 3: Example 309C A 0.5 M solution of 9-BBN (88 mL, 44 mmol) in THF was added dropwise to a solution of Example 309B (6.50 g, 22.0 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The reaction was allowed to warm slowly to room temperature overnight. The reaction was cooled to 0° C. and diluted with EtOH (7 mL), 3N NaOH solution (20 mL), and H 2 O 2(33%, 20 mL). The resulting mixture was stirred at room temperature overnight. The resulting residue was filtered and washed with EtOAc (200 mL). To this suspension was added water (150 mL) and after separation of the phases the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated to dryness. The crude product was purified on silica gel (eluent: 1:1 heptane:EtOAc) to give Example 309C (6.0 g, 19.3 mmol, 87%) as a yellow oil. LCMS [M+H] + =313.1H NMR(400MHz,CDCl3)δ 7.35-7.25(m,10H,CH-arom.),4.52(s,2H,CH2-benzyl),4.49(d,1H,J=11.8Hz,CHH-benzyl),4.44(d,1 H,J=11.8Hz,CHH-benzyl),4.33-4.28(m,1H,H-1),4.07(ddd,1H,J=6.6Hz,6.6Hz,4.1Hz,H-3),3.53(d d,1H,J=9.0Hz,4.2Hz,OCHH),3.49(d,1H,J=9.0Hz,4.3Hz,OCHH),2.35-2.25(m,2H,H-4,H-5a),2.05 (dddd,1H,J=13.5Hz,6.7Hz,3.5Hz,1.7Hz,H-2a),1.89-1.82(m,1H,H-2b),1.52-1.46(m,1H,H-5b).

[0447] Step 4: Example 309D Compound Example 309C (6.0 g, 19.3 mmol) was dissolved in dry pyridine (30 mL) and cooled to 0° C. TosCl (5.5 g, 28.9 mmol) was added in portions over 30 minutes. After the addition, the reaction was stirred at room temperature for 18 hours. The suspension was diluted with ethyl acetate (300 mL) and H 2The mixture was diluted with 200 mL of HO (200 mL). The organic phase was separated, washed with saturated NH4Cl solution (3 x 200 mL), brine (100 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (hexane / ethyl acetate 5:1) to give (1R,3S,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)cyclopentyl 4-methylbenzenesulfonate (1.4 g, 3.0 mmol, 15%) as a colorless oil. Rf=0.26 (20% ethyl acetate in hexane). LCMS [M+H] + =467.1H NMR(400MHz,CDCl3)δ7.79(m,2H),7.38-7.27(m,12H),5.05-4.99(m,1H),4.50(s,2H),4.45(s,2H),3.96-3.9 2(m,1H),3.48-3.40(td,2H,J=6.3Hz),2.45(s,3H),2.33-2.20(m,2H),2.14-2.01(m,2H),1.69-1.62(m,1H).

[0448] The compound (1R,3S,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)cyclopentyl 4-methylbenzenesulfonate (1.4 g, 3.0 mmol) was dissolved in dry DMF (20 mL) and added with NaN 3 (2.1 g, 15.4 mmol) was added. The mixture was stirred at 60° C. for 14 h. After addition of ethyl acetate (300 mL), the organic layer was washed with NaHCO 3 Wash with saturated solution (2 × 100 mL) and brine (100 mL), then MgSO 4 The mixture was dried at 75° C. for 1 hour. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (hexanes / ethyl acetate 10:1) to give Example 309D (1.0 g, 2.95 mmol, 95%) as a colorless oil. Rf=0.54 (20% ethyl acetate in hexanes). LCMS [M+H] + =338. 1H NMR(400MHz,CDCl3)δ 7.39-7.25(m,10H),4.52(dd,J=26.0,18.6Hz,2H),4.49(s,2H),3.97-3.89(m,1H),3.86(td,J=7.0,5.1Hz,1H),3.44(d,J=5.5Hz,2H) ,2.54-2.43(m,1H),2.24(td,J=13.8,6.8Hz,1H),1.99(dddd,J=13.4,8.7,4.7,1.3Hz,1H),1.84(dddd,J=28.2,20.8,9.5,4.2Hz,2H).

[0449] Step 5: Example 309E Compound Example 309D (1.0 g, 2.95 mmol) was dissolved in dry CH 2 Cl 2 (20 mL) and cooled to -78°C. 2 Cl 2 1M BCl in 3 A solution of (40 mL) was added via addition funnel over 45 min and the mixture was stirred at -78 °C for 3 h and then allowed to warm to room temperature. The reaction was quenched with dry MeOH (20 mL) at -78 °C and allowed to warm to room temperature overnight. The solvent was evaporated and the residue was purified on silica gel (hexanes / ethyl acetate 1:1) to give (1S,2R,4S)-4-azido-2-(hydroxymethyl)cyclopentanol (420 mg, 2.67 mmol, 90%) as a yellow oil. LCMS [M+H] + =158. 1 H NMR(400MHz,CDCl3)δ 4.07(dd,J=13.3,6.0Hz,1H),4.02-3.95(m,1H),3.79(ddd,J=10.4,5.2,3.0Hz,1H),3.56(dd,J=10.4,8.0Hz,1H), 2.36-2.20(m,4H),1.99-1.92(m,1H),1.77(dddd,J=14.0,6.0,4.5,1.6Hz,1H),1.58(ddd,J=13.9,9.8,6.8Hz,1H).

[0450] The compound (1S,2R,4S)-4-azido-2-(hydroxymethyl)cyclopentanol (0.42 g, 2.67 mmol) was dissolved in dry DMF (10 mL) and imidazole (198 mg, 2.94 mmol) was added at room temperature. After portionwise addition of TBDPSCl (808 mg, 2.94 mmol) at 0° C., the mixture was stirred at room temperature for 16 h. The reaction was cooled to 5° C. and cooled to 5° C. for 1 h. 2 Cl 2 (200 mL) and saturated NH 4 Cl (70 mL) and once with brine (50 mL), then MgSO 4 The solvent was removed under vacuum and the crude product was purified on silica gel (hexane / ethyl acetate 10:1) to give Example 309E (630 mg, 1.6 mmol, 60%) as a yellow oil. LCMS [M+H] + =360. 1 H NMR (400 MHz, CDCl 3 )δ 7.69-7.66(m,4H),7.49-7.40(m,6H),4.15(dd,J=7.0,7.0Hz,1H),4.02-3.99(m,1H),3.81(dd,J=4.8,4.8Hz,1H),3 .59(dd,J=7.2,7.2Hz,1H),2.35-2.28(m,2H),1.91-1.88(m,1H),1.83-1.78(m,1H),1.70-1.62(m,1H),1.08(s,9H).

