Benzazole compounds and methods for making and using the compounds

ES 2 811 136 T3

DESCRIPTION

Benzazole compounds and methods for obtaining and using the compounds

COUNTRYSIDE

This description relates to benzazole compounds, and to embodiments of a method for obtaining and using the compounds, such as to inhibit kinases, including interleukin receptor associated kinase (IRAK), and to treat related diseases and conditions.

BACKGROUND

Interleukin-1 receptor associated kinases (IRAKs) are important mediators of signaling processes, such as toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling processes. IRAKs have been implicated in the modulation of signaling networks that control inflammation, apoptosis, and cell differentiation. Four IRAK genes have been identified in the human genome (IRAK1, IRAK2, IRAK3 and IRAK4), and studies have revealed different non-redundant biological roles. IRAK1 and IRAK4 have been shown to exhibit kinase activity.

SUMMARY

Described herein are benzazole compounds, and compositions comprising such compounds, which are useful as, inter alia, immunomodulators; in particular, the present compounds are kinase inhibitors, such as, by way of example, IRAKs inhibitors. Certain described embodiments relate to benzazole compounds having a formula I

<img file="ES2811136T3_D0001.tif" />

or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, or prodrug thereof. With respect to formula I, X is O or S; Y is O or S; Z is N or CR9; Het-1 is heteroaryl; R¹ and R² they are independently H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with the nitrogen to which they are attached, form a heterocyclic ring; R³, R⁴, R⁶ and R9 are independently H, aliphatic, halo, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxylic ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl , sulfinyl, or haloalkyl; R⁵ is amino, aryl or heteroaryl or; R7 is H, aliphatic, heteroaliphatic, heterocyclyl, aryl, or araliphatic; each R⁸ is independently aliphatic, halo, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxylic ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, or haloalkyl ; and m is 0 to 6. In some embodiments, X is O, and in other embodiments, X is S.

Het-1 can be a heteroaryl. Exemplary Het-1 can be selected from furan, thiophene, pyrazole, pyrrole, imidazole, oxazole, thiazole, isoxazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3, 4-thiadiazole, 1,2,5-thiadiazole, tetrazole, pyrimidine, pyridine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, pyrazine, pyridazine, quinoline, isoquinoline, indole, isoindole, benzofuran, benzothiophene, benzoimidazole, benzopyrazole, benzotriazole, pyrrolo [2,3-b] pyridine, pyrrolo [3,2-b] pyridine, pyrrolo [2,3c] pyridine, pyrrolo [3,2-c] pyridine, pyrrolo [3,4-b] pyridine or pyrrolo [3,4-c] pyridine. In some embodiments, Het-1 is pyridine, pyrazole, or pyrrolo [2,3-b] pyridine, and in particular embodiments,

<img file="ES2811136T3_D0002.tif" />

is selected from

<img file="ES2811136T3_D0003.tif" />

ES 2 811 136 T3

<img file="ES2811136T3_D0004.tif" />

<img file="ES2811136T3_D0005.tif" />

In some embodiments, the compound has a formula selected from

<img file="ES2811136T3_D0006.tif" />

<img file="ES2811136T3_D0007.tif" />

<img file="ES2811136T3_D0008.tif" />

<img file="ES2811136T3_D0009.tif" />

<img file="ES2811136T3_D0010.tif" />

<img file="ES2811136T3_D0011.tif" />

With respect to these formulas, R¹⁰ and R²³ are independently H, aliphatic, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxylic ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl, typically H, aliphatic, aryl, or heterocyclyl; and R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are independently H, aliphatic, halogen, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, -Oheterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxylic ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, or haloalkyl.

ES 2 811 136 T3

In any of the above embodiments, R⁵ it is amino, aryl, or heteroaryl. R⁵ it can be amino having a formula -NRR in which each R is independently aliphatic, or both R groups, together with the nitrogen attached to them, form an optionally substituted heterocyclic ring.

R¹ and R² independently they can be H, aliphatic, heteroaliphatic, or, together with the nitrogen attached to them, form a heteroaliphatic ring. In some embodiments, R¹ is H or alkyl, and R² it is aliphatic or heteroaliphatic.

In particular embodiments, R³, R⁴, R⁶ and R7 are H.

Also described herein are embodiments of a composition comprising a benzazole compound within the scope of the present invention and a pharmaceutically acceptable excipient. The exemplary compositions described may also comprise a benzazole compound within the scope of the present invention and an additional therapeutic agent. Alternatively, the benzazole compounds, or compositions comprising the benzazole compounds, can be administered as a combination with one or more additional therapeutic agents. The additional therapeutic agent (s) may comprise an immuno-oncological agent. The benzazole compounds, or compositions comprising the benzazole compounds, and the additional therapeutic agent (s) may be administered to a subject substantially simultaneously, sequentially in any order, or within a period of time such that the subject experiences an overlapping beneficial effect of both the benzazole compound or the composition comprising the benzazole compound and the additional therapeutic agent (s).

Also described is a method of administering a benzazole compound or composition comprising a benzazole compound or compounds. For example, embodiments of a method for inhibiting or modulating an IRAK protein are described herein, which comprises contacting the IRAK protein with an effective amount of a benzazole compound. In some embodiments, the method comprises contacting the protein in vitro. In other embodiments, the IRAK protein can be in a subject. Exemplary compounds have an EC50 of greater than 0 to 5 µM, such as greater than 0 to 1 µM. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a benzazole compound or composition comprising the benzazole compound. The method may be a method of treating a disease or condition for which an IRAK modulator or inhibitor is indicated.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION

I. Definitions

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those skilled in the art in practicing the present disclosure. The singular forms "a", "an" and "the" refer to one or more than one, unless the context clearly indicates otherwise. The term "or" refers to a single element of established alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprise" means "includes." Thus, "comprising A or B" means "including A, B, or A and B", without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference.

Unless otherwise indicated, all numbers expressing component amounts, molecular weights, percentages, temperatures, times, etc., as used in the specification or claims, are to be understood as modified by the expression " about". Consequently, unless otherwise stated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and / or the limits of detection under standard test conditions / methods. When directly and explicitly distinguishing embodiments of the prior art discussed, the embodiment numbers are not approximate unless the term "about" is cited.

Unless otherwise explained, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this description belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

When depicting or describing chemical structures, unless explicitly stated otherwise, all carbons are assumed to include hydrogen such that each carbon adjusts to a valence of four. For example, in the structure on the left side of the following scheme there are nine hydrogen atoms involved. The nine hydrogen atoms are represented in the structure on the right.

ES 2 811 136 T3

<img file="ES2811136T3_D0012.tif" />

Sometimes a particular atom in a structure is described in a textual formula as having one or more hydrogen atoms, for example -CH2CH2-. A person skilled in the art will understand that the descriptive techniques mentioned above are common in chemical arts to provide brevity and simplicity in the description of organic structures.

One skilled in the art will appreciate that the definitions can be combined to better describe a particular compound. For example, hydroxyaliphatic refers to an aliphatic group substituted with a hydroxy group (-Oh), and haloalkylaryl refers to an aryl group substituted with an alkyl group, in which the alkyl group is also substituted with a halogen, and in the that the point of attachment to the original structure is through the aryl moiety, since aryl is the base name of the substituent.

As used herein, the term "substituted" refers to all subsequent modifiers in a term; for example, in the term "substituted arylalkyl C1-8", the substitution can occur on the "C1-8 alkyl" portion, on the "aryl" portion, or on both portions of the arylC 1-8 alkyl group. . Also by way of example, alkyl includes substituted cycloalkyl groups.

"Substituted", when used to modify a specified group or moiety, means that at least one, and perhaps two or more, hydrogen atoms of the specified group or moiety are independently replaced by the same or different substituent groups as defined below . In a particular embodiment, a group, moiety or substituent may be substituted or unsubstituted, unless it is expressly defined as "unsubstituted" or "substituted". Accordingly, any of the groups specified herein may be unsubstituted or substituted. In particular embodiments, the substituent may or may not be expressly defined as substituted, but it is still contemplated to be optionally substituted. For example, an "alkyl" substituent may be unsubstituted or substituted, but an "unsubstituted alkyl" may be unsubstituted.

The "substituents" or "substituent groups" for substituting one or more hydrogen atoms on saturated carbon atoms in the specified group or moiety can be any atom, or group of atoms, that a person of ordinary skill in the art would recognize as a substituent. or suitable substituent group. The "substituents" or "substituent groups" are, unless otherwise specified, -R⁶⁰, halo, = O, -OR⁷⁰, -MR⁷⁰, -N (R⁸⁰) 2, haloalkyl, perhaloalkyl, -CN, -NO2, = N2, -N3, -SO2R⁷⁰, -SO3^-M⁺, -SO3R⁷⁰, -OSO2R⁷⁰, -OSO3^-M⁺, -OSO3R⁷⁰, -P (O) (O^-) 2 (M⁺) 2, P (O) (O^-) 2M²⁺, -P (O) (OR⁷⁰)OR^-M⁺, -P (O) (OR⁷⁰) 2, -C (O) R⁷⁰, -C (S) R⁷⁰, -C (NR⁷⁰) R⁷⁰, -CO2^-M⁺, -CO2R⁷⁰, -C (S) OR⁷⁰, C (O) N (R⁸⁰) 2, -C (NR⁷⁰) (R⁸⁰) 2, -OC (O) R⁷⁰, -OC (S) R⁷⁰, -OCO2^-M⁺, -OCO2R⁷⁰, -OC (S) OR⁷⁰, -NR⁷⁰C (O) R⁷⁰, -NR⁷⁰C (S) R⁷⁰, -NR⁷⁰CO2^-M⁺, -NR⁷⁰CO2R⁷⁰, -NR⁷⁰C (S) OR⁷⁰, -NR⁷⁰C (O) N (R⁸⁰) 2, -NR⁷⁰C (NR⁷⁰) R⁷⁰ and -NR⁷⁰C (NR⁷⁰) N (R⁸⁰) 2, where R⁶⁰ is C1-6 alkyl; each R⁷⁰ is independently, for each occurrence, hydrogen or R⁶⁰; each R⁸⁰ is independently, for each occurrence, R⁷⁰, or alternatively, two R groups⁸⁰, taken together with the nitrogen atom to which they are attached, form a 3- to 7-membered heteroalicyclyl optionally including 1 to 4 of the same or different additional heteroatoms selected from O, N, and S, of which N optionally has H or C1-C3 alkyl substitution; and each M + is a counterion with a single net positive charge. Each M + is independently, for each occurrence, for example, an alkali metal ion, such as K⁺, Na⁺, Li⁺; an ammonium ion, such as⁺N (R⁶⁰)4; or an alkaline earth metal ion, such as [Ca²⁺] 0.5, [Mg²⁺] 0.5, or [Ba²⁺] 0.5 (a subscript "0.5" means, for example, that one of the counter ions for such divalent alkaline earth ions may be an ionized form of a compound of the invention, and the other a typical counter ion such as chloride , or two ionized compounds may serve as counter ions for such divalent alkaline earth ions, or one doubly ionized compound may serve as the counter ion for such divalent alkaline earth ions). As specific examples, -N (R⁸⁰) 2 includes -NH2, -NHalkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, N-morpholinyl, and the like. Any of the two hydrogen atoms on a single carbon can be replaced by = O, = NR⁷⁰, = N-OR⁷⁰, = N2 or = S.

Substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbons are, unless otherwise specified, -R⁶⁰, halo, -O^-M⁺, -OR⁷⁰, -MR⁷⁰, -S^- M⁺, -N (R⁸⁰) 2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R⁷⁰, -SO3^-M⁺, -SO3R⁷⁰, -OSO2R⁷⁰, -OSO3^-M⁺, OSO3R⁷⁰, -PO3^-2(M⁺) 2, -PO3^-2M²⁺, -P (O) (OR⁷⁰)OR^-M⁺, -P (O) (OR⁷⁰) 2, -C (O) R⁷⁰, -C (S) R⁷⁰, -C (NR⁷⁰) R⁷⁰, -CO2^-M⁺, -CO2R⁷⁰, -C (S) OR⁷⁰, -C (O) NR⁸⁰R⁸⁰, -C (NR⁷⁰) N (R⁸⁰) 2, -OC (O) R⁷⁰, -OC (S) R⁷⁰, -OCO2^-M⁺, -OCO2R⁷⁰, -OC (S) OR⁷⁰, -NR⁷⁰C (O) R⁷⁰, -NR⁷⁰C (S) R⁷⁰, -NR⁷⁰CO2^-M⁺, -NR⁷⁰CO2R⁷⁰, -NR⁷⁰C (S) OR⁷⁰, -NR⁷⁰C (O) N (R⁸⁰) 2, -NR⁷⁰C (NR⁷⁰) R⁷⁰ and NR⁷⁰C (NR⁷⁰) N (R⁸⁰) 2, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previously defined, provided that in case of alkene or substituted alkyne, the substituents are not -O^-M⁺, -OR⁷⁰, -MR⁷⁰, or -S^-M⁺.

Substituent groups for replacing hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise specified, -R⁶⁰, -O^-M⁺, -OR⁷⁰, -MR⁷⁰, -S^-M⁺, -N (R⁸⁰) 2, perhaloalkyl, -CN, -NO, -NO2, -S (O) 2R⁷⁰, -SO3^-M⁺, -SO3R⁷⁰, -OS (O) 2R⁷⁰, -OSO3^-M⁺, -OSO3R⁷⁰, -PO3^2-(M⁺) 2, -PO3²M²⁺, -P (O) (OR⁷⁰)OR^-M⁺, -P (O) (OR⁷⁰) (OR⁷⁰), -C (O) R⁷⁰, -C (S) R⁷⁰, -C (NR⁷⁰) R⁷⁰, -CO2R⁷⁰, -C (S) OR⁷⁰, -C (O) NR⁸⁰R⁸⁰,

ES 2 811 136 T3

C (NR⁷⁰) NR⁸⁰R⁸⁰, -OC (O) R⁷⁰, -OC (S) R⁷⁰, -OCO2R⁷⁰, -OC (S) OR⁷⁰, -NR⁷⁰C (O) R⁷⁰, -NR⁷⁰C (S) R⁷⁰, -NR⁷⁰CO2R⁷⁰, NR⁷⁰C (S) OR⁷⁰, -NR⁷⁰C (O) N (R⁸⁰) 2, -NR⁷⁰C (NR⁷⁰) R⁷⁰ and -NR⁷⁰C (NR⁷⁰) N (R⁸⁰) 2, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ they are as previously defined.

In one embodiment, a group that is substituted has 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

Furthermore, in embodiments in which a group or moiety is substituted with a substituted substituent, the nesting of said substituted substituents is limited to three, thus avoiding the formation of polymers. Thus, in a group or moiety that comprises a first group that is a substituent in a second group that is itself a substituent in a third group, that is attached to the parent structure, the first (outermost) group alone it can be substituted with unsubstituted substituents. For example, in a group comprising - (aryl-1) - (aryl-2) - (aryl-3), aryl-3 can only be substituted with substituents which are not substituted.

"Acyl" refers to the group -C (O) R, where R is H, aliphatic, heteroaliphatic, heterocyclic, or aryl. Exemplary acyl moieties include, but are not limited to, -C (O) H, -C (O) alkyl, -C (O) C1-C6 alkyl, -C (O) C1-C6C haloalkyl (O ) cycloalkyl, -C (O) alkenyl, -C (O) cycloalkenyl, -C (O) aryl, -C (O) heteroaryl, or -C (O) heterocyclyl. Specific examples include -C (O) H, -C (O) Me, -C (O) Et, or -C (O) cyclopropyl.

"Aliphatic" refers to a substantially hydrocarbon group or moiety, which includes alkyl, alkenyl, alkynyl groups, cyclic versions thereof, such as cycloalkyl, cycloalkenyl, or cycloalkynyl, and which further includes straight and branched chain arrangements, and also all stereoisomers and positional isomers. Unless expressly stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms; for example, one to fifteen, one to ten, one to six, or one to four carbon atoms. Unless expressly stated otherwise, a cyclic aliphatic group contains from three to twenty-five carbon atoms; for example, three to fifteen, three to ten, or three to six carbon atoms. "Lower aliphatic" refers to an aliphatic group, including alkyl, alkenyl, and alkynyl, containing one to ten carbon atoms, such as one to six carbon atoms, or three to ten carbon atoms, such as from three to six carbon atoms, for a cyclic lower aliphatic group. An aliphatic group may be substituted or unsubstituted, unless it is expressly referred to as "unsubstituted aliphatic" or "substituted aliphatic." An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon in an aliphatic chain, or up to one substituent for each carbon of a -C = C- double bond in an aliphatic chain, or up to one substituent for a carbon of a terminal methine group).

"Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl or cycloalkyl group. In certain examples, R is a C1-6 alkyl or C3-6 cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are examples of alkoxy groups. In a substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which useful in presently disclosed compounds include haloalkoxy groups, such as -OCF2H and -OCF3.

"Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or cycloalkyl group. CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

"Alkyl" refers to a saturated aliphatic hydrocarbyl group having 1 to 25 carbon atoms, typically 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, and may be designated as C1-C6 alkyl. An alkyl moiety can be substituted or unsubstituted. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH (CH3) 2), n-butyl (CH2CH2CH2CH3 ), isobutyl (-CH2CH2 (CH3) 2), sec-butyl (-CH (CH3) (CH2CH3), t-butyl (-C (CH3) 3), n-pentyl (CH2CH2CH2CH2CH3), and neopentyl (-CH2C ( CH3) 3).

"Amino" refers to the group -NH2, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aryl, or heterocyclic, or two R groups, together with the nitrogen attached thereto, form a heterocyclic ring. Examples of such heterocyclic rings include those in which two R groups, together with the nitrogen to which they are attached, form a - (CH2) 2-5- ring optionally interrupted with one or two heteroatom groups, such as --O - or -N (R^g), just as in groups

<img file="ES2811136T3_D0013.tif" />

<img file="ES2811136T3_D0014.tif" />

in which R^g is R⁷⁰, -C (O) R⁷⁰, -C (O) OR⁶⁰ or -C (O) N (R⁸⁰)2.

"Amide" refers to the group -N (H) acyl or -C (O) amino.

ES 2 811 136 T3 "Aryl" or "aromatic" refers to an aromatic group of, unless otherwise specified, 5 to 15 ring atoms having a single ring (eg phenyl) or multiple fused rings wherein at least one ring is aromatic (eg, naphthyl). Aryl groups can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. For groups that have multiple rings, at least one of which is aromatic and the other is not, these groups are however called "aryl" as long as the point of attachment to the rest of the compound is through an atom of an aromatic moiety. of the aryl group. Unless otherwise indicated, an aryl group can be substituted or unsubstituted.

"Araliphatic" refers to an aryl group attached to the parent through an aliphatic moiety. Araliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

"Azole" refers to a five-membered nitrogen heterocyclic ring containing at least one other non-carbon atom typically selected from nitrogen, sulfur, or oxygen. A "benzazole" is a fused ring comprising an azole ring and a phenyl ring. Examples of benzazoles include, but are not limited to, benzthiazole, benzoxazole, and benzimidazole.

"Carboxyl" or "carboxy" refers to -CO2H.

"Carboxylate" refers to -C (O) O^- or its salts.

"Carboxyl ester" or "carboxylic ester" refers to the group -C (O) OR, where R is aliphatic, aryl, heteroaliphatic, and heterocyclic, including heteroaryl.

"Cyano" refers to the group -CN.

"Cycloaliphatic" refers to a cyclic aliphatic group having a single ring (eg, cyclohexyl), or multiple rings, such as in a fused, bridged, or spirocyclic system, at least one of which is aliphatic, provided the point of attachment is through an atom of an aliphatic region of the cycloaliphatic group. Cycloaliphatic includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

"Halo", "halide" or "halogen" refers to fluorine, chlorine, bromine or iodine.

"Heteroaliphatic" refers to an aliphatic compound or group that has at least one hetero atom, that is, one or more carbon atoms have been replaced by an atom that has at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon or sulfur. Heteroaliphatic compounds or groups can be substituted or unsubstituted, branched or unbranched, acyclic or cyclic, such as a heteroalicyclic, chiral or achiral group, and can include heterocycle, heterocyclyl, heterocycloaliphatic, or heterocyclic groups. An example of a heteroaliphatic group is CH3OCH2CH2-.

"Heteroaryl" refers to an aryl group in which one or more carbon atoms, such as methine (-CH =) or vinylene (-CH = CH-) groups, have been replaced by trivalent or divalent heteroatoms, respectively, of so that aromaticity is maintained, as determined by the delocalized continuous π-electron system characteristic of the aromatic group, and the number of out-of-plane π electrons corresponding to Hückel's rule (4n + 2).

"Heterocycloalkyl" and "heterocyclylalkyl" refer to a heterocyclyl moiety attached to the parent structure via an alkyl moiety, for example (tetrahydropyran-4-yl) methyl, (pyridin-4-yl) methyl, morpholinoethyl, or piperazin-1-ylethyl. .

"Heterocyclyl", "heterocycle", "heterocyclic" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically refer to a stable three to fifteen membered ring moiety comprising carbon atoms and at least one heteroatom , such as one to five heteroatoms. Typical heteroatoms include, but are not limited to, N, O, S, P, Si, or B. The heterocyclyl moiety may be a monocyclic moiety, or it may comprise multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such a multiple ring moiety can include fused or bridged ring systems, as well as spirocyclic systems; and the nitrogen, phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moiety can optionally be oxidized to various oxidation states. For convenience, nitrogens, particularly but not exclusively, those defined as ring aromatic (ring) nitrogens, should include their corresponding N-oxide form, although they are not explicitly defined as such in a particular example. Thus, for a compound having, for example, a pyridyl ring, the corresponding pyridyl N-oxide is included as another compound of the invention, unless expressly excluded by context. Furthermore, the ring nitrogen atoms can optionally be quaternized. Heterocyclyl includes heteroaryl moieties and heteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclyl rings that are partially or fully saturated. Thus, a term such as "heterocyclylalkyl" includes heteroalicyclylalkyls and heteroarylalkyls. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenazinyl, phenazinyl, phenazinyl,

ES 2 811 136 T3 pteridinyl, purinyl, pyrrolopyridinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxypyrrolyne-pyropyrrolyl, 2-oxopiperidinyl, 2-oxypyrrolyne-pyrrolyne , pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothielyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulphone, dioxaphospholanyl, and oxadiazolyl.

"Hydroxyl" refers to the group -OH.

"Nitro" refers to the group -NO2.

"Patient" or "subject" refers to mammals and other animals, particularly humans. Thus, the described methods are applicable to both human therapy and veterinary applications.

"Pharmaceutically acceptable excipient" refers to a substance, other than an active ingredient, that is included in an active ingredient formulation. As used herein, an excipient can be incorporated into the particles of a pharmaceutical composition, or it can be physically mixed with particles of a pharmaceutical composition. An excipient can be used, for example, to dilute an active agent and / or modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, release agents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, sorbents, preservatives, adjuvants, carriers, or vehicles. Excipients can be starches and modified starches, cellulose and cellulose derivatives, saccharides and their derivatives, such as disaccharides, polysaccharides and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PVP), polyethyleneglycol (PEG). 1000 Tocopheryl Succinate (also known as Vitamin E TPGS, or TPGS), Carboxymethyl Cellulose, Dipalmitoyl Phosphatidylcholine (DPPC), Vitamin A, Vitamin E, Vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

An "adjuvant" is an excipient that modifies the effect of other agents, typically the active ingredient. Adjuvants are often pharmacological and / or immunological agents. An adjuvant can modify the effect of an active ingredient by increasing the immune response. An adjuvant can also act as a stabilizing agent for a formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combined adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant. Freund.

"Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspension aid, solubilization aid, or aerosolization aid. See, for example, Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, &amp; Wilkins, Philadelphia, PA, 21^to Edition (2005), incorporated herein by reference, describing compositions and formulations suitable for pharmaceutical delivery of one or more additional therapeutic compositions and pharmaceutical agents.

In general, the nature of the carrier will depend on the particular mode of administration employed. For example, parenteral formulations generally comprise injectable fluids including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, or the like, as a carrier. In some examples, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (eg, by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, and the like, for example sodium acetate or sorbitan monolaurate.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound that are derived from a variety of organic and inorganic counterions, as will be known to one of ordinary skill in the art, and include, by way of example only, sodium, potassium, calcium. , magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The "pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free bases while they are formed by acid partners. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, without limitation, acids

ES 2 811 136 T3 inorganics such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like. The "pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" that are derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Examples of salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Examples of organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, SM Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference). In particularly described embodiments, the benzazole compound can be a formate or a sodium salt.

"Pharmaceutically effective amount" and "therapeutically effective amount" refer to an amount of a compound sufficient to treat a specific disorder or disease, or to ameliorate or eradicate one or more of its symptoms, and / or to prevent the onset of the disease. or disorder. The therapeutically effective amount can be determined by one of ordinary skill in the art.

"Prodrug" refers to a compound that is transformed in vivo to produce a biologically active compound, particularly the parent compound, for example by hydrolysis in the gut or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form that possesses a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (eg, C1-6 alkyl esters). Other prodrug moieties include phosphate esters, such as -CH2-OP (O) (OR ') 2 or a salt thereof, where R' is H or lower alkyl, such as C1-6 alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but are not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides and secondary and tertiary alkylamides (eg, with between about one and about six carbons). The amides and esters of the described exemplary embodiments of compounds according to the present invention can be prepared according to conventional methods. In T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes, a comprehensive discussion of prodrugs is provided.

"Solvate" refers to a complex formed by a combination of solvent molecules with solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. The compounds described herein can exist in unsolvated or solvated forms when combined with solvents, pharmaceutically acceptable or not, such as water, ethanol, and the like. The solvated forms of the currently described compounds are within the scope of the embodiments described herein. A "hydrate" is a complex formed by a combination of water molecules with solute molecules or ions.

"Sulfonamide" refers to the group or moiety -SO2amino or -N (R^C) sulfonyl, in which R^C is H, aliphatic, aryl, heteroaliphatic, cyclic, and heterocyclic, including heteroaryl.

"Sulfanyl" refers to the group or moiety -SH, -S-aliphatic, -S-aryl, -S-heteroaliphatic, -S-cyclic, -S-heterocyclyl, including -S-heteroaryl.

"Sulfinyl" refers to the group or moiety -S (O) H, -S (O) aliphatic, -S (O) aryl, -S (O) heteroaliphatic, -S (O) cyclic, S (O) heterocyclyl, -S (O) heteroaryl.

"Sulfonyl" refers to the group: -SO2H, -SO2aliphatic, -SO2aryl, -SO2heteroaliphatic, -SO2cyclic, -SO2heterocyclyl, including -SO2heteroaryl.

"Treating" or "treatment", as used herein, refers to the treatment of a disease or condition of interest in a patient or subject, including human or animal subjects, particularly a human having the disease or condition of interest, and includes, by way of example, and without limitation:

(i) prevent the disease or condition from occurring in a patient or subject, in particular, when said patient or subject is predisposed to the condition but has not yet been diagnosed as having it;

ES 2 811 136 T3 (ii) inhibiting the disease or condition, for example arresting or slowing its development;

(iii) alleviating the disease or condition, for example causing regression of the disease or condition or a symptom thereof; or (iv) stabilize the disease or condition.

As used herein, the terms "disease" and "condition" may be used interchangeably, or they may be different in that the particular disease or condition may not have a known etiologic agent (so the etiology has yet to be determined ) and, therefore, it is not yet recognized as a disease but only as an undesirable condition or syndrome, in which doctors have identified a more or less specific set of symptoms.

The above definitions and the following general formulas are not intended to include illegal substitution patterns (eg, methyl substituted with 5 fluoro groups). Such unacceptable substitution patterns are readily recognized by one of ordinary skill in the art.

Any of the groups referred to herein may be optionally substituted with at least one, possibly two or more substituents as defined herein. That is, a substituted group has at least one, possibly two or more substitutable hydrogens replaced by a substituent or substituents as defined herein, unless the context indicates otherwise or a particular structural formula precludes substitution.

One of ordinary skill in the art will appreciate that the compounds can exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds and, as a consequence, may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures of the above. themselves, such as racemic mixtures. As another example, certain disclosed compounds can exist in various tautomeric forms, including the enol form, the keto form, and mixtures thereof. Since the various compound names, formulas, and compound drawings within the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, it will be understood that the disclosed compounds encompass any forms. tautomeric, conformational isomeric, optical isomeric, and / or geometric isomeric of the compounds described herein, as well as mixtures of these various different isomeric forms, unless the context indicates that a single such isomer is intended. In cases of limited rotation, for example around the amide bond or between two directly linked rings, such as the thiazole and pyridyl rings, atropisomers are also possible, and are also specifically included in the compounds of the invention.

II. Benzazole compounds and compositions thereof

A. Benzazole compounds

Described herein are benzazole compounds, methods of preparing the compounds, and methods of using the compounds. In one embodiment, the disclosed compounds are tyrosine kinase inhibitors. In a particular embodiment, the compounds are useful for blocking one or more cytokine signaling pathways, such as the IL-17 signaling pathway. For certain embodiments, benzazole compounds are useful for treating conditions in which inhibition of an interleukin-1 receptor associated kinase (IRAK) pathway is therapeutically useful. In some embodiments, the compounds directly inhibit an IRAK protein, such as IRAK1, IRAK2, IRAK3, or IRAK4.

Exemplary benzazole compounds within the scope of the present disclosure have a general formula I

<img file="ES2811136T3_D0015.tif" />

I or a pharmaceutically acceptable salt, solvent, hydrate, N-oxide, prodrug, or combination thereof. With respect to formula I, Het-1 is a heteroaryl; X is OS; Y is ON; and Z is S or CR9. R¹ and R² are independently H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl; heteroaliphatic; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl or araliphatic; or, together with the nitrogen to which they are attached, they form an optionally substituted heterocyclic ring. R³, R⁴, R⁶ and R9 are independently H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl; halogen; heteroaliphatic; -O-aliphatic, such as alkoxy;

ES 2 811 136 T3 heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl; araliphatic; -O-heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxylic ester; acyl; amide; Not me; sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl; R⁵ is amino, aryl, or heteroaryl; R7 is H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl; heteroaliphatic; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl or araliphatic; or two adjacent groups, such as R⁷and R⁶ and / or R⁶ and R⁹Together, independently, they can form an aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Each R⁸ independently it is aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl; halogen; heteroaliphatic; -O-aliphatic, such as alkoxy; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl; araliphatic; -O-heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxylic ester; acyl; amide; Not me; sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl; and m is 0 to 6, such as 0 to 1,2, 3, 4, 5, or at least 6. Het-1 can be unsubstituted (when m is 0) or substituted. If Het-1 is unsubstituted, one of ordinary skill in the art will appreciate that there are enough implicit hydrogens at all carbons and heteroatoms to satisfy the valence requirements. In particular embodiments of the benzazole compounds described, each R⁸independently selected from halo, C1-6 haloalkyl, such as -CF3, -CF2H and -CH2CF3, C1-6 alkyl, -O C1-6alkyl, amino, or -CH2OP (O) (OR²⁴) 2, in which each R²⁴ it is independently H, C1-6 alkyl or a counter ion which forms, for example, a pharmaceutically acceptable base addition salt with the phosphate moiety. In certain embodiments, at least one R⁸ is amino, such as -NH2; alkyl, such as C1-C6 alkyl, such as methyl; or haloalkyl, such as -CF3, -CF2H, or -CH2CF3. In particular embodiments, m is 1 and R⁸ is -NH2 or methyl.

For certain embodiments, Het-1 can be an optionally substituted 5- or 6-membered monocyclic heteroaryl or a fused heteroaryl comprising a 5 and / or 6-membered heteroaryl. In some examples, Het-1 is furan; thiophene; pyrazole; pyrrole; imidazole; oxazole; thiazole; isoxazole; isothiazole; triazole, such as 1,2,3-triazole, 1,2,4-triazole, or 1,3,4-triazole; oxadiazole, such as 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, or 1,2,5-oxadiazole; thiadiazole, such as 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, or 1,2,5-thiadiazole; tetrazole; pyrimidine; pyridine; triazine, such as 1,2,3-triazine, 1,2,4-triazine, or 1,3,5-triazine; pyrazine; pyridazine; quinoline; isoquinoline; indole; isoindole; benzofuran; benzothiophene; benzoimidazole; benzopyrazole; benzotriazole; or pyrrolopyridine, such as pyrrolo [2,3-b] pyridine, pyrrolo [3,2b] pyridine, pyrrolo [2,3-c] pyridine, pyrrolo [3,2-c] pyridine, pyrrolo [3,4-b ] pyridine or pyrrolo [3,4-c] pyridine. In particular examples, Het-1 is pyrazole, pyridine, or pyrrolo [2,3-b] pyridine, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol5-yl, pyridin-2- yl, pyridin-3-yl, pyridin-4-yl, pyrrolo [2,3-b] pyridin-5-yl, pyrrolo [2,3-b] pyridin-2-yl, pyrrolo [2,3-b] pyridin-3-yl, pyrrolo [2,3-b] pyridin-4-yl, or pyrrolo [2,3-b] pyridin-6-yl.

Examples of such Het-1 groups are represented by

<img file="ES2811136T3_D0016.tif" />

<img file="ES2811136T3_D0017.tif" />

in which R¹⁰ and R²³ are selected from H, aliphatic, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, -Oheterocyclyl, hydroxyl, cyano, carboxyl, carboxylic ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.

