Thiazole compounds, compositions and methods of treating disorders associated with missfolding of alpha-synuclein protein

Abstract

The present disclosure provides compounds of formula (I): (I) useful for treating or lessening the severity of diseases or conditions, including those associated with alpha-synuclein protein.

Description

[0001] THIAZOLE COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISORDERS ASSOCIATED WITH MISSFOLDING OF ALPHA-SYNUCLEIN PROTEIN

[0002] Cross-reference to related applications

[0003]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 618,482, tiled on January 8, 2024, which is incorporated by reference in its entirety.

[0004] Background

[0005]

[0002] a-Synuclein (a-syn) is a 140 amino acid protein encoded by the SNCA gene, and is one of the most abundantly expressed proteins in the nervous system (1 % of total cytosolic protein). It is intrinsically disordered in aqueous solutions, but forms a-helical structures on binding to negatively charged lipids. It is predominantly neuronal and localises to presynaptic terminals under physiological conditions. Physiological functions are only partially understood, protein is thought to be involved in membrane interactions, (particularly mitochondrial), and to play a role in regulating dopamine levels. Aggregated forms of a-syn (“Lewy bodies” & “Lewy neurites”) are a hallmark of Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA). There is a strong body of pre- clinical data demonstrating that it is smaller, soluble aggregated forms of a-syn, termed “oligomers'”, which are a key driver of neurotoxicity. These oligomeric forms of a-synuclein have been shown to have wide-ranging neurotoxicity and underlie the onset and progression of Parkinson’s Disease (PD). These oligomers bind to membranes, receptors and organelles, disrupt metabolic and neuronal functional pathways and ultimately cause neuronal death.

[0006] Summary

[0007]

[0003] The present disclosure includes a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, Ring A, Ring C, m, and p are defined herein.

[0008]

[0004] Additionally, the present disclosure includes methods of preparing a compound of Formula (I) and methods of using a compound of Formula (I). Detailed Description

[0009] Definitions

[0010]

[0005] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0011]

[0006] The term "haloaliphatic" refers to an aliphatic group that is substituted with one or more halogen atoms.

[0012]

[0007] The term "alkyl" refers to a straight or branched alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0013]

[0008] The term "haloalkyl" refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.

[0014]

[0009] The term "halogen" means F, Cl, Br, or I.

[0015]

[0010] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0016]

[0011] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 147t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0017]

[0012] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in alkyl-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0018]

[0013] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0019]

[0014] As described herein, compounds of the present disclosure may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0020]

[0015] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; — (CH2)O-4R°; — (CH2)O-4 OR°; — 0(CH2)0-4R°, — O— (CH2)O-4C(O)OR°; — (CH2)O-4CH(OR°)2; — (CH2)O-4SR°; — (CH2)0-4Ph, which may be substituted with R°; — (CH2)0-40(CH2)0-1Ph which may be substituted with R°; — CH=CHPh, which may be substituted with R°; — (CH2)0-4O(CH2)o-i-pyridyl which may be substituted with R°; — NO2; — CN; — N3; — (CH2)O-4N(R°)2; — (CH2)O-4N(R°)C(0)R°; — N(R°)C(S)R°; — (CH2)O-4N(R°)C(0)NR° 2; — N(R°)C(S)NR° 2; — (CH2)0-4N(R°)C(0)OR°; — N(R°)N(R°)C(O)R°; — N(R°)N(R°)C(O)NR° 2; — N(R°)N(R°)C(O)OR°; — (CH2)0-4C(0)R°; — C(S)R°; — (CH2)O-4C(0)OR°; — (CH2)O-4C(0)SR°; — (CH2)0-4C(0)OSiR° 3; — (CH2)o-4OC(O)R°; — OC(0)(CH2)O-4SR°, SC(S)SR°; — (CH2)O-4SC(0)R°; — (CH2)O-4C(0)NR°2; — C(S)NR° 2; — C(S)SR°; — SC(S)SR°, — (CH2)0-40C(0)NR°2; — C(O)N(OR°)R°; — C(O)C(O)R°; — C(O)CH2C(O)R°; — C(NOR°)R°; — (CH2)0-4SSR°; — (CH2)0-4S(0)2R°; — (CH2)O-4S(0)2OR°; — (CH2)O-40S(0)2R°; — S(O)2NR°2; — (CH2)0-4S(0)R°; — N(R°)S(O)2NR° 2; — N(R°)S(O)2R°; — N(OR°)R°; — C(NH)NR° 2; — P(O)2R°; — P(O)R° 2; — OP(O)R° 2; — 0P(0)(0R°)2; SiR° 3; — (C1-4 straight or branched alkylene)O — N(R°)2; or — (C1-4 straight or branched alkylene)C(O)O — N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, — CH2Ph, — 0(CH2)o-iPh, — CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0021]

[0016] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, — (CH2)o-2R*, -(haloR*), — (CH2)o-2OH, — (CH2)o-2OR*, — (CH2)o-2CH(OR*)2; — O(haloR’), — CN, — N3, — (CH2)O-2C(0)R*, — (CH2)O-2C(0)OH, — (CH2)O-2C(0)OR*, — (CH2)O-2SR*, — (CH2)o-2SH, — (CH2)O-2NH2, — (CH2)o-2NHR*, — (CH2)o-2NR* 2, — NO2, — SiR* 3, — OSiR* 3, — C(O)SR*, — (C1-4 straight or branched alkylene)C(O)OR*, or — SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, — CH2Ph, — 0(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0022]

[0017] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, — O(C(R*2))2-3O— , or — S(C(R*2))2- 3S — , wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: — O(CR*2)2-sO — , wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0023]

[0018] Suitable substituents on the aliphatic group of R* include halogen, — R*, -(haloR*), —OH, —OR’, — O(haloR’), — CN, — C(O)OH, — C(O)OR*, — NH2, — NHR*, —NR*2, or — NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, — CH2PI1, — 0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0024]

[0019] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted — OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R\ taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0025]

[0020] Suitable substituents on the aliphatic group of R:are independently halogen, — R*, - (haloR*), —OH, —OR*, — O(haloR*), — CN, — C(O)OH, — C(O)OR*, — NH2, —NHR*, — NR* 2, or — NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, — CH2PI1, — 0(CH2)o- iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026]

[0021] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0027]

[0022] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0028]

[0023] Combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0024] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0029]

[0025] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0030]

[0026] As used herein, a "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. I

[0031]

[0027] As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and / or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.

[0032]

[0028] The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0033]

[0029] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound(s) with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the compounds disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0034]

[0030] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitory active metabolite or residue thereof.

[0035]

[0031] The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that total daily usage of compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. Specific effective dose level for any particular patient or organism will depend upon a variety of factors including disorder being treated and severity of the disorder; activity of specific compound employed; specific composition employed; age, body weight, general health, sex and diet of the patient; time of administration, route of administration, and rate of excretion of a specific compound employed; duration of treatment; drugs used in combination or coincidental with a specific compound employed, and like factors well known in the medical arts.

[0036] Compounds

[0037]

[0032] The present disclosure includes a compound of Formula ( I): or a pharmaceutically acceptable salt thereof wherein

[0038] Ring A is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 5-10 membered heterocyclyl; Ring C is optionally substituted 5-6-membered heteroaryl or optionally substituted 9-10 membered heterocyclyl;

[0039] R1is independently selected from the group consisting of halogen, -OH, -ORC, -NH2, - CN, -NO2, -C(O)OH, -C(O)ORC, -C(O)RC, -NHRC, -N(RC)2, -C(O)NHRC, - C(O)N(RC)2, -S(O)2RC, -(CH2)I-3RC, -(CH2)1-3OH, -(CH2)I-3ORC, -P(O)(RC)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;

[0040] R2is hydrogen or optionally substituted C1-C3 alkyl; or wherein R1and R2along with their intervening atoms together form an optionally substituted 7-membered aryl ring;

[0041] R3is independently selected from the group consisting of halogen, -OH, -ORC, -NH2, - CN, -NO2, -C(O)OH, -C(O)ORC, -C(O)RC, -NHRC, -N(RC)2, -C(O)NHRC, - C(O)N(RC)2, -S(O)2RC, -(CH2)I-3RC, -(CH2)I-3OH, -(CH2)I-3ORC, -P(O)(RC)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl; each Rcis independently selected from the group consisting of optionally substituted Ci- C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of Rcare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, 4, or 5.

[0042]

[0033] In some embodiments, a compound of Formula (I) is not

[0043]

[0034] In some embodiments, the compound is of Formula (la): or a pharmaceutically acceptable salt thereof', wherein R1, R2, RJ, Ring C, m and p are defined herein.

[0044]

[0035] In some embodiments, the compound is of Formula (Ia~l):

[0045] (la-1) or a pharmaceutically acceptable salt thereof, wherein R1, R3Ring C, and p are defined herein.

[0046]

[0036] In some embodiments, the compound is of Formula (lb): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, Ring C, m and p are defined herein.

[0047]

[0037] In some embodiments, the compound is of Formula (Ib-1): or a pharmaceutically acceptable salt thereof, whereinR1, R3Ring C, and p are defined herein.

[0048]

[0038] In some embodiments, the compound is of Formula ( Ic): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, Ring C, m and p are defined herein .

[0049]

[0039] In some embodiments, the compound is of Formula (Ic-1): or a pharmaceutically acceptable salt thereof, wherein , R\ Ring CR, a1nd p are defined herein.

[0050] Ring A

[0051]

[0040] In some embodiments, Ring A is optionally substituted phenyl, optionally substituted 5- 10 membered heteroaryl or optionally substituted 5-10 membered heterocyclyl . In some embodiments, Ring A is optionally substituted phenyl. In some embodiments. Ring A is optionally substituted 5-10 membered heteroaryl. In some embodiments, Ring A is optionally substituted 5-10 membered heterocyclyl.

[0052]

[0041] In some embodiments, Ring A is optionally substituted phenyl. In some In some embodiments, Ring A is some embodiments. Ring A is

[0053]

[0042] In some embodiments, Ring A is optionally substituted 5-membered heteroaryl. In some embodiments, Ring A is optionally substituted thiazolyl or optionally substituted imidazolyl.

[0054]

[0043] In some embodiments, Ring A is optionally substituted thiazolyl. In some embodiments, Ring In some embodiments. Ring A is selected from the group consisting of

[0055]

[0044] In some embodiments, Ring A is optionally substituted imidazolyl. In some embodiments, Ring In some embodiments, Ring A is selected from the group consisting of

[0056]

[0045] In some embodiments, Ring A is optionally substituted oxazolyl. In some embodiments. Ring some embodiments, Ring

[0057]

[0046] In some embodiments, Ring A is optionally substituted 6- membered heteroaryl. In some embodiments, Ring A is optionally substituted pyridinyl.

[0058]

[0047] In some embodiments, Ring A is selected from the group consisting of

[0048] In some embodiments, Ring A is

[0059] Ring C

[0060]

[0049] In some embodiments, Ring C is optionally substituted 5-6 membered heteroaryl or optionally substituted 9-10 membered heterocyclyl. In some embodiments, Ring C is optionally substituted 6-membered heteroaryl selected from the group consisting of pyridinyl, pyramidinyl, and pyrazinyl. In some embodiments. Ring C is optionally substituted 9-10 membered heterocyclyl. In some embodiments, Ring C is optionally substituted 9-membered heterocyclyl . In some embodiments, Ring C is optionally substituted 10-membered heterocyclyl .

[0061]

[0050] In some embodiments, Ring C is selected from the group consisting of

[0062]

[0051] In some embodiments, Ring C is selected from the group consisting of

[0063]

[0053] In some embodiments, Ring C is

[0064] R

[0065]

[0055] In some embodiments, R:is independently selected from the group consisting of R1 some embodiments, R1is -NMe2. In some embodiments, R1is -CH2NH2. In some embodiments, R1is fluoro. In some embodiments, R;is methyl. R2

[0066]

[0056] In some embodiments, R2is hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, R2is hydrogen.

[0067] R3

[0068]

[0057] In some embodiments, R3is independently selected from the group consisting of membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 m embered heteroaryl .

[0069]

[0058] In some embodiments, R3is halogen or -ON. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is -CN.

[0070]

[0059] In some embodiments, R3is OR'i In some embodiments, In some embodiments, R3’ is -CF3. In some embodiments, R

[0071]

[0060] The present disclosure includes a compound from Table 1 or a pharmaceutically acceptable salt thereof

[0072] Table 1

[0073]

[0074]

[0075]

[0076]

[0077] Alternative Embodiments

[0078]

[0061] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0079]

[0062] Unless otherwise specified, the stereochemistry of the compounds of Table 1 and the synthetic intermediates of the Exemplification has been arbitrarily assigned for clarity. A person of skill in the art will understand the present disclosure includes compounds with the stereochemistry which are the opposite of how they have been drawn. Additionally, the present disclosure contemplates tautomers of the compounds as drawn herein.

[0080]

[0063] The present disclosure includes the racemate of any compound disclosed herein.

[0081] Pharmaceutical Compositions

[0082]

[0064] In some embodiments, the present disclosure provides a composition comprising a compound of Formula (I) and Formula (II) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions contemplated herein is such that is effective to measurably treat a disease or disorder in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that is effective to measurably treat a disease or disorder in a biological sample or in a patient. In certain embodiments, a composition contemplated by this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition contemplated by this disclosure is formulated for oral administration to a patient.

[0083]

[0065] In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some preferred embodiments, compositions are administered orally, intraperitoneally or intravenously. In some embodiments, sterile injectable forms of the compositions comprising one or more compounds of Formula (I) and Formula (II) may be aqueous or oleaginous suspension. In some embodiments, suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. In some embodiments, among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0084]

[0066] The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0085]

[0067] Pharmaceutically acceptable compositions comprising one or more compounds of Formula (I) and Formula (II) may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. In some embodiments, useful diluents include lactose and dried cornstarch. In some embodiments, when aqueous suspensions are required for oral use, an active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweetening, flavoring or coloring agents may also be added.

[0086]

[0068] Alternatively, pharmaceutically acceptable compositions comprising a compound of Formula (I) and Formula (II) may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0069] Pharmaceutically acceptable compositions comprising a compound of Formula (I) and Formula (II) may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. In some embodiments, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0087]

[0070] Pharmaceutically acceptable compositions comprising a compound of Formula (I) and Formula (II) may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0088]

[0071] In some embodiments, an amount of a compound of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0089]

[0072] The presently disclosed compounds can be formulated into pharmaceutical compositions along with a pharmaceutically acceptable carrier or excipient. According to this aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) in association with a pharmaceutically acceptable excipient, diluent or carrier.

[0090]

[0073] The formulations of Compounds of Formula (I) or Formula (II) include those suitable for the administration routes detailed herein. They may conveniently be presented in unit dosage form and can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Techniques and formulations generally and suitable for use herein are found in Remington’s Pharmaceutical Sciences (16lnedition, Osol, A. Ed. (1980), Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the excipient or carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or carriers or finely divided solid excipients or carriers or both, and then, if necessary, shaping the product.

[0091]

[0074] A typical formulation is prepared by mixing a compound of Formula (I) or Formula (II), and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon die means and purpose for which the compound of Formula (I) or Formula (II), is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are nontoxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e. , a compound of Formula (I) or Formula (II), or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0092]

[0075] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of Formula (I) or Formula (II), or stabilized form of the Compound of Formula (I) or Formula (II), (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of Formula (I) or Formula (II) is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0093]

[0076] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package, hi addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0094]

[0077] Pharmaceutical formulations may be prepared for various routes and types of administration. For example, a compound of Formula (I) or Formula (II) having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington5s Pharmaceutical Sciences (1980) 16thedition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution.

[0095]

[0078] Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable excipients or carriers, i.e. , excipients or earners that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends main ly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment,

[0096]

[0079] The compounds of Formula (I) or Formula (II) can be sterile. In particular, formulations to be used for in vivo administration should be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

[0097]

[0080] The compound of Formula (I) or Formula (II) ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.

[0098]

[0081] The pharmaceutical compositions comprising a compound of Formula (I) or Formula (II) can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The ‘Therapeutically effective amount" of the compound to be admini stered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the coagulation factor mediated disorder. In some embodiments, the amount is below the amount that is toxic to the host or renders the host more susceptible to bleeding.

[0099]

[0082] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine, monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poiy-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16thedition, Osol, A. Ed. (1980).

[0100]

[0083] Sustained-release preparations of Formula (I) or Formula (II) compounds may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula (I) or Formula (II), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxy ethyl- methacrylate), or poly(vi nyl alcohol)), polylactides, copolymers ofL-glutamic acid and ganmm-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT'™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3- hydroxybutyric acid.

[0101]

[0084] Formulations of a compound of Formula (I) or Formula (II) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of Formula (I) or Formula (II).

[0085] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow7or controlled release of the active i ngredi en t th erefrom .

