New regulations for compounds

Abstract

The present invention relates to a compound of formula I, I, wherein R1, R2, R3, R4, R5, R6, R7a, R7b, Q, A, E, and L are as defined herein, or to a pharmaceutically acceptable salt, solvate, or deuterated analog thereof, which is useful for treating diseases or conditions that respond to treatment with transglutaminase inhibitors. [C148] TIFF2026525231000190.tif74167

Description

[Technical Field]

[0001] This invention relates to novel compounds and the use of such compounds in medicine. In particular, this invention relates to compounds useful for treating disorders or conditions that respond to treatment with transglutaminase inhibitors. [Background technology]

[0002] Transglutaminases (TGs or TGases) are a group of enzymes that can modify proteins by mediating acyl transfer reactions between the γ-carboxamide group of peptide-linked glutamine and primary amines. The result of this reaction is a post-translational modification of peptide glutamine, either via protein crosslinking when the amine is the ε-amino group of peptide-linked lysine, or by crosslinking to a primary amine such as a polyamine. Under certain conditions and in the absence of a suitable primary amine, deamidation of peptide-linked glutamine can also occur. Due to their ability to crosslink proteins into high molecular weight protein aggregates, TGs are referred to as "natural biological glues" (Griffin et al., 2002). Although TGs are widely found in nature, in mammals, their enzymatic activity is limited to Ca 2+It is dependent on other factors, including GTP / GDP, which may also influence the activity of some mammalian TGs (Verderio et al., 2004). Not all eight active members of the mammalian TG family (TG1-7 and factor XIII) are fully characterized (Collighan and Griffin, 2009). Another member of this family, band 4.2, is catalytically inactive and is primarily associated with the regulation of the erythrocyte cytoskeleton. TG2 (tissue transglutaminase, TG2M, tTG) is perhaps the most ubiquitous member of the mammalian TG family, found both in the intracellular and extracellular environments. In addition to its transamidation, GTPase, and ATPase activity (Nakaoka et al., 1994), further novel activities of TG2, such as protein disulfide isomerase (PDI) (Hasegawa et al., 2003) and protein kinase activity (Mishra and Murphy, 2004), have recently been reported, thus further expanding the potential physiological and pathological importance of this diverse group of enzymes. Abnormal levels of transglutaminases, particularly TG2 and / or activity, have been observed in many disease states such as celiac disease, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), fibrosis, cataracts, and cancer metastases, and this list is certainly not intended to be exhaustive. Furthermore, proof-of-concept studies using either TG2- / - animal models (Bailey and Johnson, 2005; Mastroberardino et al., 2002) or inhibitor studies (Huang et al., 2009; Johnson et al., 2008) have shown that the enzyme is a potential novel candidate for therapeutic intervention.

[0003] Due to its diverse biological processes and pathological implications, the development of chemical tools to further investigate the multifunctional role of TG2 is an active area of ​​research. Most inhibitors developed to date target the catalytic site of the enzyme, but there have also been reports of small molecules competing for the TG2 cofactor binding site. Depending on their ability to reach and react with the catalytic cysteine ​​residue (CYS277 in the case of hTG2), they can be further divided into reversible and irreversible inhibitors. Peptide inhibitors with various electrophilic moieties (e.g., chloroacetamide (Pardin et al., 2006), α,β-unsaturated amide (Pardin et al., 2006), maleimide (Halim et al., 2007), sulfonium methyl ketone (Griffin et al., 2008), dihydroisoxazole (Dafik and Khosla, 2011), cinnamoyl derivatives (Pardin et al., 2008a, Pardin et al., 2008b), oxyndol (Klock et al., 2011), sulfonamide piperazine (Prime et al., 2012) are examples of such derivatives. Irreversible inhibitors (Lindemann et al., 2012, Pinkas et al., 2007) or nucleotides (Han et al., 2010, Liu et al.) are examples. The elucidated TG2 structure, co-crystallized with one of the studies (al., 2002), reveals the massive conformational change of the enzyme when it transitions from the inactive to the active state, which will undoubtedly enhance the design of more potent inhibitors in the future.

[0004] Small molecule inhibitors of TG2 have been shown to be a potentially effective treatment for various fibrotic diseases. For example, Wang et al., 2018 reported that cardiac fibrosis can be alleviated by blocking TG2 activity using selective small molecule inhibitors. Furthermore, both Huang et al., 2009 and Johnson et al., 2007 reported that TG2 inhibition improves fibrous kidney disease. Moreover, Fell et al., 2021 identified TG2 as a potential therapeutic target for idiopathic pulmonary fibrosis.

[0005] An example of a TG2 inhibitor is compound 1-155 (i.e., reference compound 1), which was first disclosed in WO2014 / 057266. [ka]

[0006] As TG2 inhibitors, compounds 1-155 are useful for the treatment or prevention of diseases or conditions that respond to treatment with tissue transglutaminase inhibitors. For example, such compounds may be useful in the treatment of fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, pathological angiogenesis, proliferative disorders, AIDS, psoriasis, and inflammation.

[0007] The present invention aims to provide novel compounds that inhibit transglutaminase activity for medical use, and which exhibit remarkably improved pharmacokinetic properties compared to known TG2 inhibitors.

[0008] Any listing or discussion of documents that are clearly previously published in this specification should not necessarily be considered an acknowledgment that such documents are part of the latest technology or common knowledge. [Modes for carrying out the invention]

[0009] In a first aspect of the present invention, the compound of formula I is, [ka] During the ceremony, Q is selected from the group consisting of O and NH. A is N, -EL-linker, [ka] This represents, R 1 However, this represents a 9-membered bicyclic heteroaryl group that is optionally substituted with one or more X groups. Each X is independently a halogen (e.g., F, 18 F, Cl, Br, or I), -N(R 8a )R 8b , -OR 9 , -C(O)OR 10 , -C(O)N(R 11a )R 11b , C 1-4 alkyl group, and C 3-6 cycloalkyl group selected from the group consisting of, C 1-4 alkyl and C 3-6 cycloalkyl group is optionally substituted by one or more deuterium atoms and / or halogen (e.g., F, 18 F, Cl, Br, or I) atoms, R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen and C 1-3 alkyl, and C 1-3 alkyl group is optionally substituted by one or more halogen (e.g., F, 18 F, Cl, Br, or I) atoms, or R 2 and R 3 together with the carbon atom to which they are attached form a 5- or 6-membered heterocycloalkyl group, or R 2 and R 4 together with the carbon atom to which they are attached form a 5- or 6-membered heterocycloalkyl group, R 5 is selected from the group consisting of hydrogen, C 1-3 alkyl, and C 3-6 cycloalkyl, and C 1-3 alkyl and C 3-6 cycloalkyl group is optionally substituted by one or more groups selected from the group consisting of deuterium atoms and halogen (e.g., F, 18 F, Cl, Br, or I) atoms, R 6 is hydrogen, halogen (e.g., F, 18 F, Cl, Br, or I), deuterium, and C1-3 Alkyl, C 1-3 An alkyl group contains one or more halogens (e.g., F, 18 C is optionally substituted with an atom of F, Cl, Br, or I. 1-3 Alkyl, -CH2N(R 12 Selected from the group consisting of )Ph and -CH2OCH2Ph, R 7a and R 7b However, each independently, hydrogen, halogen (for example, F, 18 Selected from the group consisting of F, Cl, Br, or I), methyl, and deuterium, R 8a , R 8b , R 9 , R 10 , R 11a , and R 11b However, each independently, hydrogen, C 1-3 Alkyl, and C 3-6 Selected from the group consisting of cycloalkyls, C 1-3 Alkyl and C 3-6 A cycloalkyl group contains one or more deuterium atoms and / or halogens (e.g., F, 18 It is optionally substituted with an atom of F, Cl, Br, or I, or or R 8a and R 8b Furthermore / or R 11a and R 11b However, together with the nitrogen atom to which they are bonded, they form a 3-6 member heterocycloalkyl group. R 12 However, hydrogen and C 1-3 Selected from the group consisting of alkyl groups, C 1-3 An alkyl group contains one or more halogens (e.g., F, 18 It is optionally substituted with an atom of F, Cl, Br, or I. Ph is one or more halogens (for example, F, 18 F, Cl, Br, or I) atoms or C 1-3 Phenyl is optionally substituted with an alkyl group, C 1-3 An alkyl group contains one or more halogens (e.g., F,18 Compounds that are optionally substituted with F, Cl, Br, or I atoms. or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof.

[0010] These compounds, including pharmaceutically acceptable salts, solvates, and deuterated analogs of these compounds (in particular pharmaceutically acceptable salts and solvates of these compounds), may be referred to herein as “compounds of the present invention.”

[0011] In an alternative first aspect of the present invention, the compound of the present invention (i.e., the compound of formula I, or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof (in particular, a pharmaceutically acceptable salt or solvate thereof)) wherein, A is selected from the group consisting of N and CH. E represents a direct bond or -C(O)-, L is directly bonded, or C 1-3 It represents a group selected from the group consisting of alkylene, 4-6 membered cycloalkylene, 4-6 membered heterocycloalkylene, arylene, and heteroarylene. Alternatively, A, E, and L may combine to form a 4-6 membered cycloalkylene group, or L and R 5 However, R 5 A compound is provided in which the nitrogen atom to which the compound is bonded forms a 4-6 membered heterocycloalkylene group.

[0012] Examples of pharmaceutically acceptable salts of potential utility are those discussed by Berge et al. in J. Pharmaceutical Sciences, 66:1-19 (1977). Pharmacopoeia acceptable salts of the compound of formula I may be prepared according to techniques well known to those skilled in the art.

[0013] Examples of pharmaceutically acceptable addition salts include acid addition salts, such as those formed with inorganic acids, carboxylic acids, or organic sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; base addition salts, such as metal salts formed with bases, such as sodium salts and potassium salts.

[0014] A pharmaceutically acceptable salt of the compound of formula I may be prepared according to techniques well known to those skilled in the art. For example, the compound of formula I may be reacted with a suitable organic or inorganic acid. One salt may be converted to the other using salt-switching techniques.

[0015] The compounds disclosed herein may exist in both non-solvated and solvated forms with pharmaceutically acceptable solvents such as water and ethanol, and the present invention is intended to encompass both solvated and non-solvated forms of the compounds of the present invention.

[0016] The term "solvate" refers to a variable stoichiometric complex formed by a solute and a solvent. Such a solvent for the purposes of the present invention must not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0017] Unless otherwise specified, alkyl groups as defined herein may be linear or branched if they have a sufficient number of carbon atoms.

[0018] As used herein, “alkylene” (i.e., alkanediyl) refers to a divalent alkyl group. Specific alkylene groups that may be mentioned include, for example, propylene (n-propylene or isopropylene), ethylene, and especially methylene (i.e., -CH2-).

[0019] If there are a sufficient number of carbon atoms (i.e., at least three as necessary), the alkyl group may be cyclic and thus form a cycloalkyl group. Cycloalkyl groups that can be mentioned include monocyclic groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Such cycloalkyl groups may be crosslinked (thus forming fused ring systems, e.g., three-condensed cycloalkyl groups). Furthermore, such cycloalkyl groups may be saturated or unsaturated, e.g., containing one or more double bonds (e.g., forming a cycloalkenyl group). Furthermore, if there are a sufficient number (i.e., at least four), such cycloalkyl groups may be partially cyclic and, e.g., form alkylene-cycloalkyl groups (e.g., -CH2-C3H5). The bonding sites of the cycloalkyl group may be via any atom in the ring system. To avoid doubt, optional substituents may also be other cyclic groups that are bonded via a single carbon atom common to both rings and thus form a spirocycle.

[0020] As used herein, "cycloalkylene" refers to a divalent cycloalkyl group. Specific cycloalkylene groups that may be referred to include, for example, cyclobutylene (i.e., -(C4H6)-).

[0021] Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic heterocycloalkyl groups in which at least one (e.g., 1 to 4) of the atoms in the ring system is other than carbon (i.e., a heteroatom, such as sulfur, oxygen, or especially nitrogen), and the total number of atoms in the ring system is 3 to 10. Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated, for example, contain one or more double bonds to form a heterocycloalkenyl group. The point(s) of attachment of the heterocycloalkyl group may, where appropriate, be through any atom within the ring system that includes a heteroatom (such as a nitrogen atom) or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidized form (i.e., those heteroatoms may optionally be substituted with one or two =O substituents). To avoid doubt, optional substituents may also be attached through a single carbon atom common to both rings and thus may be other cyclic groups that form a spiro ring.

[0022] As used herein, "heterocycloalkylene" refers to a divalent heterocycloalkyl group. Specific heterocycloalkylene groups that may be mentioned include, for example, azetidinylene (e.g.,

Chemical formula

[0025] As used herein, the term "heteroaryl" preferably refers to an aromatic group containing one or more heteroatoms (e.g., 1 to 4 heteroatoms) selected from N, O, and S. Heteroaryl groups include those having 5 to 10 members and may be monocyclic or bicyclic, provided that at least one of the rings is aromatic (thus, for example, forming a monocyclic or bicyclic heteroaromatic group). The point of attachment of a heteroaryl group may, where appropriate, be through any atom within a ring system containing a heteroatom (such as a nitrogen atom) or through any atom on a fused carbocyclic ring that may be present as part of the ring system. Substituents on a heteroaryl group may, where appropriate, be located on any atom within a ring system containing a heteroatom. To avoid doubt, optional substituents include those defined herein and also =O substituents that may be attached to any non-aromatic ring of a bicyclic heteroaryl group (however, in one embodiment, =O substituents are not included).

[0026] When it is specified that a heteroaryl is bicyclic (e.g., a 9-member bicyclic heteroaryl group), it may consist of a 5- or 6-member monocyclic ring (e.g., a monocyclic heteroaryl ring) fused, where necessary, to another 5- or 6-member ring (e.g., a monocyclic aryl or heteroaryl ring).

[0027] Heteroaryl groups that may be mentioned include, for example, pyrrolopyridinyl, pyrrolopyrimidinyl, thienopyridinyl, indolyl, thienopyrimidinyl, benzothiophenyl, and indazolyl.

[0028] As used herein, "heteroarylene" refers to a divalent heteroaryl group. Specific heteroarylene groups that may be mentioned include, for example, pyridinylene.

[0029] The term "halogen" refers to fluorine (its radioactive isotopes, for example, fluorine-18 (i.e., 18 Contains F), chlorine, bromine, and iodine.

[0030] To avoid any doubt, if two or more substituents in a compound of formula I may be identical, then the actual identity of each substituent is never interdependent.

[0031] Where a group is referred to herein as being optionally substituted, it is particularly intended that such optional substituents may be absent (i.e., references to such optional substituents may be omitted), in which case the optionally substituted group may be referred to as unsubstituted in certain embodiments.

[0032] To avoid any doubt, when cyclic substituents (e.g., cycloalkyl or heterocycloalkyl groups) are present on a group (such as an alkyl group), these cyclic substituents may be bonded to the same carbon atom, and thus, for example, form a spirocyclic group. For example, a compound of the present invention in which A, E, and L together form a 4-6 membered cycloalkylene group (e.g., a cyclobutylene group) can be considered a spirocyclic compound.

[0033] The compounds of formula I contain double bonds, and each individual double bond may exist as E (entgegen) and Z (zusammen) geometric isomers. All such isomers and mixtures thereof are within the scope of the present invention.

[0034] The compound of formula I may exist as a positional isomer and may also exhibit tautomerism. All tautomer forms and mixtures thereof are included within the scope of the present invention.

[0035] The compounds of the present invention may also contain one or more chiral carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. Diastereomers can be separated using conventional techniques, e.g., chromatography or fractional crystallization. Various stereoisomers can be isolated by separating racemic or other mixtures of the compound using conventional techniques, e.g., fractional crystallization or HPLC techniques. Alternatively, the desired optical isomer may be produced, all under conditions known to those skilled in the art, by reacting a suitable optically active starting material under conditions that will not cause racemization or epimerization (i.e., the "chiral pool" method), by reacting a suitable starting material with a "chiral auxiliary" that can then be removed in a suitable step, by derivatization with a homochiral acid (i.e., optical resolution including dynamic optical resolution), by separation by conventional means such as chromatography of the diastereomer derivative, or by reaction with a suitable chiral reagent or chiral catalyst.

[0036] All stereoisomers (including, but not limited to, diastereomers, enantiomers, and atropisomers) and mixtures thereof (e.g., racemic mixtures) are included within the scope of the present invention.

[0037] In structures shown herein where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are intended and included as compounds of the present invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, the stereoisomers are therefore specified and defined in that manner.

[0038] The present invention also includes isotope-labeled compounds of formula I, which are identical to those described herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature (or most abundantly found in nature). All isotopes of any particular atom or element specified herein are intended to be within the scope of the present invention. Accordingly, compounds of formula I also include deuterium compounds, i.e., compounds of formula I in which one or more hydrogen atoms are replaced by hydrogen isotopes of mass hydrogen.

[0039] Therefore, the particular compounds of the present invention that may be mentioned are compounds of formula IM, [ka] In the formula, R 1 , R 5 , R 6 , R 7a , R 7b The compounds include, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof, where A, E, L, and Q are as defined with respect to the compounds of formula I. In certain embodiments of the compounds of formula IM, Q is O.

[0040] Additional isotope-labeled compounds of formula I that may be mentioned include fluorine-18 (i.e., 18 F) Compounds, i.e., compounds of formula I in which one or more fluorine atoms (if present) are replaced by the fluorine radioisotope fluorine-18.

[0041] Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include stable compounds. That is, the compounds of the present invention include compounds that are robust enough to survive, for example, isolation from a reaction mixture to a useful purity.

[0042] Throughout this specification, structures may or may not be presented together with chemical names. In case of any doubt regarding nomenclature, the structure shall prevail. If a compound may exist as tautomers (e.g., in alternative resonance forms), the structure shown represents one of the possible tautomeric forms, and the actual tautomeric form(s) observed may vary depending on environmental factors such as solvent, temperature, or pH. All tautomeric (and resonance) forms and their mixtures are included within the scope of the present invention.

[0043] Unless otherwise noted, all technical and scientific terms used in this specification have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0044] To avoid doubt, one of ordinary skill in the art will understand that references in this specification to particular aspects of the invention (such as a first aspect of the invention) include references to all embodiments and their particular features, and that combinations of those embodiments and particular features may form further embodiments and features of the invention.

[0045] Particular compounds of the invention that may be referred to are compounds in which Q is O. For example, a compound of formula I-A, wherein

Chemical formula

[0046] As shown herein, R 1This represents a nine-membered bicyclic heteroaryl group optionally substituted with one or more X groups. Therefore, the nine-membered bicyclic heteroaryl group may be substituted with, for example, 0, 1, 2, 3, 4, 5, 6, or 7 X groups.