[0451] Step 6: Example 309F 10% Pd / C (63 mg) was added to a suspension of compound Example 309E (630 g, 1.6 mmol) in dry EtOH (100 mL). The reaction was evaporated twice to exchange the inert gas atmosphere, followed by H 2 The suspension was stirred vigorously at room temperature for 15 h. The palladium catalyst was removed by using a PTFE-filter (Whatman Puradisc) and the solvent was removed under reduced pressure. The amine (588 g, 100%) was obtained as a colorless liquid, which was used without further purification. LCMS [M+H] + =370.

[0452] To a solution of the amine (588 mg, 1.6 mmol) in DCM (50 mL) at 0° C. was added Boc 2 0 (700 mg, 3.2 mmol) was added and stirred at 0° C. followed by stirring at room temperature for 2 h. The reaction mixture was concentrated and the crude product was purified on silica gel (hexane / ethyl acetate 5:1) to give Example 309F (650 mg, 1.38 mmol, 87%) as a colorless oil. LCMS [M+H] + =470. 1 H NMR(400MHz,CDCl3)δ 7.68-7.65(m,4H),7.48-7.40(m,6H),4.97(br s,1H),4.20(m,1H),4.02(br s,1H),3.74(dd,J=4.2,4.2Hz,1H),3.51(dd,J=8.4,8.4Hz,1H),2.29-2.22(m,2H),1.78-1.57(m,3H),1.45(s,9H),1.07(s,9H).

[0453] Step 7: Example 309G To compound Example 309F (630 mg, 1.34 mmol), DIEA (300 mg, 2.28 mmol) and DMAP (278 mg, 2.28 mmol) in DCM (50 mL) was added TosCl (384 mg, 2.0 mmol) at 0° C. The mixture was stirred at room temperature for 14 h and then concentrated to dryness. The crude product was purified by silica gel (hexane / ethyl acetate 10:1) to give (1S,2R,4S)-4-((tert-butoxycarbonyl)amino)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl 4-methylbenzenesulfonate (590 mg, 0.94 mmol, 70%) as a colorless oil. LCMS [M+H] + =625.

[0454] (1S,2R,4S)-4-((tert-butoxycarbonyl)amino)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl 4-methylbenzenesulfonate (590 g, 0.94 mmol) was dissolved in dry DMF (10 mL) and added NaN 3(92 mg, 1.4 mmol) was added. The mixture was stirred at 60° C. for 14 h. After addition of ethyl acetate (100 mL), the organic layer was washed with NaHCO 3 Wash with saturated solution (2 × 50 mL) and brine (50 mL), then MgSO 4 The mixture was dried at 75° C. for 12 hours. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (hexanes / ethyl acetate 5:1) to give tert-butyl ((1S,3R,4S)-3-azido-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl)carbamate (460 mg, 0.93 mmol, 99%) as a colorless oil. Rf=0.54 (20% ethyl acetate in hexanes). LCMS [M+H] + =496. 1 H NMR(400MHz,CDCl3)δ 7.72-7.67(m,4H),7.46-7.40(m,6H),4.45(br s,1H),4.20(m,1H),4.08(br s,1H),3.79-3.72(m,1H),3.68-3.62(m,1H),2.41-2.35(m,2H),1.80-1.47(m,5H),1.46(s,9H),1.08(s,9H).

[0455] 10% Pd / C (46 mg) was added to a suspension of tert-butyl ((1S,3R,4S)-3-azido-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopentyl)carbamate (460 g, 0.93 mmol) in dry EtOH (50 mL). The reaction was evaporated twice to exchange the inert gas atmosphere, followed by H 2 The suspension was stirred vigorously for 15 h at room temperature. The palladium catalyst was removed by using a PTFE-filter (Whatman Puradisc) and the solvent was removed under reduced pressure. The amine Example 309G (460 mg, 0.93 mmol, quantitative) was obtained as a colorless liquid, which was used without further purification. LCMS [M+H] + =470

[0456] Step 8: Example 309H To a solution of compound Example 309G (70 mg, 0.17 mmol) in THF (5 mL), 1M TBAF (1.7 mL, 0.17 mmol) was added with N 2 The mixture was added at 0° C. under reduced pressure, followed by stirring at room temperature for 2 h. The reaction mixture was concentrated to give crude product 13, which was used in the next step. LCMS [M+H] + =231.

[0457] Step 9: Example 309I A mixture of compound Example 309H (crude, 0.17 mmol), 2-chloro-N,N-dimethylbenzo[d]thiazole-6-sulfonamide (46 mg, 0.17 mmol) and DIEA (65 mg, 0.51 mmol) in DMSO was stirred at 60° C. overnight. The mixture was purified by preparative HPLC to give compound Example 309I (38 mg, 47%) as a white solid. LCMS [M+H] + =472.

[0458] Step 10: Example 309J A solution of 4M HCl / dioxane (5 L) was added to compound Example 309I (38 mg, 0.08 mmol) in DCM (1 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to give compound Example 309J (30 mg, 100%) as a white solid. LCMS [M+H] + =372.

[0459] Step 16: Example 309 A mixture of compound Example 309J (30 mg, 0.08 mmol), 2-chloro-5-(methylthio)pyrimidine (15 mg, 0.09 mmol) and DIEA (34 mg, 0.25 mmol) in DMSO (2.5 mL) was stirred at 120° C. for 4 hours. The mixture was purified by preparative HPLC to give compound Example 309 (5 mg, 12%) as a white solid. LCMS [M+H] + =496. 1H NMR(400MHz,CD3OD)δ 8.36(s,2H),8.09(d,J=1.6Hz,1H),7.68(dd,J=2.0,1.6Hz,1H),7.56(d,J=8.4Hz,1H),4.62(br s,5H),4.54(br m,1H),3.63-3.58(m,2H),2.70(s,3H),2.69-2.65(m,1H),2.37(s,3H),2. 36-2.28(m,1H),2.16-2.10(m,1H),2.05-1.99(m,1H),1.86-1.82(m,1H).

[0460] Scheme 50 [ka]

[0461] Step 1: Example 310A To a mixture of tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (1.5 g, 7.5 mmol), 2-chloro-5-(methylthio)pyrimidine (1.3 g, 8.3 mmol) in dimethyl sulfoxide (28 mL) was added N,N-diisopropylethylamine (3.7 mL, 22.5 mmol) at room temperature. 2 The mixture was stirred at 130° C. under atmospheric pressure for 6.5 hours. Then, water (90 mL) and ethyl acetate (160 mL) were added to the mixture. The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (PE:EA=20:1 to PE:EA=6:1) to give Example 310A (1.8 g, 76% yield) as a yellow oil. LCMS [M+H] + =325.