[0102]

[0086] Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of compounds of Formula (I) or Formula (II) intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl disiearate alone or with a wax may be employed.

[0103]

[0087] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredients) in an amount of, for example, 0.075 to 20% w / w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base.

[0104]

[0088] If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e. , an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulations may desirably Include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

[0105]

[0089] The oily phase of the emulsions may be constituted from known ingredients in a known manner. While the phase may comprise solely an emulsifier, it may also comprise a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. A hydrophilic emulsifier included together with a lipophilic emulsifier may act as a stabilizer. Together, the emulsifier(s) with or without stabili zer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

[0090] Aqueous suspensions of Formula (I) or Formula (II) compounds contain the acti ve materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxyrn ethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0106]

[0091] The pharmaceutical compositions of compounds of Formula (I) or Formula (II), may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such 1 ,3 -butanediol. The sterile injectable preparation may also be prepared as a lyophilized pow'der. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono* or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0107]

[0092] The amount of active ingredient that may be combined with the excipient or carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of excipient or carrier material which may vary from about 5 to about 95% of the total compositions (weight / weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL / hr can occur.

[0108]

[0093] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0109]

[0094] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable excipient or carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w / w, for example about 0.5 to 10% w / w, for example about 1 .5% w / w.

[0110]

[0095] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0111]

[0096] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0112]

[0097] Formulations suitable for intrapul monary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1 , 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of disorders as described below.

[0113]

[0098] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such excipients or carriers as are known in the art to be appropriate.

[0114]

[0099] 1 'he formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient or carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

[0115] Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0116]

[0100] The subject matter further provides veterinary’ compositions comprising at least one active ingredient as above defined together with a veterinary excipient or carrier therefore. Veterinary excipients or carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary' art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[0117]

[0101] In particular embodiments the pharmaceutical composition comprising the presently disclosed compounds further compose a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapeutic agent.

[0118] Kits

[0119]

[0102] Further provided are kits for carrying out the methods detailed herein, which kits comprise one or more compounds described herein or a pharmaceutical composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of a disorder such as cancer. In some embodiments, the kit contains instructions for use in the treatment of a cancer.

[0103] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.

[0120]

[0104] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disorder (e.g., cancer) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and may be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0121]

[0105] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to a subject.

[0122] Methods of Using Compounds of the Present Disclosure

[0123]

[0106] In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein. In some embodiments, a method is used for treating, lessening the severity of, or preventing alpha-synucleinopathies. In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein comprises the step of administering to said patient a composition according to the present disclosure. In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein comprises the steps of selecting a composition according to the present disclosure and administering to said patient a composition according to the present disclosure.

[0124]

[0107] The term “disease or condition associated with alpha-synuclein”, as used herein means any disease or other deleterious condition in which alpha-synuclein or alpha-synuclein protein misfolding is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which alpha synuclein or alpha-synuclein protein misfolding is known to play a role. Accordingly, another embodiment of the present disclosure relates to preventing or preventing the severity of one or more diseases in which alpha-synuclein or alpha-synuclein protein misfolding is known to play a role. In some embodiments, a disease or condition associated with alpha-synuclein is a neurodegenerative disease.

[0125]

[0108] The term “dementia with Lewy Bodies”, as used herein means any disease or other deleterious condition in which dementia occurs with along with the deposition, aggregation, or accumulation of Lewy bodies in the brain. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which dementia with Lewy bodies is known to play a role. Accordingly, another embodiment of the present disclosure relates to preventing or preventing the severity of one or more diseases in which dementia with Lewy bodies or dementia with Lewy body protein misfolding is known to play a role. In some embodiments, a disease or condition associated with dementia with Lewy bodies is a neurodegenerative disease. In some embodiments, a disease or condition associated with dementia does not occur with Lewy bodies.

[0126]

[0109] In some embodiments, administration of a compound of the present disclosure results in treating of the prevention of protein misfolding. In some embodiments, administration of a compound of the present disclosure results in prevention of alpha-synuclein protein misfolding. In some embodiments, the present disclosure results in treating or preventing a disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates.

[0127]

[0110] In some embodiments, preventing protein misfolding is defined as a 10-100% reduction in misfolding of protein misfolding. In some embodiments, preventing protein misfolding is defined as a 20-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 30-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 40-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 50- 100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 60-100% reduction in protein misfolding. In some embodiments preventing protein misfolding is defined as a 70-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 80-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 90-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 100% reduction in protein misfolding.

[0128] [Hl] In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 10-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 20-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 30- 100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 40-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 50-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 60-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, protofibrils, fibrils, or aggregates is defined as a 70-100% reduction in protein oligomers, protofibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 80-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 90-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates.

[0129]

[0112] In some embodiments, compounds and compositions, according to a method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of protein misfolding. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, severity of the infection, particular agent, its mode of administration, and the like. Compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.

[0130]

[0113] In some embodiments, compounds and compositions, according to a method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, severity of the infection, particular agent, its mode of administration, and the like. Compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.

[0131]

[0114] In some embodiments, the compounds of the present disclosure act as an antibody. In some embodiments, a compound of the present disclosure bind to at least a portion the alpha- synuclein and prevent at least a portion of alpha-synuclein from aggregating. In some embodiments, a compound of the present disclosure act as an antibody. In some embodiments, a compound of the present disclosure bind to at least a portion the alpha- synuclein and prevent at least a portion of alpha-synuclein from binding to a cell receptor. In some embodiments, a compound of the present disclosure bind to at least a portion of misfolded alpha-synuclein and prevent at least a portion of misfolded alpha-synuclein from aggregating. In some embodiments, a compound of the present disclosure bind to at least a portion of misfolded alpha-synuclein and prevent at least a portion of misfolded alpha- synuclein from binding to cell receptors.

[0132]

[0115] In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be formulated into a single dosage form.

[0133]

[0116] In some embodiments, a compound of the present disclosure inhibits or reduces the severity of alpha-synuclein induced cytotoxicity. In some embodiments, cytotoxicity is reduced or inhibited in human neurons and glial cells. In some embodiments, a compound of the present disclosure inhibits or reduces the severity of cel l-to-cel I transmission of oligomeric alpha-synuclein. In some embodiments, cell-to-cell transmission is reduced or inhibited between neurons and glial cells. In some embodiments, a compound of the present disclosure inhibits or reduces the production of caspase. In some embodiments, caspase production is reduced or inhibited in neurons and glial cells.

[0134]

[0117] In some embodiments, a compound or pharmaceutical composition of the present disclosure is used to treat one or more diseases or conditions associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Parkinson’s disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer’s disease, Lewv bodv variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher’s Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synudeinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt- Jakob’s disease.

[0135]

[0118] In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein comprising administering to a subject in need there a therapeutically effective amount of or a pharmaceutically acceptable salt thereof.

[0136]

[0119] In some embodiments, the compound is administered to the subject at a dose of between about 0.001 pg / kg and about 1 ,000 mg / kg, including but not limited to about 0.001 pg / kg, about 0.01 pg / kg, about 0.05 pg / kg, about 0.1 pg / kg, about 0.5 pg / kg, about 1 pg / kg, about 10 pg / kg, about 25 pg / kg, about 50 pg / kg, about 100 pg / kg, about 250 pg / kg, about 500 pg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, and about 200 mg / kg.

[0137] EXEMPLIFICATION

[0138] Synthesis of compounds of the invention

[0139] The compounds of the invention may be synthesised by analogy with methods known to the person skilled in the art, and by analogy with the synthesis of the specific compounds described in the following examples.

[0140] Examples RT room temperature / retention time sat. saturated

[0141] SCX strong cation exchange resin

[0142] TFA trifluoroacetic acid

[0143] THF tetrahydrofuran

[0144] Synthetic Method A

[0145] Example 1. 5-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}pyridine-2-amine

[0146] Step 1: l-benzoyl-3-(5-chloropyridin-2-yl)thiourea (01-1)

[0147]

[0120] To a stirred solution of 2-amino-5-chloropyridine (1.00 g, 7.78 mmol) in DCM was added benzoyl isothiocyanate (1 .52 g, 9.31 mmol ) at. RT. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with n-hexane (20 ml..). The solids were collected by filtration and washed with n-hexane (3 x 10 mL) to afford the title compound (1.5 g, 66%) as a light yellow solid. L CMS . (ES, m / z)

[0148] Step 2: 5-chloropyridin-2-ylthiourea (01-2)

[0149]

[0121] To a stirred solution of l-benzoyl~3-(5-chloropyridin-2~yl)thiourea (1 50 g, 5. 14 mmol) in THF (15 mL) was added 1 N NaOH (30 mL) dropwise at RT. The resulting mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 x 20 ml..). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by trituration with Et2O (10 mL). The solids were collected by filtration and washed with Et2O (3 x 5 mL) to afford the title compound (800 mg, 83%) as a yellow solid. LCMS: (ES, m / z): [M+H]+188.

[0150] Step 3: l-(6-aminopyridin-3-yl)-2-bromoethanone (01-3) To a stirred solution of 1 -(6-aminopyri din-3 -yl)ethanone (500 mg, 3.67 mmol) in HBr in AcOH (33%) (5 mL) was added Br2 (0.19 mL, 3.7 mmol) dissolved in dioxane (5 mL) dropwise at 0 °C under N2. The resulting mixture was stirred for 1.5 h at RT under N2. The resulting mixture was diluted with water (10 mL). The mixture was basified to pH 10 with sat. aq. NaHCO3. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by trituration with n-pentane (5 mL) and Et2O (5 mL). The precipitated solids were collected by filtration and washed with Et2O (3 x 5 mL) to afford the title compound (300 mg, 38%) as a light yellow solid. LCMS: (ES, m / z). [M+H]+215.

[0151] Step 4: 5-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}pyridine -2-amine (Example 1)

[0152]

[0122] To a stirred solution of 5-chloropyridin-2-ylthiourea (182 mg, 0.385 mmol) in EtOH (7.5 mL) were added l-(6-aminopyridin-3-yl)-2-bromoethanone (250 mg, 0.465 mmol) at RT. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na4SP4. filtered and concentrated under vacuum. The residue was purified by prep HPLC (SunFire Prep Cl 8 OBD Column; A: water (0.1% FA), B: ACN; 25 ml. / min; 5%-39% B in 8 min, 39% B; 254 / RT (min): 6.98) to afford the title compound (70 mg, 21%) as a light yellow solid. LCMS: (ES, m / z): (300 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.49 (s, 1 H), 8.34 (d, J 2.5 Hz, 1 H), 7.83 (m, 2H), 7.20-7.09 (m, 2H), 6.49 (d, J 8.6 Hz, 1H), 6.08 (s, 2H).

[0153] Examples in Table A were synthesised using Synthetic Method A:

[0154] Example 12. 5-[2-[(5-chloro-2-pyridyl)amino]thiazol-4-yl]-4-methyl-thiazol-2-ol

[0155]

[0123] Intermediate 12-1 was prepared using the procedure described in WO2005 / 42525, then Synthetic Method A was used to deliver the title compound. LCMS: (ES, m / z): [M+H] 325. 'H NMR (300 MHz, DMiSO-de) b 1 1.61 (s, 1H), 11.25 (s, 1H), 8.35 (d, J 2.5 Hz, 1H), 7.82 (dd, J 8.9, 2.6 Hz, 1H), 7.10 (d, J 8.9 Hz, 1H), 6.91 (s, 1H), 2.29 (s, 3H).

[0156] Synthetic Method B

[0157] Example 13. 5-chloro-N-[4-(4-methyl-lH-l,3-benzimidazol-5-yl)-l,3-thiazol-2- yl]pyridin-2-amine

[0158] Step 1: l-(4-methyl-lH-l,3-benzimidazol-5-yl) ethanone (11-1)

[0159]

[0124] To a stirred solution of 5-bromo-4-methyl-1H-l,3-benzimidazole (200 mg, 0.948 mmol) and Pd(OAc)2 (21 mg, 0.095 mmol) in DMF (5 mL) and n-butyl vinyl ether (1 mL) were added l,3-bis(diphenylphosphino)propane (78 mg, 0.190 mmol) and K2CO3 (157 mg, 1. 14 mmol) dropwise at RT under N?. The reaction mixture was irradiated at 100 °C for 3 h in the microwave. The resulting mixture was diluted with water (5 mL) and acidified to pH 6 with aq. HC1. The resulting mixture was extracted with EA (3 x 10 mL). The combined organics were concentrated under vacuum to afford l-(4-methyl-lH-l,3-benzimidazol-5-yl) ethanone (150 mg, 61%) as a yellow solid. LCMS: (ES, m / z): [M+H]+175.

[0160] Step 2: 2-bromo-l-(4-methyl-lH-l,3-benzimidazol-5-yl) ethanone (11-2)

[0161]

[0125] To a stirred mixture of l-(4-methyl-lH-l,3-benzimidazol-5-yl) ethanone (500 mg, 2.9 mmol) in HBr (7 mL, 33% in AcOH) was added Br2 (460 mg, 2.9 mmol) in dioxane (1 mL) dropwise at 10 °C. The resulting mixture was stirred for 2 h at RT under N2. The resulting mixture was diluted with water (5 mL). The residue was basified to pH 8 with sat. aq. NaHCO3. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford 2-bromo-l-(4~methyl-lH-L3~benzimidazol-5~yl) ethanone (170 mg, 23%) as a yellow solid. LCMS: (ES, m / z): [M+H]+253.

[0162] Step 3: 5-chloro-N-[4-(4-methyl-lH-l,3-benzimidazol-5-yl)-l,3-thiazol-2-yl]pyridin-2- amine

[0163]

[0126] A solution of 2-bromo-l-(4-methyl-lH-l,3-benzimidazol-5-yl) ethanone (170 mg, 0.672 mmol) and 5-chloropyridin-2-ylthiourea (126 mg, 0.672 mmol) in EtOH (5 mL) was stirred for 2 h at 80 °C under N?. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (5 mL). The mixture was basified to pH 8 with sat. aq. Na2SO4. The resulting mixture was extracted with EA (3 - 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum. The residue was purified by prep HPLC (SunFire Prep C18 OBD Column; A: water (0.1% FA), B: ACN; gradient: 17%-36% B in 8 min; RT (min): 7.27) to afford the title compound (66 mg, 30%) as a light yellow solid. LCMS: (ES, m / z): 342.1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.37 (d, J 2.6 Hz, 1H), 8.24 (s, 1H), 7.82 (dd, J 8.9, 2.6 Hz, 1H), 7.51 (d, ,1 8.2 Hz, 1H), 7.45 (d, ,1 8.5 Hz, 1H), 7.16 (d, ,1 8.8 Hz, 1H), 7.03 (s, IH), 2.70 (s, 3H).

[0164] Example in Table B was synthesised using Synthetic Method B:

[0165] Synthetic Method C

[0166] Example 15. 5-chloro-N-[4-[4-methyl-2-(4-methylpiperazin-l-yl)-l,3-thiazol-5-yl]-l,3

[0167] -thiazol-2-yl]pyridine-2-amine 22-3

[0168] Step 1: 4-methylpiperazine-l-carbothioamide (22-1)

[0169]

[0127] To a stirred solution of 1 -(imidazole- l-carbothioyl)imidazole (1.00 g, 5.61 mmol) in THF (12 mL) was added 1-methyl-piperazine, (0.562 g, 5.61 mmol) at RT. The resulting mixture was stirred for I h at R.T, ami then the resulting mixture was stirred for additional 1 h at 55 °C. Half the volume was removed under vacuum, then 2 N NHt in MeOH (6 mL) added. The mixture stirred overnight at RT, then for 2 h at 55 °C. The resulting mixture was concentrated under vacuum to afford the title compound (400 mg, 45%) as a light yellow solid. LCMS: (ES, m / z):

[0170] Step 2: l-[4-methyl-2-(4-methylpiperazin-l-yl)-l,3-thiazol-5-yl]ethanone (22-2)

[0171]

[0128] To a stirred solution of 3 -chloropentane-2, 4-dione (253 mg, 1.88 mmol) in EtOH (6 mL) was added 4-methylpiperazine-1 -carbothioamide (300 mg, 1.88 mmol) at RT. The resulting mixture was stirred for 30 min at 100 °C. The mixture was concentrated under vacuum then suspended in 2 N Na2CO3(6 mL) and extracted with CH2CI2 (3 x 5 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous NajSO^ filtered and concentrated under vacuum to afford the title compound (200 nig, 44%) as a red solid. LCMS: (ES, m / z): [M+H]4240.