[0047] R, which exhibits a strong TG2 inhibitory effect 1 Such compounds have been found in which a 9-membered bicyclic heteroaryl group is optionally substituted with one or more X groups. Furthermore, structural variations are found in R 1 It has been found to be well tolerable, and good TG2 inhibitory efficacy has been found for various different structures at this position. As demonstrated by the data of the examples, R 1 Compounds of the present invention containing a specific nine-membered bicyclic heteroaryl group are relatively bioavailable and have therefore been found to exhibit remarkably improved pharmacokinetic properties compared to known TG2 inhibitors.

[0048] The specific compounds of the present invention that may be mentioned also include a 9-membered bicyclic heteroaryl group, (a) Containing one, two, three, or four ring heteroatoms independently selected from the group consisting of N and S, (b) Substituted with 0, 1, 2, 3, 4, or 5 X groups.

[0049] Specific X groups that may be mentioned include hydrogen, -OCH3, -OCHF2, -OCHF[ 18 F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -NH2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)CH3, [ka] -CH3, -CH2CH3, -CH(CH3)2, [ka] -CD3, Cl, and F are examples.

[0050] In certain embodiments, R 1 is

Chemical formula

[0051] As provided herein, [ka] The symbol indicates the bonding site to the compound of formula I.

[0052] Those skilled in the art, [ka] You will recognize that this indicates a double bond or a single bond. Therefore, [ka] This is understood to represent the following: [ka]

[0053] In a particular embodiment, R 1 The following is true: [ka] In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , X 1 , X 2 , X 3 , X 5 , X 6 , X 7, and X 8 This is as defined herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0054] In a particular embodiment, R 1 teeth, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 13 , R 14 , and R 15 This is defined herein.

[0055] In a particular embodiment, R 1 teeth, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 3 , R 14 , and R 15 This is defined herein.

[0056] In a particular embodiment, R 1 teeth, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 4 , R 13 , R 14 , and R 15 This is defined herein.

[0057] In a particular embodiment, R 1 The following is true: [ka] In the formula, X 1 , X 2 , R 14 , and R 15 This is defined herein.

[0058] In a particular embodiment, X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , R 14 , and R 15 These are, independently, hydrogen, -OCH3, -OCHF2, and -OCHF[ 18 F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -CH3, -CH2CH3, -CH(CH3)2, [ka] - Selected from the group consisting of CD3, Cl, and F, X 4 and R 13 These are, independently, hydrogen, -CH3, -CH2CH3, and -CH(CH3)2. [ka] The group is selected from the group consisting of -CD3.

[0059] In a particular embodiment, X 1 is hydrogen, -OCH3, -OCHF2, -OCHF[ 18 Selected from the group consisting of F], -OCHFCl, -CF3, -OCH2F, -OCF2Cl, and -OH, X 4It is selected from the group consisting of hydrogen -CH3 and -CH2CH3, R 14 It is selected from the group consisting of hydrogen, F, Cl, and -CH3, X 2 , R 13 , and R 14 Each is independently selected from the group consisting of hydrogen and -CH3, X 3 , X 5 , X 6 , X 7 , and X 8 Each of these is hydrogen.

[0060] In a particular embodiment of the present invention, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0061] In a particular embodiment of the present invention, R 1 teeth, [ka] It is selected from the group consisting of the following.

[0062] The specific compounds of the present invention that may be mentioned are R 1 but, [ka] A selection from the group consisting of, for example, R 1 but, [ka] It is a compound that is [this compound].

[0063] Other compounds of the present invention that may be mentioned are: A is N, E is a -C(O)- or direct bond, L, C 1-3 Alkylene, or L and R5 However, R 5 It combines with the nitrogen atom to which it is bonded to form an azetidine ring.

[0064] In a particular embodiment, A is N, -EL-linker is, [ka] (for example, [ka] ) represents.

[0065] Preferably, A is N, -EL-linker is, [ka] It represents.

[0066] Therefore, the particular compounds of the present invention that may be mentioned are compounds of formula IB, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b The compounds include, and Q as defined with respect to the compounds of formula I, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof. In certain embodiments of the compounds of formula IB, Q is O.

[0067] In an alternative embodiment, A is CH, E is a direct bond, L is directly bonded, C 1-3 Alkilen, R 5L and R, together with the nitrogen atom to which they are bonded, form an azetidine ring. 5 It represents.

[0068] To avoid any doubt, in the case of the compound of the present invention in which A is CH and E and L both represent direct bonds, A is the compound of formula I. [ka] It is directly bonded to the part.

[0069] Therefore, the specific compounds of the present invention that may be mentioned are compounds of formula IC, compounds of formula ID, or compounds of formula IE, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 (if present), R 6 , R 7a , R 7b The compounds, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof, wherein Q is as defined with respect to the compounds of formula I. In certain embodiments of the compounds of formula IC, formula ID, or formula IE, Q is O.

[0070] In other alternative embodiments, A, E, and L combine to form a cyclobutyl ring, and thus form the spirocyclic compound of the present invention.

[0071] Therefore, the particular compounds of the present invention that may be mentioned are compounds of formula IF, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R7b The compounds, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof, wherein Q is as defined with respect to the compounds of formula I. In certain embodiments of the compounds of formula IF, Q is O.

[0072] Specific compounds of the present invention that may be mentioned include the compounds of formula IB and the compounds of formula IC as defined above.

[0073] The specific compounds of formula IC that may be mentioned are R 1 but, [ka] Selected from the group consisting of, In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , and X 8 However, this is as defined herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0074] More specifically, the compounds of formula IC that may be mentioned are R 1 but, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 13 , R 14 , and R 15However, this is as defined herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0075] Certain compounds of formula IC that may be mentioned are R 1 but, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 13 , R 14 , and R 15 However, this is as defined herein (i.e., as described in the first aspect of the present invention, including all embodiments and specific features, and combinations thereof).

[0076] In a particular embodiment, R 2 , R 3 , and R 4 Each of these is independently selected from the group consisting of hydrogen, methyl, and ethyl, or R 2 and R 4 These atoms, together with the carbon atoms to which they are bonded, form a five-membered heterocycloalkyl group. In a particular embodiment, R 2 , R 3 , and R 4 Each of these is hydrogen.

[0077] As described herein, compounds of the first embodiment of the present invention may also contain one or more chiral carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. For example, R 2 and R 3 C 1-3A compound of formula I that is alkyl (e.g., methyl or ethyl). To avoid ambiguity, R 2 and R 3 Both are C 1-3 If it is an alkyl group, then C 1-3 The alkyl groups may be the same or different.

[0078] For example, a compound of formula I is a compound of formula IG, a compound of formula IH, a compound of formula II, a compound of formula IJ, a compound of formula IK, or a compound of formula IL. [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b A, E, L, and Q may be compounds, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof, as defined herein (i.e., as defined in the First Aspect of the Invention, including all embodiments and specific features, and combinations thereof). In certain embodiments of the compounds of formula IG, formula IH, formula II, formula IJ, formula IK, or formula IL, Q is O.

[0079] The specific compounds of the present invention that may be mentioned are R 3 However, it is methyl, and R 2 and R 4 However, each is hydrogen and is a compound that can exhibit improved solubility properties. Therefore, specific compounds of the present invention that can be mentioned are compounds of formula IN, compounds of formula IO, or compounds of formula IP (for example, compounds of formula IN), [ka] In the formula, R 1 , R 5 , R 6 , R 7a, R 7b A, E, L, and Q may be compounds, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof, as defined herein (i.e., as defined in the First Aspect of the Invention, including all embodiments and specific features, and combinations thereof). In certain embodiments of the compounds of formula IN, formula IO, and formula IP, Q is O.

[0080] Other compounds of the present invention that may be mentioned are R 4 However, it is methyl, and R 2 and R 3 However, each is hydrogen and is a compound that can exhibit improved solubility characteristics. Therefore, in certain embodiments, the compound of formula I is a compound of formula IQ, a compound of formula IR, or a compound of formula IS, [ka] In the formula, R 1 , R 5 , R 6 , R 7a , R 7b A, E, L, and Q may be compounds, or pharmaceutically acceptable salts, solvates, or deuterated analogs thereof, as defined herein (i.e., as defined in the First Aspect of the Invention, including all embodiments and specific features, and combinations thereof). In certain embodiments of the compounds of formula IQ, formula IR, and formula IS, Q is O.

[0081] Specific compounds of the present invention that may be mentioned include compounds of formula I, where R 2 , R 3 , and R 4 However, each of these compounds is hydrogen.

[0082] In a particular embodiment, R 5The group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with 1, 2, or 3 deuterium atoms. For example, R 5 is hydrogen or methyl. Preferably, R 5 It is hydrogen.

[0083] In a particular embodiment, R 6 is hydrogen and halogens (e.g., F, 18 F, Cl, Br, or I), C 1-3 Alkyl (e.g., methyl, ethyl, or propyl), C 1-3 Alkyl groups consist of one or more halogens (e.g., F, 18 C is optionally substituted by an atom (e.g., -CF3) such as F, Cl, Br, or I. 1-3 Alkyl, -CH2N(R 12 Selected from the group consisting of )Ph and -CH2OCH2Ph.

[0084] In a particular embodiment, R 12 It is methyl.

[0085] In certain embodiments, Ph is phenyl.

[0086] Therefore, in a particular embodiment, R 6 These are hydrogen, -F, -Cl, -Br, -CH3, -CF3, [ka] It is selected from the group consisting of the following.

[0087] In other embodiments, R 6 It is hydrogen.

[0088] In a particular embodiment, R 7a and R 7b Each is independently selected from the group consisting of hydrogen and deuterium. For example, R 7a and R 7bEach of these is hydrogen.

[0089] Certain compounds of the first aspect of the present invention that may be mentioned (including all embodiments and specific features, as well as combinations thereof) are R 6 However, it is hydrogen, R 7a and R 7b However, each is independently selected from the group consisting of hydrogen and deuterium.

[0090] A particular embodiment of the present invention is a compound of formula I (including all embodiments and specific features, as well as combinations thereof), R 6 However, it is hydrogen, R 5 However, the group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with 1, 2, or 3 deuterium atoms. R 7a and R 7b However, each independently comprises a compound selected from the group consisting of hydrogen and deuterium.

[0091] A particular embodiment of the present invention is a compound of formula I (including all embodiments and specific features, as well as combinations thereof), R 2 , R 4 , and R 6 However, each of them is hydrogen, R 3 However, selected from the group consisting of hydrogen and methyl, R 5 However, the group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with 1, 2, or 3 deuterium atoms. R 7a and R 7b However, each independently comprises a compound selected from the group consisting of hydrogen and deuterium.

[0092] A particular embodiment of the present invention is a compound of formula I (including all embodiments and specific features, as well as combinations thereof), R 2 , R 3 , R 4 , and R 6 However, each of them is hydrogen, R 5 However, the group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with 1, 2, or 3 deuterium atoms. R 7a and R 7b However, each independently comprises a compound selected from the group consisting of hydrogen and deuterium.

[0093] A particular embodiment of the present invention is a compound of formula I (including all embodiments and specific features, as well as combinations thereof), R 2 , R 4 , and R 6 However, each of them is hydrogen, R 3 However, selected from the group consisting of hydrogen and methyl, R 5 However, the group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with 1, 2, or 3 deuterium atoms. R 7a and R 7b However, each independently comprises a compound selected from the group consisting of hydrogen and deuterium.

[0094] In a particular embodiment, R 2 , R 3 , R 4 , and R 6 Each of them is hydrogen, R 5 It is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl. R 7a and R 7bEach of these is independently selected from the group consisting of hydrogen and deuterium.

[0095] In a particular embodiment, R 2 , R 4 , and R 6 Each of them is hydrogen, R 3 It is selected from the group consisting of hydrogen and methyl, R 5 It is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl. R 7a and R 7b Each of these is independently selected from the group consisting of hydrogen and deuterium.

[0096] In a further specific embodiment, R 2 , R 3 , R 4 , R 6 R 7a and R 7b Each of them is hydrogen, R 5 The compound is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl.

[0097] In a further specific embodiment, R 2 , R 4 , R 6 R 7a and R 7b Each of them is hydrogen, R 3 It is selected from the group consisting of hydrogen and methyl, R 5 The compound is selected from the group consisting of hydrogen, methyl, ethyl, -CD3, and cyclopropyl.

[0098] In another embodiment, R 2 , R 3 , R 4 , R 5 , and R 6Each of them is hydrogen, R 7a and R 7b Each of these is independently selected from the group consisting of hydrogen and deuterium.

[0099] In another embodiment, R 2 , R 4 , R 5 , and R 6 Each of them is hydrogen, R 3 It is selected from the group consisting of hydrogen and methyl, R 7a and R 7b Each of these is independently selected from the group consisting of hydrogen and deuterium.

[0100] Other embodiments of the present invention include R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , and R 7b However, each of them contains hydrogen.

[0101] Other embodiments of the present invention include R 2 , R 4 , R 5 , R 6 , R 7a , and R 7b However, each is hydrogen, and R 3 However, it includes those that are methyl.

[0102] Particularly preferred compounds of the present invention (or their pharmaceutically acceptable salts, solvates, or deuterated analogs) are shown in Table 1 below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0103] Certain preferred compounds of the present invention (or their pharmaceutically acceptable salts, solvates, or deuterated analogs) are shown in Table 2 below. [Table 6] [Table 7]

[0104] Preferred compounds of the present invention (or their pharmaceutically acceptable salts, solvates, or deuterated analogs) are shown in Table 3 below. [Table 8]

[0105] The compounds of the present invention described herein may be prepared according to techniques well known to those skilled in the art, as described in the examples provided below.

[0106] Compounds of formula I may be obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions, either by analogy with processes known in the literature or according to standard techniques. In this regard, those skilled in the art may refer, in particular, to "Comprehensive Organic Synthesis" by BMTrost and I. Fleming, Pergamon Press, 1991.

[0107] For example, a process for preparing the compound of the present invention as defined above is provided, the process for the compound of formula II, [ka] The reaction with the compound of formula III, [ka] In the formula, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b A, E, and L are as defined above, and G 1 However, the reaction involves a suitable leaving group (such as a chlorine atom) and the presence of a suitable base (e.g., triethylamine) and a suitable solvent (e.g., dichloromethane), following a procedure known to those skilled in the art.

[0108] Similarly, compounds of formula II or III can be obtained from readily available starting materials using appropriate reagents and reaction conditions, either commercially available, known in the literature, or by analogy with the processes described herein or by conventional synthetic procedures, according to standard techniques.

[0109] For example, the compound of formula II is a reaction of the compound of formula IV, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 A, E, and L are as defined above, and P 1 However, a suitable protecting group (such as a tert-butyloxycarbonyl group) may be used, and it may be prepared by reaction with a suitable deprotecting agent (e.g., trifluoroacetic acid) in the presence of a suitable solvent (e.g., dichloromethane) according to procedures known to those skilled in the art.

[0110] Compounds of formula IV (for example, A is N, E is -C(O)-, and L is C) 1-3Compounds that are alkyl (e.g., methyl), 4-6 membered cycloalkylene, 4-6 membered heterocycloalkylene, arylene, or heteroarylene are compounds of formula V. [ka] The reaction with the compound of formula VI, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and P 1 However, as defined above, it may also be prepared by a reaction using a suitable coupling agent (e.g., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) in the presence of a suitable base (e.g., N,N-diisopropylethylamine) and a suitable solvent (e.g., dichloromethane and dimethylformamide), according to procedures known to those skilled in the art.

[0111] The compound of formula V is a reaction of the compound of formula VII, [ka] In the formula, R 1 , R 2 , R 3 , and R 4 However, as defined above, P 2 However, a suitable protecting group (such as a tert-butyloxycarbonyl group) may be used, and it may be prepared by reaction with a suitable deprotecting agent (e.g., trifluoroacetic acid) in the presence of a suitable solvent (e.g., dichloromethane) according to procedures known to those skilled in the art.

[0112] The compound of formula VII is the same as the compound of formula VIII. [ka] The reaction with the compound of formula IX, [ka] In the formula, Q, R 1 , R 2 , R 3 , R 4 , and P 2 However, as stated above, G 2 However, a suitable leaving group (such as a chlorine atom) may be used, and it may be prepared by a reaction in the presence of a suitable base (e.g., triethylamine) and a suitable solvent (e.g., dichloromethane) according to a procedure known to those skilled in the art.

[0113] The compounds of formulas VIII and IX may be obtained by conventional synthetic procedures from commercially available starting materials, known in the literature, or by appropriate reagents and reaction conditions according to standard techniques.

[0114] Alternatively, the compound of formula VII where Q is O is the compound of formula X. [ka] A reaction with the compound of formula IX as defined above, where R 1 However, as defined above, M 1 However, a suitable metal cation (such as a sodium cation) may be prepared by a reaction in the presence of a suitable halide reagent (e.g., iodine) and a suitable solvent (e.g., ethanol), according to a procedure known to those skilled in the art.

[0115] The compound of formula X may be commercially available, known in the literature, or obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, the compound of formula X may be obtained by the reaction of the compound of formula XI, [ka] In the formula, R 1However, as defined above, it may also be prepared by a reaction of a suitable base (e.g., sodium ethoxide) in the presence of a suitable solvent (e.g., ethanol) according to a procedure known to those skilled in the art.

[0116] The compound of formula XI may be commercially available, known in the literature, or obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, the compound of formula XI is obtained by the reaction of the compound of formula XII, [ka] In the formula, R 1 However, as defined above, it may also be prepared by a reaction with a suitable oxidizing agent (e.g., 3-chloroperbenzoic acid or Oxone®) in the presence of a suitable solvent (e.g., ethanol) according to procedures known to those skilled in the art.

[0117] The compound of formula XII may be commercially available, known in the literature, or obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, the compound of formula XII may be a compound of the compound of formula XIII. [ka] A reaction with the compound of formula XIV, [ka] In the formula, R 1 However, as defined above, J is a suitable halide atom (e.g., a Br atom), and may be prepared by a reaction in the presence of a suitable palladium coupling reagent (e.g., tris(dibenzylideneacetone)dipalladium(0)), a suitable diphosphine ligand (e.g., xanthophos), a suitable base (e.g., N,N-diisopropylethylamine), and a suitable solvent (e.g., toluene), according to a procedure known to those skilled in the art.

[0118] The compounds of formulas XIII and XIV may be obtained from commercially available starting materials, known in the literature, or by conventional synthetic procedures using appropriate reagents and reaction conditions according to standard techniques.

[0119] Alternatively, a compound of formula VII, where R 1 However, the following applies: [ka] X 1 However, -OR 9 The compound is a reaction of the compound of formula XV, [ka] In the formula, R 2 , R 3 , R 4 , X 2 , X 3 , Z 2 , Z 3 , Z 4 , and P 2 However, as defined above, it may also be prepared by reaction with a suitable metal alkoxide (e.g., sodium methoxide) in the presence of a suitable solvent (e.g., methanol) according to procedures known to those skilled in the art.

[0120] The compound of formula XV may be prepared according to the procedure for preparing the compound of formula VII as described herein.