[0462] Step 2: Example 310B To a mixture of Example 310A (1.8 g, 5.7 mmol) in methanol (2 mL) was added HCl / dioxane (8.0 mL, 4 mol / L) at room temperature. The resulting mixture was diluted with N 2The mixture was stirred at room temperature under atmosphere for 2.5 hours. The mixture was then evaporated to give Example 310B (1.5 g, 100% yield) as a brown solid. LCMS [M+H] + =225.

[0463] Step 3: Example 310C To a mixture of Example 310B (1.5 g, 5.7 mmol), ethyl 2-chlorobenzo[d]thiazole-6-carboxylate (1.4 g, 5.7 mmol) in DMSO (28 mL) was added DIEA (2.9 mL, 17.3 mmol) at room temperature. The resulting mixture was diluted with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 18 hours. Then, water (80 mL) and ethyl acetate (150 mL) were added to the mixture. The combined organic layer was washed with brine (90 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (PE:EA=30:1-5:1) to give Example 310C (1.9 g, 77% yield) as a yellow solid. LCMS [M+H] + =430.

[0464] Step 4: Example 310D To a mixture of Example 310C (1.9 g, 4.4 mmol) in ethanol (20 mL) and water (10 mL) was added lithium hydroxide monohydrate (372 mg, 8.9 mmol) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 18 h. The mixture was then concentrated. To the residue was added water (60 mL) and HCl (3 mol / L) until pH=5. The precipitate was filtered and the cake was dried to give Example 310D (1.5 g, 84% yield) as a brown solid. LCMS [M+H] + =402. 1 H NMR (400MHz, DMSO-d 6)δ 8.49-8.47(d,J=6.8Hz,1H),8.34(s,2H),8.26-8.25(d,J=1.6Hz,1H),7.81-7.79(m,1H),7.55-7.53(d,J=7.2Hz,1H),7.40 -7.38(d,J=8.4Hz,1H),4.39-4.33(m,2H),2.35(s,3H),2.21-2.19(m,2H),2.12-2.10(m,2H),1.98-1.94(t,J=13.6Hz,1H).

[0465] Step E: Example 310 A mixture of Example 310D (30 mg, 0.075 mmol), dimethylamine (6.75 mg, 0.15 mmol), HATU (28.5 mg, 0.075 mmol) in DCM was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound Example 310 (20 mg) as a yellow solid. LCMS [M+H] + =429. 1 H NMR (600MHz, DMSO-d 6 )δ 1.54-1.64(m,2H),1.98(t,J=6.75Hz,2H),2.09-2.16(m,1H),2.18-2.27(m,1H),2.36(s,3H),2.97(s,6H),4.35(br s,2H),7.30(dd,J=8.35,1.49Hz,1H),7.40(d,J=8.24Hz,1H),7.57(br s,1H),7.74-7.81(m,1H),8.35(s,2H),8.58(br s,1H).

[0466] Using the above procedures, the following examples were synthesized.

[0467] [Table 38]

[0468] [Table 39]

[0469]

Table 40

[0470]

Table 41

[0471]

Table 42

[0472]

Table 43

[0473]

Table 44

[0474]

Table 45

[0475]

Table 46

[0476]

Table 47

[0477]

Table 48

[0478]

Table 49

[0479]

Table 50

[0480] [Table 51]

[0481] [Table 52]

[0482] [Table 53]

[0483] [Table 54]

[0484] [Table 55]

[0485] [Table 56]

[0486] Scheme 51 [ka]

[0487] Step 1: Example 371A Dioxane:H 2 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.0 g, 4.5 mmol), 3-bromo-2-methoxypyridine (930 mg, 4.9 mmol), Pd(dppf)Cl in O=4:1 (50 mL) 2 (320 mg, 0.45 mmol) and Na 2 CO 3 A mixture of (950 mg, 9.0 mmol) was added to N 2The mixture was stirred under atmospheric pressure at 110° C. overnight. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with EtOAc (20 mL×3), and the combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated; the residue was purified by chromatography on silica gel eluting with petroleum ether:EtOAc=5:1 to give Example 371A (660 mg, 72%) as a white solid.

[0488] Step 2: Example 371 (1S,3S)-N1-(5-(methylthio)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (100 mg, 0.38 mmol), Example 371A (86 mg, 0.42 mmol) and Cs in DMSO (5 mL). 2 CO 3 (376 mg, 1.15 mmol) was stirred at 130° C. for 2 days. The mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (10 mL×5), and the combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The residue was purified by preparative HPLC to give Example 371 (10 mg, 6.4%). LCMS [M+H] += 409. 1 H NMR (400MHz, CD 3 OD)δ 8.41(s,2H),8.20-8.17(m,2H),8.09(s,1H),7.82(d,J=7.2Hz,1H),7.13-7.07(m,2H),4.51-4.49(m,1H) ),4.29-4.27(m,1H),3.99(s,1H),2.41-2.33(m,2H),2.38(s,3H),2.19-2.15(m,2H),1.78-1.75(m,1H).

[0489] Scheme 52 [ka]

[0490] Step 1: Example 372A 2-Fluoro-4-iodopyridine (200 mg, 0.9 mmol), pyridin-2(1H)-one (102 mg, 1.1 mmol), CuI (17 mg, 0.09 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (19 mg, 0.17 mmol) and K in DMSO (5 mL). 3 PO 4 A mixture of (381 mg, 1.8 mmol) was added to N 2 The mixture was stirred at 100° C. under atmospheric pressure for 3 hours. The mixture was cooled and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL×3), and the combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product which was purified by chromatography on silica gel eluting with petroleum ether:EtOAc=5:1 to 1:1 to give Example 372A (97 mg, 57%) as an off-white solid.

[0491] Step 2: Example 372 Example 372A (50 mg, 0.19 mmol), (1S,3S)-N1-(5-(methylthio)pyrimidin-2-yl)cyclopentane-1,3-diamine hydrochloride (40 mg, 0.21 mmol) and Cs in DMSO (3 mL). 2 CO 3 (185 mg, 0.57 mmol) was stirred at 130° C. for 2 days. The mixture was cooled and water (10 mL) was added. The mixture was extracted with EtOAc (10 mL×5), and the combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was purified by preparative HPLC to give Example 372 (10 mg, 13%). LCMS [M+H] += 395. 1 H NMR (400MHz, CD 3OD)δ 8.39(s,2H),7.99(d,J=7.2Hz,1H),7.70-7.64(m,2H),7.20(s,1H),7.05-7.03(m,1H),7.67(d,J=9.2Hz,1H),6.58-6. 54(m,1H),4.51-4.47(m,1H),4.29-4.27(m,1H),2.42-2.33(m,2H),2.38(s,3H),2.20-2.14(m,2H),1.78-1.74(m,1H).

