Compositions and methods of use for treating 12-lipoxygenase (12-LOX) mediated diseases

Abstract

The present disclosure provides compounds, compositions containing them, and compositions suitable for their pharmaceutical uses, such as for treating 12-lipoxygenase (12-LOX) mediated diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is an international patent application claiming priority to U.S. Provisional Application No. 63 / 381,191, filed October 27, 2022, No. 63 / 390,380, filed July 19, 2022, No. 63 / 338,111, filed May 4, 2022, and No. 63 / 293,132, filed December 23, 2021, the entire disclosures of each of which are incorporated herein by reference for all purposes.

[0002] The present disclosure provides compounds, compositions comprising them, and pharmaceutical uses thereof, e.g., compositions suitable for treating 12-lipoxygenase (12-LOX) mediated diseases. The present disclosure further provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions, e.g., for the treatment of heparin-induced thrombocytopenia (HIT) and type 1 diabetes (T1D). [Background technology]

[0003] Regulation of platelet function is essential for the prevention and treatment of cardiovascular atherothrombotic events such as coronary artery disease and stroke. Current antiplatelet drugs effectively inhibit platelet function and prevent thrombotic complications, but these treatments often increase the risk of unwanted bleeding. Thus, there is an unmet need for the identification of novel antiplatelet targets that block unwanted platelet activation in disease states and reverse platelet inhibition with minimal risk of bleeding. Platelet adhesion and aggregation at the site of vascular injury is essential to maintain normal hemostasis and prevent blood loss. However, when the integrity of the vessel wall is compromised by the rupture of atherosclerotic plaques, the same process can also lead to the development of arterial thrombosis and vascular occlusion. Excessive platelet activation and aggregation can lead to the formation of occlusive thrombi, which can have severe consequences such as myocardial infarction, ischemic stroke, and pulmonary embolism, which are major causes of morbidity and mortality worldwide. Antiplatelet therapy is the gold standard for its effectiveness in preventing abnormal platelet activation and is considered crucial in the treatment of cardiovascular atherothrombotic events to reduce morbidity and mortality. Currently approved antiplatelet therapies inhibit platelet function by targeting platelet enzymes, receptors, and glycoproteins. These therapeutic approaches limit platelet function but are often accompanied by an increased risk of bleeding. Thus, there is a need for the identification of novel antiplatelet therapeutic targets that limit bleeding.

[0004] 12-Lipoxygenase (12-LOX) is an enzyme that oxidizes fatty acids, produces inflammatory metabolites, and is involved in a myriad of diseases, including heparin-induced thrombocytopenia (HIT) and type 1 diabetes (T1D). Thus, there is a need to develop therapies for these diseases. Summary of the Invention

[0005] Provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein Z is [ka] R1 is hydrogen or an optionally substituted cycloalkyl, aryl, or C1-C3 alkylaryl, each of which is optionally substituted by one or more substituents independently selected from halogen, alkyl, haloalkyl, alkyloxy, C1-C3 haloalkyloxy, or heterocycle; R2 is H, halogen, deuterium, alkyl, haloalkyl, C1-C3 alkyloxy and C1-C3 haloalkyl, hydroxyalkyl, alkyoxyalkyl, cycloalkyl including cyclopropyl, C1-C3 Alkylaryl, or [ka] or substituted or unsubstituted aryl and aralkyl, including [ka] wherein R9 is independently selected from C1-C3 alkyl, cycloalkyl (including cyclopropyl), and substituted or unsubstituted phenyl;

[0006] or R1 and R2 together with the thiazole ring form an optionally substituted 5-, 6-, or 7-membered fused 1,2-carbocyclic ring system, in which the ring carbons of the 5-, 6-, or 7-membered fused ring are optionally substituted by one or more atoms selected from N, O, and S. The fused 5-, 6-, or 7-membered ring is optionally substituted independently by one or more halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, C1-C3 haloalkyloxy, or an optionally substituted aryl ring;

[0007] or R1 and R2 taken together with the carbon to which they are attached form a substituted or unsubstituted: [ka] R3 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each R4 is independently hydrogen, CD3, substituted or unsubstituted phenyl, cycloalkyl including cyclopropyl, C1-C3 alkyl, C1-C3 haloalkyl, -OR, C1-C3 haloalkyloxy, or halogen; R5 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is hydrogen, CD3, alkyl, cycloalkyl, haloalkyl, or [ka] each R7 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halogen; R8 is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; n is 0, 1, or 2; p is 0, 1, 2, or 3; or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] 1. General Description of Certain Embodiments of the Invention: In one aspect, the present invention provides a compound of formula (I'): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring Z' is an optionally substituted 5-6 membered monocyclic aromatic or heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. One or more optional substituents in ring Z' independently replace one or more of the hydrogen atoms in the C-H bonds of the ring with a halogen, C-C alkyl, C-C haloalkyl, -OR 10 , -N(R)2, or one or more of the following: [ka] In the formula, R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cycloalkyl, C 1-6 halocycloalkyl, phenyl.

[0009] L1 is a covalent bond or C 1-6 wherein one or two methylene units of the chain are independently and optionally selected from -OC(O)-, -C(O)O-, -OC(O)-, -N(R 11 )-, -C(O)N(R 11 )-, -(R 11 )NC(O)-, -OC(O)N(R 11 )-, -(R 11 )NC(O)O-, -N(R 11 )C(O)N(R 11 )-, -S-, -SO-, -SO2-, -SO2N(R 11 )-, -(R 11 )NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R 11 )-, -(R 11 )NC(S)- or -(R 11 )NC(S)N(R 11 )-, R 11 are independently hydrogen or C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cycloalkyl, or C1-6 an optionally substituted group selected from halocycloalkyl, or 1-6 an optionally substituted group selected from an aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0010] In some embodiments, the present invention provides a compound of formula (I): [ka] (I) or a pharma- ceutically acceptable salt thereof, wherein Z is [ka] R1 is hydrogen or an optionally substituted cycloalkyl, aryl, or C1-C3 alkylaryl, each of which is independently substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkyloxy, C1-C3 haloalkyloxy, and heterocycle; R2 is H, halogen, deuterium, alkyl, haloalkyl, C1-C3 alkyloxy and C1-C3 haloalkyloxy, hydroxyalkyl, alkyoxyalkyl, cycloalkyl including cyclopropyl, C1-C3 alkylaryl, or [ka] or substituted or unsubstituted aryl and aralkyl, including [ka] wherein R9 is independently selected from C1-C3 alkyl, cycloalkyl (including cyclopropyl), and substituted or unsubstituted phenyl;

[0011] or R1 and R2 together with the thiazole ring form an optionally substituted 5-, 6-, or 7-membered fused 1,2-carbocyclic ring system, in which the ring carbons of the 5-, 6-, or 7-membered fused ring are optionally substituted by one or more atoms selected from N, O, and S. The fused 5-, 6-, or 7-membered ring is optionally substituted independently by one or more halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, C1-C3 haloalkyloxy, or an optionally substituted aryl ring;

[0012] or R1 and R2 taken together with the carbon to which they are attached form a substituted or unsubstituted: [ka] R3 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each R4 is independently hydrogen, CD3, substituted or unsubstituted phenyl, cycloalkyl including cyclopropyl, halogen, C1-C3 alkyl, C1-C3 alkylaryl, C1-C3 haloalkyl, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R5 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is hydrogen, CD3, alkyl, cycloalkyl, haloalkyl, or [ka] each R7 is independently hydrogen, halogenalkyl, haloalkyl, or cycloalkyl; R8 is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; n is 0, 1, or 2; p is 0, 1, 2, or 3;

[0013] or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof.

[0014] Also described herein are methods of treating a disease amenable to treatment with the disclosed compounds in a patient in need thereof by administering to the patient an effective amount of the disclosed compounds.

[0015] Also described herein are methods of treating a disease or disorder by administering to a patient in need thereof an effective amount of the disclosed compounds.

[0016] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharma- ceutically acceptable carrier. The compositions are useful for treating or preventing a disease or disorder. The present disclosure includes the disclosed compounds provided as pharma- ceutically acceptable prodrugs, hydrates, salts, stereoisomers, or mixtures thereof.

[0017] Details of the present disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular form includes the plural form unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0018] 2. Compounds and Definitions: The compounds of the present invention include those described generally herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise specified. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: (2001), the contents of which are incorporated herein by reference in their entireties.

[0019] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0020] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise specified.

[0021] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0022] As used herein, "divalent C 1-n "Saturated or unsaturated straight or branched hydrocarbon chain" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0023] The term "aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic and has one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "carbocyclic" (or "carbocycle," or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is substituted or contains one or more units of unsaturation, but is not aromatic and has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0024] The term "hydrogen" as used herein when referring to an atomic substituent means a covalently bonded hydrogen atom, for example, as in HO, -CH, -NH, -OH, (methyl radical), or CH, and does not refer to diatomic hydrogen gas (H).

[0025] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is preferably a positive integer of 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0026] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0027] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group of the following structure: [ka]

[0028] The term "halogen" or "halo" refers to a covalently bonded halogen atom, such as -F, -Cl, -Br, or -I. The term "fluorine" as used herein refers to a covalently bonded fluorine atom, for example, as in CF3CO2H, -CF3. Unless otherwise specified, it does not refer to diatomic fluorine gas (F2). The same is true for chlorine, bromine, and iodine as used herein.

[0029] The term "aryl" used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including 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 used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0030] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, sharing 6, 10, or 14 pi electrons in a cyclic array, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes the oxidized forms of nitrogen or sulfur, and the quaternized forms of a basic nitrogen. Heteroaryl groups include, but are not limited to, 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, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic 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, where the alkyl and heteroaryl portions independently are optionally substituted.

[0031] The terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably herein and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic moiety that is either saturated or partially unsaturated and has, 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 substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or . + It may be NR (as in N-substituted pyrrolidinyl).

[0032] 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, but are not limited to, 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 alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl portions are independently optionally substituted.

[0033] 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 defined herein.

[0034] As described herein, the compounds of the invention 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 specified 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 if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. The combinations of substituents envisioned by the present invention 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 substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0035] Each optional substituent on a substitutable carbon is independently selected from halogen, -(CH), 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph (which may be substituted by R°), -(CH2) 0-4 O(CH2) 0-1 Ph (which may be substituted with R°), -CH=CHPh (which may be substituted with R°), -(CH2) 0-4 O(CH2) 0-1-pyridyl (can be substituted by R°), -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR-, SC(S)SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -S(O)(NR°)R°, -S(O)2N=C(NR°2)2, -(CH2) 0-4 S(O)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, -OP(O)(OR°)2, SiR°3, -(C 1-4 Linear or branched alkylene)ON(R°)2, or -(C 1-4 A monovalent substituent selected from the group consisting of linear or branched alkylene)C(O)ON(R°)2.

