DEGRADADORES IRAK E USOS DOS MESMOS

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Description

Iraqi Degraders, Their Uses and Pharmaceutical Composition REFERENCE TO RELATED ORDERS

[001] This application claims benefit and priority of the Application Provisional Application Serial No. US 63 / 510,011, filed on June 23, 2023, Provisional Application Serial No. US 63 / 579,477, filed on August 29, 2023, Provisional Application Serial No. US 63 / 593,445, filed on October 26, 2023, Provisional Application Serial No. US 63 / 604,610, filed on November 30, 2023, Provisional Application Serial No. US 63 / 625,710, filed on January 26, 2024, and Provisional Application Serial No. US 63 / 570,564, filed on March 27, 2024, the content of which is incorporated herein in its entirety by reference. TECHNICAL FIELD OF THE INVENTION

[002] The present invention relates to compounds and methods useful for modulating one or more interleukin-1 receptor-associated kinases (IRAK) through ubiquitination and / or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION

[003] The Ubiquitin-Proteasome (UPP) pathway or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulatory proteins and degrades folded or abnormal proteins. The UPP is central to multiple cellular processes and, if defective or unbalanced, leads to the pathogenesis of a variety of diseases. The covalent binding of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[004] UPP plays an important role in the degradation of Petition 870250093594, dated 10 / 13 / 2025, pp. 418 / 829 2 / 384 short-lived and regulatory proteins are important in a variety of basic cellular processes, including cell cycle regulation, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of various genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), in immune surveillance / viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and extracellular modulators, neuronal network morphogenesis, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and organelle biogenesis.

[005] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and small molecule synthetic probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins through their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression.These compounds are capable of inducing the inactivation of a protein of interest by adding them to cells or administering them to an animal or human, and could be useful as biochemical reagents, leading to a new paradigm for the treatment of diseases through the removal of pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).

[006] There is a continuing need in the field for effective treatments for disease, especially inflammatory diseases. Among Petition 870250093594, dated 10 / 13 / 2025, pp. 419 / 829 3 / 384 However, non-specific effects and the inability to target and modulate certain classes of proteins together, such as regulatory proteins, remain obstacles to the development of effective therapeutic agents. As such, small molecule therapeutic agents that leverage E3 ligase-mediated protein degradation for target proteins such as interleukin-1 receptor-associated kinases (IRAKs) are promising as therapeutic agents. Consequently, a need persists to find compounds that are useful IRAK degraders as therapeutic agents. SUMMARY OF THE INVENTION

[007] This application relates to innovative bifunctional compounds that function to recruit IRAK kinases to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds that are useful as modulators of targeted ubiquitination of IRAK kinases, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a wide range of pharmacological activities is possible, consistent with the degradation / inhibition of IRAK kinases. Furthermore, the description provides methods of using an effective amount of the compounds as described herein for the treatment or improvement of a disease condition, such as cancer or an inflammatory disorder.

[008] It has now been found that the compounds of this invention and pharmaceutically acceptable compositions thereof are effective for modulating targeted ubiquitination. Such compounds have formulas Ia to Ii: Petition 870250093594, dated 10 / 13 / 2025, pp. 420 / 829 4 / 384 Ia (ROn Ib ID (ROn Ie Petition 870250093594, dated 10 / 13 / 2025, pp. 421 / 829 5 / 384 or a pharmaceutically acceptable salt thereof, where each variable is as defined and described in this document.

[009] The compounds of the present invention and pharmaceutical compositions Petition 870250093594, dated 10 / 13 / 2025, pp. 422 / 829 6 / 384 ceutically acceptable versions thereof are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signaling pathways involving IRAK kinases. Such diseases, disorders, or conditions include those described in this document.