[0492] Using the above procedures, the following examples were synthesized.

[0493] [Table 57]

[0494] Scheme 54 [ka]

[0495] Common method 1 6'-Chloro-5-methoxy-2H-[1,3'-bipyridin]-2-one (Example 400A) Compounds 2-chloro-5-iodopyridine (191 mg, 0.8 mmol, 1.0 equiv.), 5-methoxypyridin-2(1H)-one (100 mg, 0.8 mmol, 1.0 equiv.), CuI (15 mg, 0.08 mmol, 0.1 equiv.), N,N'-dimethyl-1,2-cyclohexanediamine (23 mg, 0.16 mmol, 0.2 equiv.) and K in DMSO (5 mL). 3 PO 4 (339 mg, 1.6 mmol, 0.2 equiv.) was dissolved in N 2 The mixture was stirred under atmosphere at 120° C. overnight. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (30 mL) and diluted with Na 2 SO 4The mixture was dried at rt, filtered, concentrated and purified by chromatography on silica gel eluting with PE:EA=1:1 to give 400A (60 mg, 0.23 mmol, 32%) as an off-white solid.

[0496] General Procedure 2 5-Methoxy-6'-(((1S,3S)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one (Example 400) A mixture of 400A (53 mg, 0.22 mmol, 1.0 equiv), 131C (50 mg, 0.22 mmol, 1.0 equiv), tBuXphos Pd G3 (18 mg, 0.022 mmol, 0.1 equiv) and tBuOK (49 mg, 0.44 mmol, 0.2 equiv) in dioxane (5 mL) was reacted with N 2 The mixture was stirred overnight at 110° C. under atmospheric pressure. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by preparative TLC followed by preparative HPLC to give compound 400 (50 mg, 53%, TFA salt) as an off-white solid. LCMS [M+H] + =425. 1 H NMR (400MHz, CD 3 OD)δ 8.36(s,2H),8.09(s,1H),7.95(d,J=9.6Hz,1H),7.50(d,J=9.6Hz,1H),7.23(s,1H),7.10(d,J=9.6Hz,1H),6.61(d,J=9 .6Hz,1H),4.48-4.46(m,1H),4.25-4.23(m,1H),3.73(s,3H),2.40-2.35(m,5H),2.16-2.13(m,2H),1.76-1.74(m,2H).

[0497] Using the above procedures, the following examples were synthesized.

[0498] [Table 58]

[0499] Scheme 55 [ka]

[0500] 5-Hydroxy-6'-(((1S,3S)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,3'-bipyridin]-2-one (Example 402) To a solution of 400 (50 mg, 0.12 mmol, 1.0 equiv) in DCM (10 mL) was added BBr 3 (1 mL) was added at 0° C. The mixture was stirred at room temperature overnight, quenched with MeOH, and then concentrated. The residue was purified by preparative TLC followed by preparative HPLC to give compound Example 402 (50 mg, 53%, TFA salt) as an off-white solid. 1 H NMR (400MHz, CD 3 OD)δ 8.37(s,2H),8.06(s,1H),7.94(d,J=9.6Hz,1H),7.45(d,J=9.6Hz,1H),7.12-7.09(m,2H),6.58(d,J=9.6Hz ,1H),4.49-4.46(m,1H),4.31-4.28(m,1H),2.42-2.30(m,5H),2.17-2.13(m,2H),1.79-1.73(m,2H).[M+H] + =411.

[0501] Scheme 56 [ka]

[0502] 4-Hydroxy-5'-(((1S,3S)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)-2H-[1,2'-bipyridin]-2-one (Example 403) The title compound was obtained from the starting material 4-(benzyloxy)pyridin-2(1H)-one by methods similar to those described in General Method 1, General Method 2 and General Method 3. 1 H NMR (400MHz, CD 3OD)δ 8.32(s,2H),7.89(d,J=2.2Hz,1H),7.45(d,J=7.5Hz,2H),7.39(dd,J=9.0,2.7Hz,1H),6.60(d,J=8.6Hz,1H),6.13(dd,J=7.5,2.6 Hz,1H),5.88(d,J=8.6,2.5Hz,1H),4.48-4.25(m,2H),2.35(s,3H),2.32-2.19(m,2H),2.06-1.92(m,2H),1.70-1.52(m,2H).[M+H] + =411.49.

[0503] Scheme 57 [ka]

[0504] General Procedure 4 6'-Chloro-4-methoxy-3,3'-bipyridine (404) (6-chloropyridin-3-yl)boronic acid (1.0 g, 6.4 mmol, 1 equiv.), 3-bromo-4-methoxypyridine (1.2 g, 6.4 mmol, 1 equiv.), Pd(dppf)Cl in dioxane (8 mL) and water (2 mL). 2 (468 mg, 0.64 mmol, 0.1 eq.) and Na 2 CO 3 (1.3 g, 12.8 mmol, 2 equiv.) was added to a mixture of N 2 The mixture was stirred under atmosphere at 105° C. overnight. The mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel eluted with petroleum ether:EtOAc=5:1 to give compound 404 (200 mg, 14%) as a brown solid.

[0505] Using the above procedures, the following examples were synthesized.

[0506] [Table 59]

[0507] Scheme 58 [ka]

[0508] 2-Chloro-5-(2,2,2-trifluoroethoxy)pyrimidine (408) 2-Chloropyrimidin-5-ol (0.5 g, 3.8 mmol, 1.0 equiv) and CS in DMF (20 mL) 2 CO 3 To a solution of (1.49 g, 4.6 mmol, 1.2 equiv.) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.97 g, 4.2 mmol, 1.1 equiv.). The resulting suspension was stirred at room temperature for 16 h and then partitioned between EtOAc (30 mL) and water (80 mL). The separated aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 Drying at 407° C., filtration and concentration gave 408 (0.74 g), which was used directly in the next step. LCMS [M+H] + =213.

[0509] Scheme 59 [ka]

[0510] 2-Chloro-5-(difluoromethoxy)pyridine (409) A solution of 2-chloropyrimidin-5-ol (101.6 g, 0.76 mol, 1.0 equiv) in DMF (2000 mL) was added to Cs 2 CO 3(300 g, 0.92 mol, 1.2 eq) was added and the reaction mixture was stirred at room temperature for 1.5 h. Sodium 2-chloro-2,2-difluoroacetate (340 g, 2.3 mol, 3.0 eq) was added and the reaction mixture was stirred at 100° C. for 3.5 h. The reaction mixture was poured into water (5 L) and extracted with EA (3×1 L). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by flash chromatography on silica gel (PE:EA=10:1) to give 409 (70 g).