[0172] Step 3: 2-bromo-l-[4-methyl-2-(4-methylpiperazin-l-yl)-l,3-thiazol-5-yl]ethanone (22-3)

[0173]

[0129] To a stirred solution of l -[4~nKfoyl-2-(4~methylpiperazin-l ~yi)-l,3-thiazoi~5- yljethanone (300 mg, 1.25 mmol) in HBr (3 mL, 48% in water) was added Br2(0.07 mL, 1.4 mmol) in dioxane (2 mL) dropwise at R.T. The resulting mixture was stirred for 1 .5 h at 60 °C. The resulting mixture was concentrated under vacuum to afford the title compound. LCMS: (ES, m / z): [MHT]:318.

[0174] Step 4: 5-chloro-N-[4-[4-methyl-2-(4-methylpiperazin-l-yl)-l,3-thiazol-5-yl]-l,3 -thiazol-2-yl]pyridine-2-amine (Example 15)

[0175]

[0130] To a stirred solution of 5-chloropyridin-2-ylthiourea (assume 1.25 mmol) in EtOH (4 mL) was added 2-bromo-l-[4-methyl-2-(4-methylpiperazin-l-yl)-l,3-thiazol-5-yl]ethanone (200 mg, 0.6.31 mmol) at RT. The resulting mixture was stirred for 3 h at 80 °C, then diluted with vrater, basified to pH 9 with sat. aq. NaHCCfi. The resulting mixture was filtered, the filler cake was washed with water to obtain a solid. The solid was purified by prep HPLC (XBridge Prep Cl 8 OBD Column, A: water (0.1% NH4HCO3). B: ACN; 25 mL / min; 40%- 60% B in 8 min, 60% B; 254 / 220 nm) to afford the title compound (50 mg, 10%, 2 steps) as a pink solid. L CM S (ES, m / z): [M+H]4407.1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.32 (d, J 2.6 Hz, 1H), 7.79 (dd, J 8.9, 2.6 Hz, 1H), 7.11 (d, J 8.9 Hz, 1H), 6.83 (s, 1H), 3.38 (m, 4H), 2.41 (m, 4H), 2.38 (s, 3H), 2.21 (s, 3H).

[0176] Examples in Table C were synthesised using Synthetic Method C:

[0177] Example 17. 4-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]pyridin-2-amine

[0178] Step 1: l-(2-aminopyridin-4-yl)ethanone (33-1)

[0179]

[0131] To a stirred solution of 2-aminopyridine-4-carbonitrile (240 mg, 2 02 mmol) in EtzO (4 mL) was added methylmagnesium bromide (6.0 ml, 12 mmol, 2 M in THF) dropwise at 0 °C under N?.. The resulting mixture was stirred overnight at 40 °C under Nz. The reaction was quenched with ice water (5 mL). The mixture was extracted with EA (3 x 40 mL), the combined organic layers washed with brine (50 mL), dried over anhydrous NazSCU, concentrated and triturated with tert-butyl methyl ether to afford the title compound (4.6 g, 56%). LC IMS: (ES, m / z): [M+Hp 137.

[0180] Step 2: l-(2-aminopyridin-4-yl)-2-bromoethanone (33-2)

[0181]

[0132] To a stirred mixture of l-(2~aminopyridin-4~yl)ethanone (270 mg, 1.98 mmol) in a solution of HBr (2.7 ml., 33% in AcOH) was added Br?. (0. 1 mL, 2.0 mmol) dissolved in dioxane (2 mL) dropwise at 0 °C under 1%, the resulting mixture was stirred for I h at 0 °C under Nz. The reaction was quenched with sat.aq NaHCOj (20 mL), diluted with water (2.0 mL), extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NazSOa, and concentrated to afford the title compound (622 mg, 44%) which was used in the next step without further purification. LCMS: (ES, m / z):

[0182] Step 3: 4-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]pyridin-2-amine (Example 17)

[0183]

[0133] To a stirred mixture of 1 -(2-aminopyridin-4-yl)-2-bromoethanone (200 mg, 0.279 mmol) in EtOH (2 mL) was added 5-chloropyridin-2-ylthiourea (262 mg, 1.40 mmol) at RT and the resulting mixture was stirred overnight under Nz at 80 °C. The mixture was concentrated under vacuum, diluted with water (50 mL), extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous NazSO^, concentrated to afford a residue which was purified by prep HPLC (SunFire Prep Cl 8 OBD Column; .A: water (0.05% TFA), B: ACN; 25 mL / min; 2-5%-34% B in 10 min, 34% B; RT (min): 6. 12) to afford the title compound TFA salt (47 mg, 17%) as a yellow' solid. LCMS: (ES, m / z): [M+Hp 304.1H NMR (400 MHz, DMSO-d6): δ I 1 .75 (s, 1H), 8.38 id. J 2.5 Hz,

[0184] 1 H), 8. 18 (s, 211), 8.07 (s, 1 H), 7.97 (d, J 6.7 Hz, H I), 7.86 (dd, J 8.9, 2.6 Hz, 1 H), 7.83 (m, H i). 7.42-7.30 (m, 2H), 7.18 (d, J 9.0 Hz, H I) Synthetic Method D

[0185] Example 18. 5-chloro-N-(4-{2H,3H,4H-pyrido[3,2-b][l,4]oxazin-8-yl}-l,3-thiazol-2- yl)pyridin-2-amine

[0186] Step 1: 2-amino-4-bromopyridin-3-ol (43-1)

[0187]

[0134] To a stirred solution of 2-aminopyri din-3 -ol (5.00 g, 45.4 mmol) in EtOH (100 mL) was added Br2(14.5 g, 90.8 mmol) dropwise at 0 °C under N2. The resulting mixture was stirred for 48 h at RT under N2. The resulting mixture was concentrated under vacuum. The residue was stirred in EA (100 mL) for 1.5 h at RT. The solids were collected by filtration and washed with EA (3 x ] 00 mL) to afford the title compound hydrobromide (5.5 g, 64%) as a black solid. LCMS: (ES, m / z): [M+H]+189, 191.

[0188] Step 2: 8-bromo-2H,3H,4H-pyrido[3,2-b][l,4]oxazine (43-2)

[0189]

[0135] To a stirred solution of 2-amino-4-brom opyri din-3 -ol hydrobromide (4.50 g, 23.8 mmol) in ACN (70 mL) was added CS2CO3 (23.3 g, 71.4 mmol) at RT followed by the addition of dibromoethane (6.71 g, 35.7 mmol ). The resulting mixture was stirred overnight at 85 °C. The resulting mixture was concentrated under vacuum. The residue was purified by ) to afford the title compound (1.1 g, 21%) as a yellow solid.

[0190] Step 3: l-{2H,3H,4H-pyrido[3,2-b][l,4]oxazin-8-yl}ethanone (43-3)

[0191]

[0136] To a stirred solution of 8-bromo-2H,3H,4H-pyrido[3,2-b][l,4]oxazine (1.14 g, 5.30 mmol) in toluene (34 mL) was added tributyl(l-ethoxyethenyl)stannane (2.11 g, 5.83 mmol) and PdlPPhAi (613 mg, 0.530 mmol) at RT under N2. The resulting mixture was stirred for 2.5 h at 1 10 °C under Nz. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. To the residue were added THF (20 mL) and 1 N HC1 (20 ml.) at RT, and the resulting mixture was stirred for 2 h. The mixture was basified to pH 8 with sat. NaHCO?, (aq.). The aq. layer was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NazSCU, filtered and concentrated under vacuum. The residue was purified by FCC (PE / EA (1 :2)) to afford the tide compound (200 mg, 21%) as a light yellow solid.

[0192] Step 4: 2-bromo-l-{2H,3H,4H-pyrido[3,2-b][l,4]oxazin-8-yl}ethanone (43-4)

[0193]

[0137] To a stirred solution of l-{2H,3H,4H-pyrido[3,2-b][l,4]oxazin-8-yl (ethanone (100 mg, 0.561 mmol) in 33% HBr / AcOH (2 mL) was added Br? (0.028 mL, 0.56 mmol) in dioxane ( 1 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was concentrated under vacuum to leave the title compound. LCMS: (ES, m / z): [M+Hf 257, 259.

[0194] Step 5: 5-chloro-N-(4-{2H,3H,4H-pyrido[3,2-b] [l,4]oxazin-8-yl}-l,3-thiazol-2- yl)pyridin-2-amine (Example 18)

[0195]

[0138] To a stirred solution of 5-chloropyridin-2-ylthiourea (40 mg, 0.21 mmol) in EtOH (4 mL) was added 2-bromo-l-{ 2H,3H,4H-pyrido[3,2-b][l,4]oxazin-8-yl}ethanone (assume 0.561 mmol) at RT. The resulting mixture was stirred overnight at 80 °C. The precipitated solids were collected by filtration and washed with EtOH (3 x 3 mL). The residue was purified by prep HPLC (SunFire Prep Cl 8 OBD Column; A: water (0.1% FA), B. ACN; 25 rnL / min; 19%-37% B in 8 min, 37% B; 254 / RT (min): 6.17) to afford the title compound FA salt (35 mg, 18% over 2 steps) as a white solid. LCMS: (ES, m / z): [M+H]+346.1H NMR (300 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.35 (d, J 2.6 Hz, 1H), 8.17 (s, 1H), 7.82 (dd, J 8.9, 2.6 Hz, 1H), 7.66 (s. 1 H), 7.60 (d, J 5.3 Hz, H I). 7.19 (d, J 5.3 Hz, H I). 7.14 (d, J 8.9 Hz, 1 H), 6.72 (s, 1H), 4.27 (m, 2H), 3.47 (d, J 10.3 Hz, 2H).

[0196] Example in Table D was synthesised using Synthetic Method D:

[0197] Synthetic Method E

[0198] Example 20. 5-chloro-6-methyl-N-[4-[4-methyl-2-amino-l,3-thiazol-5-yl]-l,3-thiazol-2- yl]pyridine-2-amine

[0199] Step 1: tert-butyl (5-acetyl-4-methylthiazol-2-yl)carbamate (4115-31)

[0200]

[0139] To a stirred suspension of l-(2-amino-4-methylthiazol-5-yl)ethan-l-one (6.0 g, 38mmol), N,N-dimethylpyridin-4-amine (94 mg, 0.77 mmol) and EtsN (21 mL, 150 mmol) in THF (150 mL) was added a solution of di-tert -butyl di carbonate (26.5 mL, 1 15 mmol) in THF (50 mL). The reaction was stirred at 70 °C for 30 min and then was cooled to RT.

[0201] Imidazole (2.62 g, 38.4 mmol) was added and the reaction was stirred for 30 min. The mixture was concentrated under vacuum, redissolved in EA (50 mL) and washed with 0.02 M HC1 (2 z 50 mL). The combined aq. layers were extracted with EA (3 x 70 mL) and the combined organics were passed through a hydrophobic frit and concentrated under vacuum.

[0202] The residue was dissolved in a minimum volume of DCM and purified by FCC (0-30% EA in cyclohexane) to afford the title compound (12.0 g, 88% yield) as a yellow solid. NMR (600 MHz, DMSO-d6) δ 2.55 (m, 1H), 2.54 (s, 3H), 2.49 (s, 3H), 1 .53 (s, 18H).

[0203] Step 2: 2-bis-BOC-amino-(5-(2-bromoacetyl)-4-methylthiazole and tert-butyl (5-(2- bromoacetyl)-4-methylthiazol-2-yl)carbamate (4115-48-1 and 4115-48-2)

[0204]

[0140] To a stirred solution of tert-butyl (5-acetyl-4-methylthiazol-2-yl)carbamate (12 g, 34 mmol) in THi- (200 mL) was added N-bromosuccinimide (18.0 g, 101 mmol) portionwise. The reaction was stirred for 16 h. Additional N-bromosuccinimide (18.0 g, 101 mmol) w7as added and the reaction was stirred for 24 h. The reaction mixture was concentrated under vacuum, dissolved in a minimum volume of DCM and purified by FCC (0-40% EA in cyclohexane) to afford: (i) 2-bis-BOC-amino-(5-(2-bromoacetyl)-4-methylthiazole (3.8 g, 8.7 mmol, 26%) as a yellow solid1.H NMR (600 MHz, CDCh) 34.21 (s, 2H), 2.65 (s, 3H), 1.60 (s, 181-1); and (ii ) tert-butyl (5-(2-bromoacetyl)-4-methylthiazol-2-yl)carbamate (3.1 g, 9.3 mmol, 28%) as a pale yellow solid.;H NMR (600 MHz, CDCl3) δ 10.01 (s, 1H), 4.21 (s, 2H), 2.69 (s, 3H), 1.57 (s, 9H).

[0205] Step 3: l-(5-chloro-6-methylpyridin-2-yl)thiourea (4115-58)

[0206]

[0141] A stirred solution of 5-chloro-6-raethylpyridin-2-amine (200 mg, 1.4 mmol) and benzoyl isothiocyanate (0.189 ml, 1.40 mmol) in acetone (10 mL) was stirred at reflux for 1.5 h. The reaction was cooled to RT and concentrated under vacuum. The residue was dissolved in MeOH (12 mL) then water (6 mL) and K2CO3 (290 mg, 2.10 mmol ) added. The mixture was stirred at 90 °C for 1 h, then concentrated under vacuum and the residue was dissolved in a minimum volume of DCM and purified by FCC (0-55% EA in cyclohexane) to afford the title compound (240 mg, 1.19 mmol, 85%) as an off-white solid.1HNMR (600 MHz, DMSO-d6) δ 10.56 (s, IH). 10.23 (s, IH), 8.90 (s, 1H), 7.80 (d, J 8.8 Hz, IH), 7.05 (d, J 8.8 Hz, IH), 2.47 (s, 3H).

[0207] Step 4: 5-chloro-6-methyl-N-[4-[4-methyl-2-amino-l,3-thiazol-5-yl]-l,3-thiazol-2- yl]pyridine-2-amine (Example 20)

[0208]

[0142] To a stirred suspension of tert-butyl (5-(2-bromoacetyl)-4-methylthiazol-2- yl)carbamate (201 mg, 0.60 mmol ) and l -(5-chloro-6-methylpyridin-2-yl)thiourea. (121 mg, 0.60 mmol) in EtOH (20 mL) was added EtsN (0. 17 mL, 1.2 mmol) and the reaction was stirred at 80 °C for 2.5 h. After this time, the reaction was concentrated under vacuum and redissolved in DCM (5 mL) and TFA (I mL) added. The reaction stirred for 16 h and then was concentrated under vacuum. The residue was dissolved in a minimum volume of DMSO and purified by MDAP (5-95% ACN in water + 0.1% NH3)). Desired fractions were freeze- dried to afford the title compound (109 mg, 54%) as an off-white solid. LCMS: (ES, m / z): [M+H]+338.1H NMR (600 MHz, DMSO-d6) δ 1 1 .41 (s, 1H), 7.72 (d, J 8.6 Hz, IH), 6.94 (d, J 8.8 Hz, IH), 6.89 (s, 2H), 6.7 / (s, IH), 2.53 (s, 3H), 2.31 (s, 3H).

[0209] Examples in Table E were synthesised using Synthetic Method E: Synthetic Method F

[0210] Example 43. 5-chloro-6-isopropoxy-N-[4-[4-methyl-2-amino-l,3-thiazol-5-yl]-l,3- thiazol-2-yl] pyridine-2-amine

[0211] Step 1: 5-chloro-6-isopropoxypyridin-2-amine (4185-36)

[0212]

[0143] To a stirred solution of isopropanol (0.63 mL, 8.2 mmol) in dioxane (0.35 mL) at 0 °C was added NaH (328 mg, 8.19 mmol) slowly. After stirring for 30 min, a solution of 5- chloro-6-fluoropyridin-2-a.mine (600 mg, 4.09 mmol ) in dioxane (0.35 mL) was added dropw'ise. The reaction was stirred at 90 °C for 16 h and then was concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and purified by FCC (0 - 50% EA in cyclohexane) to afford the title compound (607 mg, 3.25 mmol, 79 % yield) as a pale brown oil.1H NMR (600 MHz, CDCl3) δ 7.34 (d. J 8.1 Hz, IH), 5.99 (d, J 8.1 Hz, I H), 5.27 (sept, J 6.2 Hz, IH), 4.26 (s, 2H), 1 .36 (d, J 6.2 Hz, 6H).

[0213] Analytical data for 5-chloro-6-isopropoxy-N-[4-[4-methyl-2-amino-l,3-thiazol-5-yl]-l,3- thiazol-2-yl]pyridine-2-amine (Example 43)

[0214] LCMS: (ES, m / z): [M+H]+382. *HNMR (600 MHz, DMSO-d6) δ 11.40 (s, IH), 7.72 (d, J 8.4 Hz, IH), 6.90 (s, 2H), 6.80 (s, IH), 6.63 (d, J 8.4 Hz, IH), 5.54 (sept, J 6.1 Hz, IH), 2.30 (s, 3H), 1.39 (d, J 6.1 Hz, 6H).