[0036] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 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 above definition, two independent occurrences of R° taken together with their intervening atoms independently form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur (which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S); or each R° is independently selected from halogen, -(CH2) 0-2 R ● , -(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 S.R. ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● is optionally substituted with a monovalent substituent selected from

[0037] Each R ●is independently 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R ● is unsubstituted or, if preceded by halo, is substituted only with one or more halogens, or the optional substituents on the saturated carbons are independently: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, or a divalent substituent attached to adjacent substitutable carbons of an "optionally substituted" group is -O(CR * 2) 2-3 O- and R * Each independent occurrence of is hydrogen, C 1-6 selected from aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or nitrogen.

[0038] R * C 1-6 If aliphatic, R * is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is independently 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by halo, is substituted only with one or more halogens.

[0039] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † And each R † are independently hydrogen, C 1-6 an aliphatic, 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 two independent R † occurrences of, taken together with their intervening atoms, form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; † C 1-6 If aliphatic, R † is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is independently 1-4 Aliphatic, -CH2Ph, -O(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; ● is unsubstituted or, if preceded by halo, is substituted only with one or more halogens.

[0040] "C1-C3 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 3 carbon atoms. Examples of C1-C3 alkyl groups include, but are not limited to, methyl, ethyl, propyl, and isopropyl.

[0041] "C1-C5 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 5 carbon atoms. Examples of C1-C5 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.

[0042] Alkyl can generally be a lower alkyl, or a C1-C6 alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0043] Alkyloxy can generally be lower alkyl, or C1-C6 alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Alkyloxy is generally an alkyl covalently bonded to oxygen.

[0044] The halogen can be F, Cl, Br, or I.

[0045] Haloalkyl can generally be a lower haloalkyl, or a C1-C6 haloalkyl, or a C1-C3 alkyl. Examples of C1-C3 haloalkyl include -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CF2CF3, -CF2CF2H, and -CH2CF3.

[0046] Haloalkyloxy can generally be a haloalkyl, such as a lower alkyl, i.e., a C1-C6 haloalkyl bonded to an oxygen, or a C1-C3 haloalkyl. Examples of C1-C3 haloalkyl include CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CF2CF3, CF2CF2H, and CH2CF3.

[0047] Cycloalkyl means a monocyclic saturated carbocycle derived from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl.

[0048] Heterocycloalkyl means a monocyclic saturated carbocyclic ring derived from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl, in which heteroatoms such as nitrogen, oxygen, or sulfur are bonded to two carbons within the ring.

[0049] Spirocycle means a monocyclic saturated carbocyclic ring derived from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl, optionally with heteroatoms such as nitrogen, oxygen, or sulfur bonded to two carbons within the ring.

[0050] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that 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, etc., 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups 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 using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxybenzoate, and the like. -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, and valerate salts.

[0051] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+ (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0052] The present disclosure also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharma- ceutically acceptable carrier. Exemplary "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, anthonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, hydrogen sulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothioate, lactate, la, and the like. Examples of suitable salts include but are not limited to, but are not limited to, carbohydrates, oleates, magnesium salts, malates, maleates, mandelates, mesylates, methyl bromides, methyl nitrates, methyl sulfates, mucates, napsylates, nitrates, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoates, oleates, oxalates, palmitates, pamoates (l,1-methene-bis-2-hydroxy-3-naphthoates, einbonates), pantothenates, phosphates / diphosphates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, subacetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, theoclates, tosylates, triethiodides, and valerates.

[0053] A "subject" is a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig) or a non-human primate (e.g., a monkey, chimpanzee, baboon, or rhesus monkey).

[0054] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject, as described herein.

[0055] The term "carrier" as used in this disclosure includes a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0056] The term "treating" with respect to a subject refers to improving at least one symptom of a disorder in a subject. Treatment includes curing, ameliorating, or at least partially alleviating the disorder.

[0057] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, a disease, condition, or illness, unless otherwise indicated.

[0058] The terms "administer," "administering," or "administration" as used in this disclosure refer to either administering a disclosed compound, or a pharma- ceutically acceptable salt of a disclosed compound or composition, directly to a subject, or administering to a subject a prodrug derivative or analog of the compound, or a pharma- ceutically acceptable salt of the compound or composition, that is capable of forming an equivalent amount of the active compound in the subject's body.

[0059] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (eg, hydrolysis, glucuronidation, etc.) to the disclosed compound.

[0060] 2.1 Stereoisomers The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and hindered rotation bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Thus, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds of any chemical structure disclosed herein (in whole or in part), including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomeric pure) and stereoisomeric mixtures (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixtures of any of the foregoing), unless stereochemistry is specifically specified.

[0061] If the stereochemistry of a structure or a portion of a structure is not shown, for example, in bold or dashed lines, the structure or portion of a structure should be interpreted as including all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is shown, for example, in bold or dashed lines, the structure or portion of a structure should be interpreted as including only the stereoisomer shown. For example, (lR)-l-methyl-2-(trifluoromethyl)cyclohexane is meant to include (lR, 2R)-l-methyl-2-(trifluoromethyl)cyclohexane and (lR, 2S)-l-methyl-2-(trifluoromethyl)cyclohexane. A bond drawn with a wavy line indicates that both stereoisomers are included. This should not be confused with a wavy line drawn perpendicular to a bond, which indicates the point of attachment of a group to the rest of the molecule.

[0062] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropoisomers) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the enantiomer of the mirror image of the compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomers and diastereomers of the compound. Exemplary stereoisomerically pure compounds include more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. The present disclosure also encompasses pharmaceutical compositions comprising the stereoisomerically pure forms and the use of the stereoisomerically pure forms of any of the compounds disclosed herein. Furthermore, the present disclosure also encompasses pharmaceutical compositions comprising the stereoisomers of any of the compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al, Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon

[0063] See, for example, W. E. Wilson, "Chemical Compounds" (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0064] 2.2 Tautomers As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms.Since only one specific chemical structure may be used to represent one tautomeric form, for convenience, it will be understood that a reference to a compound of a given structural formula includes all other possible tautomers of that structural formula.For example, the following is an illustrative tautomer of a compound of formula I', where R5=H: [ka] Those skilled in the art will recognize that under standard conditions, the tautomer on the left is clearly the predominant tautomer for these two structures, and this example is given for illustrative purposes only. Thus, the scope of the present disclosure is understood to encompass all tautomeric forms of the compounds disclosed herein.

[0065] 2.3 Isotope labeled compounds Additionally, the scope of the present disclosure includes all pharma- ceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from that typically found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein are: 2 H and 3 Hydrogen such as H n C. 13 C, and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125Iodine, such as I 13 N and 15 Nitrogen such as N 15 O 17 O and 18 Oxygen, such as O 32 Phosphorus, such as P, 35 Certain isotopically labeled compounds of formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Substitution with isotopes such as H or D can offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some situations. n C. 18 F, 15 O, and 13 Substitution with positron-emitting isotopes, such as N, may be useful in positron emission topography (PET) studies, for example, to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein may generally be prepared by conventional techniques known to those of skill in the art, or by processes analogous to those described in the accompanying general synthetic schemes and examples, using an appropriate isotopically labeled reagent in place of a previously used non-labeled reagent.

[0066] 2.4 Solvates As mentioned above, the compounds disclosed herein, and the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharma- ceutically acceptable salts of any of the foregoing, may exist in solvated or unsolvated forms.

[0067] The term "solvate" as used herein refers to a molecular complex comprising a compound described herein or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutical acceptable solvent molecules in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0068] Thus, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharma- ceutically acceptable salts of any of the foregoing.

[0069] 3. Description of Exemplary Embodiments: In some embodiments, the present invention provides a compound of formula (I): [ka] wherein Z is: [ka] R1 is selected from hydrogen, or optionally substituted cycloalkyl, aryl, or C1-C3 alkylaryl, each of which is optionally substituted by one or more substituents independently selected from halogen, alkyl, haloalkyl, alkyloxy, C1-C3 haloalkyloxy, or heterocycle;

[0070] R2 is H, halogen, deuterium, alkyl, haloalkyl, C1-C3 alkyloxy and C1-C3 haloalkyloxy, hydroxyalkyl, alkyoxyalkyl, cycloalkyl including cyclopropyl, C1-C3 alkylaryl, or [ka] or substituted or unsubstituted aryl and aralkyl, including [ka] wherein R9 is independently selected from C1-C3 alkyl, cycloalkyl (including cyclopropyl), and substituted or unsubstituted phenyl;

[0071] or R1 and R2 together with the thiazole ring form an optionally substituted 5-, 6-, or 7-membered fused 1,2-carbocyclic ring system, in which the ring carbons of the 5-, 6-, or 7-membered fused ring are optionally substituted by one or more atoms selected from N, O, and S. The fused 5-, 6-, or 7-membered ring is optionally substituted, independently, by one or more halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, C1-C3 haloalkyloxy, or an optionally substituted aryl ring;

[0072] or R1 and R2 taken together with the carbon to which they are attached form a substituted or unsubstituted: [ka] R3 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; each R4 is independently hydrogen, CD3, halogen, substituted or unsubstituted phenyl, cycloalkyl including cyclopropyl, C1-C3 alkyl, C1-C3 alkylaryl, C1-C3 haloalkyl, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R5 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is hydrogen, CD3, alkyl, cycloalkyl, haloalkyl, or [ka] each R7 is independently hydrogen, halogenalkyl, haloalkyl, or cycloalkyl; R8 is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; n is 0, 1, or 2; Compounds in which p is 0, 1, 2, or 3; or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof. As generally defined above, R1 is an optionally substituted aryl or C1-C3 alkylaryl (independently substituted by one or more substituents selected from halogen, alkyl, haloalkyl, alkyloxy, 3-F, 4-oxetanephenyl, and C1-C3 haloalkyloxy).

[0073] In some embodiments, R1 is optionally substituted aryl.

[0074] In some embodiments, R1 is: [ka] wherein R is independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Cycloalkyl, or C 1-3 It is halocycloalkyl, and m is 0 to 4.

[0075] In some embodiments, R1 is: [ka] wherein R is independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Cycloalkyl, or C 1-3 halocycloalkyl, and m is 1 to 4.

[0076] In some embodiments, R1 is: [ka] wherein R is independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Cycloalkyl, or C 1-3 halocycloalkyl, and m is 1 to 3.

[0077] In some embodiments, R1 is: [ka] wherein R is independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Cycloalkyl, or C 1-3 halocycloalkyl, and m is 1 to 2.

[0078] In some embodiments, R1 is: [ka] wherein R is independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Cycloalkyl, or C 1-3 halocycloalkyl and m is 1.

[0079] In some embodiments, R1 is [ka]

[0080] In some embodiments, R1 is [ka]

[0081] In some embodiments, R1 is [ka]

[0082] In some embodiments, R1 is [ka]

[0083] In some embodiments, R1 is [ka]

[0084] In some embodiments, R1 is [ka]

[0085] In some embodiments, R1 is [ka]

[0086] In some embodiments, R1 is [ka]

[0087] In some embodiments, R1 is [ka]

[0088] In some embodiments, R1 is [ka]

[0089] In some embodiments, R1 is [ka]

[0090] In some embodiments, R1 is selected from the group consisting of, but not limited to, the following: [ka] and the aryl may be optionally substituted with 3-halogen.