In particular embodiments,

<img file="ES2811136T3_D0018.tif" />

is selected from

<img file="ES2811136T3_D0019.tif" />

<img file="ES2811136T3_D0020.tif" />

In certain embodiments, R⁵ it is amino, aryl, or heterocyclyl. In some embodiments, R⁵ is amino having a formula -NRR in which each R is independently H or aliphatic, or both R groups, together with the nitrogen attached thereto, form a heterocyclic ring. In a certain embodiment, R⁵ is a cyclic amino selected from

ES 2 811 136 T3

<img file="ES2811136T3_D0021.tif" />

In other embodiments, R⁵ is selected from

<img file="ES2811136T3_D0022.tif" />

In some embodiments, R¹ and R², together with the nitrogen attached thereto, form a heterocyclic ring, typically a heteroaliphatic ring. In certain embodiments, the heteroaliphatic ring is morpholine, piperidine, or piperazine. In other embodiments, R¹ and R² they are independently H, aliphatic or heteroaliphatic. In certain examples, R¹ is H or alkyl, such as methyl, ethyl, propyl, or isopropyl. In other embodiments, R² it is aliphatic or heteroaliphatic. In certain embodiments, R² it is aliphatic substituted with a heterocycloaliphatic. In particular embodiments, the remainder -N (R¹) (R²) is selected from

<img file="ES2811136T3_D0023.tif" />

in which R^to it is aliphatic, haloalkyl, or acyl; n is 1 or 2; and p is 0, 1, or 2.

R^to can be alkyl, haloalkyl, or acyl, such as CH3, CF3, CF2H, or R^bCO)-. In some embodiments, R^b is aliphatic or haloalkyl, such as alkyl or haloalkyl, and in certain embodiments, Rb is CH3, CF3, or CF2H.

Also with respect to formula I, Het-1 can be: 1A) a 5-membered heteroaryl; 1B) a 6-membered heteroaryl; 1C) a fused heteroaryl; 1D) selected from pyridine, pyrazole or pyrrolopyridine; 1E) pyridine; 1F) pyrazole; 1G) pyrrolopyridine; 1H) pyridin-4-yl; 1I) pyridin-4-yl substituted at least in position 2; 1J) pyridin-4-yl substituted at least in position 2 with an alkyl moiety; 1K) 2-methylpyridin-4-yl; 1L) pyridin-3-yl; 1M) pyridin-3-yl substituted at least in position 6; 1N) pyridin-3-yl substituted at least in position 6 with an amino residue; 10) 6-aminopyridine-3-yl; 1P) pyrazol-4-yl; 1Q) pyrazol-3-yl; or 1R) pyrrolo [2,3-b] pyridin-5-yl.

With respect to Het-1 embodiments 1A to 1R, R⁵ may be, in combination with 1A to 1R: 2A) 5-membered heterocyclyl; 2B) 6-membered heterocyclyl; 2C) selected from piperidine, morpholine or pyrrolidine; 2D) piperidine; 2E) morpholine; 2F) pyrrolidine; 2G) piperidin-1-yl; 2H) 4-fluoropiperidin-1-yl; 21) 4,4-difluoropiperidin-1-yl; 2J) 3-fluoropiperidin-1-yl; 2K) 3,3-difluoropiperidin-1-yl; 2L) pyrrolidin-1-yl; or 2M) morpholino.

One of ordinary skill in the art will understand that any of 2A to 2M can be combined with any of 1A to 1R, to form any and all combinations of such substituents.

With respect to Het-1 embodiments 1A to 1R and R embodiments 2A to 2M⁵, the remainder -N (R¹) (R²) can be, in any combination with 1A to 1R and 2A to 2M: 3A) heterocyclyl; 3B) selected so that R¹ and R² they are independently H, aliphatic or heteroaliphatic; 3C) morpholine; 3D) piperidine; 3E) piperazine; 3F) 4-methyl-1piperazinyl; 3G) morpholino; 3H) piperidin-1 -yl; 31) selected in such a way that R¹ is alkyl and R² it is heteroaliphatic; 3J) selected in such a way that R¹ is H or alkyl and R² is alkyl substituted with a heterocycloaliphatic; 3K) N- (2-methoxyethyl) -N-methylamino; 3L) N-methyl-N- (2-morpholinoethyl) amino; or 3M) (2-morpholinoethyl) amino.

ES 2 811 136 T3

One of ordinary skill in the art will understand that any of 3A to 3M can be combined with any of 1A to 1R and 2A to 2M, to form any and all combinations of such substituents.

With respect to Het-1 embodiments 1A to 1R, R embodiments 2A to 2M⁵, and embodiments 3A to 3M of moiety -N (R¹) (R²), X can be, in any combination with 1A to 1R, 2A to 2M and 3A to 3M: 4A) oxygen; or 4B) sulfur.

One of ordinary skill in the art will understand that 4A or 4B can be combined with any of 1A to 1R, 2A to 2M, and 3A to 3M, to form any and all combinations of such substituents.

With respect to Het-1 embodiments 1A to 1R, R embodiments 2A to 2M⁵, embodiments 3A to 3M of moiety -N (R¹) (R²) and embodiments 4A to 4B of X, Y may be, in any combination with 1A to 1R, 2A to 2M, 3A to 3M and 4A to 4B: 5A) oxygen; or 5B) sulfur.

One skilled in the art will understand that any of 5A or 5B can be combined with any of 1A to 1R, 2A to

2M, 3A to 3M and 4A to 4B, to form any and all combinations of said substituents.

With respect to Het-1 embodiments 1A to 1R, R embodiments 2A to 2M⁵, embodiments 3A to 3M of moiety -N (R¹) (R²), Embodiments 4A to 4B of X, and Embodiments 5A to 5B of Y, Z can be, in any combination with 1A to 1R, 2A to 2M, 3A to 3M, 4A to 4B and 5A to 5B: 6A) Nitrogen ; or 6B) CH.

One skilled in the art will understand that any of 6A or 6B can be combined with any of 1A to 1R, 2A to 2M, 3A to 3M, 4A to 4B, and 5A to 5B to form any and all combinations of such substituents.

In some embodiments of formula I, Y is O, and Z is CR9, leading to compounds having a formula II

<img file="ES2811136T3_D0024.tif" />

II.

In other embodiments of formula I, Y is S, and Z is N, leading to compounds having a formula III

<img file="ES2811136T3_D0025.tif" />

III.

With respect to formulas II and III, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, Het-1 and X are as previously defined for formula I.

In some examples of Formula I, Het-1 is pyrazole, pyridine, or pyrrolopyridine, leading to compounds having a formula selected from

<img file="ES2811136T3_D0026.tif" />

ES 2 811 136 T3

<img file="ES2811136T3_D0027.tif" />

With respect to formulas IV, V and VI, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X, YZ are as previously defined for formula I, and R¹⁰ and R²³ they are selected from H, aliphatic, heteroaliphatic, -O-aliphatic, heterocyclyl, aryl, araliphatic, O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxylic ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl. Certain substituents, such as R⁸They are not shown directly attached to a ring atom in these formulas. This indicates that the substituents can be attached to any available position or combinations of positions on the ring. This is a particular consideration when the substituent is other than hydrogen.

In some embodiments of Formula IV, the compound has a formula selected from

R¹ R¹ / „ /

<img file="ES2811136T3_D0028.tif" />

VII VIII or

With respect to formulas VII and VIII, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, X, YZ are as previously defined for formula I. R¹⁰ is H, aliphatic, aryl, or heterocyclyl. R¹¹, R¹² and R¹³ are independently H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl; heteroaliphatic halogen; -O-aliphatic, such as alkoxy; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl; araliphatic; -O-heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxylic ester; acyl; amide; Not me; sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl. In some examples, R¹⁰, R¹¹, R¹² and R¹³ are all H.

In some embodiments of Formula V, the compound has a formula selected from

<img file="ES2811136T3_D0029.tif" />

With respect to formulas IX and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, X, YZ are as previously defined for formula I, and R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are independently H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl; halogen; heteroaliphatic; -O-aliphatic, such as alkoxy; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl; araliphatic; -O-heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxylic ester; acyl; amide; Not me; sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl.

In some embodiments of formula IX, R¹⁴ is alkyl, and can be lower alkyl, particularly C1-6 alkyl, such as methyl. In other embodiments of formula IX, R¹⁵, R¹⁶ and R¹⁷ are H.

In some embodiments of formula X, R¹⁴ it is amino, and it can be NH2. In other embodiments of formula X, R¹⁵ is alkyl, and can be C1-C6 alkyl such as methyl. In certain embodiments of formula X, R¹⁵, R¹⁶ and R¹⁸ are H.

In some embodiments of formula VI, the compound has a formula XI

ES 2 811 136 T3

<img file="ES2811136T3_D0030.tif" />

With respect to formula XI, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, X, YZ are as previously defined for formula I. R¹⁹, R²⁰, R²¹ and R²² are independently H; aliphatic, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl; halogen; heteroaliphatic; -O-aliphatic, such as alkoxy; heterocyclyl, including heteroaryl and heterocycloaliphatic; aryl; araliphatic; -O-heterocyclyl; hydroxyl; nitro; cyano; carboxyl; carboxylic ester; acyl; amide; Not me; sulfonyl; sulfonamide; sulfanyl; sulfinyl; or haloalkyl. R²³ is H, aliphatic, aryl, or heterocyclyl. In some embodiments of formula XI, R¹⁹, R²⁰, R²¹, R²² and R²³ are H.

In some embodiments of Formula II, the compound has a formula selected from

<img file="ES2811136T3_D0031.tif" />

ES 2 811 136 T3

<img file="ES2811136T3_D0032.tif" />

In some embodiments of Formula III, the compound has a formula selected from

<img file="ES2811136T3_D0033.tif" />

<img file="ES2811136T3_D0034.tif" />

<img file="ES2811136T3_D0035.tif" />

ES 2 811 136 T3

<img file="ES2811136T3_D0036.tif" />

With respect to formulas XII to XXXI, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²² and R²³ they are as described above for formulas I to XI. In some examples, R³, R⁴, R⁶, R⁷, R¹⁰, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²² and / or R²³ are H and / or R¹⁴ is H, alkyl, such as methyl, or amino, such as -NH2.

In some embodiments of formulas I-XXXI, R³, R⁴, R⁶ and / or R⁷ are H.

Exemplary compounds according to formula I include, without limitation, the compounds in the table below and / or their pharmaceutically acceptable salts:

<img file="ES2811136T3_D0037.tif" />

ES 2 811 136 T3

<td>ífA — Ah Ck A. / \। VN S ^ X ^ NH 3 ,ⁿA 1 J 1-7</td><td>í / A - / 'nh γ₀Α yes,ⁿA j jl Ύ Ν ^^, θ 1-8</td><td>ITVA ^ ° AoAⁿ/ - \ 3 ^ χζγχ^ΝΗYes,^N AJY^N^ O 1-9</td>

<td>pa / A ° Yc / w ° v,^NA jj '-¹ ΝΑΑιθ 1-10</td><td>/ r³z = m AnAA²o ^^ nh 9,^N~&lt;\ 1! .1 1-11</td><td>, ^ s 1 λ — Ynh A \ ^{1 υ}γΝ VN Ο ^ χχ ^ ΝΗ 9,ⁿAJ 1 '-¹ Ν ^ Χχχ ^_Ν^\] 1-12</td>

<td>// A__Z ^ 'NH ^ογ / \ Α o ^ / ^ nh ° k,^NA 1 1^N^ O 1-13</td><td>H^s / = / Y¿wy ^ O ^ X ^ NH ° x,ⁿAJ Λ Ν ^ Α_Νθ 1-14</td><td>ITV-A ^ ° Y ^ O^ZVY ~^NHtwo o ~ zv^NH—NN — 4 Jj 1 1-15</td>

<td>/ ΤΛν Anh ck Y '' \ ¹Ao \ = n o ^ / v ^ —NN — ζ Ί | 1 1-16</td><td>iW'NH AoA Ο ^ χχ ^ ΝΗ —NN — ζ J 1 1-17</td><td>° A_orA \ j Ο ^ χ ^ χΝΗ —NN — ζ 1 1 Yy _ΝΑ ^ Υ_Νθ 1-18</td>

<td>go \ / = n ^oryVYA^NH2O ^ A —NN — ζ J | T Ί-Άθ 1-19</td><td>rS 1 λ ~ χ7 NH O ~. &gt; ί. v \¹N \ = N Ο ^ χ ^ χΝΗ —NN — ζ 1 1 \ - / nAAjQ 1-20</td><td>ΐΑ-Α'ΝΠ γ_ΝΑ ^ y ^ Ο-γΧ- ^ ΑΗ —NN — ζ 1 1 \ - / ΝΑΑ, θ 1-21</td>

<td>TO^s / = / YnH / o ^^ nh —NN — 4 1 1 nYA_nQ 1-22</td><td>// A — Z ^ NH ΥΆ Vn O ^ zx-NH ° v,ⁿA 1 J VY Ν ^ χΑ&gt;_Νγ ΥχΎρ 1-23</td><td>Ο ^ ΥχΝΗ 9.,ⁿA \ 1 I ΥχχΎρ 1-24</td>

<td>1 λ- # nh Vn o ^^. nh o,^NA jj 1-25</td><td>YnYⁿΟ ^ χ ^ χΝΗ S, Ά jj 1-26</td><td>/ A — Ah Υ-Ά Vn Ο ^ χχ ^ χΝΗ ° x,ⁿAJ Λ '-¹ nAA_nAnd AA^FF 1-27</td>

ES 2 811 136 T3

<td>° k,^NY 1 A '-⁷XX ^FF 1-28</td><td>^ S 1 λ — χζ^ΝΗΎ ^ ν Yn o ^ x ^ nh ° v,^NA 1 A ^ a F 1-29</td><td>r ^^s /=/ ^ογΧ^ζ&gt;ν / O ^ x ^ NH or,^NX JE A - AA_toF 1-30</td>

<td>| X _ / 'NH ex JL / \। ^{u &lt;}Y ^ o Vn οχαθ 1-31</td><td>₀&lt;Y ^ V-XjNH οχαθ ° " 1-32</td><td>θγο ^ ογαθ 1-33</td>

<td>tr^S\ z = n CYYAjYn, οζαθ 1-34</td><td>Y . 1 z \ - # NH \ sN οταθ 1-35</td><td>/ ΤΑ — Υ '^νηοχαθ 1-36</td>

<td>γί / Ό / - \ ργγ^ΝΗ ' ΟΛΌ ζθ 1-37</td><td>ίΓΑ — z ^ nh Y ^ O \ ^ N ογγπ ° κ,^NX JE A Y F 1-38</td><td>ίΎ-Ζ ^ θγΥ ^ ΥΧ Ο ^ Χ ^ χΝΗ ° κ,^ΝΧ JE Α Υ F 1-39</td>

<td>s 1 λ — xYNH O. x &lt;r \ ¹VN o ^ x ^ nh Q? X JE A F 1-40</td><td>Y — AND OW^NH° k,^NX JE A Y F 1-41</td><td>ίΥ \ —Ζνη γ ^ ο Vn ο ^ χν^ΝΗ° κ,^ΝΧ JE Α Q FF 1-42</td>

<td>ΓΆ ./^ ° γ^Λ(/ 1Χ o ^^ nh ° v,^NX 1 A FF 1-43</td><td>fí zX Υ^ΝΗY ^ N Vn Ο-γΥ / ΝΗ ° κ,^NX JE JE FF 1-44</td><td>γ / = / ογ ^ Λχγ Ο ^ χ ^ χΝΗ ° κ,^ΝΥ JE Α FF 1-45</td>

ES 2 811 136 T3

<img file="ES2811136T3_D0038.tif" />

Exemplary compounds according to formula I include, without limitation, the compounds listed below and their pharmaceutically acceptable salts:

I-1: 5- (6-aminopyridin-3-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) furan-2-carboxamide;

I-2: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrrolo [2,3-b] pyridin-5-yl ) furan-2-carboxamide;

I-3: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide;

I-4: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-3-yl) furan-2-carboxamide;

I-5: 5- (6-aminopyridin-3-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) furan-2-carboxamide;

I-6: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) -5- (1 H-pyrrolo [2,3-b] pyridin-5-yl ) furan-2-carboxamide;

I-7: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide;

I-8: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) -5- (1 H-pyrazol-3-yl) furan-2-carboxamide;

I-9: 5- (2-methylpyridin-4-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) furan-2-carboxamide;

I-10: 5- (2-methylpyridin-4-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) furan-2-carboxamide;

I-11: 2- (6-aminopyridin-3-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide;

I-12: N- (2-morpholino-5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide;

I-13: N- (2-morpholino-5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-3-yl) thiazole-4-carboxamide;

I-14: 2- (2-methylpyridin-4-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide;

I-15: 5- (6-aminopyridin-3-yl) -N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) furan-2-carboxamide;

I-16: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl ) furan-2-carboxamide;

I-17: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-3-yl ) furan-2-carboxamide;

I-18: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide;

ES 2 811 136 T3

- 19: 2- (6-aminopyridin-3-yl) -N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole -4-carboxamide;

- 20: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide;

- 21: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-3-yl) thiazole-4-carboxamide;

- 22: N- (2- (4-methylpiperazin-1-yl) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole -4-carboxamide;

- 23: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide;

- 24: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide;

- 25: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide;

- 26: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide;

- 27: N- (5- (4,4-difluoropiperidin-1 -yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide ;

- 28: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide;

- 29: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide ;

- 30: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide;

- 31: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1H-pyrazol-4-yl) furan-2-carboxamide;

- 32: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1H-pyrazol-3-yl) furan-2-carboxamide;

- 33: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide;

- 34: 2- (6-aminopyridin-3-yl) -N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide;

- 35: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide;

- 36: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1H-pyrazol-3-yl) thiazole-4-carboxamide;

- 37: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide;

- 38: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1H-pyrazol-4-yl) furan-2-carboxamide;

- 39: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide;

- 40: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide;

- 41: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide;

- 42: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide ;

- 43: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide;

- 44: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide ;

- 45: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide;

- 46: N- (2-morpholino-5- (pyrrolidin-1-yl) benzo [d] oxazol-6-yl) -5- (1H-pyrazol-4-yl) furan-2-carboxamide;

- 47: N- (2-morpholino-5- (pyrrolidin-1-yl) benzo [d] oxazol-6-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide;

- 48: N- (2,5-dimorpholinobenzo [d] oxazol-6-yl) -5- (1H-pyrazol-4-yl) furan-2-carboxamide;

- 49: N- (2,5-dimorpholinobenzo [d] oxazol-6-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide;

- 50: N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4- yl) furan-2-carboxamide;

- 51: N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4- yl) thiazole-4-carboxamide;

- 52: N- (2 - ((2-morpholinoethyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole -4-carboxamide;

- 53: N- (2- (methyl (2-morpholinoethyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide;

- 54: N- (2- (methyl (2-morpholinoethyl) amino) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide; or

ES 2 811 136 T3

I-55: N- (2 - ((2-morpholinoethyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

B. Synthesis

The benzazole compounds described can be prepared as exemplified below, and as will be understood by one of ordinary skill in the art in organic synthesis. An exemplary synthesis may include the following first reaction step according to Scheme 1:

<img file="ES2811136T3_D0039.tif" />

Scheme 1

Aniline 2 is reacted with CS2 in the presence of a base to form benzazole 4. X is typically oxygen or sulfur, and LG¹ It is an outgoing group. Suitable leaving groups include, but are not limited to, fluoride, chloride, bromide, iodide, mesylate, or tosylate. The reaction is carried out in a suitable solvent, such as a polar solvent. Suitable solvents include, but are not limited to, alcohols, such as methanol, ethanol, propanol, isopropanol, or combinations thereof. The base can be any base that facilitates the reaction. Exemplary bases include, but are not limited to, hydroxides, particularly metal hydroxides, such as potassium hydroxide, sodium hydroxide, and lithium hydroxide. The reaction is carried out at a suitable temperature to facilitate the reaction. A suitable reaction is typically 50 ° C to 100 ° C.