[0215] Examples in Table F were synthesised using Synthetic Method F:

[0216] Example 57. (R)-N8-(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-5,6-dihydro- 4H-cyclohepta[l,2-d:3,4-d']bis(thiazole)-2,8-diamine

[0217]

[0144] 2 -amino-7-bromo-4,5,6,7-teirahydro-8H-cyclohepta[d]thiazol-8-one 4408-39 was synthesised according to the procedures described in J. Med. Chem., 2008, 51 , 19, 6044- 6054.

[0218] Analytical data for (R)-N8-(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-5,6- dihydro-4H-cyclohepta[l,2-d:3,4-d']bis(thiazole)-2,8-diamine (Example 57)

[0219] LCMS: (ES, m / z): [M+H]+436. *HNMR (600 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.71 (d, J 8.44 Hz, 1H), 6.81 (s, 2H), 6.63 (d, J 8.44 Hz, 1H), 5.78 (m, 1H), 4.02 (dd, J 10.45, 4.22 Hz, 1H), 3.91-3.78 (m, 3H), 2.93 (m, 2H), 2.86 (m, 2H), 2.35 (m, 1H), 2.08 (m, 1H), 1.97 (m, 2H).

[0220] Example 58. N2-(5-chloro-6-isopropylpyridin-2-yl)-4'-methyl-[4,5'-bithiazole]-2,2'- diamine

[0221] Step 1: 2-nitro-6-(prop-l-en-2-yl)pyridine (4185-30)

[0222]

[0145] A microwave was charged with 2-chloro-6-nitropyridine (500 mg, 3.15 mmol), dioxane (8 mL), 4,4,5,5-tetramethyl-2-(prop~l-en-2-yl)-l,3,2~dioxaborolane (0.70 mL, 3.7 mmol), Pd(PPh3)4 (364 mg, 0.315 mmol ) and sat. aq. NaHCOa (4 mL) and was sealed. The reaction was heated in the microwave at 160 °C for 15 min and then was filtered through a pad of celite. The filter cake was washed with EA and the filtrate was concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and was purified by FCC (0-30% EA in cyclohexane) to afford the title compound (305 mg, 59%) as an off-white solid.1H NMR (600 MHZ, CDCI3) 58.09 (d, J 8.1 Hz, I H), 7.98 (t, J 7.9 Hz, I H ), 7.83 (d, J 7.7 Hz, I H), 6.07 (m, IH), 5.49 (rn, I H), 2.27 (s, 3H).

[0223] Step 2: 6-isopropylpyridin-2-amine (4185-33)

[0224]

[0146] A flask was charged with 2-nitro-6-(prop-l-en-2-yl)pyridine (1.04 g, 6.34 mmol), Pd / C (0.674 g) and EtOH (20 mL) and was purged with N2. The flask was evacuated and backfilled with H2 thrice. The reaction then stirred under H2 (1 atm) for 15 h. After this time, the reaction mixture was filtered through a pad of celite eluting with EA and concentrated under vacuum to afford the title compound (796 mg, 92%) as a colourless oil which was used without further purification.1HNMR (600 MHz, CDCh) 57.36 (t, J 7.7 Hz, IH), 6.54 (d, J 7.7 Hz, IH), 6.32 (d, J 7.7 Hz, I H), 4.35 (s, 2H), 2.85 (sept, J 6.8 Hz, IH), 1.25 (d, J 6.8 Hz, 6H).

[0225] Step 3: 5-chloro-6-isopropylpyridin-2-amine (4185-41)

[0226]

[0147] To a stirred solution of 6-isopropylpyridin-2-amine (330 mg, 2.42 mmol) in DCM (16.5 mL) was added N-chloro succinimide (340 mg, 2.54 mmol) portionwise. The reaction was stirred at RT overnight and then was concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and purified by FCC (0-20% EA in cyclohexane) to afford the title compound (72 mg, 1 / %) as a pale brown oil1.H NMR (600 MHz, CDCl3) δ 7.34 (d, J 8.4 Hz, 1H), 6.29 (d, J 8.4 Hz, 1H), 4.35 (s, 2H), 3.42 (sept, J 6.8 Hz, 1H), 1.22 (d, J 6.8 Hz, 6H).

[0227] Analytical data for N2-(5-chloro-6-isopropylpyridin-2-yl)-4'-methyl-[4,5'-bithiazole]- 2,2'-diamine (Example 58)

[0228] LCMS: (ES, m / z): [M+H]+366. *HNMR (600 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.72 (d, J 8.6 Hz, 1H), 7.37 (br s, 2H), 6.92 (d, J 8.6 Hz, 1H), 6.90 (s, 1H), 3.49 (sept, J 6.7 Hz, 1H), 2.33 (s, 3H), 1.33 (d, J 6.8 Hz, 6H).

[0229] Synthetic Method G

[0230] Example 59. N2-(5-chloro-6-isopropylpyridin-2-yl)-4'-methyl-[4,5'-bithiazole]-2,2'- diamine

[0231] Step 1: 6-amino-3-chloropicolinonitrile (4185-57)

[0232]

[0148] To a stirred solution of 6-aminopicolinonitrile (270 mg. 2.27 mmol) in ACN (10 mL) was added N-chloro succinimide (393 mg, 2.95 mmol) portionwise. The reaction was stirred at RT for 4 d and then was concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and purified by FCC (0-5% MeOH in DCM ) to afford the title compound (175 nig, 50%) as a white solid.1H NMR (600 MHz, CDCh) 87.51 (d, J 8.8 Hz,

[0233] 1 H), 6.66 (d, J 8.8 Hz, 1 H), 4.75 (br s, 2H).

[0234] Step 2: l-(5-chloro-6-cyanopyridin-2-yl)thiourea (4185-60)

[0235]

[0149] To a solution of 6-arnino-3-chIoropicolinonitriIe (100 mg, 0.651 mmol) in I I -IF (5 mL), ''DCM (5 mL) was added Fmoc-isothiocyanate (183 mg, 0.651 mmol). After stirring at 80 °C for 16 h, tire reaction mixture was cooled to rt and concentrated under vacuum. The residue was suspended in DCM (15 mL) and piperidine (0.8 mL, 8 mmol) was added. After stirring for 2 h the precipitate was collected by filtration and dried to afford the title compound (92 mg, 0.433 mmol, 66.4 % yield) as a white solid. 'H NMR (600 MHz, DMSO-

[0236] Analytical data for N2-(5-chloro-6-isopropylpyridin-2-yl)-4'-methyl-[4,5'-bithiazole]- 2,2'-diamine (Example 59)

[0237] LCMS: (ES, m / z): [M+H]+392. *HNMR (600 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.06 (d, J 9.2 Hz, 1H), 7.38 (d, J 9.2 Hz, 1H), 6.94 (s, 2H), 6.90 (s, 1H), 2.32 (s, 3H).

[0238] Examples in Table G were synthesised using Synthetic Method G:

[0239] Synthetic Method H

[0240] Example 64. N2-(5-chloro-6-(difluoromethoxy)pyridin-2-yl)-4'-methyl-[4,5'-bithiazole]-

[0241] 2,2'-diamine

[0242] Step 1: 5-chloro-6-(difluoromethoxy)picolinic acid (4185-92)

[0243]

[0150] To a stirred solution of methyl 5-chioro-6-hydroxypicotinate (CAS: 1214386-04-5, 1.50 g, 8.0 mmol) in ACN (30 niL) was added chlorodifluoroacetic acid, sodium salt (2.44 g, 16.0 mmol) and the reaction was stirred at 85 °C for 24 h. Additional chlorodifluoroacetic acid, sodium salt (2.44 g, 16.0 mmol) was added and stirring continued for 4 d. The mixture was cooled to RT, filtered and concentrated under vacuum. The residue was taken up in THF (20 mL) and to this was added 2 M aq. LiOH (16 ml, 32 mmol). After stirring for 3 h, the reaction mixture was acidified to pH 2-3 using 2 M HC1 and the mixture was extracted with Dr Al (4 x 30 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to afford the title compound (1.62 g, 91 % yield) as a white solid. 'HNMR (600 MHz, DMSO-d6) δ 13.53 (br s, 1H), 8.26 (d, J 8.1 Hz, 1H), 7.90 (d, J 8.1 Hz, 1H), 7.80 (t, J 71.9 Hz, 1H).

[0244] Step 2: tert-butyl (5-chloro-6-(difluoromethoxy)pyridin-2-yl)carbamate (4185-94)

[0245]

[0151] To a stirred solution of 5-chloro-6-(difluoromethoxy)picolinic acid (1.62 g, 7.25 mmol) in toluene (20 ml.,) and teit-butanol (10 mL.) was added EtsN (4.0 ml.,, 29 mmol) and diphenyl azidophosphate (2.3 mL, 11 mmol) sequentially. The reaction was stirred at 100 °C for 16 h. The reaction was cooled to RT and sat. NaHCO3(30 mL) was added. The phases were separated and the organics were extracted with E.A (3 x 30 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and purified by FCC (0-10% EA in cyclohexane) to afford the title compound (1.30 g, 61%) as a colourless oil. NMR (600 MHz, DMSO- d6) 5 10.04 (s, 1H), 7.97 (d, J 8.6 Hz, 1H), 7.59 (d, J 8.6 Hz, 1H), 7.55 (t, J 72.4 Hz, 1H), 1.47 (s, 9H).

[0246] Step 3: 5-chloro-6-(difluoromethoxy)pyridin-2-amine (4185-97)

[0247]

[0152] A solution of tert-butyl (5-chloro-6~(dilluoromethoxy)pyridin-2-yl)carbamate (1.30 g, 4.41 mmol) in 4 M HC1 in dioxane (12 mL) stood for 16 h and then was concentrated under vacuum. The residue was partitioned between sat. aq. NaHCC3(30 mL) and DCM (30 mL). The phased were separated and the aq. phase was extracted with DCMi (3 x 30 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to afford the title compound (816 mg, 95%) as a pale brown oil which was used without further purification.;H NMR (600 MHz, DMSO-ds) 57.53 (d, J 8.6 Hz, 1H), 7.53 (t, J 73.7 Hz, 1H), 6.43 (br s, 2H), 6.27 (d, J 8.6 Hz, 1H).

[0248] Analytical data for N2-(5-chloro-6-(difluoromethoxy)pyridin-2-yl)-4'-methyl-[4,5'- bithiazole]-2,2'-diamine (Example 64)

[0249] LCMS: (ES, m / z): [M+H]+390. 'H NMR (600 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.93 (d, J 8.6 Hz, 1H), 7.81 (t, J 72.3 Hz, 1H), 6.95 - 6.90 (m, 3H), 6.87 (s, 1H), 2.31 (s, 3H).

[0250] Examples in Table H were synthesised using Synthetic Method H:

[0251] Synthetic Method J

[0252] Example 66. 5-((2'-amino-4'-methyl-[4,5'-bithiazol]-2-yl)amino)-2-chloro-l- methylpyridin-4(lH)-one

[0253] Step 1: 2-chloro-l-methyl-5-nitropyridin-4(lH)-one (4181-52)

[0254]

[0153] To a solution of 2-chloro-5~nitropyridin~4(lH)~one (CAS: 1211386-69-4, 800 mg, 4.58 mmol) in MeOH (16 ml) was added K2CO3 (697 mg, 5.04 mmol) and Mel (860 pl, 13.8 mmol). The resulting reaction mixture was stirred at 65 °C overnight. Mel (4.58 mmol) was added and the reaction mixture was stirred at 65 °C for 2 h. The mixture was concentrated under vacuum to dryness. The residue was dissolved in a minimum volume of DCM (+drops of MeOH) and purified by FCC (50g) (0-5% MeOH in DCM) to afford the title compound (454 mg, 53%). LCMS: (ES, m / z): fol H I 189.

[0255] Step 2: 5-amino-2-chloro-l-methylpyridin-4(lH)-one (4181-56)

[0256]

[0154] To a stirred suspension of 2-chloro-l-methyl-5-nltropyridln-4(lH)-one (450 mg, 2.39 mmol) and ammonium chloride (1.28 g, 23.9 mmol) in EtOH (75 ml.,) and water (15 ml,) was added iron (1.33 g, 23.9 mmol). The suspension was stirred at 70 °C for 20 min. After cooling down to RT, the mixture was filtered through celite (washed with MeOH) and the filtrate was concentrated under vacuum to ~5 ml., suspension. The suspension was loaded onto a prewashed (MeOH) SCX column (20 g), w'ashed through with MeOH and then eluted with 7N NH3 in MeOH. Concentration under vacuum afforded the title compound (346 mg, 91 % yield) as a pale browm solid. LCMS: (ES, m / z): fol H l 159.

[0257] Analytical Data for 5-((2'-amino-4'-methyl-[4,5'-bithiazol]-2-yl)amino)-2-chloro-l- methylpyridin-4(lH)-one (Example 66)

[0258] LCMS: (ES, m / z): [M+H]+354. 'H NMR (600 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.13 (s, 1H), 6.95 (s, 2H), 6.61 (s, 1H), 6.44 (s, 1H), 3.78 (s, 3H), 2.35 (s, 3H).

[0259] Examples in Table J were synthesised using Synthetic Method J:

[0260] Example 69. N2-(5-chloro-6-(trifluoromethoxy)pyridin-2-yl)-4'-methyl-[4,5'- bithiazole]-2,2'-diamine

[0261] Step 1: 5-chloro-6-(trifluoromethoxy)picolinic acid (4185-93)

[0262]

[0155] To a stirred solution of methyl 5-chloro-6-hydroxypicolinate (500 mg, 2.67 mmol) in nitromethane (30 mL) was added l-(trifluoromethyl)-l,2-benziodoxol-3(lH)-one (1.69 g, 5.33 mmol) and the reaction stirred at 100 °C for 3 d. After this time the reaction mixture was cooled to RT, filtered eluting with EA and washed with NaHCCh (30 mL). The organic phase was passed through a hydrophobic frit and concentrated under vacuum. The residue was dissolved in the minimum volume of DCM and purified by FCC (0-20% EA in cyclohexane) to afford the title compound (369 mg, 54%) as a white solid.1H NMR (600 MHz, DMSO-d6) δ 8.41 (d, J 8.1 Hz, 1H), 8.07 (d, J 8. 1 Hz, 1 H), 3.90 (s, 3H).

[0263] Analytical data for N2-(5-chloro-6-(trifluoromethoxy)pyridin-2-yl)-4'-methyl-[4,5'- bithiazole]-2,2'-diamine (Example 69)

[0264] LCMS: (ES, m / z): [M+H]+408. 1H NMR (600 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.04 (d, J 8.8 Hz, 1H), 7.12 (d, J 8.8 Hz, 1H), 6.93 (s, 2H), 6.91 (s, 1H), 2.31 (s, 3H).

[0265] Example 70. N2-(5- bromo-6-(methoxymethyl)pyridin-2-yl)-4'-methyl-[4,5'-bithiazole]- 2,2'-diamine

[0266] Step 1: 2-bromo-6-(methoxymethyl)pyridine (4181-79)

[0267]

[0156] To a stirred solution of (6-bromopyridin-2-yl)methanol (1.0 g, 5.3 mmol) in DMF (25 mL) was added NaH (0.234 g, 5.85 mmol) portionwise. The reaction mixture was stirred at RT for 30 min then Mel (1.0 mL, 16 mmol) was added and the mixture stirred for 90 min. The mixture was diluted with DCM and the resulting organic phase was washed with LiCl solution (3 x 50 mL). The organic phase was passed through a hydrophobic frit and concentrated under vacuum to dryness. The residue was dissolved in a minimum of DCM and purified by FCC (10-100% E A in cyclohexane) to afford the title compound (232 mg, 22%). LCMS: (ES, m / z): [M+H]%02, 204.

[0268] Step 2: 6-(methoxymethyl)pyridin-2-amine (4181-83)

[0269]

[0157] To a stirred solution of 2-bromo-6-(methoxymethyi)pyridine (230 mg, 1.14 mmol) in solution (1.4 mL) and ethylene glycol (2.3 mL, 42 mmol) was added N,N'-dimethylethylene- diamine (0.012 mL, 0.11 mmol), CU2O (8.1 mg, 0.057 mmol) and K2CO3 (31.5 mg, 0.228 mmol). The reaction was stirred at 65 °C overnight, then cooled and water added. The mixture was extracted with 10% isopropanol in DCM and the organic layer washed with brine. The organic phase was passed through a hydrophobic frit and solvent was removed under vacuum to dryness. The residue was dissolved in minimum DCM was purified by FCC using (40-100% EA in cyclohexane) to give the title compound (143 mg, 91 % yield).1H NMR (600 MHz, DMSO-d6) δ 7.35 (t, J 7.7 Hz, 1H), 6.50 (d, J 7.2 Hz, 1H), 6.33 (d, J 8.2 Hz, 1H), 5.85 (br s, 2H), 4.23 (s, 2H), 3.31 (s, 3H).