[0121] Alternatively, compounds of formula IV (for example, A is N or CH, E is directly bonded or -C(O)-, and L is directly bonded, C) 1-3 Alkylenes (e.g., methylene), or 4-6 membered cycloalkylenes, or L and R 5However, the compounds in which A, E, and L combine to form a 4-6 membered heterocycloalkylene group (e.g., an azetidinylene group), or the compounds in which A, E, and L combine to form a 4-6 membered cycloalkylene group (e.g., a cyclobutylene group), are reactions of the compounds of formula XVI. [ka] In the formula, R 2 , R 3 , R 4 , R 5 A, E, L, and P 1 However, as defined above, it may also be prepared by a reaction of the compound of formula VIII as defined above with a suitable base (e.g., triethylamine) and a suitable solvent (e.g., dichloromethane) in the presence of a suitable base, according to procedures known to those skilled in the art.

[0122] Alternatively, the compound of formula IV may be prepared by reacting the compound of formula XVI as defined above with a suitable heteroaryl (e.g., indole) in the presence of a suitable coupling agent (e.g., MSDI as described in Chem., A Eur Journal, 2019, 25, 8, 1906-1909), a suitable base (e.g., N,N-diisopropylethylamine), and a suitable solvent (e.g., dichloromethane), according to procedures known to those skilled in the art.

[0123] Alternatively, a compound of formula IV (for example, A is N, E is -C(O)-, and L is C) 1-3 Compounds with an alkylene (e.g., methylene) group are compounds of formula XVII. [ka] A reaction with a compound of formula XVI as defined above, where R 1However, as defined above, it may be prepared by a reaction in the presence of a suitable chlorinated reagent (e.g., thionyl chloride), a suitable base (e.g., triethylamine), and a suitable solvent (e.g., dichloromethane), according to procedures known to those skilled in the art.

[0124] The compound of formula XVII may be obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions, either commercially available, known in the literature, or according to standard techniques. For example, the compound of formula XVII may be obtained by the reaction of the compound of formula XVIII, [ka] In the formula, R 1 However, as defined above, it may also be prepared by a reaction of a suitable oxidizing agent (e.g., 3-chloroperbenzoic acid) in the presence of a suitable solvent (e.g., dichloromethane) according to procedures known to those skilled in the art.

[0125] The compounds of formula XVIII may be commercially available, known in the literature, or obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, the compounds of formula XVIII may be prepared by the reaction of the compound of formula XIII as defined above with a suitable sulfonylation reagent (e.g., 1,4-diazabicylco[2.2.2]octanbis(sulfur dioxide) adduct) in the presence of a suitable palladium coupling reagent (e.g., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)), a suitable base (e.g., N-cyclohexyl-N-methylcyclohexamine), and a suitable solvent (e.g., isopropanol), according to procedures known to those skilled in the art.

[0126] In addition, a process is provided for the preparation of the compounds of the present invention as defined above (for example, those compounds of the present invention in which A is N and E is -C(O)-), the process for the compound of formula V, [ka] The reaction with the compound of formula XIX, [ka] In the formula, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b The reaction involves a suitable base (e.g., N,N-diisopropylethylamine), a suitable coupling agent (e.g., (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)), a suitable base (e.g., N,N-diisopropylethylamine), and a suitable solvent (e.g., N,N-dimethylformamide), in the presence of a suitable base (e.g., N,N-diisopropylethylamine), in the presence of base (e.g., N,N-diisopropylethylamine), in the presence of a suitable solvent (e.g., N,N-dimethylformamide), in the presence of a suitable base (e.g., N,N-diisopropylethylamine).

[0127] The compound of formula XIX may be obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions, either commercially available, known in the literature, or according to standard techniques. For example, the compound of formula XIX may be obtained by the reaction of a compound of formula XX, [ka] In the formula, R 5 , R 6 , R 7a , and R 7b However, as defined above, R 16 However, C 1-3 The alkyl (e.g., ethyl) group may be prepared by reaction with a suitable base (e.g., potassium hydroxide) in the presence of a suitable solvent (e.g., ethanol) according to procedures known to those skilled in the art.

[0128] Compounds of formula XX may be commercially available, known in the literature, or obtained by conventional synthetic procedures from available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, compounds of formula XX may be obtained from compounds of formula XXI. [ka] A reaction with the compound of formula III as defined above, where R 5 and R 16 However, as defined above, it may be prepared by a reaction in the presence of a suitable base (e.g., N,N-diisopropylethylamine) and a suitable solvent (e.g., tetrahydrofuran) according to a procedure known to those skilled in the art.

[0129] Compounds of formulas XX and XXI may be obtained by conventional synthetic procedures from commercially available starting materials, known in the literature, or by appropriate reagents and reaction conditions according to standard techniques.

[0130] In addition, R 6 However, it is hydrogen, R 7a and R 7b A process is provided for the preparation of the compound of the present invention, wherein both are deuterium, and the process is a reaction of the compound of formula XXII, [ka] In the formula, Q, R 1 , R 2 , R 3 , R 4 , R 5 A, E, and L are as defined above, and each R 17 However, independently, C 1-3 The reaction involves an alkyl (e.g., ethyl) group reacting with a suitable deuterium source (e.g., paraformaldehyde d2) in the presence of a suitable base (e.g., lithium hydroxide monohydrate and / or potassium hydroxide) and a suitable solvent (e.g., a mixture of tetrahydrofuran and water) according to a procedure known to those skilled in the art.

[0131] The compound of formula XXII is the reaction of the compound of formula II, as defined above, with the compound of formula XXIIII, [ka] In the formula, R 17 However, as defined above, it may also be prepared by a reaction using a suitable coupling agent (e.g., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) in the presence of a suitable base (e.g., N,N-diisopropylethylamine) and a suitable solvent (e.g., dichloromethane and dimethylformamide), according to procedures known to those skilled in the art.

[0132] The compound of formula XXIII may be obtained by conventional synthetic procedures from commercially available starting materials, known in the literature, or by appropriate reagents and reaction conditions according to standard techniques.

[0133] Those skilled in the art will understand that in the processes described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups. Protection and deprotection of functional groups may be carried out before or after the above reactions.

[0134] Protecting groups can be removed according to techniques well known to those skilled in the art and the techniques described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The use of protecting groups is well described in “Protective Groups in Organic Synthesis”, 3rd edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (1999).

[0135] Therefore, certain transformation steps that may be used to form the compound of formula I include deprotection steps such as deprotection of the N-Boc protecting group by reaction in the presence of an acid, or deprotection of a hydroxyl group protected as a silyl ether (e.g., a tert-butyl-dimethylsilyl protecting group) by reaction with a source of acid or fluoride ions, for example by using the reagent tetrabutylammonium fluoride (TBAF).

[0136] The compounds of the present invention can be isolated from the reaction mixture and, if necessary, purified using prior art known to those skilled in the art. Accordingly, the process for preparing the compounds of the present invention as described herein may include, as a final step, isolation and optionally purification of the compounds of the present invention.

[0137] Pharmaceutical preparations As described herein, the compounds of the present invention are useful as therapeutic agents for treating various medical disorders or conditions. Typically, the compounds of the present invention are administered to subjects in need in the form of pharmaceutical formulations.

[0138] According to a second aspect of the present invention, a pharmaceutical formulation comprising a compound of formula I (or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof) is provided. Such a formulation is referred to herein as the formulation of the present invention. All embodiments and specific features described herein relating to the first aspect of the present invention are disclosed herein relating to a third aspect of the present invention.

[0139] Pharmaceutical formulations according to a second aspect of the present invention may be prepared in accordance with standard and / or acceptable pharmaceutical practices.

[0140] Formulations according to a second aspect of the present invention are generally provided as a mixture comprising the compound of the present invention (or a pharmaceutically acceptable salt solvate or deuterated analog thereof) and one or more pharmaceutically acceptable excipients, carriers, or diluents. The one or more pharmaceutically acceptable excipients, carriers, or diluents may be selected in accordance with standard pharmaceutical practice, taking into account the intended route of administration. Such pharmaceutically acceptable excipients, carriers, or diluents are preferably chemically inert to the active compound and preferably have no adverse side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations are, for example, Remington, The Science and Practice of Pharmacy, 19 th This can be found in ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief overview of drug delivery methods can also be found, for example, in Langer, Science 249, 1527 (1990).

[0141] Suitable pharmaceutically acceptable carriers are well known in the field of pharmaceuticals. The carrier(s) must be “acceptable” in the sense that they are compatible with the compounds of the present invention and must not be harmful to their recipient. Typically, the carrier is sterile, pyrogen-free water or saline solution, however, other acceptable carriers may be used. Thus, “pharmaceutically acceptable carriers” and “pharmaceutically acceptable excipients” include any compound(s) used to form part of a formulation that is intended to function merely as a carrier, i.e., not intended to have biological activity of its own. pharmaceutically acceptable carriers or excipients are generally safe, non-toxic, and not biologically or otherwise undesirable. pharmaceutically acceptable carriers or excipients as used herein include both one and more than one such carrier or excipient.

[0142] Excipients may be one or more of carbohydrates, polymers, lipids, and inorganic substances. Examples of carbohydrates include lactose, sucrose, mannitol, and cyclodextrin, which are added to compositions to facilitate freeze-drying. Examples of polymers include starch, cellulose ethers, cellulose carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, alginates, carrageenan, hyaluronic acid and their derivatives, polyacrylic acid, polysulfonates, polyethylene glycol / polyethylene oxide, polyethylene oxide / polypropylene oxide copolymers, polyvinylalcol / polyvinyl acetate with different degrees of hydrolysis, and polyvinylpyrrolidone, all of which have different molecular weights and are added to formulations, for example, for viscosity control, to achieve bioadhesion, or to protect lipids from chemical and proteolytic degradation. Examples of lipids include fatty acids, phospholipids, mono, di, and triglycerides, ceramides, sphingolipids and glycolipids, all with different acyl chain lengths and saturations, egg lecithin, soy lecithin, hydrogenated egg lecithin and hydrogenated soy lecithin, which are added to compositions for similar reasons as polymers. Examples of inorganic substances include talc, magnesium oxide, zinc oxide and titanium dioxide, which are added to compositions to obtain advantages such as reduced liquid accumulation or favorable pigment properties.

[0143] The term “diluent” is intended to mean an aqueous or non-aqueous solution used for diluting peptides in a pharmaceutical preparation. The diluent may be one or more of the following: physiological saline, water, polyethylene glycol, propylene glycol, ethanol, or oil (such as safflower oil, corn oil, peanut oil, cottonseed oil, or sesame oil).

[0144] Diluents can also function as buffers. The term “buffer” is intended to mean an aqueous solution containing an acid-base mixture for the purpose of stabilizing the pH. Examples of buffers include Trizma, Bicine, Tricin, MOPS, MOPSO, MOBS, Tris, Hepes, HEPBS, MES, Phosphate, Carbonate, Acetate, Citrate, Glycolate, Lactate, Borate, ACES, ADA, Tartrate, AMP, AMPD, AMPSO, BES, CABS, Cacodilate, CHES, DIPSO, EPPS, Ethanolamine, Glycine, HEPPSO, Imidazole, Imidazole Lactate, PIPES, SSC, SSPE, POPSO, TAPS, TABS, TAPSO, and TES.

[0145] Formulations according to a second aspect of the present invention may be conveniently presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. Such methods include the step of associating an active ingredient (i.e., a compound according to a first aspect of the present invention) with a carrier constituting one or more accessory components. Generally, formulations are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, or a finely divided solid carrier, or both, and shaping the product as needed.

[0146] Formulations according to the present invention suitable for oral administration may be provided as separate units such as capsules, cachetes, or tablets, as powders or granules, as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, each containing a predetermined amount of the active ingredient. The active ingredient may also be provided as a bolus, lick, or paste. Those skilled in the art will understand that compounds for oral administration should preferably be formulated to be protected in the intestines and to allow for bioadsorption.

[0147] A preferred unit-dose formulation contains a daily dose or unit, a daily unit subdose, or an appropriate fraction thereof of the active ingredient.

[0148] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Formulations may be supplied in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Immediate injection solutions and suspensions may be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0149] For the treatment of eye diseases and conditions, the compounds may be formulated according to routine procedures as pharmaceutical compositions adapted for application to the eye. Thus, the pharmaceutical compositions may be for topical ophthalmic use, such as aqueous eye drops, oily eye drops, eye ointments, eye lotions, ocusert, hydrogel contact lenses, collagen shields, and eye rods.

[0150] Topical compositions for the eye typically have a pH in the range of 4.5 to 8.0. Ophthalmic compositions also need to be formulated to have an osmotic pressure that is compatible with the aqueous humor and ocular tissue of the eye. Such an osmotic pressure is generally in the range of about 200 to about 400 milliosmoles ("mOsm / kg") per kilogram of water, but preferably about 300 mOsm / kg.

[0151] In yet another embodiment, the compounds of the present invention can be delivered by a controlled release system. For example, a pump may be used (see Langer, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987), Buchwald et al., Surgery 88:507 (1980), and Saudek et al., N. Engl. J. Med. 321:574 (1989), the disclosures of which are incorporated by reference).

[0152] In another embodiment, polymer materials may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974), Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984), Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983), and also see Levy et al., Science 228:190 (1985), During et al., Ann. Neurol. 25:351 (1989), and Howard et al., J. Neurosurg. 71:105 (1989), the disclosures of which are incorporated by reference).

[0153] Those skilled in the art will understand that the formulations of the present invention may contain one or more additional active agents, such as anti-inflammatory agents, local anesthetics, and antibiotics.

[0154] The compounds of the present invention may be formulated at various concentrations depending on the efficacy of the specific compound used. Preferably, the composition contains the compound at concentrations of about 1 nM to about 1 M, for example, about 0.1 μM to about 1 mM, about 1 μM or about 100 μM, about 5 μM to about 50 μM, about 10 μM to about 50 μM, about 20 μM to 40 μM, or about 30 μM. For ex vivo and in vitro applications, the composition may also contain, for example, a low concentration of modified osteopontin polypeptide of about 0.0025 μM to about 1 μM.

[0155] As used herein, the term “approximately” refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of a specified amount when referring to a measurable value such as the amount, dose, time, or temperature of a compound. In each case, such a term may be replaced by notation such as “±10%” (or by indicating a variation of a particular amount calculated based on the relevant value). In each case, such a term may also be deleted.

[0156] To avoid any doubt, in the context of the present invention, the dose administered to a subject, particularly a human subject, must be sufficient to achieve a therapeutic response in the subject over a reasonable time frame. Those skilled in the art will recognize that the precise dose and composition, as well as the selection of the most appropriate delivery regimen, are also influenced, among other things, by the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical and mental state of the recipient, as well as the potency of the particular compound, the age, condition, weight, sex, and response of the subject being treated, and the stage / severity of the disease.

[0157] In any case, physicians or other persons skilled in the art will be able to routinely determine the most appropriate actual dosage for individual subjects. The above dosages are examples of average cases, and naturally, there may be individual cases where a higher or lower dosage range is appropriate, and such cases are within the scope of the present invention.

[0158] medical use As described herein, the compounds of the present invention are useful as pharmaceuticals. The compounds of the present invention are useful because they have pharmacological activity and / or are metabolized in the body after oral or parenteral administration to form compounds that have pharmacological activity.

[0159] Accordingly, according to a third aspect of the present invention, a compound of the present invention as defined above herein (i.e., a compound as defined in the first aspect of the present invention), or a pharmaceutical formulation as defined with respect to a second aspect of the present invention, is provided for use in medicine. To avoid doubt, references to the compound as defined in the first aspect of the present invention include references to the compound of formula I (including all embodiments thereof) and its pharmaceutically acceptable salts, solvates, and deuterated analogs.

[0160] The compounds of the present invention (i.e., compounds as defined in the first aspect of the present invention) are inhibitors of transglutaminase enzymes such as TG2 (i.e., tissue transglutaminase), as demonstrated by the data of the examples. Eight transglutaminase enzymes are currently known (TG1-7 and factor XIII). "Transglutaminase" includes enzymes defined according to the Enzyme Committee System of Classification 2.3.2.13.

[0161] The term “transglutaminase enzyme inhibitor” (or “transglutaminase inhibitor”) includes any compound that partially or completely inhibits the transamidation activity of the transglutaminase enzyme (preferably in vivo).

[0162] In a preferred embodiment, the transglutaminase enzyme is TG2.

[0163] Inhibition of TG2's transamidation activity also results in partial or total inhibition of the enzyme's GTP-binding activity. TG2's transamidase activity is inhibited by inhibitor binding at the transamidase site, and GTP binding is blocked because the inhibitor interaction at the transamidase site locks the protein in an elongated / open conformation, dismantling / inactivating the GTP-binding / GTPase site (Kerr et al. 2017, Seo et al. 2019).

[0164] The transglutaminase enzyme, for example TG2, is preferably human.

[0165] In one embodiment, the compound of the present invention is an irreversible inhibitor of TG2.

[0166] In one embodiment, the compound of the present invention is a selective inhibitor of TG2. “Selective” means that the compound inhibits TG2 (preferably human TG2) to a greater extent than other transglutaminase enzymes such as factor XIII, TG1, and TG3. Advantageously, the compound inhibits the IC of other transglutaminase enzymes such as factor XIIIa, TG1, and TG3. 50 ICs with a TG2 (preferably human TG2) that is at least one order of magnitude lower than 50 This indicates.

[0167] Therefore, the compounds of the present invention and formulations containing them may be particularly useful for treating disorders or conditions that respond to treatment with transglutaminase inhibitors. Accordingly, a fourth aspect of the present invention provides a method for treating or preventing a disease or condition that responds to treatment with transglutaminase inhibitors, comprising administering the compounds of the present invention (or formulations containing said compounds) to a subject (e.g., a human) that requires such treatment.

[0168] Similarly, the use of the compounds of the present invention or formulations containing such compounds is provided in the manufacture of agents for the treatment or prevention of diseases or conditions that respond to treatment with transglutaminase inhibitors.

[0169] In a further alternative fourth embodiment of the present invention, compounds of the present invention, or formulations containing such compounds, are provided for use in the treatment or prevention of diseases or conditions that respond to treatment with transglutaminase inhibitors.

[0170] For example, a disease or condition may be responsive to treatment with TG2 inhibitors.

[0171] In one embodiment, the disease or condition is responsive to treatment with angiogenesis inhibitors. Therefore, the compounds of the present invention may be used for angiogenesis, particularly pathological angiogenesis (i.e., novel vascular formulations related to disease or disorder, see Chung & Ferrera, 2011, Ann. Rev. Cell Dev. Biol. 27:563-584, the disclosure of which is incorporated herein by reference).

[0172] "Inhibiting angiogenesis" means that administration of the compound can at least partially reduce the formation of new blood vessels in vivo. Therefore, the compound may inhibit in vivo angiogenesis by at least 10%, e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more, compared to the level of angiogenesis in the absence of the compound. It should be understood that inhibition may require repeated (i.e., chronic) administration of the compound.