A second reaction step in the exemplary synthesis according to Scheme 2 is provided below:

<img file="ES2811136T3_D0040.tif" />

Scheme 2

Benzazole 4 is reacted with amine 6 to form compound 8. The reaction is carried out in a suitable solvent to facilitate the reaction. Suitable solvents include aprotic solvents, such as dioxane. The reaction is typically heated to a suitable temperature to facilitate the reaction, such as 60 ° C to 100 ° C.

A third reaction step in the exemplary synthesis according to Scheme 3 is provided below:

<img file="ES2811136T3_D0041.tif" />

Scheme 3

Compound 8 is reacted with a nitrating agent and / or mixture to form compound 10. Suitable nitrating agents and / or mixtures include, but are not limited to, nitric acid such as fuming nitric acid, fuming nitric acid / sulfuric acid. , or nitric acid / acetic anhydride.

A fourth reaction step in the exemplary synthesis according to Scheme 4 is provided below:

<img file="ES2811136T3_D0042.tif" />

Scheme 4

Compound 10 is reacted with amine 12 to form compound 14. The reaction is carried out in a suitable solvent to facilitate the reaction. Suitable solvents include aprotic solvents, such as dioxane or acetonitrile. The reaction can be carried out in the presence of a base, such as potassium carbonate,

ES 2 811 136 T3 sodium carbonate, triethylamine or diisopropylethylamine (DIEA). Alternatively, excess amine can be used as a base, such as using two or more molar equivalents of amine 12 in the reaction. The reaction is typically heated to a suitable temperature to facilitate the reaction, such as 75 ° C to 120 ° C.

A fifth reaction step in the exemplary synthesis according to Scheme 5 is provided below:

<img file="ES2811136T3_D0043.tif" />

Scheme 5

The nitro functional group in compound 14 is reduced to form compound 16. Any suitable reducing agent can be used, such as H2 / palladium on carbon, H2 / platinum (IV) oxide, H2 / Raney nickel, Fe / HCl, Fe / acetic acid, zinc / acid, zinc / ammonium chloride, or tin chloride. The reaction is carried out in a suitable solvent, such as alcohol, including methanol, ethanol, propanol, or isopropanol; acetic acid; Water; or a combination thereof. One skilled in the art will appreciate that compound 16 can be formed as a free base or a salt, such as an HCl salt or an acetic acid salt, depending on the method used to reduce the nitro group.

A sixth reaction step in the exemplary synthesis according to Scheme 6 is provided below:

<img file="ES2811136T3_D0044.tif" />

Scheme 6

Compound 16 is reacted with carboxylic acid 18 to form compound 20. Y is oxygen or sulfur, and Z is nitrogen or CR, where R is typically H or aliphatic. Carboxylic acid 18 is activated by any suitable method, and then reacted with the amine in compound 16. Suitable activation methods include, but are not limited to: forming the acid chloride by treatment with thionyl chloride; by treatment with 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium hexafluorophosphate (HATU) and a base such as diisopropylethylamine (DIEA); by treatment with carbonyldiimidazole (CDI); or by treatment with a carbodiimide, such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). The reaction is carried out in a suitable solvent to facilitate the reaction. Suitable solvents include, but are not limited to, chloroform, dichloromethane, dioxane, toluene, acetonitrile, DMF, tetrahydrofuran, or a combination thereof.

A seventh reaction step in the exemplary synthesis according to Scheme 7 is provided below:

<img file="ES2811136T3_D0045.tif" />

Scheme 7

Compound 20 is coupled with compound 22 to form compound 24 using any suitable coupling reaction to form a bond between two rings. In the example above, a boronic acid coupling is shown, in which the leaving group LG² in compound 20 it is halo, such as bromine or iodine. Other suitable coupling functional groups include trialkyl tin or boronic esters, such as a pinacol ester of boronic acid. The coupling reaction typically proceeds in the presence of a suitable catalyst. For a boronic acid coupling, the catalyst is typically a palladium catalyst, such as PdCl2 (dppf) 2, palladium acetate and triphenylphosphine, or tetrakis (triphenylphosphine) palladium (0). The reaction is carried out in the presence of a base, such as metal carbonates, including sodium, potassium, or cesium carbonate, and is carried out in a suitable solvent or a mixture of solvents, such as dioxane / water or DME / ethanol / water. The reaction can be heated to

ES 2 811 136 T3 a suitable temperature, such as 50 ° C to 140 ° C, typically around 120 ° C, and / or stirred for a suitable period of time, such as 1 hour to 3 days, 6 hours to 24 hours, or from 12 hours to 18 hours, to facilitate the reaction to completion. The reaction can be carried out in a microwave, which typically reduces the reaction time. Compound 24 is then isolated from the reaction mixture and purified by a suitable technique.

C. Additional therapeutic agents for the combination

The compounds of the present invention can be used alone, in combination with each other, or as an adjunct to, or in combination with, other established therapies. In another aspect, the compounds of the present invention can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These compounds can be administered simultaneously or sequentially in any order. The compounds can be administered within such a period of time that a subject experiences an overlapping beneficial effect of both the benzazole compound and the additional therapeutic agent (s). The benzazole compound and the additional therapeutic agent (s) may be administered by the same route of administration, or by a different route. The present compounds are specifically intended to be administered in combination with one or more additional therapeutic agents, including in combination with one or more agents described in this section.

In some embodiments, the second therapeutic agent is an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral, an anticancer, an antifungal, or a combination. thereof. The anti-inflammatory agent can be a steroidal or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, nenoxyamic acid, naxamine, meloprofen , salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, anti-lymphocyte globulin, anti-thymocyte globulin, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds can be used with other anticancer or cytotoxic agents. Various classes of anticancer and antineoplastic compounds for use with currently described inhibitors include, but are not limited to, alkylating agents, antimetabolites, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, substituted ureas, inhibitors of kinases, hormones and hormonal antagonists, and hypomethylating agents, for example DNMT inhibitors, such as azacitidine and decitabine. Exemplary alkylating agents include, without limitation, mechlorotamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkylsulfonates (eg, busulfan), and carmustine. Examples of antimetabolites include, by way of example and without limitation, methotrexate folic acid analog; pyrimidine fluorouracil analog, cytosine arbinoside; mercaptopurine, thioguanine, and azathioprine purine analogs. Examples of vinca alkaloids include, by way of example and without limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and without limitation, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as an antineoplastic agent includes L-asparaginase. Exemplary coordination compounds include, by way of example and without limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and without limitation, adrenocorticosteroids prednisone and dexamethasone; amino glutethimide, formestane, and anastrozole aromatase inhibitors; progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

Other chemotherapeutic agents for combination include immuno-oncological agents, such as anti-PD-1 and / or anti-PD-L1 antibodies, such as nivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224 or MEDI4736; anti-CTLA-4 antibodies, such as ipilimumab or tremelimumab; anti-KIR antibodies, such as lirilumab; anti-LAG3 antibodies, such as BMS-986016; anti-CD137 antibodies, such as urelumab; anti-SLAM antibodies, such as anti-SLAMF7, for example elotuzumab; PI3K inhibitors, such as idelalisib, AZD8186, INCB40093, and INCB50465; and indole dioxygenase (IDO) and / or tryptophan dioxygenase (TDO) inhibitors, such as 1-methyltryptophan, indoximod, NSC 36398 (dihydroquercetin, taxifolin), NLG919, INCB024360 (epacodostat), and F001287. In particular embodiments, two or more immuno-oncological agents are combined with a described benzazole compound. Typically, the immuno-oncological agents in such combinations act on different targets. For example, the combination of an anti-PD-1 agent, such as nivolumab, with an anti-CTLA4 agent, such as ipilimumab, is particularly useful in combination with a benzazole compound.

In some embodiments, the benzazole compound can be used in combination with an immuno-oncological agent and / or with other anticancer or cytotoxic agents. In particular embodiments, the present compounds are combined with an immuno-oncological agent and are further combined with one or more current standard of care agents for a given malignancy. The table below lists exemplary cancers treatable in combination therapies comprising the currently described benzazole compounds and lists treatments

Additional ES 2 811 136 T3 for use in combination with the benzazole compounds and the immuno-oncological agent described here:

<td>Cancer</td><td>Drug or treatment</td>

<td>Glioma</td><td>lomustine, temozolid and / or radiation</td>

<td>hepatocellular carcinoma</td><td>sorafenib, regorafenib</td>

<td>myelodysplastic syndromes</td><td>decitabine or azacitidine</td>

<td>pancreatic cancer</td><td>Gemcitabine</td>

<td>ovarian cancer, such as epithelial ovarian carcinoma</td><td>carboplatin, cisplatin, doxorubicin, gemcitabine, paclitaxel</td>

<td>breast cancer</td><td>Trastuzumab</td>

<td>basal and squamous cell carcinomas of the skin</td><td>5-fluorouracil, imiquimod, photodynamic therapy (for example, with 5-aminolevulinic acid),</td>

<td>head and neck carcinoma</td><td>bleomycin, cisplatin, cetuximab, docetaxel, fluorouracil, methotrexate</td>

<td>triple negative breast cancer</td><td>Paclitaxel</td>

<td>Prostate</td><td>abiraterone, enzalutamide</td>

These and other useful anticancer compounds are described in the Merck Index, 13^to Ed. (O'Neil MJ et al., Ed) Merck Publishing Group (2001), and Goodman and Gilmans The Pharmacological Basis of Therapeutics, 10th Edition, Hardman, JG and Limbird, LE eds., P. 1381-1287, McGraw Hill, (1996), which are incorporated herein by reference.

Among the CTLA 4 antibodies that can be used in combination with the currently described inhibitors is ipilimumab, marketed as YERVOY® by Bristol-Myers Squibb.

Additional antiproliferative compounds useful in combination with the compounds of the present invention include, by way of example and without limitation, antibodies directed against growth factor receptors (eg, anti-Her2); and cytokines such as interferon-a and interferon-y, interleukin-2, and GM-CSF.

In particular embodiments, including the treatment of leukemias, including CLL, mantle cell lymphoma, and ALL, the currently described compounds are used in combination with a B-cell lymphoma 2 (BCL2) inhibitor, such as ABT-199 or ABT737.

Examples of kinase inhibitors that are useful in combination with the compounds described herein, particularly in the treatment of neoplasms, include: Btk inhibitors, such as ibrutinib; CDK inhibitors, such as palbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib, lapatinib, and vandetinib; Mek inhibitors, such as trametinib; Raf inhibitors, such as dabrafenib, sorafenib, and vemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib, and pazopanib; BCR-Abl inhibitors, such as bosutinib, dasatinib, imatinib, and nilotinib; PI3-kinase inhibitors, such as idelalisib; Syk inhibitors, such as fostamatinib; and JAK inhibitors, such as baricitinib, ruxolitinib, and tofacitinib. In other embodiments, the second additional therapeutic agent (s) for combination with the inhibitors described herein may be selected from any of the following:

pain relievers - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics - aminoglycosides (eg, amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (eg, ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (eg, cephalosporin, cefadrozil, cefadroin, cefadroin cefaclor, cefamandol, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (for example, teicoplanin, vancomycin, and telavancin), lincosamides (for example, clindamycin and incomysin), lipopeptides (for example, daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, and spectromycin) , monobactams (eg aztreonam), nitrofurans (eg furazolidone and nitrofurantoin), penicillins (eg amoxicillin, ampicillin, azlocillin, carbenicillin,

ES 2 811 136 T3 cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), combinations of penicillin (for example, amoxicillin / clavulanate, ampicillin / sulfate, ampicillin / clavulanate, ampicillin / sulfate tazobactam, and ticarcillin / clavulanate), polypeptides (for example, bacitracin, colistin, and polymyxin B), quinolones (for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (for example, maphenide, sulfonamidocrisoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfazimidazole-sulfametozole, sulfamethizole-sulfametozole, sulfamethoxametozole, sulfametoxin, sulfamethizole, sulfamethoxazole, ), tetracyclines (for example, demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (for example, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusupidic acid, metronidazole, linezolidin, linezolid , quinuprisine / dalfopristin, rifaximin, thiamphenicol, tigecycline, and thymidazole;

antibodies - anti-TNF-a antibodies, for example infliximab (Remicade ™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, eg, rituximab; anti-IL-6 antibodies, eg, tocilizumab; anti-IL-1 antibodies, eg anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, for example nivolumab, pembrolizumab, pidilizumab, BmS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

blood thinners - warfarin (Coumadin ™), acenocoumarol, phenprocoumon, atromenthin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, baxthroimelagatin;

anti-inflammatory agents - steroids, eg budesonide, non-steroidal anti-inflammatory agents, eg aminosalicylates (eg, sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib) , diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inhibitors of inosine deshydrolene monophosphate (IMP inhibitors such as inosine dehydrogen monophosphate) , and agents designed to suppress cellular immunity while leaving the recipient's humoral immune response intact, including various antibodies (eg, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), anti-T-cell monoclonal antibodies (OKT3)), and irradiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc., under the brand name Azasan; Mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the brand name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc .; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the brand name Rapamune; tacrolimus is currently available from Fujisawa under the brand name Prograf; cyclosporine is currently available from Novartis under the brand name Sandimmune, and from Abbott under the brand name Gengraf; IMPDH inhibitors, such as mycophenolate mofetil and mycophenolic acid, are currently available from Roche under the brand name Cellcept, and from Novartis under the brand name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the brand name Imuran; and the antibodies are currently available from Ortho Biotech under the brand name Orthoclone, from Novartis under the brand name Simulect (basiliximab), and from Roche under the brand name Zenapax (daclizumab); and guanylate cyclase-C receptor agonists or intestinal secretagogues, for example linaclotide, sold under the name Linzess.

These various agents can be used according to their standard or usual dosages, as specified in the prescribing information accompanying the forms of the commercially available drugs (see also, the prescribing information in the 2006 edition of The Physician's Desk Reference), the descriptions of which are incorporated herein by reference.

D. Compositions comprising benzazole compounds

The benzazole compounds described can be used alone, in any combination, and in combination with, or as a complement to, at least one second therapeutic agent, and further the benzazole compounds, and the at least one second therapeutic agent, can be used in combination. with any suitable additive useful to form compositions for administration to a subject. Additives can be included in pharmaceutical compositions for a variety of purposes, such as diluting a composition for administration to a subject, facilitating processing of the formulation, providing advantageous material properties to the formulation, facilitating dispersion from a delivery device, to stabilize the formulation (e.g. antioxidants or buffers), to

ES 2 811 136 T3 to provide a pleasant or palatable taste or consistency to the formulation, or the like. Typical additives include, by way of example and without limitation: pharmaceutically acceptable excipients; pharmaceutically acceptable carriers; and / or adjuvants, such as mono-, di-, and polysaccharides, sugar alcohols, and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; freight forwarders; buffers, such as phosphate and citrate buffers; release agents, such as magnesium stearate; binders, such as saccharides (including disaccharides, such as sucrose and lactose), polysaccharides (such as starches, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropylcellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropylmethylcellulose, shellac, corn protein, zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavors and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry and vanilla; lubricants (such as minerals, exemplified by talc or silica, fats, exemplified by vegetable stearin, magnesium stearate or stearic acid); preservatives (such as antioxidants, exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids, exemplified by cysteine ​​and methionine, citric acid and sodium citrate, parabens, exemplified by methyl paraben and propyl paraben); colorants; compression aids; emulsifying agents; encapsulating agents; rubbers; granulating agents; and combinations thereof.