[0091] In some embodiments, R1 is selected from the group of R1 positions listed in Table 1 below.

[0092] As generally defined above, R2 is hydrogen, halogen, alkyl, cycloalkyl, C1-C3 alkylaryl, haloalkyl, C1-C3 alkyloxy, C1-C3 haloalkyloxy, hydroxyalkyl, or alkyoxyalkyl.

[0093] In some embodiments, R2 is hydrogen or deuterium.

[0094] In some embodiments, R2 is halogen.

[0095] In some embodiments, R 2 is F, Cl, Br, or I.

[0096] In some embodiments, R2 is F, Cl, or Br.

[0097] In some embodiments, R2 is F or Cl.

[0098] In some embodiments, R2 is F.

[0099] In some embodiments, R2 is Cl.

[0100] In some embodiments, R2 is Br.

[0101] In some embodiments, R2 is I.

[0102] In some embodiments, R2 is alkyl.

[0103] In some embodiments, R2 is methyl, ethyl, n-propyl, or isopropyl.

[0104] In some embodiments, R2 is methyl.

[0105] In some embodiments, R2 is C1-C3 alkylaryl.

[0106] In some embodiments, R2 is methylaryl.

[0107] In some embodiments, R2 is [ka] and cycloalkyl, including cyclopropyl, including:

[0108] In some embodiments, R2 is [ka] embedded image is an aryl or aralkyl group containing the following:

[0109] In some embodiments, R2 is cyclopropyl.

[0110] In some embodiments, R2 is cyclobutyl.

[0111] In some embodiments, R2 is cyclopentyl.

[0112] In some embodiments, R2 is cyclopentenyl.

[0113] In some embodiments, R2 is cyclohexyl.

[0114] In some embodiments, R2 is cyclohexenyl.

[0115] In some embodiments, R2 is haloalkyl.

[0116] In some embodiments, R2 is fluoromethyl, fluoroethyl, or fluoropropyl.

[0117] In some embodiments, R2 is fluoromethyl.

[0118] In some embodiments, R2 is trifluoromethyl.

[0119] In some embodiments, R2 is C1-C3 alkyloxy.

[0120] In some embodiments, R2 is [ka] wherein R9 is independently selected from C1-C3 alkyl, cycloalkyl (including cyclopropyl), and substituted or unsubstituted phenyl.

[0121] In some embodiments, R2 is OMe, or OEt, or O i Pr.

[0122] In some embodiments, R2 is OMe.

[0123] In some embodiments, R2 is OCF3.

[0124] In some embodiments, R2 is OCH2F.

[0125] In some embodiments, R2 is CH2OH, or CH2CH2OH, or CH2CH2CH2OH, or CH2C(OH)(CH3)2.

[0126] In some embodiments, R2 is CH2OCH3, or CH2CH2OCH3, or CH2OCH2CH3.

[0127] In some embodiments, R2 is selected from the groups listed in Table 1 below for the R2 position.

[0128] As generally defined above, R1 and R2 together with the thiazole ring form a 5-, 6-, or 7-membered fused 1,2-carbocyclic ring system, in which the ring carbons of the 5-, 6-, or 7-membered ring (not including the 1,2-thiazole fused ring carbons) are replaced by one or more ring atoms selected from N, O, and S. Furthermore, R1 and R2 together with the thiazole ring may form a fused phenyl ring or a fused naphthalene ring. The fused 5-, 6-, or 7-membered ring is optionally substituted, independently, by one or more halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, or C1-C3 haloalkyloxy.

[0129] In some embodiments, R1 and R2 together form a 6-membered ring fused to the thiazole.

[0130] In some embodiments, R1 and R2 together form a 5-membered ring fused to the thiazole.

[0131] In some embodiments, R1 and R2 together form a 7-membered ring fused to the thiazole.

[0132] In some embodiments, R1 and R2, taken together, are optionally substituted: [ka]

[0133] In some embodiments, R1 and R2, taken together, are optionally substituted: [ka]

[0134] In some embodiments, R1 and R2, taken together, are selected from the R1 / R2 linking groups at the R1 and R2 positions shown in Table 1 below.

[0135] As generally described above, R3 is H, C1-C3 alkyl, or C1-C3 haloalkyl.

[0136] In some embodiments, R3 is hydrogen.

[0137] In some embodiments, R3 is halogen.

[0138] In some embodiments, R3 is F, Cl, Br, or I.

[0139] In some embodiments, R3 is F, Cl, or Br.

[0140] In some embodiments, R3 is F or Br.

[0141] In some embodiments, R3 is F or Cl.

[0142] In some embodiments, R3 is Cl or Br.

[0143] In some embodiments, R3 is Cl.

[0144] In some embodiments, R3 is F.

[0145] In some embodiments, R3 is C1-C3 alkyl or C1-C3 haloalkyl.

[0146] In some embodiments, R3 is C1-C3 alkyl.

[0147] In some embodiments, R3 is C1-C3 haloalkyl.

[0148] In some embodiments, R3 is methyl or ethyl.

[0149] In some embodiments, R3 is selected from the groups listed in Table 1 below for the R3 position.

[0150] As generally defined above, each R4 is independently hydrogen, deuterium, CD3, phenyl, cyclopropyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, -C1-C3 alkyloxy, C1-C3 alkylaryl, C1-C3 haloalkyloxy.

[0151] In some embodiments, R4 is independently H.

[0152] In some embodiments, R4 is independently halogen.

[0153] In some embodiments, R4 is independently F, Cl, Br, or I.

[0154] In some embodiments, R4 is independently F, Cl, or Br.

[0155] In some embodiments, R4 is independently F or Br.

[0156] In some embodiments, R4 is independently F or Cl.

[0157] In some embodiments, R4 is independently Cl or Br.

[0158] In some embodiments, R4 is independently Cl.

[0159] In some embodiments, R4 is independently F.

[0160] In some embodiments, R4 is independently Br.

[0161] In some embodiments, R4 is independently I.

[0162] In some embodiments, R4 is independently C1-C3 alkyl.

[0163] In some embodiments, R4 is independently methyl, ethyl, n-propyl, or independently isopropyl.

[0164] In some embodiments, R4 is independently methyl.

[0165] In some embodiments, R4 is independently C1-C3 alkylaryl.

[0166] In some embodiments, R4 is independently CH2-aryl.

[0167] In some embodiments, R4 is independently haloalkyl.

[0168] In some embodiments, R4 is independently fluoromethyl, fluoroethyl, or fluoropropyl.

[0169] In some embodiments, R4 is independently fluoromethyl.

[0170] In some embodiments, R4 is independently trifluoromethyl.

[0171] In some embodiments, R4 is independently C1-C3 alkyloxy.

[0172] In some embodiments, R4 is independently OMe, or OEt, or O i Pr.

[0173] In some embodiments, R4 is independently OMe.

[0174] In some embodiments, R4 is independently OCF3.

[0175] In some embodiments, R4 is independently OCH2F.

[0176] In some embodiments, R4 is independently CH2OH, or CH2CH2OH, or CH2CH2CH2OH, or CH2C(OH)(CH3)2.

[0177] In some embodiments, R4 is independently CH2OCH3, or CH2CH2OCH3, or CH2OCH2CH3.

[0178] In some embodiments, R4 is independently selected from the group of R4 positions listed in Table 1 below.

[0179] As generally defined above, R5 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0180] In some embodiments, R5 is H.

[0181] In some embodiments, R5 is C1-C3 alkyl or C1-C3 haloalkyl.

[0182] In some embodiments, R5 is C1-C3 alkyl.

[0183] In some embodiments, R5 is methyl, ethyl, or propyl.

[0184] In some embodiments, R5 is methyl or ethyl.

[0185] In some embodiments, R5 is methyl.

[0186] In some embodiments, R5 is ethyl or propyl.

[0187] In some embodiments, R5 is ethyl.

[0188] In some embodiments, R5 is propyl.

[0189] In some embodiments, R5 is n-propyl.

[0190] In some embodiments, R5 is isopropyl.

[0191] In some embodiments, R5 is C1-C3 haloalkyl.

[0192] In some embodiments, R5 is fluoromethyl, fluoroethyl, or fluoropropyl.

[0193] In some embodiments, R5 is fluoromethyl.

[0194] In some embodiments, R5 is trifluoromethyl.

[0195] In some embodiments, R5 is selected from the groups listed at the R5 position in Table 1 below.

[0196] As generally described above, R6 is hydrogen, CD3, alkyl, cycloalkyl, haloalkyl, or [ka]

[0197] In some embodiments, R6 is hydrogen.

[0198] In some embodiments, R6 is -CD3.

[0199] In some embodiments, R6 is C1-C6 alkyl or C1-C6 haloalkyl.

[0200] In some embodiments, R6 is C1-C3 alkyl or C1-C3 haloalkyl.

[0201] In some embodiments, R6 is C1-C3 alkyl.

[0202] In some embodiments, R5 is methyl, ethyl, or propyl.

[0203] In some embodiments, R6 is methyl or ethyl.

[0204] In some embodiments, R6 is methyl.

[0205] In some embodiments, R6 is ethyl or propyl.

[0206] In some embodiments, R6 is ethyl.

[0207] In some embodiments, R6 is propyl.

[0208] In some embodiments, R6 is n-propyl.

[0209] In some embodiments, R6 is isopropyl.

[0210] In some embodiments, R6 is C1-C3 haloalkyl.

[0211] In some embodiments, R6 is fluoromethyl, fluoroethyl, or fluoropropyl.

[0212] In some embodiments, R6 is fluoromethyl.

[0213] In some embodiments, R6 is trifluoromethyl.

[0214] In some embodiments, R6 is C1-C6 cycloalkyl.

[0215] In some embodiments, R6 is selected from the group of R6 positions listed in Table 1 below.

[0216] As generally described above, each R7 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halogen.

[0217] In some embodiments, each R7 is independently hydrogen.

[0218] In some embodiments, R7 is H.

[0219] In some embodiments, R7 is C1-C6 alkyl or C1-C6 haloalkyl.

[0220] In some embodiments, R7 is C1-C3 alkyl or C1-C3 haloalkyl.

[0221] In some embodiments, R7 is C1-C3 alkyl.

[0222] In some embodiments, R5 is methyl, ethyl, or propyl.

[0223] In some embodiments, R7 is methyl or ethyl.

[0224] In some embodiments, R7 is methyl.

[0225] In some embodiments, R7 is ethyl or propyl.

[0226] In some embodiments, R7 is ethyl.

[0227] In some embodiments, R7 is propyl.

[0228] In some embodiments, R7 is n-propyl.

[0229] In some embodiments, R7 is isopropyl.

[0230] In some embodiments, R7 is C1-C3 haloalkyl.

[0231] In some embodiments, R7 is fluoromethyl, fluoroethyl, or fluoropropyl.

[0232] In some embodiments, R7 is fluoromethyl.