[0173] In further embodiments, the disease or condition is selected from the group consisting of diseases or conditions related to fibrosis (such as cystic fibrosis, cardiac fibrosis, renal fibrosis, hepatic fibrosis, and pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)), scarring, neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, and Parkinson's disease), autoimmune diseases (such as multiple sclerosis and celiac disease), thrombosis, proliferative disorders (such as cancer), AIDS, psoriasis, inflammation (such as chronic inflammatory diseases, e.g., inflammatory bowel disease, e.g., Crohn's disease), pulmonary hypertension, and pathological angiogenesis.

[0174] For example, the disease or condition may be fibrosis. Specific fibrous diseases that may be mentioned include cystic fibrosis, cardiac fibrosis, renal fibrosis (e.g., chronic kidney disease (including chronic kidney disease associated with Alport syndrome), and diabetic nephropathy), hepatic fibrosis, and pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis). In certain embodiments, the disease or condition is idiopathic pulmonary fibrosis or cardiac fibrosis, preferably idiopathic pulmonary fibrosis.

[0175] Alternatively, the disease or condition may be a neurodegenerative disease (such as Alzheimer's disease, Huntington's disease, or Parkinson's disease).

[0176] In a further alternative embodiment, the disease or condition is an autoimmune disease (such as multiple sclerosis or celiac disease).

[0177] In one embodiment, the disease or condition is associated with pathological angiogenesis. "Pathological angiogenesis-associated disease or disorder" means a disease or disorder in which abnormal or alternative undesirable angiogenesis occurs such that partial or complete inhibition of angiogenesis results in a beneficial effect on the patient (e.g., alleviating one or more symptoms and / or slowing or preventing the progression of the disease or disorder).

[0178] For example, the disease or condition may be selected from the group consisting of hemangiomas, psoriasis, Kaposi's sarcoma, ocular angiogenesis, rheumatoid arthritis, endometriosis, atherosclerosis, and tumor growth and metastasis.

[0179] In one embodiment, the disease or condition may be cancer.

[0180] For example, cancer may be associated with solid tumors (such as prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, cervical cancer, esophageal cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, and sarcoma).

[0181] In a further embodiment, the disease or condition is an eye disease or condition such as a disease or disorder of the retina and / or choroid.

[0182] Therefore, the disease or condition may be retinopathy.

[0183] For example, the disease or condition may be selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, central retinal vein occlusion, sickle cell retinopathy, branch retinal vein occlusion and central retinal vein occlusion, and retinal trauma.

[0184] Alternatively, the disease or condition may be selected from the group consisting of chronic inflammation or infection (e.g., HSV infection of the ocular surface resulting in angiogenesis), corneal scarring, wound repair, pterygium, and neovascular glaucoma (i.e., proliferation of blood vessels on the iris and into the anterior chamber angle, iris lobeosis).

[0185] In a further embodiment, the disease or condition may respond to treatment with a factor XIII inhibitor. For example, the disease or condition may be associated with the formation of fibrin thrombi.

[0186] It will be understood that the compound needs to be administered in a therapeutically effective dose to inhibit transglutaminase activity (at least partially). As used herein, “therapeutically effective dose,” “effective dose,” or “therapeutably effective” refers to the amount that provides a therapeutic effect (through inhibition of transglutaminase activity) for a given condition and administration regimen. This is a predetermined amount of the compound of the present invention calculated to produce the desired therapeutic effect in relation to the necessary additives and diluents, i.e., the carrier or administration vehicle. Furthermore, it is intended to mean an amount sufficient to mitigate, and most preferably prevent, clinically significant deficits in the activity, function, and response of the subject. Alternatively, a therapeutically effective dose is an amount sufficient to produce a clinically significant improvement in the condition of the subject. As will be understood by those skilled in the art, the amount of compound may vary depending on its particular activity. A preferred dose may contain a predetermined amount of the active composition calculated to produce the desired therapeutic effect in relation to the necessary diluents. In the production and use of the compositions of the present invention, a therapeutically effective dose of the active ingredient is provided. The therapeutically effective dose can be determined by a conventionally skilled medical or veterinary professional based on patient characteristics such as age, weight, sex, condition, comorbidities, and other diseases, as is well known in the art.

[0187] Suitable diseases and conditions in which the compound may be used are specified above with respect to a fourth aspect of the present invention.

[0188] Preferably, the compound according to the first aspect of the present invention or the pharmaceutical formulation according to the second aspect of the present invention is administered in an amount sufficient to at least partially inhibit tTGase-mediated protein modification (i.e., crosslinking). More preferably, the compound or formulation is administered in an amount sufficient to inhibit tTGase-mediated protein crosslinking by at least 10%, for example, at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. Most preferably, the compound or formulation is administered in an amount sufficient to completely inhibit tTGase-mediated protein crosslinking.

[0189] TGase-mediated protein modification can be measured by methods known in the art. For example, the detection of the isodipeptide ε(γ-glutamyl)lysine in body fluids can be used as an indirect measure of the frequency of crosslinking in diseases involving this protein crosslinking. Thus, a reduction in isodipeptides in body fluids provides an indirect measure of reduced protein crosslinking (see Nemes et al., 2002, Minerva Biotechnology 14, 183).

[0190] Alternatively, tissue biopsies may be taken and analyzed, for example, by ion exchange or reverse-phase HPLC after proteolytic digestion of the material (Griffin & Wilson, 1984, Mol. Cell Biochem. 58:37-49), or by staining biopsy sections and analyzing them by immunohistochemistry (Skill et al., 2001, 81:705-716).

[0191] In further embodiments, the compound or formulation is administered in an amount sufficient to at least partially inhibit angiogenesis.

[0192] For example, the subjects may have, or are at risk of developing, any of the following diseases or conditions selected from the group consisting of fibrosis (such as cystic fibrosis, hepatic fibrosis, cardiac fibrosis, renal fibrosis, and pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis)), scarring, neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, and Parkinson's disease), autoimmune diseases (such as multiple sclerosis and celiac disease), thrombosis, proliferative disorders (such as cancer), AIDS, psoriasis, inflammation (such as chronic inflammatory diseases, e.g., inflammatory bowel disease, e.g., Crohn's disease), and diseases or conditions associated with pathological angiogenesis.

[0193] It will be understood by those skilled in the art that treatment may be preventive and / or therapeutic. For example, the compounds and formulations of the present invention may be used to delay and / or prevent the onset of a disease / disorder in a subject being treated. Alternatively or additionally, the compounds and formulations of the present invention may be used to alleviate or eliminate the symptoms of a disease / disorder in a subject being treated.

[0194] Those skilled in the art will understand that such treatment or prevention is carried out in subjects that require it. The need for such treatment or prevention in a subject can be assessed by those skilled in the art using routine techniques. In the context of the present invention, “subjects requiring” the compounds of the present invention include subjects suffering from a disease or condition that responds to treatment with a transglutaminase inhibitor. As used herein, the terms “disease” and “condition” (as well as similar terms such as disorder, illness, medical problem, etc.) may be used interchangeably.

[0195] Those skilled in the art will further understand that the compounds or formulations of the first and second embodiments of the present invention may each be administered by any route known or developed in the art. For example, the compounds or formulations may be administered by parenteral injection (e.g., intravenous, subcutaneous, or intramuscular), orally, topically, or by inhalation.

[0196] In one embodiment, the compound or formulation is administered systemically, for example, intravenously. Alternatively, the compound or formulation is administered locally, for example, at or near the target site where TGase-mediated protein modification is inhibited.

[0197] Treatment with the compound or formulation according to the present invention may consist of a single dose or multiple doses over a period of time. Advantageously, the compound or formulation may be administered repeatedly.

[0198] The compounds and formulations of the present invention may also be administered by a surgically implanted device that directly releases the compound or formulation to the required site, for example, near a solid tumor.

[0199] Those skilled in the art will understand that the compounds of the present invention can be used to treat any mammal. Preferably, the subject is human. Alternatively, the subject may be a dog, cat, horse, or other domestic or farm mammal.

[0200] A further aspect of the present invention provides a method for preventing or treating rejection of a transplanted organ, comprising contacting the organ with a compound according to a first aspect of the present invention or a formulation according to a second aspect of the present invention. Accordingly, the present invention provides the use of a compound according to a first aspect of the present invention in the preparation of a drug for preventing or treating rejection of a transplanted organ.

[0201] In one embodiment, the organ is the heart, lungs, kidneys, or liver.

[0202] Therefore, the organ may be a kidney. Transplanted kidneys often show upregulation of TG2 and possibly several other transglutaminases. Furthermore, kidneys rejected after transplantation often show excessive scarring and upregulation of transglutaminase activity and crosslinking (Abo-Zenah et al., 2001, J.Am.Soc.Nephrol.12, 4454A). Such tissue degeneration and subsequent organ rejection can be prevented by treating the kidney (or other organ) with transglutaminase inhibitors.

[0203] It will be understood that the compound or formulation may be delivered before, during, and / or after organ transplantation. In one embodiment, the organ is treated before transplantation, for example, by perfusion and / or immersion with a solution containing the compound according to the first aspect of the present invention.

[0204] In alternative embodiments, the organ is treated during and / or after transplantation to the patient. Advantageously, the compound or formulation is delivered to or near the transplant site, for example, by topical administration.

[0205] As described herein, the present invention encompasses isotope-labeled compounds of formula I. In particular, fluorine-18 (i.e., 18F) Compound, i.e., compound of formula I. Thus, certain compounds of the present invention may be useful in vivo imaging to enable the diagnosis of a disease or condition in imaging techniques such as, but not limited to, positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS). Specific diseases or conditions that may be mentioned are diseases or conditions that are responsive to treatment with transglutaminase inhibitors (e.g., diseases or conditions associated with fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, proliferative disorders, AIDS, psoriasis, inflammation, and pathological angiogenesis). Isotope-labeled compounds of the present invention may also be used to measure the clinical efficacy of therapeutic agents useful for treating diseases or conditions that are responsive to treatment with transglutaminase inhibitors.

[0206] Certain compounds of formula I may also be suitable as precursors for isotope-labeled compounds of formula I. Therefore, compounds of formula I (e.g., X) may be used as synthetic precursors in the process of preparing isotope-labeled compounds. 1 , X 2 , X 3 , X 5 , X 6 , X 7 , and X 8 The use of compounds of formula I, where at least one of them is -OCHFCl or -OH if present, is provided. Preferably, the label is 18 It is a fluorine atom.

[0207] While we do not wish to be bound by theory, the compounds of the present invention are considered to be potent inhibitors of transglutaminase, as demonstrated by the data from the examples. In addition, the compounds of the present invention are considered to be relatively bioavailable. Accordingly, the compounds of the present invention have been found to have remarkably improved pharmacokinetic properties compared to known TG2 inhibitors.

[0208] The compounds of the present invention (and their formulations) may have advantages over other therapies known in the prior art, whether for use in the above indications or otherwise, such as being more effective, less toxic, longer-acting, more potent, having fewer side effects, being more easily absorbed, and / or having a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or having other useful pharmacological, physical, or chemical properties. In particular, the compounds of the present invention may have the advantage of being more effective and / or exhibiting advantageous properties in vivo.

[0209] In certain embodiments, the present invention may be defined according to the following paragraphs.

[0210] 1. A compound of formula I, [ka] During the ceremony, Q is selected from the group consisting of O and NH. A is selected from the group consisting of N and CH. E represents a direct bond or -C(O)-, L is directly bonded, or C 1-3 It represents a group selected from the group consisting of alkylene, 4-6 membered cycloalkylene, 4-6 membered heterocycloalkylene, arylene, and heteroarylene. Alternatively, A, E, and L may combine to form a 4-6 membered cycloalkylene group. R 1 However, this represents a 9-membered bicyclic heteroaryl group that is optionally substituted with one or more X groups. Each X independently controls halogen, -N(R) 8a )R 8b , -OR 9 , -C(O)OR 10 ,-C(O)N(R 11a )R 11b , C 1-4 Alkyl alkyl groups, and C 3-6Selected from the group consisting of cycloalkyl groups, C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms. R 2 , R 3 , and R 4 However, each independently, hydrogen and C 1-3 Selected from the group consisting of alkyl groups, C 1-3 The alkyl group is optionally substituted with one or more halogen atoms, or R 2 and R 3 However, together with the carbon atoms to which they are bonded, they form a 5- or 6-membered heterocycloalkyl group, or R 2 and R 4 However, together with the carbon atoms to which they are bonded, they form a 5- or 6-membered heterocycloalkyl group. R 5 However, hydrogen, C 1-3 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls, C 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with one or more groups selected from the group consisting of deuterium atoms and halogen atoms, or L and R 5 However, R 5 Together with the nitrogen atom to which it is bonded, it forms a 4-6 membered heterocycloalkylene group. R 6 However, hydrogen, halogens, deuterium, and C 1-3 Alkyl, C 1-3 C in which the alkyl group is optionally substituted with one or more halogen atoms. 1-3 Alkyl, -CH2N(R 12 Selected from the group consisting of )Ph and -CH2OCH2Ph, R 7a and R 7b However, each is independently selected from the group consisting of hydrogen, halogen, methyl, and deuterium. R8a , R 8b , R 9 , R 10 , R 11a , and R 11b However, each independently, hydrogen, C 1-3 Alkyl and C 3-6 Selected from the group consisting of cycloalkyls, C 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms, or or R 8a and R 8b Furthermore / or R 11a and R 11b However, together with the nitrogen atom to which they are bonded, they form a 3-6 member heterocycloalkyl group. R 12 However, hydrogen and C 1-3 Selected from the group consisting of alkyl groups, C 1-3 The alkyl group is optionally substituted with one or more halogen atoms. Ph is one or more halogen atoms or C 1-3 Phenyl is optionally substituted with an alkyl group, C 1-3 A compound in which an alkyl group is optionally substituted with one or more halogen atoms. or a pharmaceutically acceptable salt or solvate thereof.

[0211] 2. The compound described in paragraph 1, wherein Q is O.

[0212] 3. The 9-membered bicyclic heteroaryl group, (a) Containing one, two, three, or four ring heteroatoms independently selected from the group consisting of N and S, (b) The compounds described in paragraph 1 or 2, which are substituted with 0, 1, 2, 3, 4, or 5 X groups.

[0213] 4.R 1 but, [ka] Selected from the group consisting of, During the ceremony, Z 1 However, selected from the group consisting of C and N, Z 2 However, S, NR 13 , and CR 14 Selected from the group consisting of, Z 3 , Z 4 , and Z 5 However, each operates independently, CR 15 Or selected from the group consisting of N, X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , R 14 , and R 15 However, each independently, hydrogen, halogen, -OR 9 , C 1-4 Alkyl alkyl groups, and C 3-6 Selected from the group consisting of cycloalkyl groups, C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms. X 4 and R 13 However, each independently, hydrogen, C 1-4 Alkyl alkyl groups, and C 3-6 Selected from the group consisting of cycloalkyl groups, C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms. R 9 However, the compounds are defined in paragraph 1, or any one of the compounds described in paragraphs 1 to 3.

[0214] 5.R 1 but, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 13 , R 14 , and R 15 However, as defined in paragraph 4, any compound described in any one of paragraphs 1 to 4.

[0215] 6.R 1 but, [ka] Selected from the group consisting of, In the formula, X 1 , X 2 , X 4 , R 13 , R 14 , and R 15 However, the compounds described in any one of paragraphs 1 to 5, as defined in paragraph 4 or 5.

[0216] 7. X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , R 14 , and R 15 However, each independently, hydrogen, -OCH3, -OCHF2, -OCHF[ 18 F], -OCHFCl, -CF3, -OCH2F, -OCF3, -OCF2Cl, -OCH2CH3, -OCH(CH3)2, -OCD3, -OH, -CH3, -CH2CH3, -CH(CH3)2, [ka] - Selected from the group consisting of CD3, Cl, and F, X 4 and R 13However, each independently, hydrogen, -CH3, -CH2CH3, -CH(CH3)2, [ka] A compound selected from the group consisting of and -CD3, as described in any one of paragraphs 4 to 6.

[0217] 8. X 1 However, hydrogen, -OCH3, -OCHF2, -OCHF[ 18 Selected from the group consisting of F], -OCHFCl, -CF3, -OCH2F, -OCF2Cl, and -OH, X 4 However, selected from the group consisting of hydrogen -CH3 and -CH2CH3, R 14 However, it is selected from the group consisting of hydrogen, F, Cl, and -CH3, X 2 , R 13 , and R 14 However, each is independently selected from the group consisting of hydrogen and -CH3, X 3 , X 5 , X 6 , X 7 , and X 8 However, each of these compounds is hydrogen, as described in any one of paragraphs 1 to 7.

[0218] 9. A is N, E is a -C(O)- or direct bond, L, C 1-3 Alkylene, or L and R 5 However, R 5 A compound described in any one of paragraphs 1 to 8, which, together with the nitrogen atom to which it is bonded, forms an azetidine ring.

[0219] 10. A is N, -EL-linker, [ka] A compound that represents one of the items in paragraphs 1 to 9.

[0220] 11. A is CH, E is a direct bond, L is directly bonded, C 1-3 Represents alkylene, or L and R 5 However, R 5 A compound described in any one of paragraphs 1 to 8, which, together with the nitrogen atom to which it is bonded, forms an azetidine ring.

[0221] 12. A compound described in any one of paragraphs 1 to 8, wherein A, E, and L together form a cyclobutyl ring.

[0222] 13. R 2 , R 3 , and R 4 However, each is independently selected from the group consisting of hydrogen, methyl, and ethyl, or R 2 and R 4 However, the compounds described in any one of paragraphs 1 to 12, wherein they combine with the carbon atoms to which they are bonded to form a five-membered heterocycloalkyl group.

[0223] 14.R 5 The compound described in any one of paragraphs 1 to 13, wherein the group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with one, two, or three deuterium atoms.

[0224] 15. R 6 However, it is hydrogen, R 7a and R 7b However, the compounds described in any one of paragraphs 1 to 14 are independently selected from the group consisting of hydrogen and deuterium.

[0225] 16. The compound is [ka] [ka] A compound selected from the group consisting of the compounds described in paragraph 1, or a pharmaceutically acceptable salt or solvate thereof.

[0226] 17. A pharmaceutical preparation comprising a compound of formula Ia as defined in any one of paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0227] 18. Compounds of formula I as defined in any one of paragraphs 1 to 16, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical preparations as defined in paragraph 17, for use in medicine.

[0228] 19. A method for treating or preventing a disease or condition that responds to treatment with a transglutaminase inhibitor, comprising administering a compound of formula I as defined in any one of paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical formulation as defined in paragraph 17, to a subject in need thereof.

[0229] 20. The method according to paragraph 19, wherein the disease or condition that responds to treatment with a transglutaminase inhibitor is selected from the group consisting of diseases or conditions associated with fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, proliferative disorders, AIDS, psoriasis, inflammation, pulmonary hypertension, and pathological angiogenesis.