III. Methods of use

A. Diseases / disorders

The described benzazole compounds, as well as combinations and / or compositions thereof, can be used to ameliorate, treat, or prevent a variety of diseases and / or disorders. In particular embodiments, the benzazole compound, combinations of benzazole compounds, or compositions thereof, can be used to treat or prevent autoimmune diseases, inflammatory disorders, cardiovascular diseases, nervous disorders, neurodegenerative disorders, allergic disorders, asthma, pancreatitis, insufficiency. multiorgan, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases, ischemic conditions, bacterial infections and / or viral infections.

In some embodiments, the benzazole compound, combinations of benzazole compounds, or compositions thereof, can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, disease inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

The benzazole compound, combinations of benzazole compounds, or compositions thereof, may also be useful in ameliorating, treating, or preventing immune regulatory disorders related to organ or bone marrow transplant rejection or graft versus host disease. . Examples of inflammatory and immune regulatory disorders that can be treated with the present compounds include, but are not limited to, organ or tissue transplantation, graft-versus-host diseases caused by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigoid, angiodemolysis, amphollosis, ampollosis, ampollosis, ampollosis, ampollosis, ampollosis , vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, Seasonal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, corneal cornea, corneal epithelial dystrophy, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanacoidosis-Harada syndrome, sarcoma , pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma, and hyperresponsiveness of the airways, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic intestinal diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, disease of Crohn's, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic hemolytic purpura, idiopathic hemolytic purpura autoimmune, agranulocytosis, pernicious anemia, megaloblastic anemia, anerithroplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, Idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, panarteritis nodosa, myocarditis, scleroderma, Wegeren's granuloma, Sjog's syndrome, 27

ES 2 811 136 T3 Eosinophilic fasciitis, gingival lesions, periodontia, alveolar bone, dental bone substance, glomerulonephritis, male pattern alopecia or senile alopecia by preventing depilation or providing hair germination and / or promoting the generation and growth of the hair, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs that occurs after preservation, transplantation or ischemic disease, endotoxic shock, pseudomembranous colitis, colitis caused by drugs or radiation, acute ischemic kidney failure, chronic kidney failure, toxinosis caused by pulmonary oxygen or drugs, lung cancer, pulmonary emphysema, cataracts, siderosis, retinitis pigmentosa, senile macular degeneration, vitreous scarring , corneal alkaline burn, multiform erythematous dermatitis, bullous dermatitis due to linear IgA deposits and cementum dermatitis, gingivitis, periodontitis, septicemia, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by the release of histamine or leukotrienes-C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, liver resection partial, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, hepatitis B virus, non-A / non-B hepatitis, cirrhosis, Alcoholic liver disease, including alcoholic cirrhosis, nonalcoholic steatohepatitis (NASH), liver failure, fulminant liver failure, late-onset liver failure, 'acute on chronic' liver failure, increased chemotherapy effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

In certain embodiments, the present compounds are useful for treating nervous disorders. For example, the present compounds can be used to treat nerve pain, including neuropathic pain and inflammation-induced pain.

In certain embodiments, the benzazole compound, combinations of benzazole compounds, or their compositions are useful for treating and / or preventing alcoholic liver disease (steatohepatitis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis. , ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, in particular pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, sapho syndrome , Castleman's disease, septicemia, cerebrovascular accident, atherosclerosis, celiac disease, DIRA (II-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease.

Proliferative diseases that can be treated with the benzazole compound, combinations of benzazole compounds, or compositions thereof, include benign or malignant tumors, solid tumors, and liquid tumors, including carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, head and neck, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testicles, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, an epithelial neoplasia, adenoma , adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas, Hodgkins and non-Hodgkin's disease, a breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, a MyD88 driven disorder such as diffuse ABC large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), pleural effusion lymphoma, latent or indolent multiple myeloma, or hematologic malignancies (including leukemia, DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome, myelofibrosis, polycythemia vera, sarcoma Kaposi, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds described herein are useful in the treatment of drug resistant neoplasms, such as those resistant to JAK inhibitors, those resistant to IRAK inhibitors, ibrutinib resistant neoplasms, including ibrutinib resistant hematological neoplasms, such as Ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

Examples of allergic disorders that can be treated using the benzazole compound, the benzazole compound combinations, or their compositions include, but are not limited to, asthma (eg, atopic asthma, allergic asthma, bronchial IgE-mediated atopic asthma , non-atopic asthma), bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or no apparent cause, emphysematous asthma, Exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infection, incipient asthma, wheezing infant syndrome, bronchioneumonia , asthma with variable cough or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

ES 2 811 136 T3

As another example, rheumatoid arthritis (RA) generally causes swelling, pain, loss of movement, and tenderness of target joints throughout the body. RA is characterized by a chronically inflamed synovium that is densely packed with lymphocytes. The synovium, which is generally one cell layer thick, becomes intensely cellular and assumes a shape similar to lymphoid tissue, including dendritic cells, T, B, and NK cells, macrophages, and clumps of plasma cells. This process, as well as a host of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, eventually result in the destruction of joint integrity, resulting in deformity, permanent loss of function, and / or bone erosion in or near the joint. The benzazole compound, combinations of benzazole compounds, or compositions thereof, can be used to treat, ameliorate, or prevent any one, several, or all of these RA symptoms. Thus, in the context of RA, the compounds are considered to provide a therapeutic benefit when a reduction or amelioration of any of the symptoms commonly associated with RA is achieved, regardless of whether the treatment results in concomitant treatment of the underlying AR and / or a reduction in the amount of circulating rheumatoid factor ("RF").

The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. One such parameter, ACR20 (ACR criteria for clinical improvement 20%), requires a 20% improvement in the count of tender and inflamed joints, as well as a 20% improvement in 3 of the following 5 parameters: assessment patient global assessment, physician global assessment, patient assessment of pain, degree of disability, and acute phase reagent level. These criteria have been expanded for a 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include the Paulu criteria and radiographic progression (eg, Sharp score).

In some embodiments, the therapeutic benefit in patients suffering from RA is achieved when the patient exhibits an ACR20. In specific embodiments, ACR improvements of ACRC50 or even ACR70 can be achieved.

B. Formulations and administration

Pharmaceutical compositions comprising the disclosed compounds (or prodrugs thereof) can be manufactured by conventional methods of mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing. The compositions can be formulated in a conventional manner using one or more physiologically acceptable excipients, diluents, carriers, adjuvants, or auxiliaries to provide pharmaceutically usable preparations.

The active compound or prodrug can be formulated in the pharmaceutical compositions per se, or in the form of a pharmaceutically acceptable hydrate, solvate, N-oxide or salt. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having a lower solubility than the corresponding free acids and bases can also be formed.

The pharmaceutical compositions of the invention can take a form suitable for practically any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, such as iv or ip, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound (s), hydrate, solvate, N-oxide or pharmaceutically acceptable salt or prodrug (s) can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. .

Systemic formulations include those designed for administration by injection, eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, oral, transmucosal, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions, or emulsions of the active compound (s) in aqueous or oily vehicles. The compositions may also contain formulatory agents, such as suspending, stabilizing, and / or dispersing agents. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multidose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder form for constitution with a suitable vehicle, including, but not limited to, sterile, pyrogen-free water, buffer, dextrose solution, etc., prior to use. To this end, the active compound (s) can be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

For transmucosal administration, penetrants appropriate to the barrier to be traversed are used in the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, pills, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as: binding agents (for example, pregelatinized cornstarch, polyvinylpyrrolidone or

ES 2 811 136 T3 hydroxypropylmethylcellulose); fillers (eg, lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (eg, magnesium stearate, talc, or silica); disintegrants (eg potato starch or sodium starch glycolate); and / or wetting agents (eg, sodium lauryl sulfate). Tablets can be coated by methods well known in the art with, for example, sugars, films, or enteric coatings.

Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as: suspending agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, ethyl alcohol, cremophore ™, or fractionated vegetable oils); and preservatives (eg, methyl or propyl p-hydroxybenzoates, or sorbic acid). The preparations may also contain buffer salts, preservatives, flavorings, colorants and sweeteners, as appropriate.

Preparations for oral administration can be suitably formulated to provide controlled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.

For rectal and vaginal routes of administration, the active compound (s) may be formulated as solutions (for retention enemas), suppositories or ointments containing conventional suppository bases, such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound (s), hydrate, solvate, N-oxide, pharmaceutically acceptable salt or prodrug (s) may be conveniently administered in the form of a pressurized pack aerosol or a nebulizer with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (eg, capsules and cartridges composed of gelatin) can be formulated with a powder mixture of the compound and a suitable powder base such as lactose or starch.

A specific example of an aqueous suspension formulation suitable for nasal administration using commercially available nasal spray devices includes the following ingredients: active compound or prodrug (0.5 mg / ml); benzalkonium chloride (0.1-0.2 mg / ml); polysorbate 80 (TWEEN® 80; 0.5 mg / ml); sodium carboxymethyl cellulose or microcrystalline cellulose (1 15 mg / ml); phenylethanol (14 mg / ml); and dextrose (50 mg / ml). The pH of the final suspension can be adjusted to range from about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable for the administration of the compounds by inhalation contains 20 mg / ml of compound or prodrug, 1% (v / v) of Polysorbate 80 (TWEEN® 80), 50 mM citrate and / or chloride of 0.9% sodium.

For ocular administration, the active compound (s) or prodrugs may be formulated as a solution, emulsion, suspension, etc., suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in US Pat.^you 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference.

For prolonged delivery, the active compound (s) or prodrugs may be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disk or patch that slowly releases the active compound (s) for percutaneous absorption can be used. For this purpose, permeation enhancers can be used to facilitate transdermal penetration of the active compound (s). Suitable transdermal patches are described, for example, in US Pat.^you 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well known examples of delivery vehicles that can be used to deliver the active compound (s) or prodrugs. Certain organic solvents, such as dimethylsulfoxide (DMSO), can also be used, although generally at the cost of greater toxicity.

ES 2 811 136 T3

The pharmaceutical compositions may be presented, if desired, in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound (s). The pack may comprise, for example, a metal or plastic foil, such as a blister pack. The package or dispensing device may be accompanied by instructions for administration.

C. Dose

The benzazole compound or combinations of benzazole compounds will generally be used in an amount effective to achieve the desired result, for example, in an amount effective to treat or prevent a particular condition. The benzazole compound (s), or their compositions, can be administered therapeutically to achieve a therapeutic benefit, or prophylactically to achieve a prophylactic benefit. Therapeutic benefit means the eradication or amelioration of the underlying disorder being treated and / or the eradication or amelioration of one or more of the symptoms associated with the underlying disorder, such that the patient reports an improvement in the sensation or condition, even though the patient may still be afflicted with the underlying disorder. For example, administering a compound to a patient suffering from an allergy provides a therapeutic benefit not only when the underlying allergic response is eradicated or improved, but also when the patient reports a decrease in the severity or duration of symptoms associated with allergy after exposure to allergen. As another example, the therapeutic benefit in the setting of asthma includes an improvement in breathing after the onset of an asthmatic attack, or a reduction in the frequency or severity of asthma episodes. The therapeutic benefit also includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

As those skilled in the art know, the preferred dosage of benzazole compounds will also depend on various factors, including the age, weight, general health, and severity of the condition of the patient or subject to be treated. The dose may also need to be tailored to the sex of the individual and / or the lung capacity of the individual, when administered by inhalation. The dosage can also be tailored for people with more than one condition, or for those who have additional conditions that affect lung capacity and the ability to breathe normally, for example emphysema, bronchitis, pneumonia, and respiratory infections. The dosage and frequency of administration of the benzazole compound (s) or their compositions will also depend on whether the benzazole compound (s) are formulated for the treatment of acute episodes of a condition or for the prophylactic treatment of a disorder. One of ordinary skill in the art will be able to determine the optimal dosage for a particular individual.

For prophylactic administration, the benzazole compound, combinations of benzazole compounds, or compositions thereof, can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the benzazole compound, combinations of benzazole compounds, or their compositions can be administered prior to drug administration to prevent or enhance a response. allergic to the drug. Alternatively, prophylactic administration can be used to prevent or ameliorate the onset of symptoms in a patient diagnosed with the underlying disorder. For example, a benzazole compound (s), or a composition thereof, can be administered to an allergic person prior to expected exposure to the allergen. A benzazole compound, combinations of benzazole compounds, or compositions thereof, can also be administered prophylactically to healthy individuals who are repeatedly exposed to agents known for one of the diseases described above, to prevent the onset of the disorder. For example, a benzazole compound, combinations of benzazole compounds, or compositions thereof, can be administered to a healthy individual who is repeatedly exposed to an allergen known to induce allergies, such as latex, in an effort to avoid that the individual develops an allergy. Alternatively, a benzazole compound, combinations of benzazole compounds, or compositions thereof, may be administered to a patient suffering from asthma prior to participating in activities that trigger asthma attacks, to lessen the severity of an asthmatic episode or prevent it by full.

Effective doses can be estimated initially from in vitro tests. For example, an initial dose for use in subjects can be formulated to achieve a circulating blood or serum concentration of the active compound that is at or above an IC50 or EC50 for the particular compound, as measured in an in vitro assay. Doses can be calculated to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound. Fingl &amp; Woodbury, "General Principles," in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and the references cited there, provide additional guidance on effective dosages.

In some embodiments, the disclosed compounds have an EC50 of greater than 0 to 20 µM, such as greater than 0 to 10 µM, greater than 0 to 5 µM, greater than 0 to 1 µM, greater than 0 to 0. , 5 µM, or greater than 0 to 0.1 µM.

Starting doses can also be estimated from in vivo data, such as animal models. Animal models useful for evaluating the efficacy of compounds to treat or prevent the various diseases described above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21Suppl): 6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy

ES 2 811 136 T3

Clin. Immunol. 107 (6): 1025-1033. Suitable animal models of allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50 (11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24 (3): 238-244 and Sugimoto et al., (2000), Immunopharmacology 48 (1): 1-7. Those of ordinary skill in the art can adapt such information to determine appropriate doses for human administration.

Dosage amounts of the disclosed benzazole compounds will typically be in the range of greater than 0 mg / kg / day, such as 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day. day, up to at least 100 mg / kg / day. More typically, the dose (or effective amount) can range from 0.0025 mg / kg to about 1 mg / kg, administered at least once a day, such as 0.01 mg / kg to 0.5 mg / kg, or 0.05 mg / kg to 0.15 mg / kg. The total daily dose generally ranges from 0.1 mg / kg to 5 mg / kg, or 20 mg / kg per day, such as 0.5 mg / kg to 10 mg / kg per day, or 0.7 mg / kg per day to 2.5 mg / kg / day. Dosage amounts may be higher or lower depending, among other factors, on the activity of the benzazole compound, its bioavailability, the mode of administration, and various factors discussed above.

The dosage amount and dosage range can be adjusted so that individuals provide plasma levels of the benzazole compound that are sufficient to maintain the therapeutic or prophylactic effect. For example, the compounds can be administered once a day, several times a day, once a week, several times a week (for example, every other day), once a month, several times a month, or once a month. once a year, depending on, among others, the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Those of ordinary skill in the art will be able to optimize effective local doses without undue experimentation.

Compositions comprising one or more of the described benzazole compounds typically comprise more than 0 to 99% of the benzazole compound (s) and / or other therapeutic agent in percent by total weight. More typically, compositions comprising one or more of the described benzazole compounds comprise 1 to 20 percent by total weight of the benzazole compound and another therapeutic agent, and 80 to 99 percent by weight of a pharmaceutically acceptable additive.

Preferably, the benzazole compound, combinations of benzazole compounds, or their compositions will provide a therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of the benzazole compound can be determined using standard pharmaceutical procedures. The dose relationship between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Benzazole compounds that exhibit high therapeutic indices are preferred.

IV. Examples

Example 1

Preparation of 5-fluorobenzo [d] oxazol-2-thiol

<img file="ES2811136T3_D0046.tif" />

A solution of 2-amino-4-fluorophenol (10 g, 78.8 mmol), carbon disulfide (35 ml) and potassium hydroxide (5.3 g, 94.6 mmol) in ethanol (200 ml) was heated refluxing overnight. The reaction mixture was concentrated to dryness, and then diluted with water. This solution was neutralized with 1M HCl, and then washed with ethyl acetate several times. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 9.3 g (70% yield) of the desired 5-fluorobenzo [d] oxazole-2-thiol. ¹H NMR (300 MHz, DMSO-d6) δ 7.51 (ddd, J = 8.8, 4.2, 0.6 Hz, 1H), 7.150-7.04 (m, 2H), 3.31 (brs, 1H). LC-MS (m / z): 170.2.