[0233] In some embodiments, R7 is trifluoromethyl.

[0234] In some embodiments, R7 is C1-C6 cycloalkyl.

[0235] In some embodiments, R7 is selected from the group of R7 positions listed in Table 1 below.

[0236] As generally described above, R8 is hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl.

[0237] In some embodiments, R8 is hydrogen.

[0238] In some embodiments, R8 is C1-C6 alkyl or C1-C6 haloalkyl.

[0239] In some embodiments, R8 is C1-C3 alkyl or C1-C3 haloalkyl.

[0240] In some embodiments, R8 is C1-C3 alkyl.

[0241] In some embodiments, R5 is ethyl or propyl.

[0242] In some embodiments, R8 is methyl or ethyl.

[0243] In some embodiments, R8 is methyl.

[0244] In some embodiments, R8 is ethyl or propyl.

[0245] In some embodiments, R8 is ethyl.

[0246] In some embodiments, R8 is propyl.

[0247] In some embodiments, R8 is n-propyl.

[0248] In some embodiments, R8 is isopropyl.

[0249] In some embodiments, R8 is C1-C3 haloalkyl.

[0250] In some embodiments, R8 is fluoromethyl, fluoroethyl, or fluoropropyl.

[0251] In some embodiments, R8 is fluoromethyl.

[0252] In some embodiments, R8 is trifluoromethyl.

[0253] In some embodiments, R8 is C1-C8 cycloalkyl.

[0254] In some embodiments, R8 is selected from the groups listed at the R8 position in Table 1 below.

[0255] As generally described above, n is 0, 1, or 2.

[0256] In some embodiments, n is 0 or 1.

[0257] In some embodiments, n is 0 or 2.

[0258] In some embodiments, n is 1 or 2.

[0259] In some embodiments, n is 0.

[0260] In some embodiments, n is 1.

[0261] In some embodiments, n is 2.

[0262] As generally described above, p is 0, 1, 2, or 3.

[0263] In some embodiments, p is 0, 1, or 2.

[0264] In some embodiments, p is 0, 1, or 3.

[0265] In some embodiments, p is 1, 2, or 3.

[0266] In some embodiments, p is 0 or 1.

[0267] In some embodiments, p is 0 or 2.

[0268] In some embodiments, p is 0 or 3.

[0269] In some embodiments, p is 1 or 2.

[0270] In some embodiments, p is 1 or 3.

[0271] In some embodiments, p is 2 or 3.

[0272] In some embodiments, p is 0.

[0273] In some embodiments, p is 1.

[0274] In some embodiments, p is 2.

[0275] In some embodiments, p is 3.

[0276] 4. General Methods for Providing the Compounds The compounds described herein may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those of skill in the art for similar compounds, as well as by methods detailed in the Examples herein.

[0277] Those skilled in the art will recognize that various functional groups present in the compounds of the present invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the aforementioned techniques, and specific methods for synthesizing the compounds of the present invention are described herein.

[0278] Scheme 1 illustrates a general method for preparing compounds of formula (I). In one aspect, certain compounds of the invention of formula (I), or subformulas thereof, are generally prepared according to Scheme 1 as shown below. [ka] [ka]

[0279] In one embodiment, the compound of formula (II) is [ka] (wherein R3, R4, and n are defined above), and a compound of formula (III): [ka] wherein R1, R2, and R5 are defined above to produce a compound of formula (IV): [ka] The compound of formula (IV) may be hydrolyzed according to methods known to those skilled in the art, for example, basic hydrolysis, to provide a compound of formula (V): [ka] (wherein R1 to R5 and n are defined above), or a salt thereof.

[0280] Then, the compound of formula (V) or a salt thereof is reacted with a compound of formula (VI) [ka] (In the formula, R6, R7, R8, and p are defined above; optionally reacting in the presence of a strong acid to provide a salt of formula (VIIa) or a compound of formula (VII) or a salt thereof; [ka] wherein R1-R8, n, and p are defined above, and A is a counter ion known to those of skill in the art.

[0281] The salt of formula (VIIa) and / or the compound of formula (VII), or a salt thereof, may be reacted with a reducing agent, for example a borohydride such as triacetoxyborohydride, to provide a compound of formula (I). Scheme 2.

[0282] As generally shown in Scheme 1, a starting compound comprising structure (II) is combined with a compound of general structure (III) to provide a compound of general structure (IV). The compound of general structure (IV) can then be deprotected via a hydrolysis reaction to yield a compound of general structure (V). Reaction of (V) with an aldehyde (VI) yields compound (VIIa), which can be reduced by a variety of well-known methods to yield compound (I). Those skilled in the art will recognize that compound (V) can be converted to compound (I) via well-known reductive amination or other similar methods.

[0283] When R3 in the compound of structure (V) is hydrogen, a Schiff base of formula (VII) may be formed, which may be concomitantly or subsequently reduced to give compound (I'') where R3 is hydrogen.

[0284] 4.1. Synthesis of specific intermediates Abbreviation The following abbreviations are used herein: equiv or eq: molar equivalent o / n: overnight rt: room temperature UV: Ultraviolet light h: time or times HPLC: High-performance liquid chromatography Rt: retention time LC-MS: Liquid chromatography-mass spectrometry NMR: nuclear magnetic resonance CC: Column chromatography TLC: Thin Layer Chromatography sat: saturation aq: aqueous solution Ac: Acetyl DCM: dichloromethane DCE: Dichloroethane DEA: Diethylamine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide ACN or MeCN: Acetonitrile DIPEA: Diisopropylethylamine EA or EtOAc: Ethyl acetate TEA: Triethylamine THF: tetrahydrofuran NCS: N-chlorosuccinimide PE: Petroleum ether Prep.:Preparation TFA: Trifluoroacetic acid FA: Formic acid h: hour(s) min:minutes s or sec: Second(s) STAB: Sodium triacetoxyborohydride Cy: Cyclohexyl Tol: Toluene

[0285] General information All air or moisture sensitive reactions were carried out under a positive pressure of nitrogen using oven-dried glassware. Chemical reagents and anhydrous solvents were obtained from commercial sources and used as received. Preparative purification was performed on a Waters semi-preparative HPLC. The column used was a Phenomenex Luna C18 (10 μm, 250 × 75 mm) with a flow rate of 45 mL / min. The mobile phase consisted of acetonitrile and water (each containing 0.1% hydrochloric acid). A gradient of 50-80% acetonitrile over 23 min was used during purification. Fraction collection was triggered by UV detection (220 nm). Analytical analysis of purity was determined by one method indicated as final QC. Methods: Analysis was performed on an Agilent 1260 Infinity Series LCMS: LCMS long gradient of 5 to 100% equivalent acetonitrile (0.018% trifluoroacetic acid) in water (0.037% trifluoroacetic acid) over a run time of 4 minutes at a flow rate of 1 mL / min. A Shim-pack Velox SP-C18 2.7 μm column (3.0 × 30 mm) was used at a temperature of 50 °C. For the method, purity determination was performed using an Agilent diode array detector. Mass determination was performed using an Agilent 1260 mass spectrometer with electrospray ionization in positive mode. 1H and 19F NMR spectra were recorded on a Bruker 400 (400) MHz or 600 (376) MHz mass spectrometer.

[0286] Intermediate compounds of formula II, II-1 and II-2 [ka]

[0287] Intermediate II may be reacted with intermediate III to produce a compound of formula (IV).

[0288] In another embodiment, the compounds of formula II-1 and / or II-2 are reacted with certain intermediate compounds of formula III to produce compounds of formula (IV): [ka]

[0289] Preparation of intermediates Preparative Example 1: Synthesis of 5-acetamidopyridine-2-sulfonyl chloride (II-1, Scheme 4). [ka] Synthesis of 4-nitro-2-thiopyridine (C). To a mixture of 2-chloro-4-nitropyridine ((A) 8 g, 50.46 mmol, 1 equiv.) in EtOH (120 mL), thiourea (3.99 g, 52.48 mmol, 1.04 equiv.) was added in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 10 min, then heated to 85° C. and stirred for 48 h. LC-MS showed that the starting material was completely consumed. The mixture was cooled to 25° C. and filtered to give crude compound B. The residue was poured into water (20 mL) treated with 20% NaOH (100 mL). The mixture was stirred for 30 min and filtered. The pH of the solution was adjusted to 7 with HCl (2 M) and the precipitated solid was collected by filtration to give compound C (3.5 g, 42% yield, 95% purity) as a red solid. 1 H NMR(400MHz, CDCl3) δ8.48(d,J=2.5Hz,1H),7.92(dd,J=9.6,2.6Hz,1H),7.39(d,J=9.6Hz,1H).

[0290] N-(6-mercapto-3-pyridyl)acetamide (D). To a mixture of compound C (1.58 g, 9.61 mmol, 1 equiv) in H2O (15 mL) was added Na2(S2O4) (5.85 g, 33.62 mmol, 7.32 mL, 3.5 equiv) in one portion at 0 °C under N2. Acetic anhydride (1.37 g, 13.45 mmol, 1.26 mL, 1.4 equiv) was then added. The mixture was stirred at 0 °C for 2 h. LC-MS showed that the starting material was completely consumed. The yellow precipitate was filtered, washed with water, and dried to give a yellow solid. (940 mg, 58% yield) was obtained as a yellow solid. 1H NMR(400MHz,DMSO)δ13.35(s,1H),10.07(s,1H),8.22(d,J=3.8Hz,1H),7.37-7.22(m,2H),2.03(s,3H).

[0291] 5-Acetamidopyridine-2-sulfonyl chloride (II-1). To a mixture of compound D (700 mg, 4.16 mmol, 1 equiv.) in acetic acid (18 mL) and H2O (2 mL) was added N-chlorosuccinimide (2.2 g, 16.65 mmol, 4 equiv.) in one portion at 0° C. under N2. The mixture was stirred at 25° C. for 4 h. Thin layer chromatography showed that the starting material was completely consumed. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-acetamidopyridine-2-sulfonyl chloride (II-1) (800 mg, 78% yield, 95% purity) as an orange solid. 1 H NMR(400MHz,DMSO)δ11.30(s,1H),9.07(s,1H),8.52(d,J=8.8Hz,1H),8.15(d,J=8.7Hz,1H),2.18(d,J=11.4Hz,3H).

[0292] Preparation Example 2: Synthesis of 5-acetamido-3-methylpyridine-2-sulfonyl chloride (II-2, Scheme 5). [ka] A mixture of thiourea (2.21 g, 28.97 mmol) and 2-chloro-3-methyl-5-nitropyridine (5 g, 28.97 mmol) in EtOH (50 mL) was degassed and purged with dry N2 three times. The mixture was stirred under N2 atmosphere at 85 °C for 4 h to give a yellow precipitate. The precipitate was filtered, washed with water (200 mL), and dried to give a yellow solid. Excess water was removed from the residue under vacuum to give 3-methyl-5-nitropyridin-2-yl carbamiditothioate (4.64 g, 21.9 mmol, 75.5% yield) as a yellow solid.