[0230] 21. The method according to paragraph 20, wherein the disease or condition is selected from the group consisting of cystic fibrosis, scarring, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, celiac disease, thrombosis, prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, cervical cancer, esophageal cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, sarcoma, AIDS, psoriasis, chronic inflammatory disease, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, central retinal vein occlusion, sickle cell retinopathy, branch retinal vein occlusion and central retinal vein occlusion, and retinal trauma.

[0231] 22. A method for preventing or treating rejection of a transplanted organ, comprising contacting the organ with a compound as defined in any one of paragraphs 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical preparation as defined in the paragraph, wherein the organ is, optionally, (a) Before transplantation, or (b) During and / or after transplantation in the patient, Preferably, the organ is the heart, lungs, kidneys, or liver.

[0232] 23. A process for preparing a compound of formula I as defined in any one of paragraphs 1 to 16, wherein the process is a compound of formula II, [ka] The reaction with the compound of formula III, [ka] In the formula, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b A, E, and L are defined in any one of paragraphs 1-16, and G 1However, a suitable leaving group is required for the reaction. (b) In the case of a compound of formula I where A is N and E is -C(O)-, the compound of formula V [ka] The reaction with the compound of formula XIXa, [ka] In the formula, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b , and L is as defined in any one of paragraphs 1 to 16, and M is a preferred metal atom, the reaction, (c)R 7a and R 7b In the case of the compound of formula I in which both are deuterium, the compound of formula XXII, [ka] A reaction with a suitable source of deuterium, where Q and R are present in the formula. 1 , R 2 , R 3 , R 4 , R 5 A, E, and L are defined in any one of paragraphs 1-16, and each R 17 However, independently, C 1-3 A process involving an alkyl group, including a reaction. [Examples]

[0233] The present invention will be described in more detail by the following non-limiting embodiments.

[0234] The reaction schemes described below are intended to provide a general description of the methodology used in the preparation of the compounds of the present invention. The examples provided herein are provided to illustrate, but are not limited to, the preparation of the compounds of the present invention, as well as such compounds and intermediates.

[0235] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be routinely prepared by procedures described in the literature, e.g., Houben-Weyl “Science of Synthesis” volumes 1-48, Georg Thieme Verlag, and subsequent versions. Commercially available reagents were used without further purification. Microwave reactions were performed using a CEM Discover (200W). Flash column chromatography was performed using a Biotage® Sfar silica (High Capacity Duo 20μm) cartridge pre-packaged for flash column chromatography. Ion exchange chromatography was performed using an Isolute® SCX2 cartridge. The organic layer was separated from the aqueous layer during workup using a Biotage® phase separator ("Phase Separator").

[0236] The reaction may be carried out in the presence of a suitable solvent or diluent, or a mixture thereof, in a manner known to those skilled in the art of organic synthesis. The reaction may also be carried out in the presence of an acid or base, as needed, and by cooling or heating, for example, in a temperature range of about -30°C to about 150°C. In some embodiments, the reaction is carried out in an open or closed reaction vessel and / or in an atmosphere of an inert gas, such as nitrogen, in a temperature range of about 0°C to about 100°C, more specifically, in a temperature range of room temperature to about 80°C.

[0237] Abbreviation The abbreviations used herein will be familiar to those skilled in the art. In particular, the following abbreviations may be used herein. [Table 9]

[0238] Analysis method Several compounds were purified by reverse-phase preparative HPLC-MS: mass-directed purification by preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18(2), 250×21.2 mm, 5 μm, or Waters Exbridge OBD C18, 250×19 mm, 5 μm).

[0239] The products and intermediates were analyzed using reversed-phase HPLC-MS with the parameters shown below.

[0240] HPLC analysis method: Method A: Anal pH 2 MeCN 2MIN: ACQUITY UPLC BEH C18 1.7μm, 50×2.1mm, A=Water + 0.1% Formic Acid, B=MeCN, 45℃, %B: 0.0 min 5% 0.6mL / min, 0.05 min 5% 0.6mL / min, 1.6 min 95% 0.6mL / min, 2.25 min 95% 0.75mL / min, 2.26 min 5% 0.6mL / min, 2.6 min 5% 0.6mL / min.

[0241] Method B: Anal pH 9 MeCN 2MIN: ACQUITY UPLC BEH C18 1.7μm, 50×2.1mm, A=10mM ammonium bicarbonate, B=MeCN, 45℃, %B: 0.0 min 5% 0.6mL / min, 0.05 min 5% 0.6mL / min, 1.6 min 95% 0.6mL / min, 2.25 min 95% 0.75mL / min, 2.26 min 5% 0.6mL / min, 2.6 min 5% 0.6mL / min.

[0242] Method C: AnalpH2_MeOH_4MIN: Waters Sunfire C18 3.5 μm, 50 x 4.6 mm, A = Water + 0.1% formic acid, B = MeCN, 45 °C, %B: 0.0 min 5% 2.25 mL / min, 1.0 min 37.5% 2.2 mL / min, 3.0 min 95% 2.2 mL / min, 3.5 min 95% 2.3mL / min, 3.51 minutes 100% 2.3mL / min, 4.0 minutes 100% 2.3mL / min.

[0243] Method D: Anal pH 2 MeOH 4 MIN: Phenomenex Luna C18(2) 3 μm, 50 × 4.6 mm, A = water + 0.1% formic acid, B = MeOH + 0.1% formic acid, 45℃, %B: 0 min 5% 2.25 mL / min, 1 min 37.5% 2.2 mL / min, 3 min 95% 2.2 mL / min, 3.5 min 95% 2.30 mL / min, 3.5 min 5% 2.3 mL / min, 4.0 min 5% 2.25 mL / min.

[0244] Method E:QC_AnalpH2_MeCN_8MIN:ACQUITY UPLC CSH C18 1.7 μm, 100 x 2.1 mm, A=water + 0.1% formic acid, B=MeCN, 45°C, %B: 0.0 min 5% 0.35 mL / min, 0.05 min 5% 0.35 mL / min, 5 min 95% 0.35mL / min, 6.5 min 95% 0.35mL / min, 6.6 min 5% 0.35mL / min, 9 min 5% 0.35mL / min.

[0245] Method F: AnalpH2_MeOH_QC_V1: Phenomenex Gemini NX C18(2) 5μm, 150×4.6mm, A=water + 0.1% formic acid, B=MeOH + 0.1% formic acid, 40℃, %B: 0 min 5% 1.5mL / min, 0.5 min 5% 1.5mL / min, 7.5 min 95% 1.5mL / min, 10 min 95% 1.5mL / min, 10.10 min 5% 1.5mL / min, 13.0 min 5% 1.5mL / min.

[0246] NMR spectrum: 1 ¹H-NMR: Spectra are acquired using a Jeol ECS 400 MHz or Bruker Avance 400 MHz spectrometer. Spectra are measured at 294 K (unless otherwise specified), and chemical shifts (δ values) are reported in parts per million (ppm). Coupling constants (J) are reported in Hertz (Hz), and spectral resolving patterns are shown as singlelines (s), doublelines (d), triplelines (t), quadruples (q), multilines or more overlapping signals (m), and broad signals (br), with the solvent indicated in parentheses.

[0247] General procedure A general route for preparing a specific example compound. An exemplary compound of formula I, R 2 , R 3 , R 4 , R 6 , R 7a , and R 7b However, each is hydrogen, Q is O, A is N, and the -EL-linker is [ka] The compound was synthesized according to the routes shown in schemes 1 and 2 below. [ka] [ka]

[0248] Other example compounds of formula I, for example, in which A is CH and E and L each represent direct bonds, were prepared by a similar method.

[0249] Preparation of intermediates (A) Literature intermediates A1 and A2. Intermediates A1 and A2 were synthesized according to the methods described in the literature, as shown in Table 4 below. [Table 10]

[0250] (B) Main intermediate A4. Synthesis of tert-butyl 4-chlorosulfonylpiperazine-1-carboxylate (A4) [ka] To a stirred solution of sulfuryl chloride (261 μL, 3.22 mmol) in DCM (10 mL) at 0°C, solutions of 1-Boc-piperazine (A3, 500 mg, 2.68 mmol) and pyridine (326 μL, 4.03 mmol) in DCM (10 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a 1 M HCl solution (50 mL). DCM (50 mL) was added to the solution, and the layers were separated. The aqueous layer was washed with DCM (2 × 25 mL), the organic layers were combined, dried, and concentrated under vacuum to obtain tert-butyl 4-chlorosulfonylpiperazine-1-carboxylate (A4, 616 mg, 81%) as a pale yellow solid, which was used without further purification.

[0251] (C) Acrylamide intermediate A7. The acrylamide intermediate potassium acryloylglycinate A7 was prepared from glycine ester hydrochloride A5 in two steps, as detailed in Scheme 3: [ka]

[0252] Example Step 7: Synthesis of ethyl acryloyl glycinate (A6) [ka] To a stirred suspension of glycine ethyl ester hydrochloride (A5, 1.00 g, 7.17 mmol) in anhydrous THF (9 mL), DIPEA (2.49 mL, 14.3 mmol) was added at 0°C, and the resulting mixture was stirred for 15 minutes. Acryloyl chloride (464 μL, 5.74 mmol) was added, and the temperature of the reaction mixture was slowly raised from 0°C to 45°C, and then heated at that temperature for 1 hour. The reaction mixture was then cooled to room temperature, washed with water (50 mL), and extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (50 mL), dried, and concentrated under vacuum in (Na₂SO₄). The crude residue was purified by silica gel column chromatography using 40-50% ethyl acetate in n-hexane to obtain ethyl acryloyl glycinate (A6, 600 mg, 67%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3):δ 6.32(dd, J=17.0, 1.4Hz, 1H), 6.16(dd, J=17.0, 10.2Hz, 1H), 5.69(dd, J=10.2, 1.4Hz, 1H), 4.23(q, J=7.1Hz, 2H), 4.12(d, J=5.1Hz, 2H), 1.29(t, J=7.1Hz, 3H).

[0253] Example Step 8: Synthesis of potassium acryloylglycinate (A7) [ka] Potassium hydroxide (313 mg, 5.60 mmol) was added to a stirred solution of ethyl acryloyl glycinate (A6, 585 mg, 3.72 mmol) in EtOH (2.3 mL) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the solvent was evaporated under vacuum, and the residue was washed with Et2O (2 × 10 mL). The solid was then filtered, washed again with Et2O (2 × 10 mL), and dried to obtain the compound potassium acryloylglycinate (A7, 443 mg, 71%) as a white solid. The compound was used without further purification. 1H NMR (400MHz, DMSO-d6): δ 7.44(s, 1H) 6.39(dd, J=17.1, 10.2Hz, 1H), 6.00(dd, J=17.1, 2.3Hz, 1H), 5.48(dd, J=10.2, 2.3Hz, 1H), 3.33(d, J=4.6Hz, 2H).

[0254] (D) Heteroaryl intermediate. Synthesis of 4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine (A9) [ka] Sodium carbonate (790 mg, 7.45 mmol) was added under nitrogen to a stirred suspension of 1H-pyrrolo[3,2-c]pyridine-4(5H)-one (A8, 250 mg, 1.86 mmol) in toluene (5 mL). The resulting mixture was heated at 60°C for 30 minutes, then cooled to room temperature, and trimethylsilylfluorosulfonyl difluoroacetate (1.40 g, 5.59 mmol) was added. The resulting reaction mixture was heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated, diluted with toluene (10 mL), washed with water (10 mL), and then washed with brine (10 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0-50% siRNA in isohexane to obtain 4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine (A9, 171 mg, 50%) as a grayish-white solid. LCMS(Method A)R t 1.48 minutes, (ESI + )m / z 185.2[M+H] + .

[0255] Synthesis of 4-chloro-3-fluoro-1H-pyrrolo[3,2-c]pyridine (A11) [ka] To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (A10, 300 mg, 1.97 mmol) dissolved in nitroethane (5 mL) at 0°C, Selectfluor (2.09 g, 5.90 mmol) was added in small amounts. The reaction mixture was warmed to room temperature, then stirred for 5 hours, after which Selectfluor (698 mg, 1.97 mmol) was added, and the mixture was stirred for a further 24 hours. The reaction mixture was quenched with ice water (20 mL) and neutralized with sodium hydroxide (1 M aqueous solution, 1 mL). The resulting mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude residue was pre-purified by silica gel column chromatography (25 g Sfar Biotage column) eluting with 0-50% ethyl acetate in isohexane, and then purified by reverse-phase chromatography. The fractions containing the desired product were mixed, and the solvent was evaporated under vacuum. The residue was dissolved in 1:1 MeCN-H2O (4 mL), and the solution was frozen. The solvent was evaporated under vacuum by freeze-drying to obtain 4-chloro-3-fluoro-1H-pyrrolo[3,2-c]pyridine (A11, 32.0 mg, 10%) as a white solid. LC-MS (Method A). R t 1.32 minutes, (ESI + )m / z 171.1, 173.0[M+H] + .

[0256] Synthesis of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (A13) [ka] 4-chloro-7H-pyrrolo(2,3-d)pyrimidine (A12, 150 mg, 0.977 mmol) was suspended in 0.5 M sodium methoxide (8.00 mL, 4.00 mmol) in MeOH, and the mixture was heated under reflux for 18 hours. During cooling to room temperature, the solvent was evaporated under vacuum, and the residue was partitioned between ELISA (50 mL) and saturated sodium bicarbonate aqueous solution (50 mL). The organic phase was washed with brine (50 mL), then dried to (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (A13, 100 mg, 69%) as a white solid. The compound was used without further purification. LC-MS (Method B). R t 1.19 minutes, (ESI + )m / z 150.1[M+H] + .

[0257] Intermediate compounds A14 and A15, shown in Table 5, were prepared from the corresponding commercially available chloro reagents using a procedure similar to that used to prepare compound A13, with reaction times ranging from 1 to 18 hours. [Table 11]

[0258] Synthesis of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (A17) [ka] Sodium methoxide (562 mg, 1.04 mmol) was added to a stirred solution of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (A16, 2.00 g, 8.02 mmol) in THF (15 mL) under argon at room temperature. The resulting mixture was heated at 60°C for 12 hours, then cooled to room temperature and concentrated under vacuum. The crude residue was diluted with ice-cold water (20 mL) and then extracted with siRNA (2 × 15 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude compound was purified by silica gel column chromatography using 10-20% siRNA in petroleum ether to obtain 7-bromo-4-methoxythieno[3,2-d]pyrimidine (A17, 1.00 g, 50%) as a grayish-white solid. 1 1H NMR (400MHz, CDCl3) 1 H NMR (400MHz, CDCl3) δ 8.90 (s, 1H), 7.88 (s, 1H), 4.22 (s, 3H).

[0259] Synthesis of 4-bromo-1-ethyl-1H-indazole (A19) [ka] To a stirred solution of 4-bromo-1H-indazole (A18, 5.00 g, 25.4 mmol) in DMF (30 mL) at 0°C, sodium hydride (1.32 g, 32.9 mmol) was added in small amounts over 15 minutes. The mixture was stirred for a further 15 minutes, and then iodoethane (2.64 mL, 32.9 mmol) was slowly added, and the resulting mixture was stirred for 4 hours. The reaction mixture was quenched by pouring it over crushed ice, and then extracted with HCl (50 mL). The combined organic layers were washed with brine (3 × 30 mL), dried, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography using 5-30% HCl in petroleum ether to obtain 4-bromo-1-ethyl-1H-indazole (A19, 3.50 g, 95%) as a pale yellow oil. 11H NMR (400MHz, CDCl3) 1 H NMR (400MHz, CDCl3)δ 8.00(d, J=1.0Hz, 1H), 7.36(dt, J=8.3, 0.9Hz, 1H), 7.29(dd, J=7.4, 0.8Hz, 1 H), 7.22 (dd, J=8.3, 7.4Hz, 1H), 4.42 (q, J=7.2Hz, 2H), 1.51 (t, J=7.3Hz, 3H).

[0260] Synthesis of 7-chlorothieno[2,3-c]pyridine-3-sulfonyl chloride (A21) [ka] 7-chlorothieno[2,3-c]pyridine (A20, 250 mg, 1.47 mmol) was suspended in 97% chlorosulfonic acid (3.00 mL, 45.1 mmol), and the mixture was heated at 100°C for 1.5 hours. The mixture was cooled to room temperature and poured onto ice water. The pH of the mixture was adjusted to 8 using an aqueous sodium hydroxide solution, and the mixture was extracted with toluene (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then dried, filtered, and concentrated under vacuum to obtain 7-chlorothieno[2,3-c]pyridine-3-sulfonyl chloride (A21, 200 mg, 51%) as a pale yellow, rubbery substance, which was used without further purification. LC-MS (Method B). R t 1.86 minutes, (ESI + )m / z 247.9, 249.9[M-H+O] + (Evidence of sulfonic acid formation).

[0261] (E) Sodium sulfinate intermediates A32-A34. Exemplary sodium sulfinates A32-A34 were prepared from the corresponding aryl bromides in three steps, as detailed in Scheme 4 below: [ka]

[0262] Example Step 9 - Preparation of sulfide: Synthesis of methyl 3-((4-methoxythieno[3,2-d]pyrimidine-7-yl)thio)propanoate (A26) [ka] A mixture of 7-bromo-4-methoxythieno[3,2-d]pyrimidine (A17, 1.00 g, 4.08 mmol), 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene (xanthophos, 236 mg, 0.408 mmol), tris(dibenzylideneacetone)dipalladium(0) (187 mg, 0.204 mmol), and DIPEA (1.5 mL, 8.16 mmol) in toluene (30 mL) was degassed under nitrogen for 5 minutes, and then methyl 3-mercaptopropionate (450 μL, 4.08 mmol) was added. The resulting mixture was heated at 70°C for 6 hours. During cooling, the reaction mixture was filtered through Celite, and the Celite pad was washed with 10% MeOH / DCM (20 mL). The resulting mixture was concentrated under vacuum to obtain a crude residue, which was purified by silica gel column chromatography using a gradient elution of 30-50% siRNA in n-hexane to obtain methyl 3-((4-methoxythieno[3,2-d]pyrimidine-7-yl)thio)propanoate (A26, 1.00 g, 86%) as a grayish-white solid. 1 1H NMR (400MHz, CDCl3) 1 H NMR (400MHz, CDCl3)δ 8.84(s, 1H), 7.75(s, 1H), 4.18(s, 3H), 3.67(s, 3H), 3.31(t, J=7.3Hz, 2H), 2.66(t, J=7.3Hz, 2H).