Example 2

Preparation of 5-fluoro-N- (2-methoxyethyl) -N-methylbenzo [d] oxazol-2-amine

<img file="ES2811136T3_D0047.tif" />

A solution of 5-fluorobenzo [d] oxazol-2-thiol (1.17 g, 6.92 mmol) and (2-methoxyethyl) methylamine (3.7 ml, 34.1 mmol) in dioxane (6 ml) was heated to 85 ° C overnight. The reaction was concentrated to dryness, and the resulting product, 5-fluoro-N- (2-methoxyethyl) -N-methylbenzo [d] oxazol-2-amine, was used crude.

ES 2 811 136 T3

Example 3

Preparation of 5-fluoro-N- (2-methoxyethyl) -N-methyl-6-nitrobenzo [d] oxazol-2-amine

<img file="ES2811136T3_D0048.tif" />

A solution of 5-fluoro-N- (2-methoxyethyl) -N-methyl-6-nitrobenzo [d] oxazol-2-amine (6.92 mmol) in H2SO4 (9 ml) cooled in an ice bath was Fuming HNO3 (600 µl) was added dropwise. The reaction was allowed to warm to room temperature and then gently warmed to 35 ° C overnight. The reaction was complete when monitored by LC-mS, and allowed to cool to room temperature. The reaction mixture was then poured onto ice and basified by addition of 4M NaOH to pH 9. The solid formed was filtered and dried to give the desired product N- (2-methoxyethyl) -N-methyl-6-nitro -5- (piperidin-1-yl) benzo [d] oxazol-2-amine (1.25 g, 4.62 mmol) in 67% yield.

Example 4

Preparation of N- (2-methoxyethyl) -N-methyl-6-nitro-5- (piperidin-1-yl) benzo [d] oxazol-2-amine

<img file="ES2811136T3_D0049.tif" />

A solution of 5-fluoro-N- (2-methoxyethyl) -N-methyl-6-nitrobenzo [d] oxazol-2-amine (1.24 g, 4.63 mmol), piperidine (915 μL, 9.26 mmol) in dioxane (40 ml) was heated at 95 ° C for 5 hours. On cooling to room temperature, the reaction was concentrated in vacuo and purified by Si gel chromatography eluting with 0-90% ethyl acetate in hexanes. The desired product of N- (2-methoxyethyl) -N-methyl-6-nitro-5- (piperidin-1-yl) benzo [d] oxazol-2-amine eluted at 35% EtOAc / Hex giving 1.22 g (79% yield). LC-MS (m / z): 335.3.

Example 5

Preparation of N2- (2-methoxyethyl) -N2-methyl-5- (piperidin-1-yl) benzo [d] oxazol-2,6-diamine hydrochloride

<img file="ES2811136T3_D0050.tif" />

To a solution of N- (2-methoxyethyl) -N-methyl-6-nitro-5- (piperidin-1-yl) benzo [d] oxazol-2-amine (1.22 g, 3.65 mmol) and Concentrated hydrochloric acid (600 µl) in water (1 ml) and ethanol (20 ml) was added iron powder (2 g, 36.5 mmol). The mixture was refluxed for about 1 hour, when the reaction was complete by LC-MS monitoring. The mixture was filtered through celite, concentrated in vacuo, and used as a crude. LC-MS (m / z): 305.7.

Example 6

Preparation of 2-bromo-N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide

<img file="ES2811136T3_D0051.tif" />

A solution of N2- (2-methoxyethyl) -N2-methyl-5- (piperidin-1-yl) benzo [d] oxazole-2,6-diamine hydrochloride (170 mg, 0.5 mmol), 2- Bromothiazole-4-carboxylic acid (125 mg, 0.6 mmol) and N, N-diisopropylethylamine (435 µl, 2.5 mmol) in CH2Cl2 (5 ml) were stirred at room temperature overnight. The solution was concentrated in vacuo, then diluted with ethyl acetate, washed with water, saturated NaHCO3 solution, and brine. After drying over Na2SO4, the solution was concentrated in vacuo and purified by Si gel chromatography eluting with 0-100% of

ES 2 811 136 T3 ethyl acetate in hexanes. The product eluted at 80-100% EtOAc / Hex to give 2-bromo-N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl ) thiazole-4-carboxamide (204 mg, 0.413 mmol, 83% yield) as a pale khaki solid.¹H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 7.21 (s, 1H), 3, 65 (t, J = 5.4 Hz, 2H), 3.56 (t, J = 5.4 Hz, 2H), 3.25 (s, 3H), 3.12 (s, 3H), 2, 82-2.75 (m, 4H), 1.77 (p, J = 6.0Hz, 4H), 1.63-1.52 (m, 2H). LC-MS (m / z): 494.8.

Example 7

Preparation of N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide (1-51)

2M Na₂CO₃(aq), Pd (PPh₃)₄dioxane

In a microwave vial a mixture of 2-bromo-N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazol- 4-carboxamide (75 mg, 0.15 mmol), pyrazole-4-boronic acid pinacholine ester (87 mg, 0.45 mmol), and 2M aqueous Na2CO3 solution (225 μL, 0.45 mmol) in dioxane ( 3.5 ml). After purging the vessel with nitrogen gas, tetrakis (triphenylphosphine) palladium (17 mg, 0.015 mmol), and the reaction was heated in a microwave at 120 ° C for 1 hour, monitoring by LC-MS. The mixture was filtered through celite, and the solvent was concentrated. The crude reaction mixture was purified by Si gel chromatography eluting with 0-12% 2M NH3 / MeOH in CH2Cl2. This solid was further triturated with EtOAc to yield N- (2 - ((2-methoxyethyl) (methyl) amino) 5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1H- pyrazol-4-yl) thiazole-4-carboxamide (38 mg, 0.079 mmol, 53% yield).

¹H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8 , 29 (s, 1H), 8.02 (s, 1H), 7.22 (s, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.25 (s, 3H), 3.13 (s, 3H), 2.85-2.77 (m, 4H), 1.87-1.76 (m, 4H ), 1.66-1.55 (m, 2H). LC-MS (m / z): 482.6

Example 8

Compounds I-1 to I-55 were prepared in a similar manner to Examples 1-7 above. Characterization data for compounds I-1 to I-54 are provided below.

I-1: 5- (6-aminopyridin-3-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) furan-2-carboxamide.

¹H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.38 (s, 1H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H) , 7.30 (s, 1H), 7.28 (d, J = 3.6Hz, 1H), 6.91 (d, J = 3.6Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 6.44 (s, 2H), 3.70 (t, J = 4.9 Hz, 4H), 2.80 (t, J = 4.9 Hz, 4H ), 1.76 (p, J = 5.7 Hz, 4H), 1.58 (brs, 2H).

LCMS (m / z): 489.7 (MH⁺).

I-2: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrrolo [2,3-b] pyridin-5-yl ) furan-2-carboxamide.

ES 2 811 136 T3 ¹H NMR (300 MHz, DMSO-d₅) δ 11.94 (s, 1H), 10.03 (s, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.41 (s, 1H), 7.57 (d, J = 3.5Hz, 1H), 7.35 (d, J = 3.6Hz, 1H), 7 , 32 (s, 1H), 7.19 (d, J = 3.6Hz, 1H), 6.47 (d, J = 3.4Hz, 1H), 3.75-3.66 (m, 4H), 3.59-3.52 (m, 4H), 2.83 (t, J = 5.2 Hz, 4H), 1.83 (p, J = 5.8 Hz, 4H) , 1.61 (brs, 2H).

LCMS (m / z): 513.8 (MH +).

I-3: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0052.tif" />

¹H NMR (300 MHz, DMSO-d₃) δ 13.26 (s, 1H), 9.79 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7 , 28 (s, 1H), 7.27 (d, J = 3.6Hz, 1H), 6.77 (d, J = 3.6Hz, 1H), 3.73-3.67 (m, 4H), 3.58-3.51 (m, 4H), 2.84-2.77 (m, 4H), 1.77 (p, J = 5.8 Hz, 4H), 1, 59 (brs, 2H).

LCMS (m / z): 463.7 (MH⁺).

I-4: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1H-pyrazol-3-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0053.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.92 (s, 1H), 8.38 (s, 1H), 7.89 (dd, J = 2 , 4, 1.4 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.29 (s, 1H), 6.91 (d, J = 3.6 Hz , 1H), 6.66 (t, J = 2.1Hz, 1H), 3.72-3.68 (m, 4H), 3.57-3.53 (m, 4H), 2, 80 (t, J = 5.2Hz, 4H), 1.80 (p, 5.8Hz, 4H), 1.59 (brs, 2H).

LCMS (m / z): 463.7 (MH⁺).

I-5: 5- (6-aminopyridin-3-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0054.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.64 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 7, 83 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.91 (d , J = 3.6 Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 6.44 (s, 2H), 3.72 (t, J = 4.8 Hz , 4H), 3.50 (t, J = 4.8 Hz, 4H), 2.83 (t, J = 5.1 Hz, 4H), 1.77 (bs, 4H), 1.58 (bs , 2H).

LCMS (m / z): 505.7 (MH⁺).

I-6: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) -5- (1 H-pyrrolo [2,3-b] pyridin-5-yl ) furan-2-carboxamide.

<img file="ES2811136T3_D0055.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 11.94 (s, 1H), 9.90 (s, 1H), 8.82 (d, J = 1.9 Hz, 1H), 8.67 (s, 1H), 8.46 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 3.5 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 3, 6Hz, 1H), 7.20 (d, J = 3.7Hz, 1H), 6.48 (d, J = 3.4Hz, 1H), 3.76-3.69 (m , 4H), 3.51 (t, J = 4.8Hz, 4H), 2.86 (t, J = 5.0Hz, 4H), 1.83 (bs, 4H), 1.61 (bs , 2H).

ES 2 811 136 T3

LCMS (m / z): 529.9 (MH⁺).

I-7: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0056.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.64 (s, 1H), 8.62 (s, 1H), 8.18 (s, 1H), 7 , 91 (s, 1H), 7.39 (s, 1H), 7.28 (d, J = 3.6Hz, 1H), 6.77 (d, J = 3.6Hz, 1H ), 3.72 (t, J = 4.8 Hz, 4H), 3.50 (t, J = 4.8 Hz, 4H), 2.83 (t, J = 5.2 Hz, 4H), 1.77 (brs, 4H), 1.59 (brs, 2H).

LCMS (m / z): 479.7 (MH⁺).

I-8: N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) -5- (1 H-pyrazol-3-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0057.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.76 (s, 1H), 8.64 (s, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 7.31 (d, J = 3.6Hz, 1H), 6.91 (d, J = 3.6Hz, 1H), 6.66 (s, 1 H), 3.72 (t, J = 4.8 Hz, 4H), 3.50 (t, J = 4.8 Hz, 4H), 2.83 (t, J = 5.1 Hz, 4H) , 1.80 (brs, 4H), 1.59 (brs, 2H).

LCMS (m / z): 479.7 (MH⁺).

I-9: 5- (2-methylpyridin-4-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] thiazol-6-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0058.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.63 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7, 70 (s, 1H), 7.64 (d, J = 5.2Hz, 1H), 7.47 (d, J = 3.7Hz, 1H), 7.43 (s, 1H ), 7.40 (d, J = 3.7 Hz, 1H), 3.75-3.69 (m, 4H), 3.54-3.48 (m, 4H), 2.85 (t , J = 5.1 Hz, 4H), 2.53 (s, 3H), 1.79 (brs, 4H), 1.61 (brs, 2H).

LCMS (m / z): 504.7 (MH⁺).

I-10: 5- (2-methylpyridin-4-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0059.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 7, 69 (s, 1H), 7.63 (d, J = 5.2Hz, 1H), 7.47 (d, J = 3.7Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 7.32 (s, 1H), 3.72-3.68 (m, 4H), 3.57-3.53 (m, 4H), 2.83 (t , J = 5.2 Hz, 4H), 2.53 (s, 3H), 1.80 (brs, 4H), 1.61 (brs, 2H).

LCMS (m / z): 488.7 (MH⁺).

ES 2 811 136 T3

I-11: 2- (6-aminopyridin-3-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0060.tif" />

¹H NMR (300 MHz, DMSO-ds) δ 10.76 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.49 (s, 1H), 8.29 (s , 1H), 7.96 (dd, J = 8.7, 2.5 Hz, 1H), 7.28 (s, 1H), 6.69 (s, 2H), 6.54 (d, J = 8.8 Hz, 1H), 3.73-3.68 (m, 4H), 3.58-3.53 (m, 4H), 2.80 (t, J = 5.1 Hz, 4H), 1.80 (brs, 4H), 1.59 (brs, 2H).

LCMS (m / z): 506.6 (MH⁺).

I-12: N- (2-morpholino-5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0061.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 13.42 (s, 1H), 10.68 (s, 1H), 8.48 (s, 1H), 8.41 (d, J = 1.3 Hz, 1H), 8.30 (s, 1H), 8.01 (d, J = 1.8Hz, 1H), 7.27 (s, 1H), 3.74-3.67 (m, 4H), 3.59-3 , 53 (m, 4H), 2.81 (t, J = 5.3Hz, 4H), 1.81 (bs, 4H), 1.61 (bs, 2H).

LCMS (m / z): 480.7 (MH⁺).

I-13: N- (2-morpholino-5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-3-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0062.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 13.40 (s, 1H), 10.72 (s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 7.99 (dd, J = 2, 4, 1.4 Hz, 1H), 7.27 (s, 1H), 6.76 (t, J = 2.1 Hz, 1H), 3.73-3.68 (m, 4H) , 3.58-3.53 (m, 4H), 2.81 (t, J = 5.2Hz, 4H), 1.83 (s, 4H), 1.61 (s, 2H).

LCMS (m / z): 480.7 (MH⁺).

I-14: 2- (2-methylpyridin-4-yl) -N- (2-morpholino-5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0063.tif" />

¹H NMR (300 MHz, DMSO-d5) δ 10.79 (s, 1H), 8.64 (d, J = 5.0 Hz, 1H), 8.62 (s, 1H), 8.49 (s , 1H), 7.91 (s, 1H), 7.77 (dd, J = 5.2, 1.6 Hz, 1H), 7.31 (s, 1H), 3.74-3, 67 (m, 4H), 3.58-3.53 (m, 4H), 2.82 (t, J = 5.1 Hz, 4H), 2.57 (s, 3H), 1.83 (s , 4H), 1.63 (s, 2H).

LCMS (m / z): 505.7 (MH⁺).

I -15: 5- (6-aminopyridin-3-yl) -N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) furan-2-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0064.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.37 (s, 1H), 7, 83 (dd, J = 8.7, 2.4 Hz, 1H), 7.30 - 7.25 (m, 2H), 6.91 (d, J = 3.6 Hz, 1H), 6 , 52 (d, J = 8.7 Hz, 1H), 6.44 (s, 2H), 3.60-3.54 (m, 4H), 2.80 (t, J = 5.1 Hz , 4H), 2.40 (t, J = 5.1 Hz, 4H), 2.21 (s, 3H), 1.76 (s, 4H), 1.58 (s, 2H).

LCMS (m / z): 502.8 (MH +).

I-16: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl ) furan-2-carboxamide.

<img file="ES2811136T3_D0065.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.79 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7 , 90 (s, 1H), 7.29-7.25 (m, 2H), 6.77 (d, J = 3.6Hz, 1H), 3.57 (t, J = 4.9Hz , 4H), 2.80 (t, J = 5.1 Hz, 4H), 2.41 (s, 4H), 2.21 (s, 3H), 1.77 (bs, 4H), 1.59 (sa, 2H).

LCMS (m / z): 476.8 (MH⁺).

I-17: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-3-yl ) furan-2-carboxamide.

<img file="ES2811136T3_D0066.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.92 (s, 1H), 8.36 (s, 1H), 7.89 (s, 1H), 7.30 (d, J = 3.4 Hz, 1H), 7.26 (s, 1H), 6.91 (d, J = 3.6 Hz, 1H), 6.66 (s, 1H), 3.57 (t, J = 4.9 Hz, 4H), 2.80 (t, J = 5.1 Hz, 4H), 2.40 (t, J = 5.0 Hz, 4H), 2, 21 (s, 3H), 1.80 (brs, 4H), 1.60 (brs, 2H).

LCMS (m / z): 476.8 (MH⁺).

I-18: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0067.tif" />

¹H NMR (300 MHz, DMSO-d5) δ 9.98 (s, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.36 (s, 1H), 7, 69 (s, 1H), 7.63 (d, J = 5.5Hz, 1H), 7.48 (d, J = 3.7Hz, 1H), 7.40 (d, J = 3.7 Hz, 1H), 7.30 (s, 1H), 3.57 (t, J = 5.0 Hz, 4H), 2.82 (t, J = 5.0 Hz, 4H) , 2.53 (s, 3H), 2.40 (t, J = 5.1Hz, 4H), 2.21 (s, 3H), 1.80 (s, 4H), 1.61 (s, 2H).

LCMS (m / z): 501.7 (MH +).