[0293] To a solution of 3-methyl-5-nitropyridin-2-yl carbamiditothioate (4.64 g, 21.86 mmol) in H2O (9 mL) was added NaOH (54 mL, 20% in H2O). The mixture was stirred at 25° C. for 1 h. The reaction mixture was filtered for undissolved material, adjusted to pH 7 with HCl (aq, 3 M in H2O) and filtered to give the crude product. Excess water was removed from the filter residue under reduced pressure to give 3-methyl-5-nitropyridine-2-thiol (3 g, 17.6 mmol, 81% yield) as a red solid. LCMS: (M+H) + =171.2.

[0294] To a mixture of 3-methyl-5-nitropyridine-2-thiol (3 g, 17.63 mmol) in H2O (60 mL) was added Na2S2O4 (10.74 g, 61.7 mmol, 13.4 mL) under N2, followed by acetyl acetate (2.52 g, 24.7 mmol, 2.31 mL), and the mixture was stirred at 0° C. under N2 atmosphere for 0.5 h. The yellow precipitate was filtered, washed with water (100 mL), and dried to give a yellow solid. Excess water was removed from the filter residue under reduced pressure to give N-(6-mercapto-5-methylpyridin-3-yl)acetamide (1.3 g, 7.13 mmol, 40.5% yield) as a yellow solid.

[0295] A solution of N-(6-mercapto-5-methylpyridin-3-yl)acetamide (1.3 g, 7.13 mmol) in AcOH (10 mL) and H2O (2 mL) was degassed and purged with N2 three times, then NCS (3.33 g, 24.97 mmol) was added. The mixture was stirred at 0 °C under N2 atmosphere for 0.5 h. The reaction mixture was diluted with ethyl acetate (10 mL x 3), washed with brine (15 mL x 2), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 70% ethyl acetate in petroleum ether). 5-acetamido-3-methylpyridine-2-sulfonyl chloride (II-2, 1.1 g, 2.48 mmol, 35% yield) was obtained as a brown solid. LCMS: (M+H) + = 249.1.

[0296] Preparative Example 3: Synthesis of 4-(4-chloro-3-fluorophenyl)thiazol-2-amine (III-1, Scheme 6). [ka] To a mixture of 1-(4-chloro-3-fluorophenyl)ethan-1-one (2.27 g, 13.15 mmol, 1 equiv), triethylamine (2.00 g, 19.73 mmol, 2.75 mL, 1.5 equiv) and thiourea (2.50 g, 32.88 mmol, 2.5 equiv) in MeCN (20 mL) was added carbon tetrabromide (6.54 g, 19.73 mmol, 1.5 equiv) in one portion under N2 at 25 °C. The mixture was stirred at 25 °C for 16 h. LC-MS showed that acetophenone was completely consumed and one new main peak was detected at the desired mass. The mixture was concentrated under reduced pressure and the resulting residue was poured into water (50 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 0, 1 / 1) to give 4-(4-chloro-3-fluorophenyl)thiazol-2-amine (III-1) as a yellow solid (2.88 g, yield 96%).

[0297] Preparative Example 4: Synthesis of 4-(3-chloro-4-fluorophenyl)-1,3-thiazol-2-ylamine (III-2, Scheme 7). [ka] A mixture of 1-(3-chloro-4-fluorophenyl)ethan-1-one (15 g, 86.91 mmol, 1 equiv.) and thiourea (9.92 g, 130.37 mmol, 1.5 equiv.) in MeCN (100 mL) was degassed and purged with N2 three times with CBr4 (43.23 g, 130.37 mmol, 1.5 equiv.) and Et3N (13.19 g, 130.37 mmol, 18.15 mL, 1.5 equiv.). The mixture was stirred under N2 atmosphere at 25° C. for 16 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was diluted with 1N HCl (50 mL) and extracted with ethyl acetate (200 mL) and water (200 mL), followed by addition of NH4Cl to precipitate a solid and filter. The filter cake was dried under reduced pressure to give 4-(3-chloro-4-fluorophenyl)-1,3-thiazol-2-ylamine (III-2) (3.5 g, 14% yield, 80% purity) as a red solid. 1 H NMR(400MHz,DMSO-d6)7.96(dd,J=2.1,7.3Hz,1H),7.79(ddd,J=2.2,4.8,8.7Hz,1H),7.40(t,J=9.0Hz,1H),7.14(s,3H).

[0298] Preparative Example 5: Synthesis of 4-(3,4-difluorophenyl)-1,3-thiazol-2-amine (III-3, Scheme 8). [ka] To a mixture of 1-(3,4-difluorophenyl)ethan-1-one (20 g, 128.10 mmol, 16.00 mL) and thiourea (14.63 g, 192.15 mmol) in acetonitrile (300 mL) was added triethylamine (19.44 g, 192.15 mmol, 26.74 mL) and carbon tetrabromide (63.72 g, 192.15 mmol). The mixture was stirred at 25° C. for 16 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting residue was triturated with water (200 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®, 220 g SepaFlash® silica flash column, gradient of 22-30% ethyl acetate / petroleum ether at 120 mL / min, petroleum ether / ethyl acetate=3:1, Rf=0.3) to give 4-(3,4-difluorophenyl)-1,3-thiazol-2-amine (III-3, 12.7 g, 58.65 mmol, 6% yield, 98% purity) as a brown solid. LC-MS: (M+H) + =212.7; 1 H NMR(400 MHz,DMSO-d6):7.78(ddd,J=1.9,8.0,12.4Hz,1H),7.66-7.61(m,1H),7.46-7.36(m,1H),7.11(br d,J=5.5Hz,3H).

[0299] Preparative Example 6: Synthesis of 4-(3-chloro-4-fluorophenyl)-5-fluorothiazol-2-amine (III-4, Scheme 9). [ka] To a solution of 4-(3-chloro-4-fluorophenyl)-1,3-thiazol-2-ylamine (III-2, 1 g, 4.37 mmol, 1.0 equiv.) in MeCN (20 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane, ditetrafluoroborate (Selectfluor™) (1.55 g, 4.37 mmol, 1.0 equiv.) in one portion under N2 at 0° C. The mixture was warmed to 25° C. and stirred for 6 h. After this time, LC-MS showed that about 12% of the starting material remained. Several new peaks were shown by LC-MS, and about 22% of the desired compound (III-4) was detected. Water (30 mL) was added and the reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phase was washed with water (2×15 mL) and brine (2×15 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, PE / EtOAc=0-100% EA). 4-(3-chloro-4-fluorophenyl)-5-fluorothiazol-2-amine (III-4) was isolated as a brown solid (230 mg, 21% yield) and used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ7.79(dd,J=7.3,2.1Hz,1H),7.68(ddd,J=8.6,4.7,2.2Hz,1H),7.48(t,J=9.0Hz,1H),7.08(s,2H).

[0300] Preparative Example 7: Synthesis of 4-(3,4-difluorophenyl)-5-fluorothiazol-2-amine (III-5, Scheme 10). [ka] To a solution of 4-(3,4-difluorophenyl)-1,3-thiazol-2-amine (III-3, 12.7 g, 59.84 mmol, 1 equiv.) in DMF (150 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane, ditetrafluoroborate (Selectfluor™ (21.20 g, 59.84 mmol, 1 equiv.) and 2,6-dimethylpyridine (6.41 g, 59.84 mmol, 6.97 mL, 1 equiv.). The mixture was stirred at 25° C. for 10 h, after which time LC-MS indicated the reaction was complete. The mixture was diluted with ethyl acetate (40 The mixture was extracted with 100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated to dryness to give the crude product, which was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, gradient elution of 22-25% ethyl acetate / petroleum ether at 80 mL / min, petroleum ether / ethyl acetate=3:1, Rf=0.4) to give the product 4-(3,4-difluorophenyl)-5-fluorothiazol-2-amine, III-5 (8.9 g, 36.65 mmol, 61.2% yield, 94.8% purity) as a grey solid. LC-MS: (M+H) + = 230.7; 1 H NMR(400 MHz,DMSO-d6):7.58(br d,J=2.0 Hz,1H),7.55-7.51(m,1H),7.45(s,1H),7.06(s,2H)

[0301] Preparative Example 8: Synthesis of 4-(4-chloro-3-fluorophenyl)-5-fluoro-1,3-thiazol-2-ylamine (III-6, Scheme 11). [ka] To a solution of 4-(4-chloro-3-fluorophenyl)thiazol-2-amine (III-1, 1 g, 4.37 mmol, 1.0 equiv) in MeCN (15 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane, ditetrafluoroborate (Selectfluor™ (1.55 g, 4.37 mmol, 1.0 equiv) under N2 at 25 °C. The mixture was stirred at 25 °C for 16 h. LC-MS showed that about 11% of the starting material remained. On LC-MS, A few new peaks were observed, with about 21% of the desired compound. The reaction mixture was diluted with EtOAc (30 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×15 mL) and brine (2×15 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, petroleum ether / EtOAc=0-100% EtOAc). The title compound (350 mg, 32% yield) was obtained as a brown solid.

[0302] Preparation Example 9: Synthesis of N-(6-(N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)sulfamoyl)pyridin-3-yl)acetamide (IV-1). [ka] To a solution of 4-(4-chloro-3-fluorophenyl)thiazol-2-amine (III-1) 1 g, 4.37 mmol, 1 equiv) in pyridine (5 mL) was added 5-acetamidopyridine-2-sulfonyl chloride (II-1 2 g, 8.52 mmol, 1.95 equiv) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 4 h. LC-MS showed that compound II-1 was completely consumed and one main peak was detected at the desired m / z. The mixture was poured into 1 M HCl (40 mL) and stirred for 10 min. The aqueous phase was filtered to give the crude product which was used without further purification.

[0303] Preparation Example 10: Synthesis of N-(6-(N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)sulfamoyl)-5-methylpyridin-3-yl)acetamide (IV-2). [ka] A mixture of 5-acetamido-3-methylpyridine-2-sulfonyl chloride (II-2, 2.9 g, 11.66 mmol) and 4-(3,4-difluorophenyl)-5-fluorothiazol-2-amine (III-5, 2.68 g, 11.66 mmol) in pyridine (15 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 25 °C for 16 h. After this time, LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The resulting crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 20 / 80) to give compound IV-2 (3.47 g, 67.26% yield) as a brown solid. LC-MS: (M+H) + =443.0 Da.

[0304] Preparation Example 11: Synthesis of 5-amino-N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)pyridine-2-sulfonamide (V-1). [ka] To a solution of N-(6-(N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)sulfamoyl)pyridin-3-yl)acetamide (IV-1, 1.5 g, 3.51 mmol, 1 equiv) in HO (987 mg, 54.8 mmol, 988 μL, 15.6 equiv) and EtOH (20 mL) was added NaOH (983 mg, 24.6 mmol, 7 equiv) in one portion at 25° C. under N. The mixture was heated to 90° C. and stirred for 1.5 h. LC-MS showed that the starting material was completely consumed and one main peak was detected at the desired mass. The mixture was concentrated under reduced pressure. The residue was poured into water (10 mL), the pH of the mixture was adjusted to 7 with 1 M HCl, and the residue was filtered to give 5-amino-N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)pyridine-2-sulfonamide (V-1) (1 g, 74% yield, yellow solid), which was used without further purification.