[0263] Intermediate compounds A27 and A28, shown in Table 6 below, were prepared from the corresponding aryl halide intermediate and methyl 3-mercaptopropionate using a procedure similar to that of Example Step 9 (for compound A26). [Table 12]

[0264] Example Step 10: Preparation of sulfone using Oxone®: Synthesis of methyl 3-((4-methoxythieno[3,2-d]pyrimidine-7-yl)sulfonyl)propanoate (A29) [ka] Oxone® (2.70 g, 8.8 mmol) was added at room temperature to a stirred solution of methyl 3-((4-methoxythieno[3,2-d]pyrimidine-7-yl)thio)propanoate (A26, 1.00 g, 3.52 mmol) in MeCN / H2O (30 mL). The resulting mixture was stirred for 12 hours. The reaction mixture was diluted with HCl (100 mL). The organic layer was separated, washed with brine (30 mL), dried, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography eluted with 30-50% n-hexane in HCl to obtain methyl 3-((4-methoxythieno[3,2-d]pyrimidine-7-yl)sulfonyl)propanoate (A29, 1.10 g, 98%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.91 (s, 1H), 8.70 (s, 1H), 4.22 (s, 3H), 3.92 (m, 2H), 3.64 (s, 3H), 2.85 (dd, J=8.2, 7.2Hz, 2H).

[0265] Intermediate compound A30, shown in Table 7 below, was prepared using a procedure similar to that of Example Step 10a (for compound A29). [Table 13]

[0266] Example Step 10b- Oxidation of sulfone using 3-chloroperbenzoic acid: Synthesis of 3-((1-methyl-1H-indazole-4-yl)sulfonyl)propanoate (A31) [ka] 3-Chloroperbenzoic acid (345 mg, 2.00 mmol) was added in small amounts at 0°C to a stirred solution of methyl 3-((1-methyl-1H-indazole-4-yl)thio)propanoate (A27, 200 mg, 0.80 mmol) in DCM (20 mL). The resulting reaction mixture was warmed to room temperature and then stirred for 4 hours. The reaction mixture was stirred with saturated sodium sulfite aqueous solution (20 mL) for 5 minutes and then washed with saturated sodium bicarbonate aqueous solution (20 mL). The organic layer was then separated and concentrated under vacuum. The crude residue was purified by silica gel column chromatography eluted with 75% ethyl ammonium in n-hexane to obtain 3-((1-methyl-1H-indazole-4-yl)sulfonyl)propanoate (A31, 175 mg, 78%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3)δ 8.40(s, 1H), 7.74(ddd, J=9.6, 7.9, 0.8Hz, 2H), 7.54(ddd, J=8.2, 7.1, 0.9Hz, 1H), 4.17(s, 3H), 3.62(s, 3H), 3.52(dd, J=8.2, 7.2Hz, 2H), 2.76(dd, J=8.2, 7.3Hz, 2H).

[0267] Example Step 11 - Preparation of sodium sulfinate: Synthesis of 4-methoxythieno[3,2-d]pyrimidine-7-sulfinate sodium (A32) [ka] To a solution of methyl 3-[(8-methyl-1,5-naphthyridine-4-yl)sulfonyl]propanoate (A29, 1.00 g, 3.32 mmol) in THF (10 mL), sodium ethoxide (271 mg, 3.99 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with siRNA (10 mL), then with Et2O (2 × 10 mL), and then dried under vacuum to obtain sodium 4-methoxythieno[3,2-d]pyrimidine-7-sulfinate (A32, 800 mg, 95%) as a yellow solid. The compound was used without further purification.

[0268] Intermediate compounds A33 and A34, shown in Table 8 below, were prepared from their corresponding sulfonyl intermediates using a procedure similar to that of Example Step 11 (for compound A32). [Table 14]

[0269] Preparation of sulfonamide intermediates (A) Example of route 1: Step 1a - Coupling of heteroarylsulfonyl chloride. Exemplary sulfonamide intermediates B1 and B2 were prepared by coupling the corresponding sulfonyl chloride with the corresponding amine, as detailed in Scheme 5 below: [ka]

[0270] Example Step 1a: Synthesis of tert-butyl 4-(7-chlorothieno[2,3-c]pyridine-3-yl)sulfonylpiperazine carboxylate (B1) [ka] To a stirred solution of 7-chlorothieno[2,3-c]pyridine-3-sulfonyl chloride (A21, 200 mg, 0.75 mmol) in DCM (5 mL), triethylamine (208 μL, 1.49 mmol) and 1-Boc-piperazine (170 mg, 0.90 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding 10% w / v citric acid (10 mL) and diluted with DCM (20 mL). The phases were separated using a phase separator, and the aqueous layer was washed with DCM (20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under vacuum to obtain tert-butyl 4-(7-chlorothieno[2,3-c]pyridine-3-yl)sulfonylpiperazine-1-carboxylate (B1, 250 mg, 80%) as a white solid. LC-MS (Method A). R t 1.94 minutes, (ESI + )m / z 418.1[M+H] + .

[0271] Intermediate compound B2, shown in Table 9 below, was prepared from the corresponding sulfonyl chloride together with compound A3 using a procedure similar to that of Example Step 1a (for compound B1). [Table 15]

[0272] Synthesis of tert-butyl(1-(benzo[b]thiophen-3-ylsulfonyl)piperidine-4-yl)carbamate (B3) [ka] Tert-butylpiperidine-4-ylcarbamate (A23, 516 mg, 2.58 mmol) and DIPEA (417 mg, 3.22 mmol) were dissolved in THF (10 mL). 1-Benzothiophene-3-sulfonyl chloride (A22, 580 mg, 2.15 mmol) was added in portions over 5 minutes, and the reaction mixture was stirred at 60°C for 1 hour. During cooling, the solvent was removed under reduced pressure. The residue was dissolved in ELISA (20 mL) and washed sequentially with saturated sodium bisulfate aqueous solution (10 mL), saturated sodium bicarbonate aqueous solution (10 mL), and brine (10 mL). The organic layer was dried in (MgSO4), filtered, and the solvent was removed under reduced pressure to obtain tert-butyl(1-(benzo[b]thiophene-3-ylsulfonyl)piperidine-4-yl)carbamate (B3, 726 mg, 99%) as a beige solid. This was used in the next step without further purification. 1 H NMR (400MHz, CDCl3)δ 8.27-8.22(m, 1H), 8.17(s, 1H), 7.91(m, 1H), 7.52-7.44(overlap m, 2H), 4.41(wide s, 1H), 3.79(d, 2H, J=11.8 4Hz, 2H), 3.40 (wide s, 1H), 2.70-2.60 (overlap m, 2H), 2.01-1.93 (overlap m, 2H), 1.52-1.41 (overlap m, 2H), 1.40 (s, 9H).

[0273] Intermediate compound B4, shown in Table 10 below, was prepared from the corresponding commercially available sulfonyl chloride together with compound A3 using a procedure similar to that used for the synthesis of compound B3. [Table 16]

[0274] (B) Coupling of a piperazine intermediate with a sulfonyl chloride prepared in situ. Exemplary sulfonamide intermediates B5-B8 were prepared by in situ preparation of the corresponding sulfonyl chloride, followed by coupling with the corresponding amine, as detailed in Scheme 6 below: [ka]

[0275] Example Step 12a / 12b: Synthesis of tert-butyl 4-((7-bromo-1-methyl-1H-indole-3-yl)sulfonyl)piperazine-1-carboxylate (B5) [ka] Chlorosulfonic acid (1.10 mL, 16.7 mmol) was added to a stirred solution of 7-bromo-1-methyl-1H-indole (A24, 1.00 g, 4.76 mmol) in MeCN (10 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated to obtain crude sulfonyl chloride (A25). The residue was diluted with THF (10 mL) under argon and cooled to 0°C. DIPEA (2.60 mL, 14.3 mmol) and 1-Boc-piperazine (1.32 g, 7.14 mmol) were added. The reaction mixture was then heated at 50°C for 12 hours, cooled, and concentrated under vacuum. The residue was diluted with siRNA (25 mL), washed with brine (25 mL), the organic layer was separated, dried, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography using 30-40% siRNA / petroleum ether to obtain tert-butyl 4-((7-bromo-1-methyl-1H-indole-3-yl)sulfonyl)piperazine-1-carboxylate (B5, 300 mg, 13%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3)δ 7.89(dd, J=8.1, 1.0Hz, 1H), 7.52(s, 1H), 7.48(dd, J=7.7, 1.0Hz, 1H), 7.09(t, J= 7.9Hz, 1H), 4.23(s, 3H), 3.54-3.47(overlap m, 4H), 3.05-2.99(overlap m, 4H), 1.39(s, 9H).

[0276] Intermediate compounds B6-B8, shown in Table 11 below, were prepared using commercially available reagents, if available, by following a procedure similar to that of Example Step 12a / 12b (Compound B5). [Table 17]

[0277] (C) Oxidative coupling of sodium sulfinate with a Boc-protected intermediate. Exemplary sulfonamide intermediates B9-B11 were prepared from the corresponding sodium sulfinates via oxidative coupling with the corresponding amines, as detailed in Scheme 7 below: [ka]

[0278] Example Step 13: Oxidative coupling of sodium sulfinate with a Boc-protected piperazine intermediate: Synthesis of tert-butyl 4-((4-methoxythieno[3,2-d]pyrimidine-7-yl)sulfonyl)piperazine-1-carboxylate (B9) [ka] Iodine (645 mg, 2.54 mmol) in EtOH (10 mL) Sodium 4-methoxythieno[3,2-d]pyrimidine-7-sulfinate (A32, 800 mg, 3.17 mmol) was added to a stirred solution, followed by the addition of 1-Boc-piperazine (680 mg, 3.65 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by adding crushed ice and solid sodium thiosulfate until a homogeneous solution was observed. The mixture was extracted with RINKAN (50 mL), washed with brine (20 mL), dried, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography using 30-40% n-hexane in RINKAN to obtain tert-butyl 4-((4-methoxythieno[3,2-d]pyrimidine-7-yl)sulfonyl)piperazine-1-carboxylate (B9, 100 mg, 8%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ 8.88(s, 1H), 8.53(s, 1H), 4.21(s, 3H), 3.52-3.47(overlap m, 4H), 3.35-3.31(overlap m, 4H), 1.41(s, 9H).

[0279] Intermediate compounds B10 and B11, shown in Table 12 below, were prepared from the corresponding sodium sulfinate or sulfonyl chloride along with the corresponding amine intermediate using a procedure similar to that of Example Step 13 (for compound B9). [Table 18]

[0280] (D) Preparation of sulfonamide intermediate B12 in situ. In the example, sulfonamide intermediate B12 was prepared from indole A35 as detailed below: Synthesis of tert-butyl(1-((1H-indole-1-yl)sulfonyl)piperidine-4-yl)carbamate (B12) [ka] To a stirred suspension of 1-imidazole-1-ylsulfonyl-3-methylimidazole-3-ium;trifluoromethanesulfonate (A1, 200 mg, 0.55 mmol) in MeCN (3 mL), indole (A35, 32.3 mg, 0.28 mmol), tert-butylpiperidine-4-ylcarbamate (A23, 221 mg, 1.10 mmol), and DIPEA (96.1 μL, 0.55 mmol) were added at room temperature. The reaction mixture was heated at 70 °C for 10 hours, then cooled to room temperature and quenched with ice water (10 mL). The mixture was extracted with 5% MeOH / DCM (2 × 15 mL), and the organic matter was concentrated under vacuum. The crude residue was partially purified by silica gel column chromatography to obtain tert-butyl(1-((1H-indole-1-yl)sulfonyl)piperidine-4-yl)carbamate (B12, 100 mg, 5%, purity less than 25%) as an orange oily substance. The product was proceeded to the next step without further purification. LC-MS (Method C). R t 1.48 minutes, (ESI + )m / z 380.2[M+H] + .

[0281] (E) Coupling of Boc-protected intermediate B13 with a sulfonyl chloride prepared in situ. Example: Sulfonamide intermediate B13 was prepared from intermediate A2 as detailed below: [ka] Synthesis of 1-methyl-1H-indazole-4-sulfinic acid (A37) [ka] A mixture of 4-bromo-1-methylindazole (A2, 500 mg, 2.37 mmol), 1,4-diazabicylco[2.2.2]octanbis(sulfur dioxide) adduct (A36, 610 mg, 2.54 mmol), and N-cyclohexyl-N-methylcyclohexanememine (1.64 mL, 7.66 mmol) in dry isopropanol (10 mL) was degassed for 5 minutes, and then bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropaldium(II) (100 mg, 0.14 mmol) was added. The resulting mixture was degassed for another 5 minutes and then heated at 110°C for 2.5 hours using a microwave (CEM, 200 W). The mixture was cooled to room temperature, filtered through a Celite pad, then washed with isopropanol (2 × 10 mL), and the organic matter was concentrated under vacuum to obtain crude 1-methyl-1H-indazole-4-sulfinic acid (A37, 1.00 g, quantitative yield) as a pale yellow, rubbery oil. The compound was used in subsequent steps without any further purification. LC-MS (Method D). R t 2.08 minutes, (ESI + )m / z 197.2[M+H] + .

[0282] Synthesis of 1-methyl-1H-indazole-4-sulfonic acid (A38) [ka] 3-Chloroperbenzoic acid (291 mg, 1.69 mmol) was added in one batch to a stirred solution of 1-methyl-1H-indazole-4-sulfonic acid (A37, 500 mg, 1.27 mmol) in DCM (5 mL) at 0°C under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ice water and extracted with 10% MeOH / DCM (3 × 20 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under vacuum to obtain 1-methyl-1H-indazole-4-sulfonic acid (A38, 270 mg, quantitative yield) as a grayish-white solid. The compound was used in the next step without any further purification. LC-MS (Method D). t1.54 minutes, (ESI + )m / z 213.1[M+H] + .

[0283] Synthesis of tert-butyl(2-(4-((1-methyl-1H-indazole-4-yl)sulfonyl)piperazine-1-yl)-2-oxoethyl)carbamate (B13) [ka] Thionyl chloride (1.00 mL, 13.8 mmol) was added to 1-methylindazole-4-sulfonic acid (A38, 500 mg, 1.65 mmol), and the mixture was heated at 70°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum to obtain crude sulfonyl chloride (A39), which was diluted with DCM (10 mL). In a separate flask, 1-(Boc-aminoacetyl)piperazine (A40, 401 mg, 1.65 mmol) and triethylamine (1.15 mL, 8.25 mmol) in DCM (10 mL) were stirred at 0°C, and then the solution of sulfonyl chloride (A39) in DCM was slowly added. The resulting mixture was warmed to room temperature and then stirred for 16 hours. The mixture was diluted with ice-cold water (10 mL) and washed with saturated sodium bicarbonate aqueous solution. The organic layer was separated, dried (Na2SO4), and concentrated under vacuum. The crude residue was purified by column chromatography using 0-2% MeOH in DCM to obtain tert-butyl(2-(4-((1-methyl-1H-indazole-4-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)carbamate (B13, 120 mg, 11%, purity 66%) as a grayish-white solid. LC-MS (Method D). R t 2.25 minutes, (ESI + )m / z 460.1[M+Na] + .

[0284] (F) Coupling of sulfonyl chloride with an N-heteroaryl intermediate. Exemplary sulfonamide intermediates B14-B24 were prepared from the coupling of sulfonyl chloride A4 with the corresponding N-heteroaryl intermediate, as detailed in Scheme 8 below: [ka]

[0285] Example Step 1b: Synthesis of tert-butyl 4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-carboxylate (B14) [ka] 4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine (A9, 100 mg, 0.543 mmol) and tetrabutylammonium bromide (21 mg, 0.0652 mmol) were dissolved in a mixture of DCM (5 mL) and sodium hydroxide (434 mg, 10.9 mmol) dissolved in 1.1 mL of water, and then tert-butyl4-chlorosulfonylpiperazine-1-carboxylate (A4, 170 mg, 0.597 mmol) was added. The reaction mixture was vigorously stirred for 16 hours. The reaction mixture was quenched by adding water (50 mL) and brine (50 mL), dried to (Na2SO4), and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 0-100% phenyl in the gradient eluate isohexane to obtain tert-butyl 4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-carboxylate (B14, 178 mg, 76%) as a yellow solid. LC-MS (Method A). R t 1.99 minutes, (ESI + )m / z 433.2[M+H] + , 19 F NMR (377MHz, CDCl3): δ=-88.89(d, J HF (=80Hz).

[0286] Intermediate compounds B15-B24, shown in Table 13 below, were prepared by coupling sulfonyl chloride A4 with the corresponding N-heteroaryl intermediate (commercially available*) using a procedure similar to that of Example Step 1b (for compound B14). [Table 19] a The reaction was carried out using tetrabutylammonium iodide I as a substitute for tetrabutylammonium bromide. b Indole chlorination was observed and the compound was isolated as an inseparable mixture.

[0287] Preparation of methoxy intermediates Exemplary methoxy intermediates B25–B32 were prepared from their corresponding chloro intermediates, as detailed in Scheme 9 below: [ka]

[0288] (A) Palladium-catalyzed methoxylation. Example Step 14: Synthesis of tert-butyl 4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-carboxylate (B25) [ka] A mixture of palladium(II) acetate (32.1 mg, 0.14 mmol), 2-[di(tert-butyl)phosphino]-2',4',6'-triisopropyl-1,1'-biphenyl (tBu X-phos) (122 mg, 0.29 mmol), and cesium carbonate (2.33 g, 7.16 mmol) in toluene (10 mL) was degassed for 5 minutes, and then heated at 80°C under microwave (200 W, CEM) for 5 minutes. The reaction mixture was cooled, and a solution of tert-butyl 4-((4-chloro-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-carboxylate (B17, 1.98 g, 4.77 mmol) in MeOH (10 mL) was added. The resulting mixture was degassed for a further 5 minutes, and then heated at 90°C under microwave for 30 minutes. The reaction mixture was filtered through a Celite cartridge (2.5 g) and washed with MeOH (3 CV). The combined organic matter was concentrated under vacuum, and the crude residue was purified by silica gel column chromatography using 0-10% MeOH in the gradient eluate DCM to obtain tert-butyl 4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-carboxylate (B25, 1.70 g, 87%) as a grayish-white solid. LC-MS (Method A). R t 1.99 minutes, (ESI + )m / z 411.3[M+H] + .

[0289] Intermediate compounds B26-B32, shown in Table 14 below, were prepared from the chloro intermediate using a procedure similar to that of Example Step 14 (for compound B25). [Table 20] C Conventional heating at 80°C instead of microwave heating.

[0290] (B) Synthesis of methoxy intermediate B32 via substitution. Synthesis of tert-butyl 4-(7-methoxythieno[2,3-c]pyridine-3-yl)sulfonylpiperazine-1-carboxylate (B32) [ka] Tert-butyl 4-(7-chlorothieno[2,3-c]pyridine-3-yl)sulfonylpiperazine-1-carboxylate (B1, 250 mg, 0.60 mmol) was suspended in a solution of sodium methoxide in MeOH (5.4 M, 2 mL, 10.8 mmol), and the mixture was stirred at room temperature until complete. The reaction was quenched by the addition of brine (10 mL), and the MeOH was removed under vacuum. The aqueous layer was extracted with ELISA (3 × 50 mL), the combined organic layers were separated, dried, filtered, and concentrated under vacuum to obtain tert-butyl 4-(7-methoxythieno[2,3-c]pyridine-3-yl)sulfonylpiperazine-1-carboxylate (B32, 128 mg, 52%) as a white solid. LCMS (Method A). R t 1.93 minutes, (ESI + )m / z 414.2[M+H] + .