[0010] The compounds provided by this invention are also useful for the study of IRAK enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in body tissues; and the comparative evaluation of new IRAK inhibitors or IRAK degraders or other regulators of kinases, signaling pathways and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF CERTAIN MODALITIES 1. General Description of Certain Embodiments of the Invention:

[0011] The compounds of the present invention and compositions thereof are useful as degraders and / or inhibitors of one or more IRAK protein kinases. In some embodiments, a given compound degrades and / or inhibits IRAK4. 2. Compounds and Definitions:

[0012] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999 and March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the full contents of which are incorporated herein by reference. Petition 870250093594, dated 10 / 13 / 2025, pp. 423 / 829 7 / 384

[0013] The term aliphatic or aliphatic group, as used herein, means a linear (i.e., unbranched) or branched hydrocarbon chain, substituted or unsubstituted, that is fully saturated or contains one or more unsaturation units, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturation units but is non-aromatic (also referred to herein as carbocyclic, cycloaliphatic, or cycloalkyl), which has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms.In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, cycloaliphatic (or carbocyclo or cycloalkyl) refers to a C3C6 monocyclic hydrocarbon that is fully saturated or that contains one or more unsaturation units, but is non-aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, alkynyl groups, substituted or unsubstituted, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0014] As used in this document, the term bicyclic bridge refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, that has at least one bridge. As defined by IUPAC, a bridge is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, wherein one head of Petition 870250093594, dated 10 / 13 / 2025, pp. 424 / 829 8 / 384 bridging is any structural atom of the ring system that is bonded to three or more structural atoms (excluding hydrogen). In some embodiments, a bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include the groups shown below where each group is bonded to the rest of the molecule at any replaceable carbon or nitrogen atom. Unless otherwise specified, a bridging bicyclic group is optionally replaced by one or more substituents as presented for aliphatic groups. Additionally or alternatively, any replaceable nitrogen of a bridging bicyclic group is optionally substituted. Exemplary bridging bicyclics include:

[0015] The term lower alkyl refers to a linear or branched C1-4 alkyl group. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. Petition 870250093594, dated 10 / 13 / 2025, pp. 425 / 829 9 / 384

[0016] The term lower haloalkyl refers to a linear or branched C1-4 alkyl group that is substituted by one or more halogen atoms.

[0017] The term heteroatom means one or more of the following: oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[0018] The term unsaturated, as used in this document, means that a portion has one or more unsaturation units.

[0019] As used in this document, the term linear or branched saturated or unsaturated divalent C1-8 (or C1-6) hydrocarbon chain refers to divalent alkylene, alkenylene and alkynylene chains that are linear or branched as defined in this document.

[0020] The term alkylene refers to a divalent alkyl group. An alkylene chain is a polymethylene group, that is, -(CH2)n-, where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0021] The term alkenylene refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. The substituents Petition 870250093594, dated 10 / 13 / 2025, pp. 426 / 829 Suitable 10 / 384 include those described below for a substituted aliphatic group.

[0022] As used herein, the term cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure: .

[0023] The term halogen means F, Cl, Br or I.

[0024] The term aryl, used alone or as part of a larger portion such as aralkyl, aralkoxy, or aryloxyalkyl, refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term aryl may be used interchangeably with the term aryl ring. In certain embodiments of the present invention, aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracycline, and the like, which may bear one or more substituents. Also included within the scope of the term aryl, as used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl and the like.

[0025] The terms heteroaryl and heteroar- used alone or as part of a larger moiety, for example, heteroaralkyl or heteroaralkoxy, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 shared π electrons in a cyclic arrangement; and having, in addition to carbon atoms, one to five heteroatoms. The term heteroatom refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, tienyl, Petition 870250093594, dated 10 / 13 / 2025, pp. 427 / 829 11 / 384 furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms heteroaryl and heteroar-, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group can be monocyclic or bicyclic.A heteroaryl ring may include one or more oxo (=O) or thioxo (=S) substituents. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic, any of which include rings that are optionally substituted. The term heteroaralkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl moieties are independently and optionally substituted.

[0026] As used in this document, the terms heterocycle, heterocyclyl, heterocyclic radical, and heterocyclic ring are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and that has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term nitrogen includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring... Petition 870250093594, dated 10 / 13 / 2025, pp. 428 / 829 12 / 384 fully unsaturated which has 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or +NR (as in substituted Npyrrolidinyl).

[0027] A heterocyclic ring can be attached to its pendant group on any heteroatom or carbon atom resulting in a stable structure, and any of the ring atoms can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms heterocycle, heterocyclyl, heterocyclyl ring, heterocyclic group, heterocyclic moiety, and heterocyclic radical are used interchangeably in this document and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl.A heterocyclic group can be monocyclic, bicyclic, bridging bicyclic, or spirocyclic. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituents. The term heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently and optionally substituted.