[0305] Preparation Example 12: Synthesis of 5-amino-N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-3-methylpyridine-2-sulfonamide (V-2). [ka] To a solution of N-(6-(N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)sulfamoyl)-5-methylpyridin-3-yl)acetamide (IV-2, 4.64 g, 10.49 mmol) in ethanol (50 mL) and water (50 mL) was added sodium hydroxide (3.36 g, 83.90 mmol). The mixture was stirred at 80° C. for 0.5 h. After this time, LC-MS showed the reaction was complete. The reaction mixture was extracted with ethyl acetate (500 mL×3), washed with brine (120 mL×2), and dried over Na2SO4 to give crude 5-amino-N-(4-3,4-difluorophenyl)-5-fluorothiazol-2-yl)-3-methylpyridine-2-sulfonamide (V-2, 3.77 g, 90% yield) as a red oil. LC-MS: (M+H) + = 400.9;1 H NMR (400 MHz,DMSO-d6):7.64-7.54(m,2H),7.54-7.47(m,1H),7.47-7.37(m,1H),6.72(d,J=2.0 Hz,1H),5.60(brs,2H),2.42(s,3H).

[0306] Preparation Example 13: Synthesis of N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)-5-((2-hydroxy-3-methoxybenzylidene)amino)pyridine-2-sulfonamide (VII-1). [ka] To 5-amino-N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)pyridine-2-sulfonamide (V-1, 200 mg, 520 μmol, 1 eq.) and 2-hydroxy-3-methoxybenzaldehyde (118.6 mg, 780 μmol, 1.5 eq., Formula VI,) in EtOH (5 mL) was added trifluoroacetic acid (59.3 mg, 519.7 μmol, 38.5 μL, 1 eq.) in one portion at 25° C. under N2. The mixture was heated to 25° C. and stirred for 7 h. LC-MS showed that the starting amine was completely consumed. The mixture was cooled to 25° C. and concentrated under reduced pressure. The crude product of N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)-5-((2-hydroxy-3-methoxybenzylidene)amino)pyridine-2-sulfonamide (VII-1, 260 mg, 96% yield) was used in the next step without further purification.

[0307] Preparation Example 14: Synthesis of N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-5-((2-hydroxy-3-methoxybenzylidene)amino)-3-methylpyridine-2-sulfonamide (VII-2). [ka] To a solution of 2-hydroxy-3-methoxy-benzaldehyde (567 mg, 3.75 mmol) in toluene (10 mL) was added 5-amino-N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-3-methylpyridine-2-sulfonamide (V-2, 1 g, 2.50 mmol). The mixture was stirred at 140° C. for 2 h. After this time, LC-MS showed the reaction was complete. The solvent was removed under reduced pressure to give crude N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-5-((2-hydroxy-3-methoxybenzylidene)amino)-3-methylpyridine-2-sulfonamide (VII-2, 1.2 g, crude) as a brown solid.

[0308] Preparation of Compounds of Formula (I) Preparation Example 15: Synthesis of N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)-5-((2-hydroxy-3-methoxybenzyl)amino)pyridine-2-sulfonamide (compound I-8). [ka] To a solution of N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)-5-((2-hydroxy-3-methoxybenzylidene)amino)pyridine-2-sulfonamide (VII-1, 260 mg, 501 μmol, 1 equiv.) in DMF (5 mL), sodium triacetoxyborohydride (STAB, 425 mg, 2.00 mmol, 4 equiv.) was added in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 16 h. LC-MS showed that the starting material was completely consumed and one main peak was detected at the desired m / z. The reaction mixture was poured into water (50 mL) and stirred for 10 min. The aqueous phase was filtered to give the crude product. The residue was purified by preparative high pressure liquid chromatography (TFA conditions) to afford N-(4-(4-chloro-3-fluorophenyl)thiazol-2-yl)-5-((2-hydroxy-3-methoxybenzyl)amino)pyridine-2-sulfonamide, I-8, as a white solid (58.6 mg, 22% yield).

[0309] Preparation Example 16: Synthesis of N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-5-((2-hydroxy-3-methoxybenzyl)amino)-3-methylpyridine-2-sulfonamide (I-18). Compound I-18 can be prepared according to Scheme 12. [ka] To a solution of N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-5-((2-hydroxy-3-methoxybenzylidene)amino)-3-methylpyridine-2-sulfonamide (VII-2, 1.2 g, 2.24 mmol) in DCE (15 mL) was added sodium triacetoxyborohydride (9.52 g, 44.90 mmol) at 25° C. The mixture was stirred at 25° C. for 0.5 h. After this time, LC-MS showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (30 mL×3), washed with brine (50 mL×2), dried over Na2SO4, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 60% ethyl acetate in petroleum ether) to give N-(4-(3,4-difluorophenyl)-5-fluorothiazol-2-yl)-5-((2-hydroxy-3-methoxybenzyl)amino)-3-methylpyridine-2-sulfonamide (I-18, 0.360 g, 29.9% yield) as a brown solid. LC-MS: (M+H) + = 537.0; 1 H NMR(400 MHz,DMSO-d6): 8.82(s,1H),7.76(d,J = 2.3 Hz,1H),7.70 - 7.63(m,1H),7.61 - 7.54(m,1H),7.53(br d,J = 3.4 Hz,1H),7.02(br t,J =5.4 Hz,1H),6.89 - 6.83(m,2H),6.79 - 6.69(m,2H),4.27(br d,J = 5.8 Hz,2H),3.79(s,3H),2.46(s,3H)

[0310] DCE / MeOH and DCE / DMF can also be used in place of DCE, for example, to improve reagent solubility.

[0311] The compounds set forth in Table 1 were prepared in the manner described herein and by variations in processes and methods that will be apparent to one of skill in the art. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0312] In some embodiments, the present invention provides a compound shown in Table 1, or a pharma- ceutically acceptable salt thereof.

[0313] Compositions and Formulations Parenteral dosage forms. In one embodiment, the novel compounds described herein can be administered in parenteral dosage forms. The term "parenteral" as used herein includes, but is not limited to, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or infusion techniques. In one embodiment, the parenteral pharmaceutical formulation described herein comprises the compound described herein and a pharma- ceutically acceptable carrier. In one embodiment, the parenteral pharmaceutical formulation may contain a liquid carrier comprising a vegetable oil, such as peanut oil, cottonseed oil, sesame oil, and organic solvents, PEG, propylene glycol, glycerol, and surfactants. In certain embodiments for parenteral administration, the conjugate of the present invention is mixed with a solubilizing agent, such as Cremophor™, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0314] In another embodiment, the parenteral pharmaceutical formulation is aqueous. In one embodiment, the parenteral aqueous pharmaceutical formulation comprises at least 50% water, preferably 70% or more water. In another embodiment, the pharmaceutical carrier comprises a solubilizer. In a particular embodiment, the solubilizer is 2-hydroxyalkylated β-cyclodextrin, such as hydroxyethyl β-CD, hydroxypropyl-β-CD, hydroxybutyl β-CD, or sulfobutylether-β-cyclodextrin.

[0315] The pharma- ceutically acceptable 2-hydroxyalkylated β-cyclodextrin may be present in any suitable amount in the parenteral aqueous pharmaceutical formulations described herein. The pharma-ceutically acceptable 2-hydroxyalkylated β-cyclodextrin may be present in an amount of about 5% to 50% w / v. For example, the pharma-ceutically acceptable solubilizer, optionally HP-β-CD, may be in an amount of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% w / v. In certain embodiments, the HP-β-CD may be present in an amount of about 10% to about 40%, about 20% to about 40%, about 30% to about 40%, about 10% to about 30%, or about 10% to about 20% of the total formulation. In one embodiment, the 2-hydroxyalkylated β-cyclodextrin may be present in an amount of about 25% w / v of the total formulation.

[0316] For parenteral administration, sterile solutions and suspensions are desired. Generally, isotonic preparations containing suitable preservatives are used when intravenous administration is desired. Pharmaceutical preparations may be administered parenterally by injection of pharmaceutical preparations containing the compound dissolved in an inert liquid carrier such as sterile water or other pharma-ceutical acceptable diluent.

[0317] Pharmaceutical compositions or formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, sealed ampoules, and vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, saline, dextrose in water (D5W), lactated Ringer's solution, immediately prior to use. Extemporaneous immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0318] The parenteral formulation may further comprise at least one of any suitable auxiliary agent, including, but not limited to, diluents, crystal inhibitors, tonicifiers, water structure forming or disrupting agents, polymers, ion pairing agents, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable auxiliary agents are preferred. Examples and methods of preparing such sterile solutions are well known in the art and are described in REMINGTON'S PHARMACEUTICAL SCIENCES (Adejare, Ed., 123rd Edition, Academic Press. (2020), Handbook of Pharmaceutical Excipients, 9th Edition, Academic Press. (2020), and others. th Pharmaceuticals and Pharmaceuticals, Inc., 1999. Edition, Pharmaceutical Press (2020), etc. Pharmaceutically acceptable carriers suitable for the mode of administration, solubility, and / or stability of the compound can be routinely selected.

[0319] Non-limiting examples of pharmaceutical excipients and additives useful in the parenteral pharmaceutical formulations described herein include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, derivatized sugars such as alditols, aldonic acids, esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and may range from 1 to 99.99% by weight or volume, alone or in combination. Exemplary protein excipients include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, and casein. Representative amino acid components that can also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, and aspartame.

[0320] Carbohydrate excipients suitable for use in the parenteral pharmaceutical formulations described herein include, but are not limited to, monosaccharides such as dextrose, fructose, maltose, galactose, glucose, D-mannose, and sorbose; disaccharides such as lactose, sucrose, trehalose, and cellobiose; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, and starch; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), and myo-inositol.

[0321] The pharmaceutical preparations containing the compounds described herein can also be pH adjusting agents.The pH adjusting agent can be a base, optionally sodium hydroxide.The pH adjusting agent can also be an acid, optionally hydrochloric acid.

[0322] In one embodiment, the present disclosure provides stable parenteral pharmaceutical formulations comprising at least one compound disclosed herein in a pharma- ceutically acceptable formulation, as well as preservative-containing storage solutions and formulations, and versatile storage formulations suitable for pharmaceutical or veterinary use. Pharmaceutical formulations according to the present disclosure may optionally contain at least one known preservative. Preservatives include phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal in an aqueous diluent, or mixtures thereof. Any suitable concentration or mixture, such as 0.001-5% or any range or value therein, may be used as known in the art. Non-limiting examples include no preservatives, 0.1-2% m-cresol, 0.1-3% benzyl alcohol, 0.001-0.5% thimerosal, 0.001-2.0% phenol, 0.0005-1.0% alkylparaben(s).