I-19: 2- (6-aminopyridin-3-yl) -N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0068.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 10.76 (s, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.96 (dd , J = 8.7, 2.5 Hz, 1H), 7.26 (s, 1H), 6.69 (s, 2H), 6.54 (d, J = 8.7 Hz, 1H) , 3.57 (t, J = 5.0 Hz, 4H), 2.80 (t, J = 5.1 Hz, 4H), 2.40 (t, J = 5.0 Hz, 6H), 2 , 21 (s, 3H), 1.80 (brs, 4H), 1.59 (brs, 2H).

LCMS (m / z): 519.7 (MH +).

I-20: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl ) thiazole-4-carboxamide.

<img file="ES2811136T3_D0069.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 10.68 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8 , 30 (s, 1H), 8.02 (s, 1H), 7.25 (s, 1H), 3.57 (t, J = 5.0 Hz, 4H), 2.81 (t, J = 4.9 Hz, 4H), 2.41 (t, J = 5.0 Hz, 4H), 2.21 (s, 3H), 1.82 (p, J = 5.7 Hz, 5H), 1.60 (brs, 2H).

LCMS (m / z): 493.7 (MH⁺).

I-21: N- (2- (4-methylpiperazin-1 -yl) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-3-yl ) thiazole-4-carboxamide.

<img file="ES2811136T3_D0070.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.71 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 7 , 99 (s, 1H), 7.25 (s, 1H), 6.76 (s, 1H), 3.62-3.52 (am, 4H), 2.86-2.77 (am, 4H), 2.45-2.38 (am, 4H), 2.21 (s, 3H), 1.83 (s, 4H), 1.62 (br, 2H).

LCMS (m / z): 493.8 (MH⁺).

I-22: N- (2- (4-methylpiperazin-1-yl) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0071.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 10.80 (s, 1H), 8.68-8.61 (m, 2H), 8.49 (s, 1H), 7.93 (s, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.29 (s, 1H), 3.61-3.55 (am, 4H), 2.86-2.80 (am, 4H), 2.58 (s, 3H), 2.41 (brs, 4H), 2.21 (s, 3H), 1.83 (brs, 4H), 1.65 (brs, 2H).

LCMS (m / z): 518.7 (MH +).

I-23: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0072.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 13.25 (s, 1H), 9.65 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.29 (d, J = 3.7 Hz, 2H), 6.77 (d, J = 3.7 Hz, 1H), 4.86 (ad, J = 48.3 Hz, 1H), 3.73-3 , 67 (am, 4H), 3.58-3.52 (am, 4H), 3.04-2.93 (am, 2H), 2.88-2.75 (am, 1H), 2.21 - 1.90 (am, 1H).

LCMS (m / z): 481.8 (MH⁺).

I-24: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0073.tif" />

¹H NMR (300 MHz, DMSO-d_s) δ 9.86 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.35 (s, 1H), 7.68 (s, 1H), 7.62 (d , J = 5.4 Hz, 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H), 7.33 (s, 1H ), 4.88 (ad, J = 48.0 Hz, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.56 (t, J = 4.8 Hz, 4H), 3.05-2.96 (am, 2H), 2.88-2.80 (am, 2H), 2.52 (s, 3H), 2.21-1.95 (am, 4H).

LCMS (m / z): 506.7 (MH⁺).

I-25: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0074.tif" />

¹H NMR (300 MHz, DMSO-d_s) δ 13.43 (s, 1H), 10.56 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.29 (s, 1H), 4.88 (ad, J = 48.7 Hz, 1H), 3.70 (t, J = 4.8 Hz, 4H), 3.56 (t, J = 4.8 Hz, 4H), 3.04-2.93 (am, 2H), 2.90-2.78 (am, 2H), 2.24-2.00 (am, 4H ).

LCMS (m / z): 498.7 (MH⁺).

I-26: N- (5- (4-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0075.tif" />

¹H NMR (300 MHz, DMSO-d_s) δ 10.65 (s, 1H), 8.63 (s, 1H), 8.61 (d, J = 5.8 Hz, 1H), 8.49 (s, 1H), 7.85 (s , 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.32 (s, 1H), 4.88 (ad, J = 48.4 Hz, 1H), 3.71 (t , J = 4.8 Hz, 4H), 3.56 (t, J = 4.8 Hz, 4H), 3.07 2.94 (am, 2H), 2.90-2.79 (am, 2H ), 2.56 (s, 3H), 2.25-1.98 (am, 4H).

LCMS (m / z): 523.8 (MH⁺).

I-27: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2- carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0076.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 13.27 (s, 1H), 9.59 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.34 (s, 1H), 7.30 (d, J = 3.6Hz, 1H), 6.77 (d, J = 3.6Hz, 1H), 3.70 (t, J = 4.8 Hz, 4H), 3.55 (t, J = 4.8 Hz, 4H), 2.98 (t, J = 5.5 Hz, 4H), 2.31-2 , 14 (am, 4H).

LCMS (m / z): 499.7 (MH⁺).

I-28: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide .

<img file="ES2811136T3_D0077.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 9.80 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 7.69 (s , 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 3.7 Hz, 1H), 7.42 (d, J = 3.7 Hz, 1H ), 7.37 (s, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.56 (t, J = 4.8 Hz, 4H), 2.99 (t, J = 5.5 Hz, 4H), 2.51 (s, 3H), 2.30-2.16 (am, 4H).

LCMS (m / z): 524.8 (MH⁺).

I-29: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazol-4- carboxamide.

<img file="ES2811136T3_D0078.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.50 (s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.35 (s, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.56 (t, J = 4, 8Hz, 4H), 2.99 (t, J = 5.6Hz, 4H), 2.36-2.21 (am, 4H).

LCMS (m / z): 516.6 (MH⁺).

I-30: N- (5- (4,4-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide .

<img file="ES2811136T3_D0079.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.65 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.49 (s , 1H), 7.83 (s, 1H), 7.74 (d, J = 5.7 Hz, 1H), 7.39 (s, 1H), 3.71 (t, J = 4.8 Hz , 4H), 3.57 (t, J = 4.8 Hz, 4H), 3.01 (t, J = 5.6 Hz, 4H), 2.56 (s, 3H), 2.34-2 , 20 (am, 4H).

LCMS (m / z): 541.9 (MH⁺).

I-31: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0080.tif" />

¹H NMR (300 MHz, DMSO-d5) δ 13.26 (s, 1H), 9.78 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H) , 7.90 (s, 1H), 7.33-7.17 (m, 2H), 6.77 (d, J = 3.7Hz, 1H), 3.56 (brs, 4H), 2.80 (t, J = 5.1Hz, 4H), 1.77 (brs, 4H), 1.60 (brs, 8H).

LCMS (m / z): 461.7 (MH⁺).

I-32: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-3-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0081.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 13.21 (s, 1H), 9.91 (s, 1H), 8.35 (s, 1H), 7.90 (s, 1H), 7.29 (d, J = 3.7 Hz , 1H), 7.24 (s, 1H), 6.91 (d, J = 3.7Hz, 1H), 6.66 (s, 1H), 3.56 (brs, 4H), 2.80 (brs, 4H), 1.80 (brs, 4H), 1.59 (brs, 8H).

LCMS (m / z): 461.7 (MH⁺).

I-33: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0082.tif" />

¹H NMR (300 MHz, DMSO-ds) δ 9.97 (s, 1H), 8.55 (d, J = 5.0 Hz, 1H), 8.35 (s, 1H), 7, 69 (s, 1H), 7.63 (d, J = 5.0Hz, 1H), 7.47 (dd, J = 3.6, 1.3Hz, 1H), 7.39 ( dd, J = 3.6, 1.3 Hz, 1H), 7.28 (d, J = 1.3 Hz, 1H), 3.58-3.52 (m, 4H), 2.84 2.80 (m, 4H), 2.53 (s, 3H), 1.84-1.78 (m, 4H), 1.63-1.54 (m, 8H).

LCMS (m / z): 486.8 (MH⁺).

I-34: 2- (6-aminopyridin-3-yl) -N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0083.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 10.75 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.29 (s , 1H), 7.96 (dd, J = 8.7, 2.4 Hz, 1H), 7.24 (s, 1H), 6.69 (s, 2H), 6.54 (d, J = 9.3 Hz, 1H), 3.57-3.53 (m, 4H), 2.84-2.76 (m, 4H), 1.84-1.75 (m, 4H), 1 , 65-1.52 (m, 8H).

LCMS (m / z): 504.3 (MH⁺).

I-35: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0084.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8 , 29 (s, 1H), 8.02 (s, 1H), 7.22 (s, 1H), 3.60-3.52 (m, 4H), 2.84-2.77 (m, 4H), 1.86-1.75 (m, 4H), 1.60 (brs, 8H).

LCMS (m / z): 478.7 (MH +).

I-36: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-3-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0085.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 13.40 (s, 1H), 10.71 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7 , 23 (s, 1H), 6.76 (s, 1H), 3.60-3.52 (m, 4H), 2.85-2.77 (m, 4H), 1.86-1, 79 (m, 4H), 1.60 (brs, 8H).

LCMS (m / z): 478.7 (MH⁺).

I-37: N- (2,5-di (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0086.tif" />

¹H NMR (300 MHz, DMSO-d5) δ 10.78 (s, 1H), 8.68 - 8.59 (m, 2H), 8.46 (s, 1H), 7.92 (s, 1H ), 7.78 (d, J = 6.6 Hz, 1H), 7.26 (s, 1H), 3.59-3.52 (m, 4H), 2.89-2.74 ( m, 4H), 1.83 (q, J = 6.8, 5.6 Hz, 4H), 1.60 (brs, 8H).

LCMS (m / z): 503.7 (MH⁺).

I-38: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0087.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 13.22 (s, 1H), 9.77 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.34 (s, 1H), 7.26 (d, J = 3.6Hz, 1H), 6.76 (d, J = 3.6Hz, 1 H), 4.96 (d, J = 47.0 Hz, 1H), 3.74-3.68 (m, 4H), 3.57-3.53 (m, 4H), 3.13 3 .02 (m, 2H), 2.86-2.79 (m, 2H), 2.09-1.65 (m, 4H).

LCMS (m / z): 481.7 (MH +).

I-39: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0088.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 9.94 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 7.74 (s, 1H), 7 , 66 (d, J = 5.2Hz, 1H), 7.46 (d, J = 3.7Hz, 1H), 7.40-7.36 (m, 2H), 4.97 ( d, J = 47.4 Hz, 1H), 3.74-3.68 (m, 4H), 3.59-3.53 (m, 4H), 3.14-3.02 (m, 2H) , 2.89-2.82 (m, 2H), 2.52 (s, 3H), 2.13-1.69 (m, 4H).

LCMS (m / z): 506.9 (MH +).

I-40: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (lH-pyrazol-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0089.tif" />

¹H NMR (300 MHz, DMSO-d5) δ 13.39 (s, 1H), 10.60 (s, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8 , 29 (s, 1H), 8.08 (s, 1H), 7.32 (s, 1H), 4.97 (d, J = 47.2 Hz, 1H), 3.75-3, 67 (m, 4H), 3.60-3.53 (m, 4H), 3.21 (dd, J = 25.5, 11.5 Hz, 1H), 3.09-2.98 (am , 1H), 2.84-2.67 (am, 2H), 2.11 (br, 1H), 2.01-1.81 (m, 2H), 1.71 (br, 1H) .

LCMS (m / z): 498.7 (MH⁺).

I-41: N- (5- (3-fluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0090.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 10.69 (s, 1H), 8.62 (m, J = 5.8 Hz, 2H), 8.53 (s, 1H), 7.97 ( s, 1H), 7.81 (d, J = 5.8Hz, 1H), 7.36 (s, 1H), 4.99 (d, J = 50.0Hz, 1H), 3.75-3.67 (m, 4H), 3.61-3.53 (m, 4H), 3.28-3.13 (am, 1H), 3.12-2.99 (am, 1H), 2.86-269 (am, 2H), 2.57 (s, 3H), 2.12 (br, 1H), 2.02-1.79 (am, 2H), 1, 72 (brs, 1H).

LCMS (m / z): 523.9 (MH⁺).

I-42: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2- carboxamide.

<img file="ES2811136T3_D0091.tif" />

¹H NMR (300 MHz, DMSO-ds) δ 13.23 (s, 1H), 9.63 (s, 1H), 8.44 (s, 1H), 8.15 (s, 1H), 7 , 93 (s, 1H), 7.40 (s, 1H), 7.26 (d, J = 3.6Hz, 1H), 6.77 (d, J = 3.6Hz, 1H) , 3.73-3.68 (m, 4H), 3.59-3.52 (m, 4H), 3.20 (at, J = 11.3 Hz, 2H), 2.89 2.82 ( am, 2H), 2.16-2.04 (am, 2H), 1.95-1.87 (am, 2H).

ES 2 811 136 T3

LCMS (m / z): 499.7 (MH⁺).

I-43: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -5- (2-methylpyridin-4-yl) furan-2-carboxamide .

¹H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.44 (s, 1H), 7, 68 (s, 1H), 7.63 (d, J = 5.1Hz, 1H), 7.47 (d, J = 3.7Hz, 1H), 7.43 (s, 1H ), 7.39 (d, J = 3.7 Hz, 1H), 3.75-3.68 (m, 4H), 3.61-3.54 (m, 4H), 3.25-3 , 15 (m, 2H), 2.92-2.86 (am, 2H), 2.53 (s, 3H), 2.20-2.03 (am, 2H), 2.01-1.88 (m, 2H).

LCMS (m / z): 524.8 (MH⁺).

I-44: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazol-4- carboxamide.

A — C ^NH

N ¹H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 10.53 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8 , 29 (s, 1H), 8.06 (s, 1H), 7.38 (s, 1H), 3.74-3.67 (m, 4H), 3.60-3.54 (m, 4H), 3.25 (ad, J = 12.0Hz, 2H), 2.78 (brs, 2H), 2.16-1.90 (am, 4H).

LCMS (m / z): 516.6 (MH⁺).

I-45: N- (5- (3,3-difluoropiperidin-1-yl) -2-morpholinobenzo [d] oxazol-6-yl) -2- (2-methylpyridin-4-yl) thiazole-4-carboxamide .

¹H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.67-8.58 (m, 2H), 8.55 (s, 1H), 7.93 (s, 1H ), 7.79 (d, J = 6.4 Hz, 1H), 7.42 (s, 1H), 3.74-3.67 (m, 4H), 3.59-3.54 ( m, 4H), 3.26 (d, J = 11.1 Hz, 2H), 2.81 (s, 0H), 2.58 (s, 3H), 2.23-2.00 (m, 0H ), 1.95 (s, 2H).

LCMS (m / z): 541.7 (MH⁺).

I-46: N- (2-morpholino-5- (pyrrolidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

¹H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.63 (s, 1H), 8.19 (s, 1H), 7.95-7.85 (m , 2H), 7.26 (d, J = 3.5 Hz, 1H), 7.13 (s, 1H), 6.72 (d, J = 3.5 Hz, 1H), 3, 74-3.66 (m, 4H), 3.60-3.52 (m, 4H), 3.10-3.05 (am, 4H), 1.95-1.88 (am, 4H).

ES 2 811 136 T3

LCMS (m / z): 449.7 (MH⁺).

I-47: N- (2-morpholino-5- (pyrrolidin-1-yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0092.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.40 (s, 1H), 8.40 (s, 2H), 8.29 (s, 1H), 7, 98 (s, 1H), 7.29 (s, 1H), 3.74-3.67 (m, 4H), 3.60-3.52 (m, 4H), 3.06-2.99 ( am, 4H), 2.00-1.96 (am, 4H).

LCMS (m / z): 466.6 (MH⁺).

I-48: N- (2,5-dimorpholinobenzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl) furan-2-carboxamide.

<img file="ES2811136T3_D0093.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 9.75 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.36 (s, 1H), 7.29 (d, J = 3.6Hz, 1H), 6.77 (d, J = 3.6Hz, 1 H), 3.87-3.79 (m, 4H), 3.74-3.67 (m, 4H), 3.59-3.53 (m, 4H), 2.90-2.82 ( m, 4H).

LCMS (m / z): 465.7 (MH⁺).

I-49: N- (2,5-dimorpholinobenzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0094.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.45 (s, 1H), 10.64 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8 , 31 (s, 1H), 8.06 (s, 1H), 7.35 (s, 1H), 3.91-3.85 (m, 4H), 3.74-3.67 (m, 4H), 3.60-3.52 (m, 4H), 2.90-2.83 (m, 4H).

LCMS (m / z): 482.7 (MH⁺).

I-50: N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4 -il) furan-2-carboxamide.

<img file="ES2811136T3_D0095.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.78 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.27 (d, J = 3.6Hz, 1H), 7.23 (s, 1H), 6.77 (d, J = 3.6Hz, 1 H), 3.65 (t, J = 5.2 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.25 (s, 3H), 3.13 (s, 3H), 2.84-2.76 (m, 4H), 1.82-1.73 (am, 4H), 1.65-1.54 (am, 2H).

LCMS (m / z): 465.7 (MH⁺).

I-51: N- (2 - ((2-methoxyethyl) (methyl) amino) -5- (piperidin-1 -yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4 -yl) thiazole-4-carboxamide.

ES 2 811 136 T3

<img file="ES2811136T3_D0096.tif" />

¹H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8 , 29 (s, 1H), 8.02 (s, 1H), 7.22 (s, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.25 (s, 3H), 3.13 (s, 3H), 2.85-2.77 (m, 4H), 1.87-1.76 (m, 4H), 1.66-1.55 (m, 2H).