[0270] Analytical data for N2-(5- bromo-6-(methoxymethyl)pyridin-2-yl)-4'-methyl-[4,5'- bithiazole]-2,2'-diamine (Example 70) LCMS: (ES, m / z): [M+H]+412, 414. *HNMR (600 MHz, DMSO-d6) δ 11.50 (s, 1H), 7.91 (d, J 8.8 Hz, 1H), 6.99 (d, J 8.6 Hz, 1H), 6.89 (s, 2H), 6.80 (s, 1H), 4.57 (s, 2H), 3.37 (s, 3H), 2.31 (s, 3H).

[0271] Example 71. 6-((2'-amino-4'-methyl-[4,5'-bithiazol]-2-yl)amino)-2-((tetrahydrofuran-3- yl)oxy)nicotinonitrile

[0272] Step 1: 5-bromo-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-amine (4298-29)

[0273]

[0158] To a stirred solution of 3 -hydroxytetrahydrofuran (0. 125 mL, 1 .54 mmol) in dioxane (5 mL) at 0 °C was added NaH (124 mg, 3.09 mmol) slowly. After stirring for 20 min, a solution of 5-bromo-6-fluoropyridin-2-amine (295 mg, 1.54 mmol) in dioxane (5 mL) was added. The reaction was stirred at 90 °C for 1 h and then was concentrated under vacuum.

[0274] Step 2: 6-amino-2-((tetrahydrofuran-3-yl)oxy)nicotinonitrile (4298-33)

[0275]

[0159] A microwave vial was charged with 5-bromo-6-((tetrahydrofuran-3-yl)oxy)pyridin-2- 10.4 Hz, 1H), 3.84 (q, J 7.9 Hz, 1H), 3.78 - 3.70 (m, 2H), 2.21 (m, 1H), 1.98 (m, 1H).

[0276] Analytical data for 6-((2'-amino-4'-methyl-[4,5'-bithiazol]-2-yl)amino)-2- ((tetrahydrofuran-3-yl)oxy)nicotinonitrile

[0277] LCMS: (ES, m / z): [M+H]+401. *HNMR (600 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.00 (d, J

[0278] 8.4 Hz, 1H), 6.95 (s, 2H), 6.91 (s, 1H), 6.73 (d, J 8.4 Hz, 1H), 5.86 (t, J 5.0 Hz, 1H), 4.02 (dd, J 4.4, 10.6 Hz, 1H), 3.94 - 3.89 (m, 2H), 3.82 (dt, J 4.6, 8.3 Hz, 1H), 2.38 (m, 1H), 2.34 (m, 1H), 2.31 (s, 3H), 2.12 (m, 1H).

[0279] Synthetic Method K

[0280] Example 72. N-[4-(4-amino-2-methylphenyl)-l,3-thiazol-2-yl]-5-chloropyridin-2-amine

[0281] Step 1: N-[4-(2-chloroacetyl)-3-methylphenyl] acetamide (06-3)

[0282]

[0160] To a stirred solution of 3-methylacetanilide (537-92-8; 1.00 g, 6.70 mmol) and Al Cl 3

[0283] Step 2: N-(4-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]-3- methylphenyl)acetamide (06-4)

[0284]

[0161] A mixture of N-[4-(2-chloroacetyl)-3-methylphenyl] acetamide (100 mg, 1.24 mmol) and 5-chloropyridin-2-ylthiourea (83 mg, 1.24 mmol) in EtOH (5 mL) was stirred for 2 h at 80 °C under N2. The resulting mixture was diluted with water (4 mL). The mixture was basified to pH 8 with sat. aq. NaHCO.u The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers w'ere dried over anhydrous Na2SO4. filtered and concentrated under vacuum. This resulted in the title compound (400 mg, 90%) as a white solid. LCMS:

[0285] Step 3: N-[4-(4-amino-2-methylphenyl)-l,3-thiazol-2-yl]-5-chloropyridin-2-amine

[0286] (Example 72)

[0287]

[0162] A solution ofN-(4-[2-[(5-chloropyridin-2~yl)amino]-l,3-thiazol-4~yl]-3-

[0288] Examples in Table K were synthesised using Synthetic Method K:

[0289] Examples 74 & 75N-(4-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-5-methyl-3H- imidazol-2-yl)benzamide (Example 74) and N-[4-(2-amino-5-methyl-3H-imidazol-4-yl)- l,3-thiazol-2-yl]-5-chloropyridin-2-amine (Example 75)

[0290] Step 1: N-cyanobenzenecarboximidamide (08-4)

[0291]

[0163] To a stirred mixture of cyanamide (4.03 g, 95.8 mmol) in water (50 mL) were addedNaOH (2.55 g, 63.9 mmol) and benzamidine hydrochloride (5.00 g, 31.9 mmol) in portions at 0 °C. The mixture was stirred for 4 h at RT under N2. The precipitated solids were collected by filtration, washed with water, dried under vacuum to afford the title compound (4.0 g, 86%) as a white solid. LCMS: (ES, M / Z): [M+H]+146.

[0292] Step 2: 5-phenyl-l,2,4-oxadiazol-3-amine (08-5)

[0293]

[0164] To a stirred solution of N-cyanobenzenecarboximidamide (4.00 g, 27.6 mmol) in

[0294] EtOH (40 mL) were added hydroxylamine hydrochloride (2.49 g, 35.8 mmol) and EtsN (5.58 g, 55.1 mmol) at RT under N2. The resulting mixture was stirred for 3 h at 80 °C under N2. The mixture was allowed to cool down to RT and concentrated under vacuum. The precipitated solids were collected by filtration, washed with water and dried under vacuum to afford the title compound (3.0 g, 68%) as a white solid. LCMS: (ES, m / z); 162.

[0295] Step 3: (3E)-4-[(5-phenyl-l,2,4-oxadiazol-3-yl)amino]pent-3-en-2-one (08-6)

[0296]

[0165] To a stirred solution of 5-phenyl-l,2,4-oxadiazol-3-amine (2.50 g, 15.5 mmol) in EA (25 mL) was added montmorillonite (25 g, 89 mmol) at RT. The resulting mixture was stirred for 10 min at RT. The resulting mixture was concentrated under vacuum. To the above mixture were added toluene (50 mL) and acetylacetone (6.21 g, 62.0 mmol) at RT. The resulting mixture was stirred overnight at 100 °C. The mixture was allowed to cool down to RT. The resulting mixture was filtered, the filter cake was washed with EA (3 x 20 mL). The filtrate was concentrated under vacuum, washed with water and dried under vacuum to afford the title compound (4.6 g, 54%) as a red solid. LCMS: (ES, m / z):

[0297] Step 4: N-(4-acetyl-5-methyl-3H-imidazol-2-yl)benzamide (08-7)

[0166] To a stirred solution of (3E)-4-[(5-phenyl-l,2,4-oxadiazol-3-yl)anuno]pent-3-en-2- one (660 mg, 2.71 mmol) in DMF (6.6 niL) was added t-BuOK (365 mg, 3.26 mmol) at RT. The resulting mixture was stirred for 3 h at 100 °C. The mixture was allowed to cool down to RT, diluted with water (20 mL) and neutralized to pH 7 with cone. HC1. The resulting mixture was extracted with EA (3 - 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound (580 mg, 88%) as a brown solid. LCMS: (ES, m / z): [M+H]!244.

[0298] Step 5: N-[4-(2-bromoacetyl)-5-methyl-3H-imidazol-2-yl] benzamide (08-8)

[0299]

[0167] To a stirred solution of 15i-(4-acetyl-5-methyl~3H-imidazol-2~yl)benzamide (500 mg, 2.06 mmol) in dioxane (5 ml.) was added HBr (5 mL, 33% in AcOH) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added Brs (0.11 mL, 2.1 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 1 h at. RT, diluted with water (20 mL) and neutralized to pH 7 with sat. aq. NaHCCL. The resulting mixture was extracted with EA (3 x 20 mL), washed with brine (2 x 20 mL), dried over anhydrous Na;SO.i, filtered and concentrated under vacuum to afford the title compound (600 mg, 50%) as a black oil. LCMS: (ES, M / Z): [M+H]+322.

[0300] Step 6: N-(4-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-5-methyl-3H-imidazol-2- yl)benzamide (Example 74)

[0301]

[0168] To a stirred solution of N-[4-(2-bromoacetyl)-5-methyl-3H-inudazol-2-yl]benzamide (600 mg, 1.86 mmol) in EtOH (10 mL) was added 5-chioropyridin-2-ylthiourea (349 mg, 1.86 mmol) at RT under N2. The resulting mixture was stirred overnight at 85 °C. The mixture was allowed to cool down to RT. The resulting mixture w7as concentrated under vacuum. The residue was purified by prep HPLC (XBridge Prep Cl 8 OBD Column, A: water (10mmol / L NH4HCO3), B: ACN; 25 mL / min; 40%-70% B in 8 min, 70% B; 254 / RT (min): 7.04) to afford the title compound (12 mg, 19%) as a light yellow' solid. LCMS: (ES, m / z): [M+H]+411.

[0302] Step 7: N-[4-(2-amino-5-methyl-3H-imidazol-4-yl)-l,3-thiazol-2-yl]-5-chloropyridin-2- amine (Example 75)

[0303]

[0169] To a stirred solution of Example 74 (500 mg, 1.22 mmol ) in w7ater (5 mL) was added 6 M HC1 (5 mL) at RT. The resulting mixture was stirred overnight at 100 °C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (20 mL). The mixture was neutralized to pH 7 with sat. aq. . TNhae2S reOs4ulting mixture was extracted with EA (3 x 20 ml.,), washed with brine (2 x 20 ml.,), dried over anhydrous Na2SO4. filtered and concentrated under vacuum. The residue was purified by prep HPLC (SunFire Prep C18 OBI) Column; A: water (0.05% IT A), B: ACN; 25 mL / min; 25%-37% B in 8 min, 37% B;

[0304] RT (min): 6.58) to afford the title compound TFA sait (20 mg, 5%) as a yellow solid. LCMS: (ES, m / z); [M+H]+307.1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 12.38 (s, 1H), 11.50 (s, 1H), 8.35, (d, J 2.6 Hz, 1H), 7.83 (dd, J 8.9, 2.6 Hz, 1H), 7.61 (s, 2H), 7.19 (d, J 8.9 Hz, 1H), 7.15 (s, 1 H), 2.45 (s, 3H).

[0305] Example 76. N-[4-(4-aminophenyl)-l,3-thiazol-2-yl]-5-chloropyridin-2-amine

[0306] Step 1: 5-chloro-N-[4-(4-nitrophenyl)-l,3-thiazol-2-yl]pyridin-2-amine) (31-1)

[0307]

[0170] To a stirred solution of 5 -chloropymdim2-yd thiourea (51 mg, 0.27 mmol) in EtOH (3 ml) was added 2-bromo-l-(4-nitrophenyf)ethanone (100 mg, 0.409 mmol) at RT. The resulting mixture was stirred for 3 h at 80 °C. The product was precipitated by the addition of water. The precipitated solids were collected by filtration and washed with water (3 x 2 ml..) to afford the title compound (58%) as a yellow solid. LCMS: (ES, m / z):

[0308] Step 2: N-[4-(4-aminophenyl)-l,3-thiazol-2-yl]-5-chloropyridin-2-amine (Example 76)

[0309]

[0171] To a stirred solution of 5-chloro-N-[4-(4-nitrophenyf)-l,3-thiazol-2-yl]pyridin-2- amine (150 mg, 0.451 mmol) in EtOH (4 ml.) was added Pd / C (30 mg, 20%wt) at RT under N2. The resulting mixture was stirred for 24 h at RT under Hj. The resulting mixture was filtered through a Celite pad, the filter cake was washed with EtOH (3 - 2 ml..). The filtrate was concentrated under vacuum. The residue was purified by prep HPLC (SunFire Prep C18 OBD Column; A: water (0. 1% FA), B: ACN; 25 mL / min; 29%-58% B in 12. min, 58% B; RT (min): 10.38) to afford the title compound (80 mg, 59%) as a pale pink solid. LCMS: (ES, M / Z); [M+H]+303.1HNMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.32 (d, J 2.6 Hz, 1H), 7.79 (dd, J 8.9, 2.6 Hz, 1 H), 7.57 (d, J 8.2 Hz, 2H), 7.14 (d, J 8.9 Hz, 1 H i. 7.04 (s, 1 H i. 6.59 id. J 8.2 Hz, 2H), 5.20 (s, 2H).

[0310] Example 77. (2-amino-5-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]-l,3-thiazol- 4-yl)methanol

[0311]

[0312] Step 1: ethyl 5-acetyl-2-amino-l,3-thiazole-4-carboxylate (23-1)

[0313]

[0172] To a stirred solution of ethyl 2,4-dioxopentanoate (10 g, 63 mmol) in DCM (15 mL) was added SO2CI2 (9.4 g, 70 mmol) dropwise at 0 °C under N2The resulting mixture was stirred for 2 h at RT. The mixture was concentrated under vacuum, redissolved in EtOH (100 mL) and thiourea (5.8 g, 76 mmol) added dropwise at RT. The resulting mixture was stirred for additional 3 h at 80 °C under N2. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with THF (10 mL). The residue was purified by reversephase FCC (C l 8 silica, ACN in water, 0%-100%; UV 254 nm) to deliver the title compound (12 g, 89%) as a yellow’ solid. LCMS: (ES, m / z): [M+H]+215.

[0314] Step 2: ethyl 2-amino-5-(2-bromoacetyl)-l,3-thiazole-4-carboxylate (23-2)

[0315]

[0173] To a stirred solution of ethyl 5-acetyl-2-amino-l,3-thiazole-4-carboxylate (300 mg, 1.40 mmol) in HBr (3 mL, 33% in AcOH) was added Br2 (224 mg, 1.40 mmol) dropwise at 0 °C. The resulting mixture was diluted with water (5 mL). The residue was neutralized to pH 8 with sat. aq. NaHCCh. The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4. filtered and concentrated under vacuum. This resulted in the title compound (400 mg, 97%) as a yellow solid. LCMS: (ES, m / z)

[0316] Step 3: ethyl 2-amino-5-[2-[(5-chloropyridin-2-yl) amino]-l,3-thiazol-4-yl]-l,3-thiazole- 4-carboxylate (23-3)

[0317]

[0174] A mixture of ethyl 2-amino-5-(2-bromoacetyl)-l,3-thiazole-4-carboxylate (200 mg, 0.680 mmol) and 5-chloropyridin-2-ylthiourea (0.10 g, 0.53 mmol) in EtOH (5 mL) was stirred overnight at 80 °C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous NajSO4filtered and concentrated under vacuum. This resulted in the title compound (overweight) as an off-white solid. LCMS: (ES, m / z)\ OH H 382.

[0318] Step 4: ethyl 2-[[(tert-butoxy)carbonyl]amino]-5-[2-[(5-chloropyridin-2-yl)amino]-l,3- thiazol-4-yl]-l,3-thiazole-4-carboxylate (23-4) and ethyl 2-[bi[(tert- butoxy)carbonyl]amino]-5-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]-l,3- thiazole-4-carboxylate (23-7)

[0319]

[0175] To a stirred solution of ethyl 2-amino-5-[2-[(5-chloropyridin-2-yl)amino]"l,3-thiazol- 4-yl]-l,3-thiazole-4-carboxylate (assume 0.68 mmol) and 4 -dimethylaminopyridine (48 mg, 0.39 mmol) in THF (2 mL) was added di-tert-butyl decarbonate (257 mg, 1.18 mmol) dropwise at 0 °C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4filtered and concentrated under vacuum. This resulted in the mixture of the title compounds (200 mg, -3:1 ratio, 58% over 2 steps) as a yellow solid. LCMS: (ES, m / z\. [M+H]+482 and 582.

[0320] Step 5: tert-butyl N-(5-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]-4- (hydroxymethyl)-l,3-thiazol-2-yl)carbamate (23-5) and bi-tert-butyl N-(5-[2-[(5- chloropyridin-2-yl)amino]- 1 ,3-thiazol-4-yl] -4-(hydroxymethyl)- 1 ,3-thiazol-2- yl)carbamate (23-8)

[0321]

[0176] To a stirred solution of ethyl 2-[(ten~butoxycarbonyl)amino]-5-[2-[(5-chloropyridin- 2-yl)amino]-l,3-thiazol-4-y1]-l,3-thiazo1e-4-carboxy1ate (920 mg, 1.91 mmol) in THF (18 mL) was added LiAIH4(0.43 g, 11 mmol) in portions at 0 °C under N2. The resulting mixture was stirred for 5 h at RT under Ns. The reaction was quenched with sodium sulfate decahydrate at 0 °C. ’The resulting mixture was filtered, the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under vacuum. The residue was purified by FCC (PE / EA (1 .1) to afford tert-butyl N-(5-[2-[(5-chloropyridin-2-yl)amino]-l ,3-thiazol-4-yl]-4- (hydroxymethyl)-l,3-thiazol-2-yl)carbamate (444 mg) as a white solid and bi-tert-butyl N-(5- [2-[(5-chloropyridin-2-yl)amino]-l,3-thiazo1-4-yl]-4-(hydroxymethyl)-l,3-thiazol-2- yl)carbamate (150 mg) as a white solid. LCMS: (ES, m / z): [M+H]+440 and 540.