[0511] Scheme 60 [ka]

[0512] 2-Chloro-5-cyclopropylpyrimidine (410A) 5-Bromo-2-chloropyrimidine (100 g, 518 mmol, 1.0 equiv.), cyclopropylboronic acid (53 g, 616 mmol, 1.2 equiv.) and Pd(dppf)Cl in dioxane (1.5 L). 2 (10 g, 13.7 mmol, 0.03 equiv.) 2 CO 3 (250 g, 769 mmol, 1.5 eq.) was added and N 2 The mixture was stirred at 110° C. for 12 hours under reduced pressure. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=15:1) to give 410A (55 g) as a yellow solid. LCMS [M+H] + =155.

[0513] General Procedure 5 ((1S,3S)-tert-butyl 3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)carbamate (410B) A mixture of 410A (40 g, 260 mmol, 1 equiv.), tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (55 g, 275 mmol, 1.05 equiv.) and DIPEA (105 g, 814 mmol, 3.13 equiv.) in DMSO (400 mL) was reacted with N 2 The mixture was stirred at 110° C. for 12 h. Then, the mixture was cooled to room temperature and diluted with water (1000 mL). The resulting mixture was extracted with EtOAc (100 mL×3), and the combined organic layers were washed with brine and added with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by chromatography on silica gel (eluting with hexane:ethyl acetate=5:1 to 4:1) to give compound 410B (55 g) as a pale solid. LCMS [M+H] + =319.

[0514] General Procedure 6 (1S,3S)-N 1 -(5-Cyclopropylpyrimidin-2-yl)cyclopentane-1,3-diamine (410C) To a solution of 410B (44 g, 13.8 mmol, 1.0 equiv) in MeOH (250 mL), HCl (4 M in dioxane, 250 mL) was added dropwise and the resulting solution was stirred at room temperature for 2.5 h. After the reaction was complete, the mixture was concentrated to dryness under vacuum. The residue was redissolved in MeOH (500 mL) and purified by ion exchange resin (Ambersep® 900 OH). - The pH was adjusted to about 8 by adding 410C (44.5) as a yellow oil. LCMS [M+H] += 219.

[0515] Using the above procedures, the following examples were synthesized.

[0516] [Table 60]

[0517] Scheme 61 [ka]

[0518] 2-Bromo-5-(methylthio)pyridine (416) A solution of 2,5-dibromopyridine (1 g, 4.22 mmol, 1 equiv.) in THF (20 mL) was diluted with N 2 The mixture was cooled to -78 °C under reduced pressure. Then, n-BuLi (2.5 M, 1.77 mL, 4.43 mmol, 1.05 equiv) was added dropwise at -78 °C. The reaction mixture was stirred for 20 min, after which 1,2-dimethyldisulfane (0.411 mL, 4.64 mmol, 1.1 equiv) was added slowly. The reaction mixture was stirred for an additional 1 h, after which it was diluted with saturated NH 4 The reaction mixture was quenched with EA (100 mL) and water (100 mL), followed by washing with brine. The organic phase was washed with anhydrous Na s SO 4 The mixture was filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (PE:EA=10:1) to give 416 (86.8 mg). ESI [M+H] + =204.1 1 H NMR (400 MHz, CDCl 3 )δ 8.25(t,J=6.2Hz,1H),7.41(ddd,J=8.9,8.3,1.6Hz,2H),2.58-2.40(m,3H).

[0519] Scheme 62 [ka]

[0520] (1S,3S)-N1-(thieno[3,2-b]pyridin-5-yl)cyclopentane-1,3-diamine (417) Starting material 5-chlorothieno[3,2-b]pyridine allowed the synthesis of the title compound by methods similar to those described in general method 2 and general method 6.

[0521] Using the above procedures, the following examples were synthesized.

[0522] [Table 61]

[0523] Scheme 63 [ka]

[0524] General Procedure 7 3-(6-chloropyridin-3-yl)pyrimidin-4(3H)-one (419) Pyrimidin-4(3H)-one (1.5 g, 15.61 mmol, 1.0 equiv), (6-chloropyridin-3-yl)boronic acid (2.9 g, 18.73 mmol, 1.2 equiv), Cu(OAc) in DCM (60 mL) 2 A solution of (7.9 g, 43.71 mmol, 2.8 equiv), pyridine (2.5 mL, 31.22 mmol, 2.0 equiv) and 4 Å molecular sieves (8 g) was stirred at room temperature for 48 h. The mixture was filtered through Celite, and the filtrate was concentrated and purified by flash column (petroleum ether:EtOAc:1:1) to give Example 419 (170 mg, 5.3% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ 8.43(d,J=2.6Hz,1H),8.15(s,1H),7.97(d,J=6.8Hz,1H),7.80(dd,J=8.4, 2.8Hz,1H),7.53(d,J=8.5Hz,1H),6.59(dd,J=6.8,0.8Hz,1H);MS(ESI+)m / z 208.0(M+H) +

[0525] The following examples were prepared using the procedures described in Scheme 63.

[0526] [Table 62]

[0527] Scheme 64 [ka]

[0528] (E)-Ethyl 3-(2-fluoropyridin-4-yl)acrylate (423A) A suspension of 60% NaH (1.54 g, 38.4 mmol, 1.2 equiv.) in THF (15 mL) was diluted with a solution of ethyl 2-(ethoxy(propoxy)phosphoryl)acetate (8.6 g, 38.4 mmol, 1.2 equiv.) in THF and diluted with N 2 The mixture was stirred at 0° C. for 25 min, and then a solution of 2-fluoroisonicotinaldehyde (4.0 g, 32.0 mmol, 1.0 equiv) in DMF (15 mL) was added. The resulting mixture was stirred at room temperature for 16 h, followed by NH 4 The mixture was quenched with saturated aqueous Cl. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and added Na. 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuum. The residue was purified by column chromatography (PE-PE:EA=1:15) to give 423A as a white solid (3.0 g, 50% yield). LCMS: m / z 196 [M+H] + ,rt 2.890 min. 1 H-NMR (400MHz, CDCl 3 )δ 8.26(d,J=5.2Hz,1H),7.59(d,J=16.1Hz,1H),7.29-7.26(m,1H),7.00(d,J=1. 7Hz,1H),6.60(d,J=16.0Hz,1H),4.30(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).