[0291] N-Boc deprotection Exemplary amine intermediates C1-C23 were prepared from their corresponding N-boc intermediates, as detailed in Scheme 10 below: [ka]

[0292] Example Step 2: Synthesis of 4-(difluoromethoxy)-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1) [ka] TFA (500 μL, 6.53 mmol) was added dropwise to a stirred solution of tert-butyl 4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-carboxylate (B14, 175 mg, 0.405 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred for 30 minutes. The reaction mixture was then concentrated under vacuum to obtain a residue, which was dissolved in DCM (5 mL), passed through an SCX-2 cartridge (5 g), and washed with MeOH (3 CV) followed by DCM (3 CV). The product was eluted with 1 M NH3 in MeOH (6 CV), and the organic matter was concentrated under vacuum to obtain 4-(difluoromethoxy)-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1, 132 mg, 98%) as a light brown solid. LC-MS (Method B). R t 1.66 minutes, (ESI + )m / z 333.1[M+H] + .

[0293] Intermediate compounds C2 to C23, shown in Table 15 below, were prepared using a procedure similar to that of Example Step 2 (to compound C1) with reaction times ranging from 10 minutes to 18 hours. [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] d It was isolated as a TFA salt. e The dechlorinated and chlorinated compounds were separated as a mixture via reverse-phase chromatography.

[0294] Preparation of difluoromethoxy intermediate C24 In this example, the difluoromethoxy intermediate C24 was prepared from intermediate C4 as detailed below: [ka] N-benzylation reaction: Synthesis of 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine (B33) [ka] Benzyl bromide (514 μL, 4.32 mmol) was added to a mixture of 4-methoxy-7-methyl-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C4, 1.34 g, 4.32 mmol) and potassium carbonate (1.19 g, 8.63 mmol) in MeCN (20 mL). The resulting mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was treated with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (25g Biotage Sfar) using 0-50% siRNA in gradient eluate isohexane to obtain 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine (B33, 1.32g, 76%) as a grayish-white solid. LC-MS (Method A). R t 1.58 minutes, (ESI + )m / z 401.3[M+H] + .

[0295] O-Demethylation reaction: Synthesis of 1-((4-benzylpiperazin-1-yl)sulfonyl)-7-methyl-1H-pyrrolo[3,2-c]pyridine-4-ol (B34) [ka] Iodotrimethylsilane (931 μL, 6.54 mmol) was added at room temperature to a suspension of 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine (B33, 1.31 g, 3.27 mmol) in MeCN (20 mL). The resulting mixture was heated at 65 °C for 3 hours. The mixture was then cooled to room temperature, and both saturated sodium bicarbonate aqueous solution (5 mL) and saturated sodium thiosulfate aqueous solution (5 mL) were added. The aqueous layer was extracted with ELISA (3 × 5 mL), the combined organic phase was washed with water (5 mL), dried to (Na₂SO₄), and the solvent was evaporated under vacuum. The crude residue was purified by silica gel column chromatography (25g Sfar Biotage) using 0-20% MeOH in the gradient eluate DCM to obtain 1-((4-benzylpiperazin-1-yl)sulfonyl)-7-methyl-1H-pyrrolo[3,2-c]pyridine-4-ol (B34, 1.15g, 91%) as a grayish-white solid. LC-MS (Method A). R t 1.21 minutes, (ESI + )m / z 387.2[M+H] + .

[0296] O-difluoromethoxylation: Synthesis of 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-(difluoromethoxy)-7-methyl-1H-pyrrolo[3,2-c]pyridine (B35) [ka] Under nitrogen, sodium carbonate (544 mg, 5.13 mmol) was added to a stirred suspension of 1-((4-benzylpiperazin-1-yl)sulfonyl)-7-methyl-1H-pyrrolo[3,2-c]pyridine-4-ol (B34, 793 mg, 2.05 mmol) in toluene (15 mL). The resulting mixture was heated at 60°C for 30 minutes, then cooled to room temperature, and trimethylsilylfluorosulfonyl difluoroacetate (621 μL, 3.08 mmol) was added. The resulting reaction mixture was heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated, diluted with HCl (10 mL), washed with water (10 mL), and then washed with brine (10 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (25 g Biotage Sfar) using 0-50% ethyl ammonium in isohexane to obtain 1-((4-benzylpiperazin-1-yl)sulfonyl)-4-(difluoromethoxy)-7-methyl-1H-pyrrolo[3,2-c]pyridine (B35, 482 mg, 54%) as a grayish-white solid. LC-MS (Method A). t 1.71 minutes, (ESI + )m / z 437.2[M+H] + , 19 F NMR (377MHz, CDCl3): δ=-88.35(d, J HF (=76.8Hz).

[0297] N-benzyl deprotection: Synthesis of 4-(difluoromethoxy)-7-methyl-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C24) [ka] Using a 10% Pd / C CatCart cartridge (70 × 4 mm), a solution of 1-((4-benzylpiperazine-1-yl)sulfonyl)-4-(difluoromethoxy)-7-methyl-1H-pyrrolo[3,2-c]pyridine (B35, 440 mg, 1.01 mmol) in EtOH (10 mL) was pumped through an H-cube at room temperature, atmospheric pressure, and a flow rate of 1 mL / min. The cycle was repeated once more, the system was washed with EtOH (10 mL), and then the organic matter was concentrated under vacuum. The crude solid was dissolved in DCM (5 mL), passed through an SCX-2 cartridge (2 g), and washed with MeOH (3 CV) followed by DCM (3 CV). The product was eluted with 1 M NH3 in MeOH(6CV), and the organic matter was concentrated under vacuum to obtain 4-(difluoromethoxy)-7-methyl-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C24, 250 mg, 72%) as a grayish-white solid. LC-MS (Method A). R t 1.69 minutes, (ESI + )m / z 347.1[M+H] + .

[0298] Amide coupling Exemplary amide intermediates B36–B45 were prepared from their corresponding amine intermediates, as detailed in Scheme 11 below: [ka]

[0299] Example Step 4: Synthesis of tert-butyl(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (B36) [ka] A mixture of Boc-N-methylglycine (27 mg, 0.141 mmol), HATU (54 mg, 0.141 mmol), and DIPEA (74 μL, 0.424 mmol) in DCM (5 mL) was stirred for 5 minutes, and then 4-(difluoromethoxy)-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1, 47 mg, 0.141 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (10 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL). The layers were separated, the organic layer was washed with brine (40 mL), dried, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (Sfar 25g) eluting with 0-10% MeOH in DCM to obtain tert-butyl(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (B36, 65.4 mg, 92%) as a grayish-white solid. LC-MS (Method A). R t 1.84 minutes, (ESI + )m / z 526.2[M+Na] + .

[0300] Intermediate compounds B37–B45, shown in Table 16, were prepared using a procedure similar to that of Example Step 4 (to compound B36) with reaction times ranging from 1 to 16 hours. [Table 26] e A reaction performed in DMF as an alternative to DCM.

[0301] N-deprotection Exemplary amine intermediates D1-D11 were prepared from their corresponding N-boc intermediates, as detailed in Scheme 12 below: [ka]

[0302] Example Step 4: Synthesis of 1-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-(methylamino)ethane-1-one (D1) [ka] TFA (0.50 mL, 6.53 mmol) was added dropwise to a stirred solution of tert-butyl(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)(methyl)carbamate (B36, 65 mg, 0.129 mmol) in DCM (2 mL) at room temperature. The resulting mixture was stirred for 30 minutes. The reaction mixture was then concentrated under vacuum to obtain a residue, which was dissolved in DCM (5 mL), passed through an SCX-2 cartridge (5 g), and washed with MeOH (3 CV) followed by DCM (3 CV). The product was eluted with 1M NH3 in MeOH(6CV), and the organic matter was concentrated under vacuum to obtain 1-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-(methylamino)ethane-1-one (D1, 52.1 mg, 98%) as a light brown solid. LC-MS (Method B). R t 1.61 minutes, (ESI + )m / z 404.2[M+H] + .

[0303] Intermediate compounds D2 to D11, shown in Table 17 below, were prepared using a procedure similar to that of Example Step 4 (for compound D1), with reaction times ranging from 30 minutes to 16 hours. [Table 27]

[0304] Preparation of acrylamide The example compounds Ex-1 to Ex-18 were prepared from their corresponding piperazine intermediates, as detailed in Scheme 13 below: [ka]

[0305] (A) Preparation of acrylamide using HATU. Example Step 3: Synthesis of N-(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-yl)-2-oxoethyl)acrylamide (Ex-1) [ka] A mixture of potassium acryloylglycinate (A7, 38 mg, 0.226 mmol), HATU (86 mg, 0.226 mmol), and DIPEA (157 μL, 0.903 mmol) in DCM (5 mL) was stirred for 5 minutes, and then 4-(difluoromethoxy)-1-(piperazine-1-ylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (C1, 75 mg, 0.226 mmol) in DCM (2 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (10 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL). The layers were separated, the organic layer was washed with brine (40 mL), dried, filtered, and concentrated under vacuum. The crude product was purified by reverse-phase chromatography to obtain N-(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide (Ex-1, 82 mg, 82%) as a white solid. LC-MS (Method E). R t 4.27 minutes, (ESI + )m / z 444.2[M+H] + .

[0306] The example compounds Ex-2 to Ex-11 shown in Table 18 below were prepared using a procedure similar to Step 3 of Example (for compound Ex-1), with reaction times varied from 30 minutes to 2 hours. [Table 28]

[0307] (B) Preparation of acrylamide using EDCI. Example Step 3: Preparation of N-(2-(4-((4-methoxythieno[3,2-d]pyrimidine-7-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide (Ex-12) [ka] DIPEA (560 μL, 3.05 mmol) was added to a stirred solution of 4-methoxy-7-(piperazine-1-ylsulfonyl)thieno[3,2-d]pyrimidine 2,2,2-trifluoroacetate (C14, 500 mg, 1.22 mmol) in DCM (10 mL). Subsequently, potassium acryloylglycinate (A7, 203 mg, 1.59 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) (304 mg, 1.59 mmol), and 1-hydroxybenzotriazole (HOBt) (82.0 mg, 0.61 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. After the reaction by TLC was complete, crushed ice was added to the mixture and extracted with ELISA (20 mL). The organic layer was separated, washed with saturated sodium bicarbonate aqueous solution (20 mL), then washed with brine (20 mL), and subsequently dried (Na2SO4), with the solvent removed under vacuum. The crude product was purified by silica gel column chromatography using 80% ethyl phosphate in isohexane to obtain N-(2-(4-((4-methoxythieno[3,2-d]pyrimidine-7-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide (Ex-12, 25.0 mg, 31%) as a grayish-white solid. LC-MS (Method E). R t 3.35 minutes, (ESI + )m / z 426.2[M+H] + , 1H NMR (400MHz, CDCl3)δ 8.86(s, 1H), 8.56(s, 1H), 6.57(br s, 1H), 6.29(dd, J=17.0, 1.5Hz, 1H), 6.15(dd, J=17.0, 10.2Hz, 1H), 5.67(dd, J=10.2, 1.5Hz, 1H), 4.20( s, 3H), 4.09 (d, J=4.1Hz, 2H), 3.76-3.72 (overlap m, 2H), 3.56-3.50 (overlap m, 2H), 3.46 (overlap m, 2H), 3.39 (overlap m, 2H).

[0308] The example compounds Ex-13 to Ex-16 shown in Table 19 below were prepared using a procedure similar to Step 3 of Example (for compound Ex-12), with reaction times varied from 30 minutes to 2 hours. [Table 29] [Table 30]

[0309] (C) Preparation of acrylamide using acryloyl chloride The example compounds Ex-17 to Ex-30 were prepared from the corresponding amine intermediates, as detailed in Scheme 14 below: [ka]

[0310] Example Step 6: Synthesis of N-(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)-N-methylacrylamide (Ex-17) [ka] To a stirred solution of 1-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-(methylamino)ethane-1-one (D1, 49 mg, 0.121 mmol) in DCM (5 mL), triethylamine (51 μL, 0.363 mmol) was added, followed by the dropwise addition of acryloyl chloride (15 μL, 0.181 mmol) at 0°C. The solution was left undisturbed and warmed to room temperature, and stirred for 30 minutes. The reaction mixture was partitioned between DCM (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL). The organic phase was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography to obtain N-(2-(4-((4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)-N-methylacrylamide (Ex-17, 43.8 mg, 79%) as a white solid. LC-MS (Method E). R t 4.36 minutes, (ESI + )m / z 458.2[M+H] + .

[0311] The example compounds Ex-18 to Ex-30 shown in Table 20 below were prepared using a procedure similar to Step 6 of Example (for compound Ex-17), with reaction times varied from 30 minutes to 2 hours. [Table 31] [Table 32] [Table 33] f The reaction was carried out using acryloyl chloride (1.2 equivalents) and DIPEA (3 equivalents) in THF. g DIPEA (3 equivalents) was used instead of Et3N.

[0312] Preparation of deuterium-substituted acrylamide The example compounds Ex-31 and Ex-32 were prepared from the corresponding amines via the reaction of the corresponding phosphonate esters followed by poly(oxymethylene-d2), as detailed in Scheme 15 below: [ka]

[0313] (A) Preparation of phosphonate esters. Example Step 15: Synthesis of diethyl(2-((2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-yl)-2-oxoethyl)amino)-2-oxoethyl)phosphonate (D12) [ka] A mixture of 2-amino-1-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)ethane-1-one (D5, 66 mg, 0.180 mmol), 2-(diethoxyphosphoryl)acetic acid (39 mg, 0.198 mmol), HATU (82 mg, 0.216 mmol), and DIPEA (38 μL, 0.216 mmol) in THF (5 mL) was stirred at room temperature for 5 hours. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were successively washed with water (20 mL) and brine (20 mL), dried, filtered, and concentrated under vacuum to obtain crude diethyl (2-((2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-yl)-2-oxoethyl)amino)-2-oxoethyl)phosphonate (D12, 98 mg, quantitative yield) as a yellow oil, which was then carried out to the next step without further purification. LCMS (Method A). R t 1.52 minutes, (ESI + )m / z 546.3[M+H] + .

[0314] The phosphonate ester intermediate D13 shown in Table 21 was prepared using a procedure similar to that of Example Step 15 (to compound D12) with a reaction time of 2 hours. [Table 34]

[0315] (B) Preparation of deuterium-substituted acrylamide via phosphonate esters. Example Step 16: Synthesis of N-(2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide-3,3-d2(Ex-31) [ka] To a solution of crude diethyl (2-((2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazine-1-yl)-2-oxoethyl)amino)-2-oxoethyl)phosphonate (D12, 98 mg, 0.180 mmol) in THF (4 mL): water (1 mL), paraformaldehyde-d2 (2.8 mg, 0.0449 mmol), lithium hydroxide monohydrate (8.3 mg, 0.198 mmol), and potassium hydroxide (20 mg, 0.359 mmol) were added. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then quenched with water (10 mL) and extracted with siRNA (3 × 10 mL). The combined organic layers were sequentially washed with water (20 mL) and brine (20 mL), dried, filtered, and concentrated under vacuum. The crude product was pre-purified by silica gel column chromatography (Sfar 25 g) eluting with 0-5% MeOH in DCM, and then purified by reverse-phase purification. The fractions containing the desired product were mixed, and the solvent was evaporated under vacuum. The residue was dissolved in 1:1 MeCN-H2O (4 mL), and the solution was frozen. The solvent was evaporated under vacuum by lyophilization to obtain N-(2-(4-((4-methoxy-7-methyl-1H-pyrrolo[3,2-c]pyridine-1-yl)sulfonyl)piperazin-1-yl)-2-oxoethyl)acrylamide-3,3-d2 (Ex-31, 18.8 mg, 25%) as a white solid. LC-MS (Method E). R t 3.88 minutes, (ESI + )m / z 424.3[M+H] + .

[0316] The example compound Ex-32 shown in Table 22 below was prepared using a procedure similar to that of Example Step 16 (for compound Ex-31) with a reaction time of 6 hours. [Table 35]

[0317] Preparation of 10-fluorine-18 analogs The example compound Ex-35 is prepared from the corresponding hydroxy compound Ex-33 or the corresponding chlorofluoromethoxy compound Ex-34 by following a procedure known to those skilled in the art, as detailed in Scheme 16 below (e.g., Gouverneur et al., Angew. Chem. Int. Ed., 2015, 54, 9991; Gouverneur et al., Nature, 2022, 606, 102). Compounds Ex-33 and Ex-34 are prepared using methods similar to those described herein. [ka]

[0318] Biological Example 1 - Inhibition of TG2 activity methodology TG2 activity was measured by incorporating biotin X-cadaverine into N,N'-dimethylcasein using recombinant human transglutaminase 2 (rhTG2). A 96-well plate was coated with 50 μL of 10 mg / mL N,N'-dimethylcasein in 50 mM Tris-HCl, pH 8.0, and then washed with TBS / Tween, pH 7.6 and TBS, pH 7.6. A 100 μL / well rhTG2 reaction mixture containing 400 ng / mL rhTG2, 0.1 mM biotin-cadaverine (BTC), 1 mM DTT, and 10 mM CaCl2 in 50 mM Tris-HCl, pH 7.4, with or without the test compound (at varying concentrations), was added to each well. The reaction mixture was allowed to proceed at 37°C for 90 minutes. Next, the plates were washed once with TBS / Tween, pH 7.6 and TBS, pH 7.6, and then blocked with 100 μL of SuperBlock reagent at 37°C for 30 minutes. Incorporation of BTC into N,N'-dimethylcasein was detected by incubation at 37°C for 1 hour with 100 μL of Extravidin-peroxidase diluted 1:2000 in Superblock buffer. After washing another set, TG2 activity was measured using ABTS substrate. Absorbance at 405 nm was measured using a microplate reader.

[0319] result TG2 IC 50 The assay results are shown in Table 23 below.

[0320] The results indicate that the compound of formula I, as illustrated, is a good inhibitor of TG2. [Table 36]

[0321] Biological Example 2: In vivo pharmacokinetic study of the example compound in C57Bl / 6 mice The in vivo pharmacokinetics of the example compounds in C57Bl / 6 mice were studied as follows.

[0322] formulation Details of the intravenous and oral formulations are summarized in Tables 24 and 25, respectively. [Table 37] [Table 38]

[0323] methodology Male C57Bl / 6 mice, weighing 20.6–26.7 g, were administered the test compound cassette either intravenously or orally. In some cases, the individual compounds were administered orally. The test compounds were formulated as solutions and administered either (a) intravenously at a dose of 0.5 mg / kg per compound, or (b) orally at a dose of 2.5 mg / kg or 10 mg / kg. The animals were given free access to food and water throughout the study.