[0322] Step 6: (2-amino-5-[2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl]-l,3-thiazol-4- yl)methanol (Example 77)

[0323]

[0177] To a stirred solution of di-tert-butyl N-(tert-butoxycarbonyl)-N-(5-[2-[(5- chloropyridin-2-yl) amino]-1 , 3-thiazol-4-yl]-4-(hydroxy methyl)-1, 3-thiazol-2-yl)carbamate (150 mg, 0.28 mmol) in DCM (3 mL) w as added TFA (1 mL) dropwise at RT under N2. The resulting mixture was stirred for 3 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by prep HPLC (SunFire Prep C18 OBD Column; A: water (0.05% IT A), B: ACN; 25 mL / min; gradient: 17-41% B in 8 min,; RT: 6.72;) to afford the title compound (90 mg, 53%) as a white solid. LCMS: (ES, m / z): [M+H]1’ 340. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.69 (s, 2H), 8.37 (d, J 2.6 Hz, 1 H), 7.84 (dd, J 8.9, 2.6 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J 8.9 Hz, 1H), 4.59 (s, 2H). OH signal not visible.

[0324] Example 78. 5-chloro-N-(4-[2-methyl-7H-imidazo[l,2-a] [l,3]diazol-3-yl]-l,3-thiazol-2- yl)pyridin-2-amine

[0325] 14-3

[0326] Step 1: l-(2-amino-5-methyl-3H-imidazol-4-yl)ethanone (14-1)

[0327]

[0178] To a stirred solution of N-(4-acetyl-5-methyl-3H-imidazol-2-yl)benzamide (700 mg, 2 88 mmol) in water (7 mL) was added 6 M HC1 (7 mL) at RT under N2. The resulting mixture was stirred overnight at 100 °C under N2. The mixture was allowed to cool down to RT. The mixture was basified to pH 9 with sat. aq. NaHCO3The resulting mixture was extracted with EA (3 v so mL), washed with brine (2 x 40 mL), dried over anhydrous NasSO4, filtered and concentrated under vacuum. The residue was purified by reverse phase FCC (Cl 8 silica, 0.1%NHj in water / ACN) to afford the title compound (230 mg, 51%) as a brown-yellow solid. LCMS: (ES, m / z): [M+H]“ 140.

[0328] Step 2: l-[2-methyl-7H-imidazo[l,2-a][l,3]diazol-3-yl]ethanone (14-2)

[0329]

[0179] To a stirred solution of l-(2-amino-5-methyl-3H-imidazol-4-yl)ethanone (250 mg, 1.80 mmol) in DMF (5 mL) was added NaH (129 mg, 5.39 mmol) in portions at 0 °C under N2. The resulting mixture was stirred for 20 min at 0 °C. To the above mixture was added 2- bromo- 1,1 -diethoxy ethane (1.06 g, 5.39 mmol) at 0 °C. The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool down to RT and diluted with water (5 mL). The resulting mixture was extracted with EA (3 x ] 0 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. To the above mixture was added HCl (5 mL) at RT. The resulting mixture was stirred for additional 2 h at 100 °C. The resulting mixture was allowed to cool down to RT. The resulting mixture was diluted with water (20 mL). The mixture was neutralized to pH 7 with sat. aq. NaHCOs. The resulting mixture was extracted with EA (3 x 20 mL), washed with NaCl solution (2 x 20 mL), dried over anhydrous Aa?SO :. filtered and concentrated under vacuum. The residue was purified by reverse phase FCC (0.1% FA in water / ACN) to afford the title compound (200 mg, 68%) as a brown-yellow solid. LCMS: (ES, m / z): [M-HI]4164.

[0330] Step 3: 2-bromo-l-[2-methyl-7H-imidazo[l,2-a][l,3]diazol-3-yl]ethanone (14-3)

[0331]

[0180] To a stirred solution of l-[2~methyl-7H-imidazo[l,2-a][l,3]diazol-3-yl]ethanone (100 mg, 0.613 mmol) in dioxane (1 mL) was added 33% HBr in AcOH (1 mL) dropwise at 0 °C. To the above mixture was added Brj (0.03 mL, 0.49 mmol) dropwise over 20 min at 0 °C. The resulting mixture was stirred for additional 1 h at RT. The resulting mixture was diluted with water (5 mL). The mixture was neutralized to pH 7 with sat. aq. NaHCOs. The resulting mixture was extracted with EA (3 x 10 mL), washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford the title compound (50 mg, 34%) as a brown oil. L C MS (ES, m / z): [M+H]4242.

[0332] Step 4: 5-chloro-N-(4-[2-methyl-7H-imidazo[l,2-a][l,3]diazol-3-yl]-l,3-thiazol-2- yl)pyridin-2-amine (Example 78)

[0333]

[0181] To a stirred solution of 2-bromo-l-[2-methyl-7H-imidazo[l,2-a][l ,3]diazol-3- yl]ethanone (150 mg, 0.620 mmol) in EtOH (3 mL) was added 5-chloropyri din-2 -ylthiourea (1 16 mg, 0.620 mmol) at RT. The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool down to RT, diluted with water (20 mL) and basified to pH 9 with sat. aq. NaHCOs. The resulting mixture was extracted with EA (3 - 5 mL), washed with brine (2 x 5 mL), dried over anhydrous NazSO4filtered and concentrated under vacuum. The residue was purified by prep HPLC (Xselect CSH F-Phenyl OBD column; A: water (0.1% FA), B: MeOH; 25 mL / min; 3()%-38% B in 10 min, 38% B, 254 / RT (min): 9.32) to afford the title compound (30 mg, 14%) as a light yellow solid. LCMS: (ES, m / z): [M+HJ+ 331.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.35 (d, J 2.6 Hz, 1H), 8. 15 (s, 1H), 7.82 (dd, .1 8.9, 2.6 Hz, I H ), 7.19 (d, J 8.9 Hz, 1H), 7. 16 (d, J 1 .9 Hz, I H i. 7.06 (s, 1 H ). 7.01 (d, J 1.9 Hz, I H i. 2.68 (s. 3 El). Example 79. Ethyl 2-(2-amino-5-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-l,3- thiazol-4-yl)acetate

[0334] Step 1: methyl 3,5-dioxohexanoate (24-1)

[0335]

[0182] To a stirred solution of 7% MglOCHsE in MeOH (689 mL) was added dehydroacetic acid (20.0 g, 119 mmol) in portions at RT. The resulting mixture was stirred overnight at 50 °C, and then concentrated under vacuum. The residue was dissolved in water (200 mL), acidified to pH 5 with I M HCI (130 mL), and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum. ’The residue was purified by distillation under 4 mm Hg and the fraction was collected at 90~92°C to afford the title compound (5.8 g, 31%) as a colorless oil. LOVIS' (ES, nffr): i \l • i H 159.

[0336] Step 2: methyl 2-(5-acetyl-2-amino-l,3-thiazol-4-yl)acetate (24-2)

[0337]

[0183] To a stirred mixture of thiourea (2.88 g, 37.8 mmol) and methyl 3,5-dioxohexanoate (3.00 g, 19.0 mmol) in MeOH (30 mL) were added tert-butyl hydroperoxide (5.13 g, 56.9 mmol) and azobisisobutyronitrile (623 mg, 3.79 mmol) at RT. The resulting mixture was stirred overnight at 65 °C. ’The resulting mixture was diluted with water (50 mL), and then basified to pH 8 with sat. aq. NaHCCL (30 ml.) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum. The residue was purified by FCC (PE / EA (1 : 1) to afford the title compound (1 .2 g, 30%) as a light yellow solid. LCMS: (ES, m / z)-. [M+H]+215.

[0338] Step 3: methyl 2-[2-amino-5-(2-bromoacetyl)-l,3-thiazol-4-yl]acetate (24-3)

[0339]

[0184] To a stirred solution of methyl 2-(5-acetyl-2-amino-l,3-thiazol-4-yl)acetate (100 mg, 0.467 mmol) in AcOH (2 ml.) was added a solution of Bn (0.02 mL, 0.47 mmol) in dioxane (0.5 mL) dropwise at 0 °C under N2. 'The resulting mixture was stirred for 1 h at 0 °C under N2, and then concentrated under vacuum to afford the title compound (140 mg, overweight).

[0340] Step 4: ethyl 2-(2-amino-5-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-l,3-thiazol- 4-yl)acetate (Example 79)

[0341]

[0185] To a stirred solution of 5-chloropyridin-2-ylthiourea (42.7 mg, 0.227 mmol) in EtOH

[0342] Example 80. 2-(2'-amino-2-((5-chloropyridin-2-yl)amino)-[4,5'-bithiazol]-4'-yl)ethan-l- ol

[0343] Step 1: methyl 2-(2-amino-5-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-l,3- thiazol-4-yl)acetate (24-4A)

[0344]

[0186] To a stirred solution of 5-chloropyridin-2-ylthiourea (340 mg, 1.81 mmol) in MeOH (24 mL) was added methyl 2-[2-amino-5-(2-bromoacelyl)-1 ,3-thiazol-4-yl]acetate (800 mg, 2.73 mmol) at RT. The resulting mixture was stirred overnight at 65 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase FCC

[0345] (C l 8 silica; 0%-100% ACM in water (0.1% FA)) to afford the title compound (500 mg, 72%) as a brown solid. LCMS: (ES, tn / z): [M+H]~ 382,

[0346] Step 2: methyl 2-{2-[(tert-butoxycarbonyl)amino]-5-{2-[(5-chloropyridin-2-yl)amino]- l,3-thiazol-4-yl}-l,3-thiazol-4-yl} acetate (24-5)

[0347]

[0187] To a stirred solution of methyl 2-(2-amino-5-{2-[(5-chloropyridin-2-yl)ammo]-l,3- thiazol-4-yl}-l,3-thiazol-4-yl)acetate (1.50 g, 3.93 mmol) in THF (15 mL) were added 4- dimethyiaminopyridine (0.33 g, 2.7 mmol) and di-tert-butyl dicarbonate (3.22 g, 14.7 mmol) at RT. The resulting mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was purified by FCC (PE / EA (4: 1)) to afford the title compound (700 mg, 37%) as a light brown solid. LCMS: (ES, m / z): (M+H] x 482.

[0348] Step 3: tert-butyl N-(5-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-4-(2- hydroxyethyl)-l,3-thiazol-2-yl)carbamate (24-6)

[0349]

[0188] To a stirred solution of tert-butyl N-(5-{2-[(5-chloropyridin-2-yl)amino]-l ,3-thiazoi- 4-yl}~4-(2 -methoxy ethyl)-l,3-thiazol-2-yl)carbamate (300 mg, 0.641 mmol) in THF (6 mL) was added Li Al FL (73 mg, 1 .9 mmol) at 0 °C under Nj. The resulting mixture was stirred overnight at RT. The reaction was quenched with NasSO^. IOH2O at 0 °C. The resulting mixture was filtered, the filter cake was washed with THF (3 x 5 mL). The filtrate was concentrated under vacuum. The residue was purified by FCC (PE / EA (1 / 1)) to afford the title compound (200 mg, 69%) as a brown solid. LCMS: (ES, m / z): (M+H]* 454.

[0350] Step 4: 2-(2'-amino-2-((5-chloropyridin-2-yl)amino)-[4,5'-bithiazol]-4'-yl)ethan-l-ol (Example 80)

[0351]

[0189] To a stirred solution of tert-butyl N-(5-{2-[(5-chloropyridin-2-y1)amino]-l,3-thiazol- 4-yl}-4-(2-hydroxyethyl)-l,3-thiazol-2-yl)carbamate (130 mg, 0.286 mmol) in DCM (3 mL) was added TFA (1 mL) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by Prep HPLC (SunFire Prep C 18 OBD Column; 0. 1% FA) 20%-44% B in 8 min, 44% B; RT (min): 5.00:) to afford the title compound formate salt (50 mg, 44%) as an off-white solid. LCMS: (ES, Hi / zy.

[0352] Example 81. 5-chloro-N-(4-{2H,3H,4H-pyrido[3,2-b][l,4]oxazin-8-yl}-l,3-thiazol-2- yl)pyridin-2-amine, trifluoracetic acid Step 1: l-(5-aminopyridin-2-yl)ethan-l-one (32-1)

[0353]

[0190] To a stirred solution of 5-aminopyridine-2-carbonitrile (3.0 g, 8.4 mmol) in THF was added chloromethyl magnesium (29.4 mmol) in portions at. -78 °C under Ns. The resulting mixture was stirred for 4 h at RT. The resulting mixture was quenched with ice water (50 ml..) and extracted with EA (3 x ] 00 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum. The residue was purified by FCC (PEZEA (1 :2)) to afford the title compound (2.2 g, 65%) as a yellow solid. LCMS: (ES, m / z): [M+H]+137.

[0354] Step 2: N-[6-(2-bromoacetyl)pyridin-3-yl]acetamide (32-3)

[0355]

[0191] To a stirred solution of l-(5-arainopyridin-2-yl)ethanone (1.5 g, 1 .5 mmol) and EtsN (2.23 g, 2.94 mmol) in DCM was added acetyl chloride (1.04 g, 1.76 mmol) dropwise at 0 °C under N2. The mixture was allowed to warm to R.T and stirred for 1 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaffCL. filtered and concentrated under vacuum. ’The residue was purified by FCC (PEZEA (4: 1)) to afford the title compound (380 mg, 19%) as a white solid. LCMS: (ES, m / zy. [M+H]4179.

[0356] Step 3: N-[6-(2-bromoacetyl)pyridin-3-yl]acetamide (32-4)

[0357]

[0192] To a stirred solution of N-(6-acetylpyridin-3-yl)acetarnide (380 mg, 0.193 mmol) in HBr (3.8 mL, 48% in AcOH ) was added Bt2 (0.1 1 mL, 0.19 mmol) dissolved in dioxane (1 mL) dropwise at 0 °C under N?. The resulting mixture was stirred for 1 h at 0 °C under Ns. The residue was basified to pH 7 with sat. aq. NaHCCE. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NazSCfo filtered and concentrated under vacuum. The residue was purified by FCC (PEZEA (3:1)) to afford the title compound (103 mg, 38%) as a yellow solid. LCMS: (ES, m / z): [M-H]" 255.

[0358] Step 4: N-(6-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}pyridin-3-yl)acetamide (32-5)

[0359]

[0193] A mixture of N-[6-(2-bromoacetyl)pyridin-3-yl]acetamide (370 mg, 1.44 mmol) and 5-chloropyridin-2-yithiourea (189 mg, 1 .01 mmol) in EtOH was stirred overnight at 80 °C under Ns. The precipitated solids were collected by filtration and washed with EA (5 x 2 ml). This resulted in the title compound (87 mg, 17%) as a yellow solid. LCMS: (ES, m / z): i M • H 1 346.

[0360] Step 5: 5-chloro-N-(4-{2H,3H,4H-pyrido[3,2-b] [l,4]oxazin-8-yl}-l,3-thiazol-2- yl)pyridin-2-amine (Example 81)

[0194] A mixture of N-(6-{2-[(5-chforopyridim2-yl)amino]-l,3-thiazol-4-yl} pyridin-3-

[0361] Example 82. 4-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-3-methylpyridin-2- amine

[0362] 47-2

[0363] Step 1: 2-bromo-4-chloro-3-methylpyridine (47-1)

[0364]

[0195] To a solution of 2,2,6, 6-tetramethyipiperi din- l-ol ate (4.87 g, 31.2 mmol) in THF (60 mL) was added n-BuLi (195 mL. 488 mmol, 2.5 M in hexane) dropwise at -78 °C under N2. The resulting mixture was stirred for 30 min at -78 °C under N2. To this mixture was added a solution of 2-bromo-4-chloropyridine (5.0 g, 26 mmol) in THF (5 mL) at -78°C under Nj.

[0365] The resulting mixture was stirred for 30 min at -78 °C under N2. And then to the above mixture was added Mel (3.72 mL, 59.8 mmol). The resulting mixture was stirred for 30 min at -78 °C under N2. The resulting mixture was allowed to warm up to RT and stirred for 15 h.