[0028] As used in this document, the term partially unsaturated refers to a ring portion that includes at least one double or triple bond. The term partially unsaturated is intended to encompass rings that have multiple unsaturation sites, but is not intended to include aryl or heteroaryl chemical portions as defined in this document. Petition 870250093594, dated 10 / 13 / 2025, pp. 429 / 829 13 / 384

[0029] As described in this document, the compounds of the invention may contain optionally substituted chemical moieties. In general, the term substituted, whether preceded by the term optionally or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each replaceable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. The combinations of substituents covered by this invention are preferably those that result in the formation of stable or chemically viable compounds.The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions that allow their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0030] Suitable monovalent substituents on a replaceable carbon atom of an optionally substituted group are, independently, halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o4Ro, -0-(CH2)o-4C(0)OR°; -(CH2)o-4CH(OR°)2; -(CH2)o-4SR°; -(CH2)o4Ph, which can be substituted for R°; -(CH2)0-4O(CH2)0-1Ph which can be substituted for R°; -CH=CHPh, which can be substituted for R°; (CH2)0-4O(CH2)0-1-pyridyl which can be substituted for R°; -NO2; -CN; -N3; ​​-(CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)o4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)o-4N(R°)C(0)OR°; N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; (CH2)o-4C(0)R°; -C(S)R°; -(CH2)o-4C(0)OR°; -(CH2)o-4C(0)SR°; (CH2)o-4C(0)OSíR°3; -(CH2)o-40C(0)R°; -OC(0)(CH2)o-4SR-, Petition 870250093594, dated 10 / 13 / 2025, pp. 430 / 829 14 / 384 SC(S)SR°; -(CH2)ü-4SC(O)R°; -(CH2)ü-4C(O)NR°2; -C(S)NRo2; C(S)SR°; -SC(S)SR°, -(CH2)ü-4OC(O)NR°2; -C(O)N(ORo)Ro; C(O)C(O)Ro; -C(0)CH2C(0)R°; -C(NOR°)R°; -(CH2)ü-4SSR°; -(CH2)ü4S(O)2R°; -(CH2)ü-4S(O)2OR°; -(CH2)ü-4OS(O)2R°; -S(O)2NR°2; (CH2)ü-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(0)2R°; -N(OR°)R°; C(NH)NR°2; -P(0)2R°; -P(0)R°2; -0P(0)R°2; -0P(0)(0R°)2; SíR°3;(C1-4 linear or branched alkylene)ON(R°)2 or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -O(CH2)ü-iPh, -CH2-(5-6 membered heteroaryl ring) or a saturated, partially unsaturated or aryl ring of 5-6 members having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, taken together with their intervening atom(s), form a saturated, partially unsaturated or aryl mono- or bicyclic ring of 3-12 members having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0031] Suitable monovalent substituents on R° (or on the ring formed by taking two independent occurrences of R° together with their intervening atoms) are, independently, halogen, -(CH2)ü-2R·, -(haloR·), -(CH2)ü-2OH, -(CH2)ü-2OR·, (CH2)ü-2CH(OR^)2; -O(haloR·), -CN, -N3, -(CH2)ü-2C(O)R·, -(CH2)ü-2C(O)OH, -(CH2)ü-2C(O)OR·, -(CH2)ü-2SR·, -(CH2)ü-2SH, -(CH2)ü2NH2, -(CH2)ü-2NHR·, -(CH2)ü-2NRà2, -NO2, -SiRS, -OSíR*3, C(O)SR· -(C1-4 linear or branched alkylene)C(O)OR· or -SSR· wherein each R· is unsubstituted or, when preceded by a halo, is substituted only by one or more halogens and is independently selected from C1-4 aphylactic, -CH2Ph, -O(CH2)o-1Ph or a saturated, partially unsaturated or aryl ring of 5 a 6 members with ü a Petition 870250093594, dated 10 / 13 / 2025, pp. 431 / 829 15 / 384 heteroatoms selected independently from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0032] Suitable divalent substituents on a saturated carbon atom of an optionally substituted group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O- or -S(C(R*2))2—3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or a 5-6 membered aryl ring saturated, partially unsaturated unsubstituted or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.Suitable divalent substituents that are attached to vicinal replaceable carbons of an optionally substituted group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or a 5-6 membered aryl ring that is saturated, partially unsaturated, unsubstituted, or has 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the aliphatic group of R* include halogen, -R\ -(haloR·), -OH, -OR·, -O(haloR·), -CN, -C(O)OH, C(O)OR·, -NH2, -NHR·, -NR^2 or -NO2, wherein each R· is unsubstituted or wherein preceded by halo is substituted only by one or more halogens and is independently C1-4 aliphatic, -CH2Ph, O(CH2)ü-1Ph or a 5-6 membered aryl ring saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] Suitable substituents on a replaceable nitrogen of an optionally substituted group include -Rt, -NRt2, C(O)Rt -C(O)ORt -C(O)C(O)Rt -C(O)CH2C(O)Rt, -S(O)2Rt, Petition 870250093594, dated 10 / 13 / 2025, pp. 432 / 829 16 / 384 S(O)2NR^2, -C(S)NR^2, -C(NH)NR^2, or -N(Rt)S(O)2Rt; wherein each Rt independently hydrogen, C1-6 aliphatic which may be substituted as defined below, -OPh unsubstituted, or an unsubstituted 5-6 membered aryl ring saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Rt, taken together with their intervening atom(s) form an unsubstituted 3-12 membered mono- or bicyclic aryl ring saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0035] Suitable substituents on the aliphatic group of Rt are independently halogen, -R·, -(haloR·), -OH, -OR·, O(haloR·), -CN, -C(O)OH, -C(O)OR·, -NH2, -NHR·, -NR^2 or -NO2, wherein each R· is unsubstituted or wherein preceded by halo is substituted only by one or more halogens and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph or a 5-6 membered aryl ring saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0036] As used in this document, the compound term supplied refers to any genus, subgenus and / or species presented in this document.