[0323] Other excipients, such as isotonicity agents, buffers, antioxidants, preservative enhancers, can be optionally added. When used, the amount of tonicity adjuster most frequently used ranges from 0.1 to 1 w / v%. Non-limiting examples of suitable tonicity adjusters include sodium chloride, glycerin, boric acid, calcium chloride, dextrose, and potassium chloride. The formulation can include a local anesthetic to reduce potential pain during injection. A physiologically tolerable buffer can be added to provide improved pH control as needed. The pharmaceutical formulation can cover a wide range of pH, such as from about pH 4 to about pH 10, specifically in the range of about pH 5 to about pH 9, more specifically in the range of about 7.0 to about 9.0. In one aspect, the formulation described herein has a pH of about 8.4 to about 8.7.

[0324] The method of preparing the pharmaceutical preparations described herein is produced in a known manner, including conventional mixing, dissolving or lyophilizing processes.Accordingly, the aqueous pharmaceutical preparations can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliary agents if desired or necessary.

[0325] Oral dosage form. The pharmaceutical formulation of the compounds described herein for oral administration may be in the form of tablets or capsules, may be an immediate release formulation, or may be a controlled or sustained release formulation, and may contain pharmaceutically acceptable excipients such as cornstarch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose, and similar substances.The pharmaceutical composition containing the compound and / or its salt may contain one or more pharmaceutically acceptable excipients known in the art.Formulations include oral films, oral disintegrating tablets, effervescent tablets, and granules or beads that can be sprinkled on food or mixed with liquid as a slurry, or poured directly into the mouth.

[0326] Pharmaceutical compositions containing the compounds, their salts and hydrates can be prepared by any method known in the art of pharmacy. In general, such methods of preparation include the step of bringing into association a 12-LOX inhibitor or a pharma- ceutically acceptable salt thereof with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0327] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0328] The relative amounts of active ingredient, pharma- ceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. Compositions used in the methods of the invention may contain from 0.001% to 100% (w / w) active ingredient.

[0329] Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

[0330] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may include a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0331] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include granulating and / or dispersing agents.Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, partially pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0332] In certain embodiments, the pharmaceutical compositions used in the methods of the invention may include a binding agent. Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, and the like), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM.RTM.), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0333] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a preservative. Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0334] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain an antioxidant. Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl formate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0335] In certain embodiments, the pharmaceutical composition used in the method of the present invention may include a chelating agent.Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0336] In certain embodiments, the pharmaceutical composition may include a buffering agent together with the 12-LOX inhibitor or its salt.Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dicalcium phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0337] In certain embodiments, the pharmaceutical compositions used in the methods of the present invention may contain a lubricant. Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0338] In other embodiments, the pharmaceutical composition comprising the 12-LOX inhibitor or its salt will be administered as a liquid oral dosage form. Liquid dosage forms for oral and parenteral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavoring agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with a solubilizing agent such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0339] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or with (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders, such as paraffin, and (f) soluble ... (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may comprise buffering agents.

[0340] Some oral compositions of the present invention relate to sustained or controlled release formulations. These may be, for example, diffusion-controlled products, dissolution-controlled products, erosion products, osmotic pump systems, or ionic resin systems. Diffusion-controlled products contain water-insoluble polymers that control the flow of water and the subsequent flow of dissolved drug out of the dosage form. Dissolution-controlled products control the dissolution rate of the drug by using slowly solubilizing polymers or by using microencapsulation of the drug - varying thickness to control the release. Erosion products control the release of the drug by the erosion rate of the carrier matrix. Osmotic pump systems release the drug based on the constant influx of water through a semi-permeable membrane into a reservoir containing an osmotic agent. Ion exchange resins may be used to bind the drug so that, upon ingestion, the release of the drug is determined by the ionic environment in the digestive tract.

[0341] Administration and Dosage Those skilled in the art will understand that administering a pharma- ceutical effective amount of the pharmaceutical formulations described herein to a patient in need thereof can be determined empirically or by standards currently recognized in the medical arts. It will be understood that when administered to a human patient, the total daily usage of the agent of the compositions described herein will be determined within the scope of sound medical judgment by the attending physician. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, namely, the type and extent of the cellular response to be achieved, the activity of the specific agent or composition used, the specific agent and composition used, the age, weight, general health, sex, and diet of the patient, the time of administration, route of administration, and excretion rate of the agent, duration of treatment, drugs used in combination or concomitantly with the specific agent, and similar factors well known in the medical arts. It is well within the skill of the art to start with a dose of the agent at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0342] Also disclosed are routes of administration and dosages of effective amounts of parenteral pharmaceutical formulations comprising 12-LOX inhibitor compounds. In one embodiment, administration is intravenous. The pharmaceutical compositions and / or formulations described herein may also be administered by infusion. The pharmaceutical formulations described herein may also be administered by bolus administration, optionally combined with administration by infusion. The compounds described herein may be administered in combination with other pharmaceutical agents in various protocols for the effective treatment of diseases.

[0343] The parenteral pharmaceutical formulation may be administered in a single daily dose, or the total daily dosage may be administered in divided doses, two, three, or four times daily. The dose may be administered over a period of one week, one month, or several months, three, six, nine, or twelve months, or at intervals known in the art and determined to be clinically relevant. In one embodiment, the parenteral pharmaceutical formulation may be administered chronically for many years, for the life of the patient. For example, the pharmaceutical formulations described herein may be administered for 7 days, 14 days, 21 days, 28 days, or 35 days. The daily dosage of the formulation may vary over a wide range, from about 0.0001 to about 1,000 mg / day per patient, more specifically from about 200 to about 700, and preferably from about 500 to about 600 mg / day. More specifically, this range may be about 1 mg / kg to 100 mg / kg body weight per day for an adult (about 60 kg), about 10 to 50 mg / kg, 20 to 60 mg / kg, preferably 10 to 20 mg / kg per day, or an equivalent dose as determined by a physician, to achieve a clinically relevant serum concentration.

[0344] Specifically, the parenteral aqueous pharmaceutical formulations described herein may be administered at least once a day for weeks, months, or years. In one embodiment, the pharmaceutical formulation is administered at least once a day for weeks to months. In another embodiment, the pharmaceutical formulation is administered once a day for at least a year.

[0345] The parenteral aqueous pharmaceutical formulation may be administered following the use of a local anesthetic, including, but not limited to, lidocaine, prilocaine, or a combination thereof. Ice or ethyl chloride spray may also be used prior to administration.

[0346] It may sometimes be desirable to deliver the compounds described herein to a subject over an extended period of time, from a single administration to a week to a year. Certain medical devices can be used to provide continuous, intermittent, or on-demand administration to a patient. The device may be a diffusion device pump or other device that contains a reservoir of the drug and optionally a diagnostic or monitoring component to regulate the delivery of the drug. A variety of sustained release, depot, or implantable dosage forms can be utilized. These may be, for example, diffusion controlled products, dissolution controlled products, erosion products, osmotic pump systems, or ionic resin systems. Diffusion controlled products include water-insoluble polymers that control the flow of water and the subsequent efflux of dissolved drug from the dosage form. Dissolution controlled products control the dissolution rate of the drug by using slowly solubilizing polymers or by microencapsulation of the drug - using variable thickness to control the release. Erosion products control the release of the drug by the erosion rate of the carrier matrix.

[0347] In one embodiment, the parenteral aqueous pharmaceutical formulations described herein may be administered by infusion. The infusion may comprise a continuous infusion of about 1 to about 1000 mg of the novel compound in the aqueous pharmaceutical formulation. In another embodiment, the infusion is administered over a period of 30 minutes to 23 hours.

[0348] The amount of compound injected may be approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 mg.

[0349] In one embodiment, the injections may be continuous or repeated at intervals. In one embodiment, the intervals are from about 1 day to 1 year, or from about 1 day to 6 months, or from 1 day to 1 month. In another embodiment, the injections may be repeated for about 1 to 14 days, optionally for about 1 to 7 days. The injections may be repeated for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. The injections may be repeated for about 1 to 7 days, 3 to 8 days, 5 to 14 days, 9 to 14 days, or 7 to 14 days.

[0350] For example, the pharmaceutical formulations described herein may be administered in an amount of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg, either continuously or over a period of 1 to 23 hours (including all intervals therebetween). In certain embodiments, the infusion is carried out over a period of 1 to 12 hours, 1 to 6 hours, or 1 to 4 hours.

[0351] Oral dosage forms or formulations, pharmaceutical compositions may be administered in a single daily dose, or the total daily dosage may be administered in divided doses, two, three or four times daily. Doses may be administered chronically for a week, a month, or several months, three, six, nine or twelve months, or at intervals known in the art and determined to be clinically relevant. Administration may be continued for the life of the patient, or discontinued as clinical judgment requires. The daily dosage of the composition may vary over a wide range of about 0.0001 to about 1,000 mg / day per patient. This range may be more specifically about 0.001 mg / kg to 10 mg / kg of body weight per day, about 0.1 to 100 mg, about 1. For an adult (about 60 kg), 0 to 50 mg or about 1.0 to 0 mg per day. Further, the dosage may be about 0.5-10 mg / kg per day, about 1.0-5.0 mg / kg per day, 5.0-10 mg / kg per day, or an equivalent dose as determined by a physician to achieve a clinically relevant plasma / serum concentration.

[0352] The aqueous pharmaceutical formulations described herein can be administered to any animal capable of experiencing the beneficial effects of the compounds of the present invention, with administration to humans being preferred.

[0353] The dosage administered will be dependent upon the age, health, and weight of the recipient, type of concurrent treatment (if any), frequency of treatment, and the nature of the effect.

[0354] Therapeutic and Prophylactic Methods The novel 2-aminothiazole compounds and other compounds described herein can be used as selective 12-lipoxygenase (12-LOX) inhibitors and can be used to prevent or treat 12-LOX mediated diseases. The disclosure further provides a method for treating or preventing a 12-LOX mediated disease or disorder comprising administering to a mammal a therapeutically or prophylactically effective amount of the novel 2-aminothiozole derived compounds described herein.

[0355] Lipoxygenases are involved in the first critical step in a cascade of metabolic pathways, and the products of these enzymes (eicosanoids) are precursors of hormones such as leukotrienes and lipoxins that mediate a wide range of cellular functions. (Serhan, et al. Chem. Rev. 2011, 111, 5922-5943). As a result, lipoxygenase enzymes and their bioactive metabolites (e.g., hydroxyeicosatetraenoic acid (HETE) and leukotriene A4) have been implicated in a variety of inflammatory diseases and cancer.

[0356] 12-LOX has been demonstrated to be useful in several conditions and / or diseases, such as skin diseases and platelet hemostasis, transplantation / xenotransplantation, cancer (including but not limited to prostate cancer, colon cancer, breast cancer, lung cancer, and hematological diseases), type 1 and type 2 diabetes, diabetic kidney disease (diabetic nephropathy), diabetic neuropathy, diabetic retinopathy, cardiovascular disease (including but not limited to myocardial infarction, congestive heart failure, heart failure, and stroke), thrombosis, heparin-induced thrombocytopenia (HIT), Alzheimer's disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, insulin resistance, arthritis, lupus (SLE), and inflammation.