[0366] The reaction was quenched with aq. NH.iCl (100 mL) at 0 °C and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous NajSO.i. filtered and concentrated under vacuum. The residue was purified by FCC (PE / EA (12: 1)) to afford the title compound (1.5 g, 28%) as a yellow solid. LCMS:

[0367] Step 2: 4-chloro-3-methylpyridin-2-amine (47-2)

[0368]

[0196] To a stirred mixture of 2-bromo-4-chloro-3-niethylpyridine (2.4 g, 12 mmol ) and

[0369] Step 5: 4-{2-[(5-chloropyridin-2-yl)amino]-l,3-thiazol-4-yl}-3-methylpyridin-2-amine (Example 82)

[0370]

[0197] To a stirred solution of l-(2-amino-3-methylpyridin-4-yl)-2-bromoethanone (70 mg, 0.31 mmol) in EtOH (2 mL) was added 5-chloropyridin~2~ylthiourea (40 mg, 0.21 mmol) at RT. The resulting mixture was stirred overnight at 80 °C under Nj. The resulting mixture was concentrated under vacuum to afford a residue, which was purified by prep HPLC (Sunfire prep Cl 8 column; A: water (0.05% TEA ), B: ACN; 60 mL / min; 20%~60% B in 8 min, 60% B; RT (min): 5.03) to afford the title compound TFA salt (3.8 mg, 3%) as a white solid. LCMS: (ES, ®Zz): 151 H l 318.1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1 H), 1 1 .70 (s, 1 H), 8.39 (d, J 2.6 Hz, 1H), 7.90-7.84 (m, 4H), 7.60 (s, 1H), 7.16-7.14 (m, 2H), 2.38 (s, 3H).

[0371] Example 83. 5-chloro-N-(4-{7H-imidazo[l,2-a] [l,3]diazol-3-yl}-l,3-thiazol-2- yl)pyridin-2-amine

[0372] Step 1: ethyl 7H-imidazo[l,2-a][l,3]diazole-3-carboxylate (40-3)

[0373]

[0198] To a stirred solution of ethyl 2-amino-3H-imidazole~4-carboxylate (2.0 g, 13 mmol) in D MF (40 ml.) was added NaH (1.55 g, 38.7 mmol, 60% in mineral oil) at 0 °C under N2. The resulting mixture was stirred for 30 min at 0 °C under N2. To the above mixture was added 2-bromo-l,l-diethoxyethane (7.62 g, 38.7 mmol) at 0 °C. The resulting mixture was stirred for additional 4 h at RT. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (2 x 30 mL) and brine (50 mL), dried over anhydrous Na2SO4. filtered and concentrated under vacuum. To the above residue was added 2 N HC1 (20 mL) at RT. The resulting mixture was stirred for additional 3 h at 100 °C. ’The mixture was allowed to cool down to RT. The resulting mixture u as extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum. The residue was purified by reverse-phase FCC (C 18 silica; 0%- 100% ACN in water (0.1% FA)) to afford the title compound (300 mg, 13%) as a light yellow solid. LCMS: (ES, m / z): [M+H]^ 180.

[0374] Step 2: N-methoxy-N-methyl-7H-imidazo[l,2-a][l,3]diazole-3-carboxamide (40-5)

[0375]

[0199] To a stirred solution of N,O-dimethyl hydroxylamine (1.13 g, 18.4 mmol) in THF (20 mL) was added AlMej (30.7 mL, 30.7 mmol, 1 M in heptane) dropwise at -15 °C under Nz. The resulting mixture was stirred for 1 h at 0 °C under N2 followed by the addition of ethyl 7H-imidazo[l,2-a][l,3]diazole-3-carboxylate (1.10 g, 6.14 mmol) dissolved in THF (10 mL), and then stirred for 2 h at 65 °C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (40 ml.,), dried over anhydrous Na2SO4filtered and concentrated under vacuum. The residue was purified by reverse-phase FCC (C18 silica, 0%-100% ACN in water (0.1 % NH4HCO3)) to afford the title compound (300 mg, 25%) as a light yellow solid. LCMS: (ES, m / z): [M+H]+195.

[0376] Step 3: l-{7H-imidazo[l,2-a][l,3]diazol-3-yl}ethanone (40-6)

[0377]

[0200] To a stirred solution of N-methoxy-N-methy1-7H-imidazo[l,2-a][l,3]diazo1e-3- carboxamide (400 mg, 2.06 mmol) in THF (8 mL) was added methylmagnesium bromide (6.18 mL, 18.5 mmol, 3 M in THF) dropwise at -78 °C under N2. The resulting mixture was stirred overnight at 0 °C under N;. The reaction was quenched with sat. aq. NH4CI (10 mL) at 0 °C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NazSCL, filtered and concentrated under vacuum. The resulting mixture was concentrated under vacuum and the residue was purified by reverse-phase FCC (Cl 8 silica; 0%-100% ACN in water (lOmmol / L NH4HCO3)) to afford the title compound (200 mg, 65%) as a brown solid. LCMS: (ES, m / z): [M-f-H]+150.

[0378] Step 4: 2-bromo-l-{7H-imidazo[l,2-a][l,3]diazol-3-yl}ethanone (40-7)

[0379]

[0201] To a stirred solution of l-{7H-imidazo[l,2-a][l,3]diazol-3-yl jethanone (200 mg, 1 .34 mmol) in HBr (5 mL, 33%wt in AcOH) was added a solution of Brz (0.07 mL, 1.34 mmol) in dioxane (1 mL) dropwise at 0 °C under Nz. The resulting mixture was stirred for 1 h at 0 °C under Nx The resulting mixture was concentrated under vacuum to afford the title compound (200 mg, 65%) as a red oil. LCMS: (ES, m / z): I M • H f 228.

[0380] Step 5: 5-chloro-N-(4-{7H-imidazo[l,2-a] [l,3]diazol-3-yl}-l,3-thiazol-2-yl)pyridin-2- amine (Example 83)

[0381]

[0202] To a stirred solution of 5-chloropyridin-2-ylthiourea (98.4 mg, 0.524 mmol) in EtOH (3 mL) was added 2-bromo-l-{7H-imidazo[l,2-a][l,3]diazol-3-yl}ethanone (179 mg, 0.786 mmol) at RT. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under vacuum. The residue w7as purified by prep HPLC ( XBridge Shield RPl 8 OBD Column; A: water (0.05% NHz), B: ACN: 3.3%~57% B: RT (min): 5.43) to afford the title compound (17 mg, 10%) as a light yellow solid. LCMS: (ES, m / z): [M+H]+317.1H NMR (400 MHz, DMSO-d6) δ 1 1.53 (s, 1H), 11.21 (s, JH), 8.34 (d, J 2.6 Hz, JH), 7.81 (dd, J 8.9, 2.7 Hz, III), 7.39 (s, 1H), 7.20 (d, .1 2.2 Hz, l H), 7.12 (d, .1 8.9 Hz, lH), 7.05 (d, .12.2 Hz, 2H).

[0382] Example 84. N-[4-(2-amino-4-propyl-l,3-thiazol-5-yl)-l,3-thiazol-2-yl]-5-chloropyridin- 2-amine

[0383] Step 1: tert-butyl N-(4-bromo-5-formyl-l,3-thiazol-2-yl)carbamate (49-6)

[0384]

[0203] To a stirred solution of tert-butyl tert-butyl N-(5-bromo-l,3-thiazol-2-yl)carbamate (5,0 g, 18 mmol) in TI IF (50 mL) was added Lithium diisopropylamine (8.0 mL, 59 mmol, 2M in THF) dropwise at 0 °C. The resulting mixture was stirred for 30 min at RT. To the above mixture was added DMF (4.6 mL, 59. mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 2 h at RT. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3 x .30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum to afford the title compound (3.2 g, 58%) as a yellow solid. LCMS: (ES, m / z): 1 M H j 307, 309.

[0385] Step 2: tert-butyl N-[4-bromo-5-(l-hydroxyethyl)-l,3-thiazol-2-yl]carbamate (49-7)

[0386]

[0204] To a stirred solution of tert-butyl N-(4-bromo-5-formyl-l ,3-thiazol-2-yl)carbamate (3.0 g, 9.8 mmol) in THF (60 mL) were added MeMgBr (9.76 mL, 29.3 mmol, 3 M in THF) dropwise at 0 °C. The resulting mixture was stirred for 2 h at RT. The reaction was quenched with water at 0 °C. The resulting mixture was diluted with water (60 mL). The resulting mixture was extracted with EA (3 x 30 ml..). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4filtered and concentrated under vacuum to afford the title compound (2.4 g, 76%) as a yellow solid. LCMS: (ES, m / z): [M+ITp 323, 325.

[0387] Step 3: tert-butyl N-(5-acetyl-4-bromo-l,3-thiazol-2-yl)carbamate (49-8)

[0388]

[0205] To a stirred solution of tert-butyl N-[4-bromo-5-(l-hydroxyethyl)-l,3-thiazol-2- yl]carbamate (2.0 g, 6.2 mmol) in DCM (20 mL) was added pyridinium chlorochromate (2.67 g, 12.4 mmol) at RT. The resulting mixture was stirred for 16 h at RT under Nz. The resulting mixture w7as filtered, the filter cake was washed with DCM (3 x 5 mL). The filtrate was concentrated under vacuum. The residue was purified by FCC (PE / EA (5 / 1)) to afford the title compound (770 mg, 39%) as a yellow solid. LCMS: (ES, m / z): [M+H]+321, 323.

[0389] Step 4: tert-butyl N-{5-acetyl-4-[(lE)-prop-l-en-l-yl]-l,3-thiazol-2-yl}carbamate (49-9)

[0390]

[0206] To a stirred mixture of tert-butyl N-(5-acetyl-4-bromo-l ,3-thiazol-2-yl)carbamate (500 mg, 1.56 mmol) and 4,4,5,5-tetramethyl-2-[(lE)-prop-l-en-l-yl]-l,3,2-dioxaborolane (523 mg, 3.1 1 mmol) in dioxane (10 mL) and water (2 mL) were added Pd(OAc)2 (35 mg, 0. 16 mmol), S-Phos (64 mg, 0.16 mmol) and K2CO3 (430 mg, 3.1 I mmol) at RT. The mixture was irradiated in the microwave for 1 h at 100 °C. The resulting mixture was diluted with water (30 mL), extracted with EA (3 10 mL), washed with brine (2 10 mL), dried over anhydrous NazSCL filtered and concentrated under vacuum. The residue was purified by FCC (PE / EA (3: 1)) to afford the title compound (360 mg, 82%) as a yellow solid. LCMS: (ES, m / z): [M+Hp 283. Step 5: tert-butyl N-(5-acetyl-4-propyl-l,3-thiazol-2-yl)carbamate (49-10)

[0391]

[0207] To a stirred solution of tert-butyl N-{5-acetyl-4-[(lE)-prop-l-en-l-yI]-l,3-thiazoI-2-

[0392] Step 6: l-(2-amino-4-propyl-l,3-thiazol-5-yl)-2-bromoethanone (49-11)

[0393]

[0208] To a stirred solution of tert-butyl N-(5-acetyl-4-propyl-l,3-tliiazol~2~yl)carbamate (80

[0394] Step 7: N-[4-(2-amino-4-propyl-l,3-thiazol-5-yl)-l,3-thiazol-2-yl]-5-chloropyridin-2- amine (Example 84)

[0395]

[0209] To a stirred solution of l-(2-araino-4-propyl-l,3-thiazol-5-yi)-2-bromoethanone (60 mg, 0.23 mmol) in EtOH (2 mL) was added 5-chloropyridin-2-ylthiourea (43 mg, 0.29 mmol) at RT. The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool down to RT and was concentrated under vacuum. The residue was purified by prep HPLC

[0396] Synthetic Method R

[0397] Example 85. (R)-4-(2-(aminomethyl)pyridin-4-yl)-N-(5-chloro-6-

[0398] ((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)thiazol-2-amine

[0399] Step 1: 2-cyanoisonicotinic acid (4367-77)

[0400]

[0210] A solution of methyl 2-cyanoisonicotinate (6.49 g, 40.0 mmol) and LiOH (1.05 g, 44.0 mmol) in THi- (42 mL) and water (14 ml.,) was stirred at RT for 3 h. The organics were removed under vacuum and the residue was diluted with EA (50 mL) and extracted with water (2 x 50 mL). The aq. layer was acidified with 2 M HC1 and extracted with EA (4 x 80 mL). The combined organics were passed through a hydrophobic frit and concentrated under

[0401] Step 2: 4-(2-bromoacetyl)picolinonitrile (4367-80)

[0402]

[0211] To a suspension of 2-cyanoisonicotinic acid (1.0 g, 6.8 mmol) in DCM (40 mL) was added DMF (4 drops) and oxalyl chloride (0.71 mL, 8.1 mmol) dropwise. After stirring for 1 h the reaction mixture was concentrated under vacuum. The residue was diluted with DCM (40 mL) and cooled to 0 °C. Trimethylsilyldiazomethane (2 M in hexanes, 4.4 mL, 8.8 mmol) was added dropwise and stirring continued at 0 °C for 45 min, then HBr (33% in AcOH, 1 .4 mL, 7.7 mmol) was added. After stirring for 10 min, the reaction mixture was basified using sat. aq. NaaCOs and was extracted with DCM (3 x 40 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and purified by FCC (0-20% EA in cyclohexane) to afford the title compound (819 mg, 54%) as a pale yellow solid.lH NMR (600 MHz, DMiSO-ck): 8 8.98 (d, J 4.8 Hz, 1H), 8.17 (s, 1H), 8.00 (dd, J 1.3, 5.0 Hz, IH), 4.40 (s, 2H).

[0403] Step 3: (R)-5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-amine (4367-16)

[0404]

[0212] To a stirred solution of (R)-tetrahydrofuran-3-ol (3.76 mL, 46.5 mmol) in dioxane (50 mL) at RT was added NaH (2.13 g, 53.1 mmol) slowly. After stirring for '20 min, a solution of 5-chloro-6-fluoropyridin-2-amine (6.49 g, 44.3 mmol) in dioxane (50 mL) was added via syringe. The reaction was stirred at 90 °C for 2 h and then was cooled to RT. The reaction mixture was concentrated under vacuum. The residue was suspended in water (100 mL) extracted with DCM (4 x 100 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum. The residue was dissolved in a minimum volume of DCM and purified by FCC (0-30% EA in cyclohexane) to afford the title compound (8.59 g, 90%) as an orange oil which solidified upon standing.SH NMR (600 MHz, DMSO-ds): S 7.35 (d, J 8.4 Hz, IH), 6.09 - 5.97 (m, 3H), 5.41 (m, IH), 3.92 (dd, J 4.8, 10.3 Hz, IH), 3.83 (m, I H), 3.75 cm. IH), 3.70 (dd, J 1.8, 10.3 Hz, 1 H), 2.20 c m. H I). 1.96 (m. 1 H ).

[0405] Step 4: (R)-l-(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)thiourea (4074-87)

[0406]

[0213] A stirred solution of (R)-5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-amine (2.2 g, 10 mmol) in acetone (8.8 mL) was treated with benzoyl isothiocyanate (1.5 mL, 11 mmol). The thick suspension was stirred at 65 °C for 25 min then acetone (8.8 mL) was added. The suspension was stirred at 65 °C for 80 min then the mixture was stood overnight at RT. The RM was concentrated under vacuum to a pale orange solid that was suspended in MeOH (8.8 mL) and water (8.8mL). K2CO3 (2.1 g, 15 mmol ) was added, and the mixture was stirred at 65 °C for 15 min. MeOH (4 mL) and water (4 mL) were added and lite mixture was stirred at 65 °C for another 75 min. The mixture was cooled to RT and the solid was filtered and dried at 60 °C for Ih to afford a cream solid. The solids were suspended in water (44 mL) for 30 min, then filtered, washed with water and dried at 60 °C under vacuum for 1.5 h to afford the title compound (2.50 g, 87%) of an off-white solid. LCMS: (ES, w / z): [M+H]“ 274.

[0407] Step 5: (R)-4-(2-((5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)amino)thiazol-4- yl)picolinonitrile (4367-82)

[0408]

[0214] A suspension of (R)-l -(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)thiourea (219 mg, 0.80 mmol), 4-(2-bromoacetyl)picolinonitrile (270 mg, 1.20 mmol) and Et3 N0.223 mL, 1.60 mmol) in EtOH (8 mL) was stirred at 80 °C for 90 min. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated under vacuum, suspended in EtOH and filtered. The combined solids were dried under vacuum to afford the title compound (253 mg, 79%) as a pale yellow solid.1H NMR (600 MHz, DMSO-d6) δ 11.67 (s, I H), 8.79 (d, J 5.1 Hz, IH), 8.46 (s, I H), 8.14 (m, IH), 8.04 (s, IH), 7.80 (d, J 8.4 Hz, I H), 6.72 id, J 8.4 Hz, I H), 5.82 (m, IH), 4.04 (dd, J 3.9, 10.5 Hz, I H), 3.93-3.80 (m, 3H), 2.37 (m, IH), 2.09 (m, I H).