[0529] Ethyl 3-(2-fluoropyridin-4-yl)propanoate (423B) To a solution of 423A (3.0 g, 20.5 mmol) in EtOH (20 mL) was added 10% Pd / C (400 mg). The reaction was cooled to 10°C. 2 Purge the mixture with H2 Stirred overnight under atmosphere. Pd / C was filtered off and the filtrate was concentrated in vacuo to give 423B (2.3 g, 76.7% yield), which was used directly. LCMS: m / z 198.1 [M+H] + ,rt 2.801 min. 1 H-NMR (400MHz, CDCl 3 )δ 8.12(d,J=5.5Hz,1H),7.04(d,J=4.8Hz,1H),6.78(d,J=4.0Hz,1H),4.13(p,J =6.8Hz,2H),3.03-2.97(m,2H),2.66(t,J=7.6Hz,2H),1.24(t,J=6.7Hz,3H).

[0530] 3-(2-oxo-1,2-dihydropyridin-4-yl)propanoic acid (423C) To a 100 mL flask containing 423B (1.53 g, 7.77 mmol) was added concentrated HCl (5 mL). The mixture was heated to 100 °C for 16 h. The mixture was then cooled to room temperature and 2 mL of water was added. Solid NaHCO 3 was added in small portions to adjust the pH to 6. The mixture was diluted with CHCl 3 The combined organic layers were extracted with 30% i-PrOH in Na 2 SO 4 The residue was purified by column chromatography (MeOH / DCM) to give 423C (1.6 g, 91% yield), which was used directly in the next step. LCMS: m / z 167.8 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 )δ 8.14(d,J=5.1Hz,1H),7.05(dt,J=5.3,1.7Hz,1H),6.82-6.76(m,1H),3.01(t,J=7.5Hz,2H),2.73(t,J=7.5Hz,2H).

[0531] Methyl 3-(2-oxo-1,2-dihydropyridin-4-yl)propanoate (423D) A 100 mL flask containing a solution of crude 423C (1.6 g) in MeOH (28 mL) was charged with 98% H2 SO 4 (0.15 mL) was added. The reaction was heated to 90° C. for 16 h and then cooled to room temperature. Saturated aqueous NaCl was added to the above mixture, which was then diluted with CHCl 3 The combined organic layers were extracted with 30% i-PrOH in Na 2 SO 4 The residue was purified by column chromatography (MeOH:DCM=1:15) to give product 423D (702 mg, 55% yield). LCMS: m / z 182.1 [M+H] + .

[0532] General Procedure 8 Methyl 3-(6'-fluoro-2-oxo-2H-[1,3'-bipyridin]-4-yl)propanoate (423) In a sealed tube, 423D (100.0 mg, 0.55 mmol, 1.0 equiv.), 2-fluoro-5-iodopyridine (147 mg, 0.66 mmol, 1.2 equiv.), CuI (21.0 mg, 0.10 mmol, 0.2 equiv.), N,N'-dimethyl-1,2-cyclohexanediamine (15.5 mg, 0.10 mmol, 0.2 equiv.), and K 2 CO 3 (151.0 mg, 1.10 mmol, 2.0 equiv.) was added. Dioxane (3 mL) was added and the resulting mixture was diluted with N 2 The mixture was purged with hexane and stirred at 110° C. for 16 h. The mixture was then diluted with dichloromethane and filtered. The filtrate was washed with water and separated. The aqueous phase was extracted three times with dichloromethane. The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 47° C., concentrated and purified by silica gel chromatography to give 423 (42 mg, 27.6% yield). LCMS: m / z 278.08 [M+H] +

[0533] Scheme 65 [ka]

[0534] 6'-Fluoro-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate methyl (424A) A mixture of 6-fluoropyridin-3-amine (1.1 g, 10 mmol, 1.0 equiv.) and methyl 2-oxo-2H-pyran-5-carboxylate (1.5 g, 10 mmol, 1.0 equiv.) in EtOH (10 mL) was stirred at reflux overnight and then cooled to room temperature. The resulting precipitate was collected by filtration and purified by chromatography on silica gel eluted with petroleum ether:EtOAc=2:1 to give compound 424A (440 mg, 18%) as an off-white solid.

[0535] 6'-(((1S,3S)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate methyl (424B) 424B was obtained from starting materials 131C and 424A by a method similar to that described above.

[0536] General Procedure 9 6'-(((1S,3S)-3-((5-(methylthio)pyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid (Example 424) MeOH:H 2 To a solution of compound 424B (100 mg, 0.22 mmol, 1.0 equiv) in EA:MeOH=5:1 (10 mL) was added NaOH (35 mg, 0.88 mmol, 4.0 equiv). The mixture was stirred at 50° C. for 3 h, then cooled to room temperature and acidified to pH=5-6. The resulting mixture was concentrated and redissolved in THF (50 mL). The solid was filtered off, and the filtrate was concentrated and triturated with EA:MeOH=5:1 to give Example 424 (90 mg, 93%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6)δ:8.35(s,2H),8.25s,1H),8.10 1H),7.87(d,J=9.2Hz,1H),7.56(s,1H),6.87(s,1H),6.51(d,J=9.2Hz,1H),4.36- 4.33(m,2H),2.35(s,3H),2.22-2.10(m,2H),2.01-1.93(m,2H),1.57-1.55(m,2H).

[0537] Using the above procedures, the following examples were synthesized.

[0538] [Table 63]

[0539] [Table 64]

[0540] [Table 65]

[0541] Scheme 66 [ka]

[0542] 2-Chloro-5-((trimethylsilyl)ethynyl)pyridine (431A) To a degassed solution of 2-chloro-5-iodopyridine (5 g, 20.88 mmol, 1.0 equiv.) in triethylamine (35 mL) was added ethynyltrimethylsilane (3.2 mL, 22.97 mmol, 1.1 equiv.), CuI (397.7 mg, 2.09 mmol, 0.1 equiv.) and Pd(PPh 3 ) 2 Cl 2 (1.5 g, 2.09 mmol, 0.1 equiv) was added. The reaction mixture was stirred at room temperature under nitrogen for 16 h. Water (150 mL) was added and the system was purified with Et 2 The combined organic layer was extracted with NaO (100 mL × 2).2 SO 4 The mixture was dried at 40° C., filtered, and then concentrated under reduced pressure. The resulting crude 431A (6.2 g, black solid) was used for the next step without further purification. MS (ESI+) m / z 209.9 (M+H). +

[0543] 2-Chloro-5-ethynylpyridine (431B) 431A (crude, 20.88 mmol, 1.0 equiv.) and K 2 CO 3 A solution of (2.9 g, 20.88 mmol, 1.0 equiv) was stirred at room temperature for 2 h. After removal of the solvent under reduced pressure, DCM was added (150 mL) and the mixture was filtered. The filtrate was concentrated and purified by flash column (petroleum ether: EtOAc = 10:1) to give compound 432B as a yellow solid (1.0 g, 34.8% yield for two steps). MS (ESI+) m / z 138.1 (M+H). + ; 1 H NMR (400MHz, DMSO-d 6 )δ:8.55(d,J=2.1Hz,1H),7.98(dd,J=8.4,2.4Hz,1H),7.57(d,J=8.3Hz,1H),4.56(s,1H).