[0357] In one embodiment, the invention provides a method of reducing U46619-induced, thrombin-induced, PAR1-AP, PAR4-AP-induced, or collagen-induced platelet aggregation comprising administering to a mammal a therapeutically or prophylactically effective amount of any of the compounds, salts, prodrugs, enantiomers, mixtures of enantiomers, or diastereomers.

[0358] In one embodiment, the invention provides a method for reducing FcγRIIA-mediated platelet activation (e.g., via anti-CD9 or IV.3+GAM-induced activation), comprising administering to a mammal a therapeutically or prophylactically effective amount of any of the compounds, salts, prodrugs, enantiomers, mixtures of enantiomers, or diastereomers.

[0359] In certain embodiments, the disorder is an immune-mediated thrombocytopenia and thrombotic disorder, including, but not limited to, sepsis-associated thrombocytopenia and heparin-induced thrombocytopenia (HIT).

[0360] In preferred embodiments, the disease or disorder treated by the disclosed 12-LOX inhibitor compounds is selected from thrombosis, HIT, and type 1 and type 2 diabetes.

[0361] In certain embodiments, the disorder is heparin-induced thrombocytopenia (HIT).

[0362] In certain embodiments, the disorder is type 1 diabetes.

[0363] In one embodiment, the invention provides a method for treating or preventing a 12-lipoxygenase-mediated disease or disorder comprising administering to a mammal a therapeutically or prophylactically effective amount of a compound or any of its salts, prodrugs, enantiomers, mixtures of enantiomers, or diastereomers.

[0364] Combination therapy The pharmaceutical formulations described herein may also include additional therapeutic agents or combinations thereof.

[0365] The additional therapeutic agent may be another 12-LOX inhibitor. The 12-LOX inhibitor may be an organic compound, an inorganic compound, a biological compound (e.g., a protein or a fragment thereof, an antibody or a fragment thereof, a nucleic acid, a nucleic acid analog, a sugar, or a peptide), or any combination thereof. The 12-LOX inhibitor may be synthetic or naturally occurring. Selective 12-LOX inhibitors are described in U.S. Patent Nos. 10,266,488 and 10,752,581.

[0366] The mixing ratio of 12-LOX inhibitors may be optimized to provide maximum therapeutic effect.

[0367] Additional agents include, but are not limited to, antithrombotic agents such as argatroban, fondaparinux, lepirudin, bivalirudin, danaparoid, and drotrecogin alfa, and antidiabetic agents such as exenatide, albiglutide, pramlintide, semaglutide, lixisenatide, and dulaglutide. Combinations with direct acting oral coagulants, including, but not limited to, apixaban, dabigatran, rivaroxaban, and edoxaban, are also contemplated.

[0368] The present invention also contemplates the co-administration of the aforementioned additional therapeutic agents in separate compositions or formulations, either simultaneously with, prior to, or following administration of a 12-LOX inhibitor compound of the present disclosure.

[0369] biological example Compounds were evaluated for inhibition of 12-LOX, as well as selectivity, by measuring the inhibition of several compounds against 15-LOX using a UV-Vis assay. Arachidonic acid (AA) was used as a substrate for 12-LOX and 15-LOX. ML355 was used as a reference inhibitor for 12-LOX. ML351 (5-(methylamino)-2-(1-naphthalenyl)-4-oxazolecarbonitrile) was used as a reference inhibitor for 15-LOX.

[0370] The reaction buffer used for the lipoxygenase assay was as follows: 25 mM HEPES, pH 7.5, with 0.01% Triton X-100. 1 mM 12-HPETE or 1 mM 15-HPETE stock solutions were prepared in 25 mM HEPES with 0.01% Triton X-100.

[0371] A standard curve of 12-HPETE was prepared by serial dilution of 0, 6.25, 12.5, 25, 50, 75, and 100 μM with a final reaction volume of 100 μL in a 96-well clear flat-bottom UV-transparent microplate. The absorbance of 12-HPETE at each concentration was measured at 234 nm.

[0372] A standard curve of 15-HPETE was prepared by serial dilution of 0, 3.125, 6.25, 12.5, 25, 50, and 100 μM in a 96-well clear flat-bottom UV-transparent microplate with a final reaction volume of 100 μL. The absorbance of 12-HPETE at each concentration was measured at 234 nm.

[0373] IC by determining the % inhibition at various inhibitor concentrations 50 The value was obtained. 50 The final concentrations of the control inhibitor and test compounds in the determination assay are 0, 0.03, 0.1, 0.3, 1, 3, 10, and 20 M. The final concentration of DMSO in the assay is 0.05%.

[0374] 12-LOX IC 50 Determination of. 12-LOX enzyme and AA were diluted to 120 nM and 200 μM, respectively, in HEPES buffer. 50 μL of the designated test compound and 25 μL, 120 nM enzyme are pre-incubated for 5 min at room temperature. The reaction is started by adding 25 μL, 200 μM AA. After a short spin (1000 rpm, 15 s), the reaction system is incubated for 5 min. A blank control was set up by adding 25 μL of HEPES to 50 μL of control inhibitor compound (ML355) and 25 μL, 200 μM AA. The final concentrations of 12-LOX enzyme and AA were 30 nM and 50 μM, respectively. The absorbance of 12-HPETE at 234 nm was measured.

[0375] 15-LOX IC 50Determination of. 15-LOX enzyme and AA were diluted to 480 nM and 200 μM, respectively, in HEPES buffer. 50 μL of the designated test compound and 25 μL, 480 nM enzyme are pre-incubated for 5 min at room temperature. The reaction is started by adding 25 μL, 200 μM AA. After a short spin (1000 rpm, 15 s), the reaction system is incubated for 3 min. A blank control was set up by adding 25 μL of HEPES to 50 μL of a control inhibitor compound (ML355) and 25 μL, 200 μM AA. The final concentrations of 15-LOX enzyme and AA were 120 nM and 50 μM, respectively. The absorbance of 15-HPETE at 234 nm was measured. The assay was performed in duplicate.

[0376] I C 50 Values ​​were calculated using GraphPad Prism 8.0.2.

[0377] I C 50 Values ​​are calculated as % residual activity and the logarithm of the inhibitor concentration. Residual activity (%) = OD value of inhibitor / OD value of vehicle × 100 Compound IC 50 The values ​​are in Table 2 below: [Table 2-1] [Table 2-2] +++ = <250 nM ++ = 250 nM-1000 nM + = > 1000 nM

[0378] The foregoing merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, to limit the disclosure in any way.

[0379] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referenced herein is incorporated by reference for all purposes.

[0380] Equivalent. The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein. The scope of the present disclosure is therefore indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A compound of formula (I) 【Chemistry 1】 wherein Z is: 【Chemistry 2】 R １ is hydrogen, or an optionally substituted cycloalkyl, aryl, or C １ -C ３ alkylaryl, each of which is independently selected from halogen, alkyl, haloalkyl, alkyloxy, C １ -C ３ optionally substituted by one or more substituents selected from haloalkyloxy, or heterocycle; R ２ H, halogen, deuterium, alkyl, haloalkyl, C １ -C ３ Alkyloxy and C １ -C ３ Haloalkyloxy, hydroxyalkyl, alkyoxyalkyl, cycloalkyl including cyclopropyl, C １ -C ３ Alkylaryl, or 【Chemistry 3】 or substituted or unsubstituted aryl and aralkyl, including 【Chemistry 4】 wherein R ９ But independently, C １ -C ３ selected from alkyl, cycloalkyl (including cyclopropyl), and substituted or unsubstituted phenyl; Or, R １ and R ２ taken together with the thiazole ring form an optionally substituted 5-, 6-, or 7-membered fused 1,2-carbocyclic ring system, wherein the ring carbons of the 5-, 6-, or 7-membered fused ring are optionally substituted by one or more atoms selected from N, O, and S. The fused 5-, 6-, or 7-membered rings may independently contain one or more halogens, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkyloxy, C １ -C ３ optionally substituted by haloalkyloxy, or an optionally substituted aryl ring; Or, R １ and R ２ together with the carbon to which they are attached form a substituted or unsubstituted: 【Chemistry 5】 R ３ is hydrogen, C １ -C ３ Alkyl, or C １ -C ３ is haloalkyl, Each R ４ are independently hydrogen, CD ３ , substituted or unsubstituted phenyl, cycloalkyl including cyclopropyl, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, -OR, C １ -C ３ haloalkyloxy or halogen; R ５ is hydrogen, C １ -C ３ Alkyl, or C １ -C ３ is haloalkyl, R ６ is hydrogen, CD3, alkyl, cycloalkyl, haloalkyl, or 【Chemistry 6】 Each R ７ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, or halogen; R ８ is hydrogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl; n is 0, 1, or 2; p is 0, 1, 2, or 3; or A pharma- ceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof.

2. The compound of claim 1 , wherein the compound is of formula (I).

3. R １ are independently selected from halogen, alkyl, haloalkyl, 3-F, 4-oxetanephenyl, and C １ -C ３ 2. The compound of claim 1, which is phenyl substituted with two or more substituents selected from haloalkyloxy.

4. R １ The compound according to any one of claims 1 to 3, wherein is phenyl substituted by one or more halogens.

5. R １ but, 【Chemistry 7】 The compound according to any one of claims 1 to 4,

6. R ２ The compound according to any one of claims 1 to 5, wherein is hydrogen or deuterium.

7. R ２ The compound according to any one of claims 1 to 6, wherein is halogen.

8. R ２ The compound according to any one of claims 1 to 7, wherein is fluorine or chlorine.

9. R ２ The compound of any one of claims 1 to 5, wherein is selected from substituted or unsubstituted aryl or aralkyl, hydroxyalkyl, cyclopropyl, or amido.

10. 10. A composition comprising a compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

11. 10. A method for treating or preventing a 12-lipoxygenase mediated disease and / or disorder, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) as defined in claim 1, or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof.

12. The compound: 【Chemistry 8】 In the formula, R ３ , R ４ and n are defined as in claim 1, or a salt thereof.

13. A compound of formula (II) 【Chemistry 9】 In the formula, R ３ , R ４、 and n is defined as in claim 1, or a pharma- ceutically acceptable salt thereof.

14. 1. A compound according to formula IV, 【Chemistry 10】 In the formula, R １ , R ２ , R ４ , R ５ and n are defined as in claim 1, or a salt thereof.

15. A compound according to formula V, 【Chemistry 11】 In the formula, R １ ~R ５ and n are defined as in claim 1, or a pharma- ceutically acceptable salt thereof.

16. A compound of formula (VII) or (VIIa), 【Chemistry 12】 In the formula, R １ ~R ８ 13. A compound, or a pharma- ceutically acceptable salt thereof, wherein n, p, and n are defined in claim 1.

17. R ４ is methyl, fluorine, or CF ３ 2. The compound of claim 1,

18. R ４ is methyl, fluorine, or CF ３ 5. The compound of claim 4,

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