LCMS (m / z): 482.6 (MH +).

I-52: N- (2 - ((2-morpholinoethyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl) thiazole-4-carboxamide.

<img file="ES2811136T3_D0097.tif" />

¹H NMR (300 MHz, DMSO-d₅) δ 13.42 (s, 1H), 10.67 (s, 1H), 8.40 (s, 2H), 8.27 (s, 1H), 8.01 (s, 1H), 7.79 (t, J = 5.8 Hz, 1H), 7.20 (s, 1H), 3.58-3.51 (m, 4H), 3.39 (c, J = 6.4 Hz, 2H), 2.84-2.77 (m, 4H), 2.53-2.49 (m, 2H), 2.44-2.37 (m, 4H), 1.86-1.76 ( m, 4H), 1.65-1.55 (m, 2H).

LCMS (m / z): 523.7 (MH⁺).

I-53: N- (2- (methyl (2-morpholinoethyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -5- (1 H-pyrazol-4-yl ) furan-2-carboxamide.

<img file="ES2811136T3_D0098.tif" />

¹H NMR (300 MHz, DMSO-d5) δ 13.26 (s, 1H), 9.78 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.26 (d, J = 3.6Hz, 1H), 7.23 (s, 1H), 6.77 (d, J = 3.6Hz, 1H), 3.59 (t, J = 6.4 Hz, 2H), 3.53-3.45 (m, 4H), 3.12 (s, 3H), 2.84-2.76 ( m, 4H), 2.54 (t, J = 6.4 Hz, 2H), 2.45-2.38 (m, 4H), 1.82-1.71 (m, 4H), 1.63 - 1.54 (m, 2H).

LCMS (m / z): 520.7 (MH⁺).

I-54: N- (2- (methyl (2-morpholinoethyl) amino) -5- (piperidin-1-yl) benzo [d] oxazol-6-yl) -2- (1 H-pyrazol-4-yl ) thiazole-4-carboxamide.

<img file="ES2811136T3_D0099.tif" />

¹H NMR (300 MHz, DMSO-d3) δ 13.42 (s, 1H), 10.66 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H) , 8.28 (s, 1H), 8.01 (s, 1H), 7.21 (s, 1H), 3.59 (t, J = 6.4 Hz, 2H), 3.54 - 3.45 (m, 4H), 3.12 (s, 3H), 2.85-2.76 (m, 4H), 2.54 (t, J = 6.4 Hz, 2H), 2, 2.39 (m, 4H), 1.86-1.77 (m, 4H), 1.66-1.55 (m, 2H).

LCMS (m / z): 537.8 (MH⁺).

Example 9

LPS-induced IL23p19 assay in THP-1 cells (primed with IFNy)

Materials and equipment

ES 2 811 136 T3

THP-1 cells (ATCC, n^s of cat. TIB-202), dimethylsulfoxide (DMSO) (Sigma-Aldrich, n^s of cat. D2650), RPMI 1640 (Cellgro, Cat. # 10-040-CM), Fetal Bovine Serum (Sigma, Cat. # F4135), Bovine Serum Albumin (BSA) (SigmaAldrich, Cat. # A7906 ), LPS (Serotype K-235, Sigma, Product Number L 2143), IFNy (Peprotech, Cat. No. 30002)

Capture Antibody: Human IL-23p19 ELISA (e-Bioscience, Cat. # 14-7238-85), Detection Antibody: Biotinylated Mouse Anti-Human IL-12 (p40 / p70) Primary Antibody (e- Bioscience, Cat. No. 13-7129-85), Secondary: HRP-Conjugated Streptavidin (R&amp;D Systems, Cat. DY998), 1x PBST wash buffer (PBS-Tween tablet) (VWR International, cat # 80058-558), ELISA blocking buffer (PBS with 1% BSA), ELISA dilution buffer (PBS with 1% BSA), Black 384-well Flat Bottom MaxiSorp Immunoplates (Thermo Scientific, Cat. # 12-565-346), 384-Well Flat-Bottom White Tissue Culture Plates (Thermo Scientific, Cat. cat. 12-565-343), Super Signal ELISA Pico Chemiluminescent Substrate (Thermo Scientific, Cat. No. 37070), Cell Titer Glo Reagent (Promega, Cat. No. G7573), Positive Control, IKK2VI Inhibitor (Calbiochem, No. Cat # 401483), AquaMax 4000 Plate Washer (Molecular Devices), Luminometer, Wallac Victor2 1420 Multilabel Counter.

Method

THP-1 cell stimulation:

On day 1, 50K THP-1 cells / well were seeded and primed with IFNy (50ng / ml) in 384-well plates for about 18 hours in RPMI medium with 10% FBS. On day 2, the compound was serially diluted in DMSO starting at 5 mM in 3-fold dilutions, and then diluted 1: 125 in RPMI medium with 10% FBS. 50 µl / well of compound 2x was added to 50 µl / well of THP-1 cells (primed with IFNy) in duplicate in 384-well tissue culture plates. The cells were pre-incubated with the compound for 1 hour at 37 ° C, 5% CO2, before the addition of 10 µl / well of 11x LPS to give a final concentration of 1 µg / ml of LPS. On day 3, after stimulation for 18 hours at 37 ° C, 5% CO2, the assay plate was centrifuged, and 70 µl / well of supernatant was collected. IL-23p19 protein in 70 µl / well of supernatant was measured by sandwich ELISA, and 25 µl / well of Cell Titer Glo reagent was added to the remaining cells to measure compound toxicity.

Human IL-23p19 sandwich ELISA:

Maxisorp immuno ELISA plates were pre-coated with 25 µl / well of anti-IL-23p19 capture antibody (2.5 ug / ml) in PBS overnight at room temperature. After washing with 1x PBST, the plates were blocked using 100 µl / well of 1% BSA in PBS for 2 hours at room temperature. The plates were washed three times with 1x PBST, and 70 µl / well of supernatant was added. Plates were incubated at room temperature for 2 hours with shaking and washed three times with 1x PBST. 25 μl / well of anti-IL-12 biotin-labeled detection antibody (p40 / p70) (100 ng / ml) in PBS with 1% BSA was added, and the plates were incubated at room temperature for 2 hours with shaking. . After washing three times with 1x PBST, 25 µl / well of streptavidin-HRP (1: 200) in PBS with 1% BSA was added, and the plates were incubated at room temperature for 20 minutes with shaking. Plates were washed three times with 1x PBST, and 25 µl / well of Super Signal ELISA Peak chemiluminescent substrate was added. Plates were read with a luminometer, and chemiluminescence values ​​were entered into Athena (Rigel) for curve fitting, EC50 calculation, and database storage. The results are shown in Table 1.

Example 10

Identification of compounds using DC cells

Materials

Human PBMC Cells (All Cells, Cat. No. PB002)

RPMI growth medium containing 10% FBS

IFNy (Peprotech, Cat. No. 300-02)

GMCSF (Peprotech, Cat. No. 300-03) and IL4 (Peprotech, Cat. No. 200-04)

96-Well White Plates with Clear Bottoms (Fisher, Cat. # 07-200-587, Corning # 3903)

LPS (Prepare a 2.5 mg / ml batch in PBS) from Sigma Aldrich (Cat. # L2018-5MG)

Cell Titer Glo Reagent (Promega, Cat. # G7573)

Positive Controls, IKK2VI Inhibitor (Calbiochem, Cat. # 401483)

ES 2 811 136 T3

Protocol

I. Differentiation of PBMCs into DC cells:

Human PBMC cells (400 million) obtained from the supplier were transferred to a T-175 flask containing 15 ml of RPMI medium (10% FBS), and incubated for 2 hours at 37 ° C. After 2 hours, the media including floating cells was carefully aspirated, and 12 ml of fresh RPMI medium (10% FBS) containing GMCSF (100 ng / ml) and IL4 (20 ng / ml) was added, and the flask was kept in an incubator at 37 ° C for 7 days.

After 3 days, fresh GMCSF (100 ng / ml) and IL4 (20 ng / ml) were added to the flask, and the incubation continued. After 7 days, fully differentiated cells were harvested by centrifuging (1200 rpm / 5 min) and aspirating the medium. Cells were suspended in fresh RPMI medium (10% FBS) containing 50 ng / ml IFNy (1000 U / ml), and then plated (50K / well in 100 μl) on a white transparent bottom plate. of 96 wells, and left in a 37 ° C incubator for 24 hours.

II. Adding compounds:

After 24 hours of incubation, 100 μl of RPMI medium containing 2X concentrated test compound per well was added to the above cell culture medium (the final concentration becomes IX), and the plates were pre-incubated for 1 hour at 37 ° C before stimulating with LPS.

After 1 hour of previous incubation of the compounds, 10 µl per well of 20X concentrated LPS solution in RPMI medium was added, to give a final concentration of 1 µg / ml. The mixture was shaken, and the plates were incubated at 37 ° C for an additional 18 hours.

155 µl of the supernatant was carefully collected from each well (without the tip touching the bottom of the well), and 50 µl of Cell Titer Glo reagent was added to the remaining 50 µl / well of the cell culture plate. The mixture was incubated for 1-2 minutes on a shaker, and the plate was read for luminescence intensity to determine the cytotoxicity of the compounds. The cell culture supernatant collected above was used to carry out the IL23 ELISA (65 µl - Supernatant) and the IL10 ELISA (90 µl - Supernatant) as described below.

Example 11

Human IL-23 (p19 / p40) ELISA protocol (e-Biosciences)

Materials:

High Junction 96-Well Opaque White Plates (from Pierce, Cat. # 15042);

1X PBS; 1x TBST wash buffer;

Blocking Solution: 0.5% casein in PBS (from BDH, Cat. No. 440203H);

Dilution solution: 1% BSA in PBS (10% Fisher's BSA, Cat. No. 37525);

Capture antibody: rat anti-human IL-23 (p19) antibody (e-Biosciences, cat # 14-7238-85);

Detection antibody: mouse anti-human IL-12 (p40 / p70) biotinylated primary antibody (e-biosciences, cat. # 13-7129-85);

Secondary: HRP-conjugated streptavidin (R&amp;D Systems, cat # DY998);

Recombinant human IL-23 (e-biosciences, cat. # 34-8239) (Suggested starting concentration = 5 ng / ml in RPMI cell culture medium);

Cell culture supernatant (65 µl of THP-1 cells primed with IFNy (50 ng / ml - 1000 U / ml) and stimulated with 0.01% SAC);

SuperSignal ELISA Peak Chemiluminescent Substrate [Pierce, Cat. 37069].

Plates coating:

To 10.5 ml of PBS, 50 µl of anti-IL23 (p19) capture antibody (2.5 µg / ml) was added. The mixture was mixed well, and 100 µl of the coating solution was added to each well of Pierce 96-well white plates. The wells were covered and incubated overnight at 4 ° C.

ES 2 811 136 T3

Plates lock:

Plates coated with anti-IL23 antibody (p19) were washed 2X using TBST (use a plate washer), and blocked using 200 µl of 0.5% casein for 1.5-2 hours at room temperature with shaking.

Supernatant addition and detection:

The plates were washed 2X using TBST, and the supernatant was transferred (65 μl / well) to the previous 96-well plate previously blocked / coated with anti-IL23 antibody (p19), and incubated at room temperature for 1.5 hours with agitation.

Plates were washed 4X using TBST (plate washer), and a 100 μl / well detection antibody solution prepared from 2 μl of biotin-labeled anti-IL-12 (p40 / p70) antibody was added at 11 ml of 1% BSA / PBS solution (1: 5000 dilution). The plates were incubated for 1 hour with shaking at room temperature.

Again, the plates were washed 4X with TBST, and 100 μl of HRP-labeled streptavidin solution (R&amp;D Systems) (10 μl / 10 ml of 1% BSA solution) was added, and the plates were incubated at room temperature for another 45 minutes with shaking.

After 45 minutes, the plates were washed with TBST 4X, and 100 ul / well of Pierce's Peak Super Signal ELISA chemiluminescent substrate (3.5 ml of A + 3.5 ml of B + 3.5 ml of water MQ). The plates were shaken for 1-2 minutes, and then read on a plate reader. The results are shown in Table 1.

Table 1

<td colspan="6">EC50 results from the tests described in Examples 9 and 11</td>

<td>Compound</td><td>IL23p19 ELISA, Dendritic, LPS, 10pt EC50 (μM)</td><td>IL23p19, THP1IFNy, LPS, 10pt EC50 (μM) ELISA</td><td>Compound</td><td>IL23p19 ELISA, Dendritic, LPS, 10pt EC50 (μM)</td><td>IL23p19, THP1IFNy, LPS, 10pt EC50 (μM) ELISA</td>

<td>I-1</td><td> 4,728</td><td> 0,8979</td><td>I-29</td><td> 0,1057</td><td> 0,3022</td>

<td>I-2</td><td> 9999</td><td> 9999</td><td>I-30</td><td> 9999</td><td> 43,48</td>

<td>I-3</td><td> 0,0391</td><td> 0,0314</td><td>I-31</td><td> 0,4438</td><td> 0,1441</td>

<td>I-4</td><td> 12,13</td><td> 0,9006</td><td>I-32</td><td> 24,1</td><td> 1,781</td>

<td>I-5</td><td> 0,2571</td><td> 0,4316</td><td>I-33</td><td> 9999</td><td> 4454</td>

<td>I-6</td><td> 13,99</td><td> 40,53</td><td>I-34</td><td> 9999</td><td> 8,325</td>

<td>I-7</td><td> 0,0136</td><td> 0,026</td><td>I-35</td><td> 0,6658</td><td> 0,3212</td>

<td>I-8</td><td> 9999</td><td> 0,6142</td><td>I-36</td><td> 9999</td><td> 5,237</td>

<td>I-9</td><td> 0,8967</td><td> 52,09</td><td>I-37</td><td> 9999</td><td> 23,09</td>

<td>I-10</td><td> 2,987</td><td> 4,631</td><td>I-38</td><td> 0,0141</td><td> 0,0316</td>

<td>I-11</td><td> 9999</td><td> 228,5</td><td>I-39</td><td> 8,074</td><td> 0,3549</td>

<td>I-12</td><td> 0,02</td><td> 0,0539</td><td>I-40</td><td> 0,041</td><td> 0,025</td>

<td>I-13</td><td> 9999</td><td> 2,934</td><td>I-41</td><td> 2,584</td><td> 0,1474</td>

<td>I-14</td><td> 17,91</td><td> 10,22</td><td>I-42</td><td> 0,0848</td><td> 0,0606</td>

<td>I-15</td><td> 1,688</td><td> 73,05</td><td>I-43</td><td> 2,624</td><td> 0,3436</td>

<td>I-16</td><td> 0,0322</td><td> 0,0258</td><td>I-44</td><td> 0,1008</td><td> 0,0887</td>

<td>I-17</td><td> 1,021</td><td> 1,228</td><td>I-45</td><td> 0,4023</td><td> 0,3422</td>

ES 2 811 136 T3

<td colspan="6">EC50 results from the tests described in Examples 9 and 11</td>

<td>Compound</td><td>IL23p19 ELISA, Dendritic, LPS, 10pt EC50 (pM)</td><td>IL23p19, THP1IFNy, LPS, 10pt EC50 (μM) ELISA</td><td>Compound</td><td>IL23p19 ELISA, Dendritic, LPS, 10pt EC50 (pM)</td><td>IL23p19, THP1IFNy, LPS, 10pt EC50 (μM) ELISA</td>

<td>I-18</td><td> 0,889</td><td> 7,511</td><td>I-46</td><td> 0,0375</td><td> 0,0587</td>

<td>I-19</td><td> 0,6743</td><td> 0,9384</td><td>I-47</td><td> 0,058</td><td> 0,0213</td>

<td>I-20</td><td> 0,018</td><td> 0,0224</td><td>I-48</td><td> 0,1231</td><td> 0,0585</td>

<td>I-21</td><td> 1,706</td><td> 2,176</td><td>I-49</td><td> 0,0481</td><td> 0,0504</td>

<td>I-22</td><td> 3,183</td><td> 0,6772</td><td>I-50</td><td> 0,0757</td><td> 0,1326</td>

<td>I-23</td><td> 0,1568</td><td> 0,0757</td><td>I-51</td><td> 0,0411</td><td> 0,0742</td>

<td>I-24</td><td> 5,774</td><td> 1,08</td><td>I-52</td><td> 0,0371</td><td> 0,02</td>

<td>I-25</td><td> 0,1215</td><td> 0,0482</td><td>I-53</td><td> 0,1213</td><td> 0,1797</td>

<td>I-26</td><td> 9999</td><td> 1,183</td><td>I-54</td><td> 0,0603</td><td> 0,1057</td>

<td>I-27</td><td> 0,7471</td><td> 0,5275</td><td>I-55</td><td> 0,0303</td><td> 0,024</td>

<td>I-28</td><td> 9999</td><td> 9999</td><td colspan="3"></td>

In view of the many possible embodiments to which the principles of the disclosed invention can be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be construed as limiting the scope of the invention. Rather, the scope of the invention is defined by the following 5 claims.