[0544] 2-Chloro-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyridine (431C) 431B (345 mg, 2.54 mmol, 1.0 equiv), (azidomethyl)trimethylsilane (327 mg, 2.54 mmol, 1.0 equiv), CuI (48 mg, 0.25 mmol, 0.1 equiv), NEt in THF (10 mL). 3 A solution of (513 mg, 5.08 mmol, 2.0 equiv) was stirred at room temperature for 16 h. The reaction mixture was then concentrated to give 431C (673 mg), which was used without further purification.

[0545] 2-Chloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine (431) To a solution of 431C in THF (10 mL) was added TBAF (0.80 g, 3.0 mmol, 1.2 equiv.) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (PE:EA=1:1) to give 431 (150 mg).

[0546] Scheme 67 [ka]

[0547] 2-Chloro-5-(iodoethynyl)pyridine (432A) LDA (4.4 mL, 8.73 mmol, 1.2 equiv) was added dropwise to a solution o...

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, A is H, halo, hydroxy, alkyl, thioalkyl, alkenyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR ６ and -C(O)NR ６ R ７ Selected from: B is selected from H, alkyl, and halo; or A and B together with the carbon atom to which they are attached 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 When n is 0, R １ and R １’ together with the atoms to which they are attached form a 4- to 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 atom to which they are attached form a 3- to 8-membered cycloalkyl or heterocyclyl ring; or R １’ and R ２ together with the atom to which they are attached form a 3- to 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’ 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- to 8-membered cycloalkyl or heterocyclyl ring; and R ５ is H or alkyl; or R １ and R ５ together with the atom to which they are attached form a 6- to 8-membered cycloalkyl or heterocyclyl ring; or R ２ and R ５ together with the atom 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).

2. A is H, hydroxy, thioalkyl, alkyl, alkoxy, acyloxy, cyano, cycloalkyl, -C(O)OR ６ and -C(O)NR ６ R ７ 2. The compound of claim 1 , selected from:

3. The compound of claim 1 , wherein A is H.

4. The compound of claim 1 , wherein A is alkyl.

5. The compound of claim 1 , wherein A is thioalkyl.

6. The compound of claim 1 , wherein A is alkoxy.

7. The compound of claim 1 , wherein A is cycloalkyl.

8. A is -SCH ３ , -SCHF ２ , and -OCHF ２ 2. The compound of claim 1 , selected from:

9. 2. The compound of claim 1, wherein A and B, together with the carbon atom to which they are attached, form a pyrrolyl or thienyl ring, which is unsubstituted or substituted with one or more alkyl.

10. The compound according to any one of claims 1 to 9, wherein B is H.

11. X is NR ５ The compound according to any one of claims 1 to 10,

12. The compound of any one of claims 1 to 11, wherein Y is heteroaryl or heterocyclyl.

13. R １ and R １ 13. The compound of any one of claims 1 to 12, wherein each ' is H.

14. n is 0 and R １ and R １’ are taken together with the atoms to which they are attached to form a 4-8 membered mono- or bicyclic cycloalkyl or cycloalkenyl ring, which is unsubstituted or substituted, for example, by one or more hydroxy.

15. R １ and R １’ The compound of claim 14, wherein, together with the atom to which they are attached, form a 4-8 membered monocyclic or bicyclic cycloalkyl.

16. R １ and R １’ The compound of claim 14, wherein: combined with the atom to which they are attached forms a 4-8 membered monocyclic or bicyclic cycloalkenyl.

17. 15. The compound of claim 14, wherein the cycloalkyl ring is a cyclopentyl ring.

18. 15. The compound of claim 14, wherein the cycloalkyl ring is substituted with hydroxyl or hydroxyalkyl.

19. R ２ The compound of any one of claims 1 to 18, wherein is selected from H, halo, alkyl, alkoxy, amidoalkyl, aminoalkyl, alkylamino, cyano, and hydroxyl.

20. R ２ But, C １～３ The compound according to any one of claims 1 to 19, which is alkyl.

21. R ２ 21. The compound of claim 20, wherein is substituted with one or more substituents selected from amino, amido, cyano, hydroxy, and heterocyclyl.

22. R ２’ But, C １～３ The compound according to any one of claims 1 to 21, which is alkyl.

23. R ２’ The compound according to any one of claims 1 to 21, wherein is H.

24. R １ and R ２ The compound according to any one of claims 1 to 12, wherein, together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring.

25. R １’ and R ２ The compound according to any one of claims 1 to 12, wherein, together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring.

26. R ２ and R ２’ The compound according to any one of claims 1 to 12, wherein: combined with the carbon atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl ring.

27. R ３ But, C １～３ The compound according to any one of claims 1 to 26, which is alkyl.

28. R ３ The compound according to any one of claims 1 to 26, wherein is H.

29. R ２ and R ３ The compound according to any one of claims 1 to 12, wherein, together with the atoms to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring.

30. R ４ The compound according to any one of claims 1 to 29, wherein is H.

31. R １ and R ５ The compound according to any one of claims 1 to 12, wherein, together with the atoms to which they are attached, form a 6-8 membered cycloalkyl or heterocyclyl ring.

32. R ２ and R ５ The compound according to any one of claims 1 to 12, wherein, together with the atoms to which they are attached, form a 5-8 membered cycloalkyl or heterocyclyl ring.

33. The compound of any one of claims 1 to 32, wherein Y is a monocyclic heteroaryl.

34. 34. The compound of claim 33, wherein Y is selected from pyridyl, pyridinyl, pyrazinyl, pyrimidinyl, and thiazolyl.

35. 34. The compound of claim 33, wherein Y is selected from triazenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, and triazolyl.

36. 36. The compound of any one of claims 33-35, wherein the monocyclic heteroaryl is 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.

37. 37. The compound of claim 36, wherein the monocyclic heteroaryl is substituted with a 6-membered 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.