[0037] As used in this document, the term pharmaceutically acceptable salt refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharma Petition 870250093594, 10 / 13 / 2025, p. 433 / 829 17 / 384 Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein in its entirety by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or through the use of other methods employed in the art, such as ion exchange.Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and similar substances.

[0038] Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N+(C1—4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Petition 870250093594, dated 10 / 13 / 2025, pp. 434 / 829 18 / 384

[0039] Unless otherwise indicated, the structures described in this document are also intended to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are included within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, the structures described in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.For example, compounds having the present structures, including the substitution of hydrogen by deuterium or tritium, or the substitution of a carbon by a carbon enriched with 13C- or 14C-, are included within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0040] As used in this document, the term inhibitor is defined as a compound that binds to and / or inhibits an IRAK kinase with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0041] As used in this document, the term degrader is defined as a heterobifunctional or monovalent compound that binds to and / or inhibits both an IRAK kinase and an E3 lymphocyte. Petition 870250093594, dated 10 / 13 / 2025, pp. 435 / 829 19 / 384 gase with measurable affinity resulting in ubiquitination and subsequent degradation of the IRAK kinase. In certain embodiments, a degrader has a DC50 of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0042] The terms measurable affinity and measurable inhibition, as used herein, mean a measurable change in IRAK kinase protein activity between a sample comprising a compound of the present invention, or a composition thereof, and an IRAK kinase protein and an equivalent sample comprising an IRAK kinase protein in the absence of said compound, or a composition thereof. 3. Description of Illustrative Modalities:

[0043] As described above, in certain embodiments, the present invention provides a compound of one of the following formulas: Ia (Rhn Ic Petition 870250093594, dated 10 / 13 / 2025, pp. 436 / 829 20 / 384 lí ° ô A i Ύ A / A ( > ) ( > ) J k J \ JN π 1 Z\ ro 3 A ) Z — X \ 7J ,__ / < ZIM < 3 r \ 1 । | 0 (R3)p (R1)n Ih Petition 870250093594, dated 10 / 13 / 2025, pp. 437 / 829 21 / 384 or a pharmaceutically acceptable salt thereof, where: X is a divalent moiety selected from either -CH2- or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-; ring A is a ring selected from phenylenyl, pyridinenyl, X Ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; each of R1, R2, and R3 is independently hydrogen, RA, halogen, -CN, -NO2, oxo, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -CR2N(R)C(O)R, CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R; Each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated carbocyclic or heterocyclic ring of 3-7 members. Petition 870250093594, dated 10 / 13 / 2025, pp. 438 / 829 22 / 384 bromides having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: Two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 4-11 membered carbocyclic or heterocyclic ring, having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur; Each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R5 is hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl, or: Two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R5 groups on two different carbon atoms combine to form, with the intervening atoms connecting the two R5 groups, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Petition 870250093594, dated 10 / 13 / 2025, pp. 439 / 829 23 / 384 each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of m, n, peq are independently 0, 1, 2, 3 or 4.