[0409] Step 6: (R)-4-(2-(aminomethyl)pyridin-4-yl)-N-(5-chloro-6- ((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)thiazol-2-amine (Example 85)

[0410]

[0215] To a suspension of (R)-4-(2-((5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-

[0411] Examples in Table R were synthesised using Synthetic Method R:

[0412] Example 88. 6-((2’-amino-4’-methyl-[4,5’-bithiazol]-2-yl)amino)-3-chloropyridin- 2(lH)-one

[0413] Final step: 6-((2'-amino-4'-methyl-[4,5'-bithiazol]-2-yl)amino)-3-chloropyridin-2(lH)- one

[0414]

[0216] A suspension of Example 24 (100 mg, 0.283 mmol) in chloroform (10 mL) was

[0415] Synthetic Method U

[0416] Example 89. (R)-N-(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-4-(6- (methylamino)pyridin-3-yl)thiazol-2-amine

[0417] 4453-22

[0418] Step 1: l-(6-(methylamino)pyridin-3-yl)ethan-l-one (4453-20)

[0419]

[0217] A suspension of l-(6-chloropyridin-3-yl)ethan-l-one (1.2 g, 8.0 mmol) in

[0420] Step 2: 2-bromo-l-(6-(methylamino)pyridin-3-yl)ethan-l-one (4453-22)

[0421]

[0218] To a solution of l-(6~(methylamino)pyridin-3-yl)ethan~l-one (300 mg, 2.00 mmol) in AcOH (5 mL) was added HBr (33 wt% in AcOH, 0.72 mL, 4.0 mmol) followed by Br? (0.10 mL, 2.0 mmol) dropwise. The reaction was stirred at RT for 1.5 h and then was concentrated under vacuum. The residue was taken up in sat. aq. NaHCOs (40 mL) and extracted w'ith EA (3 x 40 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum The residue was dissolved in a minimum volume of DCM and

[0422] Step 3: (R)-N-(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-4-(6- (methylamino)pyridin-3-yl)thiazol-2-amine (Example 89)

[0423]

[0219] A suspension of 2-bromo-l-(6-(raethylamino)pyridin-3-yl)ethan-l -one (64 mg, 0.28 mmol) and (R)-l-(5-chloro-6-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)thiourea (70 mg, 0.26 mmol) in EtOH (6 mL) was stirred at 80 °C for 1 h. The reaction mixture was cooled to RT and filtered. The solid was purified by MDAP (5-60% ACN in water + 0.1% NEE) to afford the title compound (33 mg, 32%) as a white solid. LCMS: (ES, m / z): [M+H]+404.1HNMR

[0424] Examples in Table U were synthesised using Synthetic Method U:

[0425] Example 93. N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-4-(l-methylpiperazin-2- yl)thiazol-2-amine

[0426] Step 1: tert-butyl 3-(2-bromothiazol-4-yl)piperazine-l-carboxylate (4448-26)

[0427]

[0220] To a mixture of copper(II) trifluoromethanesulfonate (78 mg, 0.22 mmol) in ACN (4 mL) under Nz was added a solution of 2,6-1utidine (0.025 ml.., 0.22 mmol) in hexafluoro-2- propanol (8 mL) and the blue-green solution was stirred at RT for 4 h, gradually becoming more blue in colour to shade of light blue over time.

[0428]

[0221] Separately, to a mixture of 2-bromothiazole-4-carbaldehyde (0.414 g, 2.158 mmol)

[0429]

[0222] This residue was loaded onto an SCX-2 cartridge (10 g), washed with DCM, then the product eluted with 2M NH3in MeOH; concentration under vacuum afforded the title compound (1 .22 g, overweight) as a yellow oil. LCMS: (ES, m / z): [M+H]+348, 350.;H NMR confirmed the presence of some Sn-butyl impurities. Step 2: tert-butyl 3-(2-bromothiazol-4-yl)-4-methylpiperazine-l-carboxylate (4448-28)

[0430]

[0223] A solution of tert-butyl 3-(2-bromothiazol-4-yl)piperazine-l-carboxylate (600 mg,

[0431] I .72 mmol) in MeOH (15 mL) and THF (15 mL) was treated with 37% aq. formaldehyde (0.385 mL, 5.17 mmol) and sodium triacetoxyborohydride (365 mg, 1.72 mmol), and the reaction was stirred at RT for 18 h. Sodium triacetoxyborohydride (250 mg) was added and the mixture stirred for 2 h then concentrated under vacuum. The residue was loaded onto an SCX-2 cartridge (10 g), then washed with DCM. The product was eluted with 2M NH3in MeOH; concentration under vacuum afforded the title compound (662 mg) as a yellow gum. LCMS: (ES, m / z): [M+H]4362, 364. NM1HR confirmed the presence of Sn-butyl impurities. Step 3: tert-butyl 3-(2-((5-chloro-6-(difluoromethyl)pyridin-2-yl)amino)thiazol-4-yl)-4- methylpiperazine-l-carboxylate (4448-32)

[0432]

[0224] Ni was bubbled through a solution of tert-butyl 3-(2-bromothiazol-4-yl)-4- methylpiperazine-1 -carboxylate (662 mg, 1.83 mmol) in dioxane (15 mL) for 10 min, then die solution added to a mixture of 5~chloro~6-(ditluorornethyl)pyridin~2-amine (326 mg, 1.83 mmol), Pds(dba)3 (84 mg, 0.091 mmol), Xantphos (127 mg, 0.219 mmol) and KfoCfi (1.16 g, 5.48 mmol) under Nz. The mixture was irradiated to 150 °C for 12 h in the microwave. The cooled mixture was filtered through Celite, washing with EA. Water (20 mL) was added to the filtrate, then the aq. extracted with EA (2 x 30 mL). The combined organic layers were washed with brine (25 mL), passed through a hydrophobic frit, and concentrated under vacuum. The residue was purified by silica chromatography (0%-100% EA-'cyclohexane, then 0-30% MeOH / EA to afford the title compound (88 mg, 9% (3 steps)) as a brown solid.

[0433] Step 4: N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-4-(l-methylpiperazin-2-yl)thiazol-2- amine (Example 93)

[0434]

[0225] A solution of tert-butyl 3-(2-((5-chioro-6-(difluoromethyl)pyridin-2-yl)amino)thiazol- 4-yl)-4-m ethylpiperazine- 1 -carboxylate (88 mg, 0.19 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 30 min then concentrated under vacuum. The residue was purified by MDAP (PhenylHexyl column, 5%-40% ACN / water (+ 0.1% FA)) afforded the FA salt. This material was loaded onto an SCX-2 cartridge (2 g), washed with MeOH, then eluted with 21X4 NH3 in MeOH; concentration under vacuum afforded the title compound (20 mg, 29%) as a dark red solid. LCMS: (ES, m / z): [M+H]+360. NMR (610H0 MHz, DMSO-d6) S

[0435] I I .74 (br s, 1 H), 7.91 (d, J 8.8 Hz, 1H), 7.17 (d, J 9.2 Hz, 1H), 7.15 (t, J 53.6 Hz, 1 H), 6.85 (s, 1 H), 2.99 (m, 1 H), 2,84-2.66 (m, 5H), 2.08 (m, H I), 1.99 (s, 3H).

[0436] Example 94. - Low Seeding Assay Protein production

[0437]

[0226] The recombinant human alpha synuclein protein synuclein was expressed in the E. coli BL21 Gold (DE3) strain (Stratagene, CA, U.S.A.) and purified as described previously with slight modifications. Briefly the procedure involved sonication of E. coli cells, boiling of the clarified supernatant to precipitate other proteins, DNA precipitation with Streptomycin Sulphate followed by protein precipitation with Ammonium Sulphate. The precipitated pellet was then solubilised with 25 mM Tris pH 7.7, 1 mM EDTA and purified by ion exchange on HiPrep Q XL 16 / 10 column (Cytiva Life Sciences, Buckinghamshire, U.K.). Eluates were selected by SDS-PAGE and further purified using HiLoad 26 / 600 Superdex 75 column (GE Healthcare, Buckinghamshire, U.K.). The fractions containing the recombinant protein were combined, frozen using liquid nitrogen, and lyophilized.

[0438] Preparation of small molecules

[0439]

[0227] Small molecules were first solubilized in 100% DMSO to a concentration of 5 mM, and then diluted in the protein solution to reach a final DMSO concentration of 1%. We verified that the addition of DMSO in the reaction mixture has no effect on aSyn aggregation.

[0440] Preparation of samples for kinetic experiments

[0441]

[0228] Solutions of monomeric aSyn were prepared by dissolving the lyophilized aSyn in 6 M GuHCl. Monomeric forms were purified from potential oligomeric species and salt using a Superdex 75 10 / 300 GL column (GE Healthcare) at a flowrate of 0.7 mL / min, and were eluted in 20 mM sodium phosphate buffer, pH 4.8 supplemented with 1 mM EDTA. The centre of the peak was collected, and the peptide concentration was determined from die absorbance of the integrated peak area using ε280 ::: 5600 L mol-1cm+1. The obtained monomer was diluted with buffer to the desired concentration and supplemented with 50 mM Thiofiavin T (ThT) from a 5 mM stock. All samples were prepared in low binding Eppendorf tubes on ice using careful pipetting to avoid introduction of air bubbles. Each sample was then pipetted into multiple wells of a 96-well half-area, low-binding, clear bottom and PEG coating plate (Corning 3881 ), 150 mL per well.

[0442]

[0229] For the seeded experiments, preformed seeds were pre-prepared by shaking 200 mM monomeric aSyn 7 days at 50 °C, and stored in a concentration of 5 mM at -80 °C before kinetic measurements. Kinetic experiments were set up as described above for 10 mM aSyn samples in 20 mM sodium phosphate buffer, pH 4.8 with 1 mM EDTA and 50 mM ThT. Seeds were added to freshly prepared monomer solution in order to reach 0.25% final concentration of seeds in the absence or the presence of small molecules.

[0443] Kinetic assays

[0444]

[0230] Assays were initiated by placing the 96-well plate at 37°C under quiescent conditions in a plate reader (Fluostar Omega, BMGFabtech, Offenburg, Germany). 'The ThT fluorescence was measured through the bottom of the plate with a 440 nm excitation filter and a 480 nm emission filter. The ThT fluorescence was followed for two or three repeats of each sample.

[0445] Theoretical framework

[0446]

[0231] kIC values are a proxy for the standard IC values that are typically extracted from binding assays in measuring the half maximal inhibitory' concentration.

[0447]

[0232] A compound's concentration-dependent delay of the aggregation kinetic can be used to determine a reference efficacy with respect to a negative control (e.g. DMSO). t-half (halftime of the aggregation kinetic) is used as a reporter of the delay.

[0448]

[0233] The fitting equation is the Hill equation. where x is the concentration, kICso is a fitted parameter corresponding to 1.5 x DMSO(t- thalf) that translates info y:::0.667 on the normalised y-axis of the Hill equation, n is the Hill coefficient (determined by the slope of the sigmoidal curve) which defines the cooperativity of the process.

[0449]

[0234] In order to obtain a x normalised range [0, 1], the t-half (or the quantity of reference) is converted into a rate as 1 / t-half and then normalised to the negative control. Upon fitting the Hill equation to the data, kIC5() and n are extracted.

[0450]

[0235] kICso is summarized in Table 2. Compounds with a kICso < 2.0 uM are graded with

[0451]

Claims

Claims1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof whereinRing A is optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl or optionally substituted 5-10 membered heterocyclyl;Ring C is optionally substituted 5-6-membered heteroaryl or optionally substituted 9-10 membered heterocyclyl;R1is independently selected from the group consisting of halogen, -OH, -ORC, -NH2, - CN, -NO2, -C(O)OH, -C(O)ORC, -C(O)RC, -NHRC, -N(RC)2, -C(O)NHRC, - C(O)N(RC)2, -S(O)2RC, -(CH2)I-3RC, -(CH2)I-3OH, -(CH2)I-3ORC, -P(O)(RC)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;R2is hydrogen or optionally substituted C1-C3 alkyl; or wherein R1and R2along with their intervening atoms together form an optionally substituted 6-7-membered ring each R3is independently selected from the group consisting of halogen, -OH, -ORC, -NH2, -CN, -NO2, -C(O)OH, -C(O)ORC, -C(O)RC, -NHRC, -N(RC)2, -C(O)NHRC, - C(O)N(RC)2, -S(O)2RC, -(CH2)I-3RC, -(CH2)I-3OH, -(CH2)I-3ORC, -P(O)(RC)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl;each Rcis independently selected from the group consisting of optionally substituted Ci- Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of Rcare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein Ring A is optionally substituted 5-membered heteroaryl.

3. The compound of claim 2, wherein Ring A is optionally substituted thiazolyl.

4. The compound of claim 3, wherein Ring5. The compound of claim 1, wherein Ring A is optionally substituted phenyl.

6. The compound of claim 1, wherein Ring A is optionally substituted 6-membered heteroaryl.

7. The compound of claim 6, wherein Ring A is optionally substituted pyridinyl or optionally substituted pyrazinyl.

8. The compound of claim 7, wherein Ring A is selected from the group consisting of9. The compound of claim 1, wherein the compound is of Formula (la), (lb), or (Ic):or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein the compound is of Formula (la-1), (Ib-1), or (Ic-or a pharmaceutically acceptable salt thereof.

11. The compound of any of claims 1-10, wherein Ring C is optionally substituted 6- membered heteroaryl.

12. The compound of claim 11, wherein Ring C is optionally substituted pyridinyl.

13. The compound of claim 12, wherein Ring C is selected from the group consisting of14. The compound of any of claims 1-10, wherein Ring C is optionally substituted 5- membered heteroaryl.

15. The compound of claim 14, wherein Ring C is selected from the group consisting of16. The compound of claim 14, wherein Ring C is selected from the group consisting of17. The compound of any of claims 1-10, wherein Ring18. The compound of claim 9, wherein the compound is of Formula (Id) or (le):or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of those found in Table 1 or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of any of claims 1-19 and a pharmaceutically acceptable adjuvant.

21. A method of treating or preventing a disease or condition associated with protein misfolding comprising administering a therapeutically effective amount of a compound of any of claims 1-19 or a pharmaceutical composition of claim 20 to a subject in need thereof.

22. The method of claim 21, wherein the protein misfolding disease is Parkinson’s disease.

23. The method of claim 21, wherein the protein misfolding disease or condition is selected from a group consisting of Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

24. The method of claim 21, wherein the protein misfolding disease or condition is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt-Jakob disease, spongiform encephalopathies, neurodegenerative disease, Down syndrome, or cystic fibrosis.

25. The method of claim 21, wherein the disease or condition associated with protein misfolding is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

26. The method of claim 21, wherein the disease or condition associated with protein misfolding is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies,diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

27. The method of claim 20, wherein the disease or condition associated with protein misfolding is Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

28. A method of treating or preventing a disease or condition associated with neurodegeneration comprising administering a therapeutically effective amount of a compound of any of claims 1-19 or a pharmaceutical composition of claim 20 to a subject in need thereof.

29. The method of claim 28, disease or condition associated with neurodegeneration is Parkinson’s disease.

30. The method of claim 28, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt- Jakob disease, spongiform encephalopathies, Down syndrome, or cystic fibrosis.

31. The method of claim 28, wherein the disease or condition associated with neurodegeneration is from Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

32. The method of claim 28, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

33. The method of claim 28, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

34. The method of claim 28, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden- Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, synucleinopathy, pure autonomic nerve failure, dementia,tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

35. A method of treating a disease or condition associated with misfolding of alpha- synuclein protein comprising administering a therapeutically effective amount of a compound of any of claims 1-19 or a pharmaceutical composition of claim 20 to a subject in need thereof.

36. The method of claim 35, wherein the disease or condition associated with misfolding of alpha-synuclein protein is Parkinson’s disease.

37. The method of claim 35, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt- Jakob disease, spongiform encephalopathies, neurodegenerative disease, Down syndrome, or cystic fibrosis.

38. The method of claim 35, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

39. The method of claim 35, wherein disease or condition associated misfolding of alpha- synuclein protein is selected from a group consisting of Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

40. The method of claim 35, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporaldementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

41. The method of claim 35, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden- Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

42. A method of treating or preventing a disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates comprising administering a therapeutically effective amount of a compound of any of claims 1-19 or a pharmaceutical composition of claim 20 to a subject in need thereof.

43. The method of claim 42, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is Parkinson’s disease.

44. The method of claim 42, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

45. The method of claim 42, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils,fibrils, or aggregates is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt- Jakob disease, spongiform encephalopathies, neurodegenerative disease, Down syndrome, or cystic fibrosis.

46. The method of claim 42, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

47. The method of claim 42, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

48. The method of claim 42 wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher'sDisease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

Images