38. The monocyclic heteroaryl is selected from the group consisting of halo, CN, alkyl, alkoxy, hydroxy, carboxy, -CO ２ 38. The compound of claim 37, which is substituted with heteroaryl or heterocyclyl substituted with one or more substituents selected from alkyl, and tetrazolyl.

39. 37. The compound of claim 36, wherein the monocyclic heteroaryl is positioned para to A relative to X.

40. The compound of any one of claims 1 to 32, wherein Y is a bicyclic heteroaryl.

41. 41. The compound of claim 40, wherein Y is selected from benzothiazolyl, benzoxazolyl, benzimidazolyl, triazolopyridinyl, thiazolopyrindinyl, quinolinyl, and quinoxalinyl.

42. 42. The compound of claim 40 or 41, wherein the bicyclic heteroaryl is unsubstituted or substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, thioalkyl, alkoxy, alkoxycarbonyl, amido, carboxy, cyano, halo, heteroaryl, nitro, and sulfonamido.

43. 42. The compound of claim 40 or 41, wherein the bicyclic heteroaryl is unsubstituted or substituted with one or more substituents selected from thioalkyl, alkoxycarbonyl, amido, carboxy, halo, and heteroaryl.

44. Y is a group of the formula -C(O)NR ８ R ９ Or -NR ９ C(O)R １０ is substituted with an amide substituent of R ８ and R ９ are each independently selected from H, alkyl, heterocyclyl, and heteroaryl; or R ８ and R ９ together with the nitrogen atom to which they are attached, forming a 4-, 5-, 6-, or 7-membered heterocyclic or heteroaryl ring; and R １０ The compound according to any one of claims 1 to 43, wherein is alkyl.

45. Y is a group represented by the formula -S(O) ２ N.R. ８ R ９ Or -NR ９ S (O) ２ R １０ is substituted with a sulfonamide substituent of R ８ and R ９ are each independently selected from H, alkyl, and heteroaryl; or R ８ and R ９ together with the nitrogen atom to which they are attached, forming a 4-, 5-, 6-, or 7-membered heterocyclic ring; and R １０ The compound according to any one of claims 1 to 42, wherein is alkyl.

46. R ８ and R ９ 46. ​​The compound of claim 44 or 45, wherein each is independently selected from H, methyl, ethyl, triazolyl, and pyrazolyl.

47. R ８ and R ９ wherein one or both are alkyl, and 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.

48. R ８ and R ９ taken together with the nitrogen atom to which they are attached form a heterocycle selected from azirazine, isothiazolidine-1,1-dioxide, azetindine, thiazol-4(5Hn)-one, morpholine, piperidine, piperazine, pyrrolidine, thiomorpholine-1,1-dioxide, 2-oxa-6-azaspiro[3.3]heptane.

49. R ８ and R ９ together with the nitrogen atom to which they are attached, 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-diaza Spiro[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.

50. 49. The compound of claim 48, wherein the heterocycle is unsubstituted or substituted with one or more substituents selected from alkyl, alkoxycarbonyl, halo, hydroxy, cyano, carboxy, and heterocyclyl.

51. 49. The compound of claim 48, wherein the heterocycle is unsubstituted or substituted with one or more substituents selected from methyl, ethoxycarbonyl, halo, hydroxy, cyano, carboxy, and oxetanyl.

52. 【Chemical 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical Formula 22】 A compound selected from:

53. 53. A pharmaceutical composition comprising a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

54. 53. A method of treating cardiovascular disease in a subject, comprising administering to the subject a compound according to any one of claims 1 to 52.

55. 55. The method of claim 54, wherein the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipidemia, atherosclerosis, fatty liver, metabolic syndrome, and coronary artery disease.

56. 56. The method of claim 54 or 55, wherein the cardiovascular disease is familial hypercholesterolemia.

57. 56. The method of claim 54 or 55, wherein the cardiovascular disease is autosomal dominant hypercholesterolemia.

58. The method of any one of claims 54 to 57, wherein the level of circulating serum cholesterol is reduced in the subject.

59. The method of any one of claims 54 to 58, wherein the level of circulating serum LDL-cholesterol is reduced in the subject.

60. 60. The method of any one of claims 54 to 59, wherein the level of circulating serum VLDL-cholesterol is reduced in the subject.

61. The method of any one of claims 54 to 60, wherein the level of circulating serum triglycerides is reduced in the subject.

62. 62. The method of any one of claims 54 to 61, wherein the level of circulating serum lipoprotein A is reduced in the subject.

63. 63. The method of any one of claims 54 to 62, wherein the subject has atherosclerosis.

64. The method of any one of claims 54 to 63, wherein atherosclerotic plaque formation is reduced in the subject.

65. The method of any one of claims 54 to 64, wherein the subject has a gain-of-function mutation in the PCSK9 gene.

66. 66. The method of any one of claims 54 to 65, further comprising conjointly administering one or more additional therapeutic agents.

67. 67. The method of claim 66, wherein the one or more additional therapeutic agents are selected from alirocumab, evolocumab, bococizumab, RG7652, LY3015014, mAb316P, berberine, quercetin, ezetimibe, policosanol, BMS-962476, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

68. 67. The method of claim 66, wherein the one or more additional therapeutic agents are selected from HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, HMG-CoA synthase gene expression inhibitors, MTP / Apo B secretion inhibitors, CETP inhibitors, bile acid absorption inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, squalene cyclase inhibitors, combined squalene epoxidase / squalene cyclase inhibitors, fibrates, niacin, combinations of niacin and lovastatin, ion exchange resins, antioxidants, ACAT inhibitors, bile acid sequestrants, and PCSK9 translation inhibitors.

69. 53. A method of treating sepsis or septic shock in a subject, comprising administering to the subject a compound according to any one of claims 1 to 52.

70. 70. The method of claim 69, further comprising conjointly administering one or more additional therapeutic agents.

71. The one or more additional therapeutic agents are selected from the group consisting of kanamycin, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, streptomycin, neomycin B, C, and E, imipenam, meropenam, ertapenam, doripenem, panipenem, biapenem, razupenem, tebipenam, lanapenam, tomopenam, thienpenam, ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, cinoxacin, nalidixic acid, moxifloxacin, oxolinic acid, piromidic acid, pipemidic acid, losoxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, 71. The method of claim 70, wherein the medicament is selected from rufloxacin, balofloxacin, grepafloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin, sitafloxacin, trovafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, nemonoxacin, zavofloxacin, doxycycline, tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, tigecycline, ampicillin, amoxicillin, augmentin, piperacillin, tazobactam, chloramphenicol, and ticarcillin.

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