[0324] Blood samples were collected by terminal cardiac puncture from a set of three mice at each of the following time points, under anesthesia (isoflurane), into labeled microcentrifuge tubes containing heparin as an anticoagulant: For intravenous administration, samples were collected at the following times: 1, 5, 15, 30, and 60 minutes after dose. For oral administration, samples were collected at the following times: 5, 15, and 30 minutes after dose, as well as 1, 2, 4, 6, and 8 hours after dose.

[0325] Blood samples were separated by centrifugation, and the resulting plasma samples were transferred to labeled microcentrifuge tubes and frozen at -20°C until analysis.

[0326] All samples were processed for analysis by protein precipitation using acetonitrile containing an internal standard (tolbutamide), and the plasma concentrations of all administered compounds were determined at each time point by analysis using LC-MS / MS. Pharmacokinetic parameters were calculated from the plasma concentration-time profiles using non-compartmental analysis.

[0327] compound [ka] This compound may be referred to herein as Compound 1-155 or Reference Compound 1, and was prepared according to the procedure described in WO2014 / 057266. Reference Compound 1 was tested according to the procedure described herein.

[0328] result The results of pharmacokinetic studies in mice are shown in Tables 26 and 27 below.

[0329] The results show that a specific example compound of formula I exhibits favorable pharmacokinetic properties. These pharmacokinetic properties are improved compared to known TG2 inhibitors. [Table 39] [Table 40]

[0330] Biological Example 3 - Inhibition of FXIIaI, TG1, and TG3 activity Methodology - FXIIIa and TG1 Following the manufacturer's instructions, a commercial microassay (TG-CovTest, Covalab) was used (Hitomi et al., 2009, Amino Acids 36, 619-624). For equivalent purposes, numerous TG2 assays were also performed using this assay. Briefly, TG-specific biotinylated peptides, including pepF11KA, pre-activated FXIII, and pepK5(TG1) (Hitomi et al., 2009), were incubated with suitable TG family members in the presence of a polyamine substrate immobilized on a 96-well microplate. The incorporated biotinylated peptides were measured using horseradish peroxidase conjugate streptavidin, and then using an o-phenylenediamine dihydrochloride substrate. Absorbance was measured at 490 nm using a microplate reader.

[0331] Methodology-TG3 The fluorescence TG3 assay was performed as described. The assay conditions were 37°C, 50 mM Hepes, pH 8.0, 20 mM CaCl2, 0.2 mM DTT, and 10 nM pre-activated TG3 in 0.05% Pluronic F-127. Kinetic measurements (excitation, 350 nm; release, 535 nm) were recorded, and the reaction rate from linear fitting was used as a measure of enzyme activity. All data points were normalized to 0% to 100% inhibition using appropriate positive (complete inhibition) and negative (no inhibition) controls.

[0332] result ICs for FXIIIa, TG1, and TG3 50 The assay results are used for the IC of TG2 as described above. 50 The assay results are shown in Table 28 below.

[0333] The results revealed selective inhibition of TG2 by the exemplary compound of formula I. [Table 41] References Bailey,C.D.,and G.V.Johnson.2005.Tissue transglutaminase contributes to disease progression in the R6 / 2 Huntington’s disease mouse model via aggregate-independent mechanisms.J Neurochem.92:83-92. Collighan,R.J.,and M.Griffin.2009.Transglutaminase 2 cross-linking of matrix proteins:biological significance and medical applications.Amino Acids.36:659-670. Dafik,L.,and C.Khosla.2011.Dihydroisoxazole analogs for labeling and visualization of catalytically active transglutaminase 2.Chem Biol.18:58-66. Fell,S.,·Z.Wang,A.Blanchard,·C.Nanthakumar and M.Griffin.2021 Transglutaminase 2:a novel therapeutic target for idiopathic pulmonary fibrosis using selective small molecule inhibitors.Amino Acids.53:205-217 Griffin,M.,R.Casadio,and C.M.Bergamini.2002.Transglutaminases:nature’s biological glues.Biochem J.368:377-396. Griffin, M., A. Mongeot, R. Collighan, RESaint, RAJones, IGCoutts, and DLRathbone. Halim,D.,K.Caron,and JWKeillor.2007.Synthesis and evaluation of peptidic maleimides as transglutaminase inhibitors.Bioorg Med Chem Lett.17:305-308. Han, B.-G., J.-W. Cho, YDCho, K.-C. Jeong, S.-Y. Kim, and BILee.2010.Crystal structure of human transglutaminase 2 in complex with adenosine triphosphate. Hasegawa, G., M. Suwa, Y. Ichikawa, T. Ohtsuka, S. Kumagai, M. Kikuchi, Y. Sato, and Y. Saito. Hitomi, K., Kitamura, M., and Sugimura, Y. (2009).Preferred substrate sequences for transglutaminase 2: screening using a phage-displayed peptide library.Amino Acids.36,619-624. Huang,L.,J.L.Haylor,Z.Hau,R.A.Jones,M.E.Vickers,B.Wagner,M.Griffin,R.E.Saint,I.G.Coutts,A.M.El Nahas,and T.S.Johnson.2009.Transglutaminase inhibition ameliorates experimental diabetic nephropathy.Kidney Int.76:383-394. Johnson,T.,M.Fisher,J.Haylor,Z.Hau,N.Skill,R.Jones,R.Saint,I.Coutts,A.El Nahas,and M.Griffin.2008.Transglutaminase inhibition ameliorates tissue scarring and fibrosis:experience in a kidney model.J Am Soc.14:2052. Kerr,C,H.Szmacinski,M.L.Fisher,B.Nance,J.R.Lakowicz,A.Akbar,J.W.Keillor,T.L.Wong,R.Godoy-Ruiz,E.A.Toth,D.J.Weber,and R.L.Eckert.2017.Oncogene.36(21):2981-2990 Klock,C.,X.Jin,K.Choi,C.Khosla,P.B.Madrid,A.Spencer,B.C.Raimundo,P.Boardman,G.Lanza,and J.H.Griffin.2011.Acylideneoxoindoles:A new class of reversible inhibitors of human transglutaminase 2.Bioorg Med Chem Lett.21:2692-2696. Lindemann,I.,A.Heine,and G.Klebe.2012.Transglutaminase 2 in complex with a novel inhibitor.PDB codes:3S3P,3S3S,3S3J. Liu,S.,R.A.Cerione,and J.Clardy.2002.Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity.Proc Natl Acad Sci U S A.99:2743-2747. Mastroberardino,P.G.,C.Iannicola,R.Nardacci,F.Bernassola,V.De Laurenzi,G.Melino,S.Moreno,F.Pavone,S.Oliverio,L.Fesus,and M.Piacentini.2002.’Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington’s disease.Cell Death Differ.9:873-880. Mishra,S.,and L.J.Murphy.2004.Tissue transglutaminase has intrinsic kinase activity:identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase.J Biol Chem.279:23863-23868. Nakaoka,H.,D.M.Perez,K.J.Baek,T.Das,A.Husain,K.Misono,M.J.Im,and R.M.Graham.1994.Gh:a GTP-binding protein with transglutaminase activity and receptor signaling function.Science.264:1593-1596. Pardin, C., SMGillet, and JWKeillor.2006.Synthesis and evaluation of peptidic irreversible inhibitors of tissue transglutaminase.Bioorg Med Chem.14:8379-8385. Pardin,C.,JNPelletier,WDLubell,andJWKeillor.2008a.Cinnamoyl inhibitors of tissue transglutaminase.J Org Chem.73:5766-5775. Pardin,C.,I.Roy,WDLubell,and JWKeillor.2008b.Reversible and competitive cinnamoyl triazole inhibitors of tissue transglutaminase.Chem Biol Drug Des.72:189-196. Pinkas, DM, P. Strop, ATBrunger, and C. Khosla.2007.Transglutaminase 2 undergoes a large conformational change upon activation.PLoS Biol.5:e327. Prime,M.E.,O.A.Andersen,J.J.Barker,M.A.Brooks,R.K.Cheng,I.Toogood-Johnson,S.M.Courtney,F.A.Brookfield,C.J.Yarnold,R.W.Marston,P.D.Johnson,S.F.Johnsen,J.J.Palfrey,D.Vaidya,S.Erfan,O.Ichihara,B.Felicetti,S.Palan,A.Pedret-Dunn,S.Schaertl,I.Sternberger,A.Ebneth,A.Scheel,D.Winkler,L.Toledo-Sherman,M.Beconi,D.Macdonald,I.Munoz-Sanjuan,C.Dominguez,and J.Wityak.2012.Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington’s disease.J Med Chem.55:1021-1046. Seo,S.,Y.Moon,J.Choi,S.Yoon,K.H.Jung,J.Cheon,W.Kim,D.Kim,C.H.Lee,S-W.Kim,K-S.Park,D.H.Lee.2019.The GTP binding activity of transglutaminase 2 promotes bone metastasis of breast cancer cells by downregulating microRNA-205.Am J Cancer Res.9(3):597-607 Verderio,E.A.,T.Johnson,and M.Griffin.2004.Tissue transglutaminase in normal and abnormal wound healing:review article.Amino Acids.26:387-404. Wang.A.,D.J.Stuckey,C.E.Murdoch,P.Camelliti,G.Y.H.Lip and M.Griffin.2018.Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor.Cell Death and Disease.9:613.

Claims

1. A compound of formula I, 【Chemistry 133】 During the ceremony, Q is selected from the group consisting of O and NH. A is N, -E-L-Linker, 【Chemistry 134】 This represents, R １ However, this represents a nine-membered bicyclic heteroaryl group that is optionally substituted with one or more X groups. Each X is independently selected from the group consisting of halogen, -N(R ８ａ ), R ８ｂ , -OR ９ , -C(O)OR １０ , -C(O)N(R １１ａ ), R １１ｂ , C １－４ alkyl group, and C ３－６ cycloalkyl group, and the C １－４ alkyl and C ３－６ cycloalkyl groups are optionally substituted by one or more deuterium atoms and / or halogen atoms, R ２ , R ３ , and R ４ However, each independently, hydrogen and C １－３ Selected from the group consisting of alkyl groups, C １－３ The alkyl group is optionally substituted with one or more halogen atoms, or R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a 5- or 6-membered heterocycloalkyl group, or R ２ and R ４ However, together with the carbon atoms to which they are bonded, they form a 5- or 6-membered heterocycloalkyl group. R ５ However, hydrogen, C １－３ Alkyl, C ３－６ Selected from the group consisting of cycloalkyl groups, C １－３ Alkyl and C ３－６ The cycloalkyl group is optionally substituted with one or more groups selected from the group consisting of deuterium atoms and halogen atoms. R ６ However, hydrogen, halogens, deuterium, C １－３ Alkyl, C １－３ C in which the alkyl group is optionally substituted with one or more halogen atoms. １－３ Alkyl, -CH ２ N(R) １２ ) Ph, and -CH ２ OCH ２ Selected from the group consisting of Ph, R ７ａ and R ７ｂ However, each is independently selected from the group consisting of hydrogen, halogen, methyl, and deuterium. R ８ａ , R ８ｂ , R ９ , R １０ , R １１ａ , and R １１ｂ However, each independently, hydrogen, C １－３ Alkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, C １－３ Alkyl and C ３－６ The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms, or or R ８ａ and R ８ｂ And / or R １１ａ and R １１ｂ However, together with the nitrogen atom to which they are bonded, they form a 3-6 member heterocycloalkyl group. R １２ However, hydrogen and C １－３ Selected from the group consisting of alkyl groups, C １－３ The alkyl group is optionally substituted with one or more halogen atoms. Ph is one or more halogen atoms or C １－３ Phenyl is optionally substituted with an alkyl group, C １－３ A compound in which an alkyl group is optionally substituted with one or more halogen atoms. or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof.

2. The compound according to claim 1, wherein Q is O.

3. The aforementioned nine-membered bicyclic heteroaryl group (a) Containing one, two, three, or four ring heteroatoms independently selected from the group consisting of N and S, (b) The compound according to claim 1 or 2, which is substituted with 0, 1, 2, 3, 4, or 5 X groups.

4. R １ but, 【Chemistry 135】 Selected from the group consisting of, During the ceremony, Z １ However, selected from the group consisting of C and N, Z ２ However, S, NR １３ , and CR １４ Selected from the group consisting of, Z ３ Z ４ , and Z ５ However, each operates independently, CR １５ Or selected from the group consisting of N, X １ , X ２ , X ３ , X ５ , X ６ , X ７ , X ８ , R １４ , and R １５ However, each independently, hydrogen, halogen, -OR ９ , C １－４ Alkyl alkyl groups, and C ３－６ Selected from the group consisting of cycloalkyl groups, C １－４ Alkyl and C ３－６ The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms. X ４ and R １３ However, each independently, hydrogen, C １－４ Alkyl alkyl groups, and C ３－６ Selected from the group consisting of cycloalkyl groups, C １－４ Alkyl and C ３－６ The cycloalkyl group is optionally substituted with one or more deuterium atoms and / or halogen atoms. R ９ The compound according to any one of claims 1 to 3, as defined in claim 1.

5. R １ but, 【Transformation 136】 Selected from the group consisting of, where X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ , R １３ , R １４ , and R １５ are as defined in claim 4, a compound according to any one of claims 1 to 4.

6. R １ is 【Chemistry 137】 Selected from the group consisting of, In the formula, X １ , X ２ , X ４ , R １３ , R １４ , and R １５ The compound according to any one of claims 1 to 5, wherein it is as defined in claim 4 or claim 5.

7. X １ , X ２ , X ３ , X ５ , X ６ , X ７ , X ８ , R １４ , and R １５ However, each independently produces hydrogen, -OCH ３ , -OCHF ２ , -OCHF[ １８ F], -OCHFCl, -CF ３ , -OCH ２ F, -OCF ３ , -OCF ２ Cl, -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCD ３ -OH, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , 【Chemistry 138】 - CD ３ Selected from the group consisting of , Cl, and F, X ４ and R １３ However, each independently produces hydrogen, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , 【Chemistry 139】 and -CD ３ A compound according to any one of claims 4 to 6, selected from the group consisting of the following.

8. X １ However, hydrogen, -OCH ３ , -OCHF ２ , -OCHF[ １８ F], -OCHFCl, -CF ３ , -OCH ２ F, -OCF ２ Selected from the group consisting of Cl and -OH, X ４ However, hydrogen -CH ３ , and -CH ２ CH ３ Selected from the group consisting of, R １４ However, hydrogen, F, Cl, and -CH ３ Selected from the group consisting of, X ２ , R １３ , and R １４ However, each independently, hydrogen and -CH ３ Selected from the group consisting of, X ３ , X ５ , X ６ , X ７ , and X ８ The compound according to any one of claims 1 to 7, wherein each of the compounds is hydrogen.

9. R ２ , R ３ , and R ４ However, each is independently selected from the group consisting of hydrogen, methyl, and ethyl, or R ２ and R ４ The compound according to any one of claims 1 to 8, wherein they combine with the carbon atoms to which they are bonded to form a five-membered heterocycloalkyl group.

10. R ５ The compound according to any one of claims 1 to 9, wherein the group is selected from the group consisting of hydrogen, methyl, ethyl, and cyclopropyl, and the methyl, ethyl, and cyclopropyl groups are optionally substituted with one, two, or three deuterium atoms.

11. R ６ However, it is hydrogen, R ７ａ and R ７ｂ The compound according to any one of claims 1 to 10, which is independently selected from the group consisting of hydrogen and deuterium.

12. The aforementioned compound, [Chemistry 140] 【Chemistry 141】 A compound according to claim 1, selected from the group consisting of the following: or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof. 【Request Item 13】 【Chemistry 142】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof.

14. A pharmaceutical formulation comprising a compound of formula I as defined in any one of claims 1 to 12, or a compound as defined in claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof, and a pharmaceutically acceptable excipient.

15. A compound of formula I as defined in any one of claims 1 to 12, or a compound as defined in claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof, or a pharmaceutical formulation as defined in claim 14, for use in medicine.

16. A method for treating or preventing a disease or condition that responds to treatment with a transglutaminase inhibitor, comprising administering to a subject in need a compound of formula I as defined in any one of claims 1 to 12, or a compound as defined in claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof, or a pharmaceutical formulation as defined in any one of claims 14.

17. The method according to claim 16, wherein the disease or condition that responds to treatment with a transglutaminase inhibitor is selected from the group consisting of diseases or conditions associated with fibrosis, scarring, neurodegenerative diseases, autoimmune diseases, thrombosis, proliferative disorders, AIDS, psoriasis, inflammation, pulmonary hypertension, and pathological angiogenesis.

18. The method according to claim 17, wherein the disease or condition is selected from the group consisting of idiopathic pulmonary fibrosis, pulmonary fibrosis, cardiac fibrosis, cystic fibrosis, hepatic fibrosis, renal fibrosis, scarring, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, celiac disease, thrombosis, prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, cervical cancer, esophageal cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, sarcoma, AIDS, psoriasis, chronic inflammatory disease, inflammatory bowel disease, Crohn's disease, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, central retinal vein occlusion, sickle cell retinopathy, branch retinal vein occlusion and central retinal vein occlusion, and retinal trauma.

19. A method for preventing or treating rejection of a transplanted organ, comprising contacting the organ with a compound as defined in any one of claims 1 to 12 or as defined in claim 13, or a pharmaceutically acceptable salt, solvate, or deuterated analog thereof, or a pharmaceutical formulation as defined in claim 14, wherein the organ is, optionally (a) Before transplantation, or (b) During and / or after transplantation in the patient, Preferably, the organ is the heart, lungs, kidneys, or liver.

20. A process for preparing a compound of formula I as defined in any one of claims 1 to 12 or a compound as defined in claim 13, wherein the process is (a) Compounds of formula II, 【Chemistry 143】 The reaction with the compound of formula III, 【Chemistry 144】 In the formula, Q, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ａ , R ７ｂ A, E, and L are as defined in any one of claims 1 to 13, and G １ However, a suitable leaving group is required for the reaction. (b) Compounds of formula I, compounds of formula V, 【Chemistry 145】 A reaction with a compound of formula XIX, 【Chemistry 146】 In the formula, Q, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ａ , R ７ｂ , and L is as defined in any one of claims 1 to 13, and M is a preferred metal atom, the reaction, or (c) R ７ａ and R ７ｂ In the case of the compound of formula I in which both are deuterium, the compound of formula XXII, 【Chemistry 147】 A reaction with a suitable source of deuterium, wherein Q and R in the formula １ , R ２ , R ３ , R ４ , R ５ A, E, and L are as defined in any one of claims 1 to 13, and each R １７ However, independently, C １－３ A process involving an alkyl group, including a reaction.

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