[0044] As described above, in certain embodiments, the present invention provides a compound of any of the following formulas: Ia' Ib' (R)n Ic' (R)n Id' Petition 870250093594, dated 10 / 13 / 2025, pp. 440 / 829 24 / 384 0=^ HN-X ' ο=(^Λτ-ζ-( A\ HN—XX (f 0^ / -Z“f AJ HN-X (R5)l-2 -N^PíCH^ ( / H í D ) χ~^νζ'Ν Ίΐ~A (CH2)0,XjH c J 0 (r3)p (R1)n ig' L) / X h ( d ) n / —\<Y π ( c j o (r3)p :R2)m (R1)n I-h' (R2)m -( A ) > ---< / R5\ / ·---\ q 0 / rA \ ) JI ID ) NA>Gf (R1)n Ii' Petition 870250093594, dated 10 / 13 / 2025, pp. 441 / 829 25 / 384 (R1)nl-j (ROn lk (Rhn ll lm Petition 870250093594, dated 10 / 13 / 2025, pp. 442 / 829 26 / 384 or a pharmaceutically acceptable salt thereof, where: X is a divalent moiety selected from either -CH2- or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-; Ring A is a ring selected from phenylenyl, pyridinenyl, Ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; Each of R1, R2, and R3 is independently hydrogen, RA, ha. Petition 870250093594, dated 10 / 13 / 2025, page 443 / 829 27 / 384 logenium, -CN, -NO2, oxo, -OR, -SR, -NR2, -S1R3, -S(O)2R, -S(O)2NR2, S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -CR2N(R)C(O)R, CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R; Each R is independently hydrogen or an optionally substituted group selected from aliphatic C1-6, phenyl, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 4-11 membered carbocyclic or heterocyclic ring, having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur; Each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R5 is hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl, or: Petition 870250093594, dated 10 / 13 / 2025, pp. 444 / 829 28 / 384 two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring with 1-3 heteroatoms selected independently from nitrogen, oxygen and sulfur, or two R5 groups on two different carbon atoms combine to form, with the intervening atoms connecting the two R5 groups, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-3 heteroatoms selected independently from nitrogen, oxygen and sulfur; Each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of m, n, peq are independently 0, 1, 2, 3 or 4.

[0045] In some forms of compounds with formulas described in this document: X is a divalent moiety selected from either -CH2- or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-; ring A is a ring selected from phenylenyl, pyridinenyl, VA e (R2)m—çBj (R2)mf Bj ír / JX rn—ic χχ <, (R* N—5 I / )—I ξ O , R4, R4 N, °-n?e (R2)m\fÊ^); J ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Petition 870250093594, dated 10 / 13 / 2025, pp. 445 / 829 29 / 384 R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; each of R1, R2, and R3 is independently hydrogen, RA, halogen, -CN, -NO2, oxo, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -CR2N(R)C(O)R, CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R; Each R is independently hydrogen or an optionally substituted group selected from aliphatic C1-6, phenyl, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 4-11 membered carbocyclic or heterocyclic ring, having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur; Each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Petition 870250093594, dated 10 / 13 / 2025, pp. 446 / 829 30 / 384 each R5 is independently hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl, or: Two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R5 groups on two different carbon atoms combine to form, with the intervening atoms connecting the two R5 groups, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of m, n, peq are independently 0, 1, 2, 3 or 4.

[0046] As defined above and described in this document, X is a divalent moiety selected from -CH2- and -C(O)-.

[0047] In some forms, X is -CH2-. In some forms, X is -C(O)-.

[0048] In some modalities, X is selected from those described in Table 1 below.

[0049] As defined above and described in this document, Y is a nitrogen atom or CH.

[0050] In some embodiments, Y is a nitrogen atom. In some embodiments, Y is CH.

[0051] In some modalities, Y is selected from those described in Table 1 below. Petition 870250093594, dated 10 / 13 / 2025, pp. 447 / 829 31 / 384

[0052] As defined above and described in this document, Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-.

[0053] In some embodiments, Z is a covalent bond. In some embodiments, Z is -CR2-. In some embodiments, Z is CONR-. In some embodiments, Z is -NR-. In some embodiments, Z is -O-.

[0054] In some forms, Z is -CH2-. In some forms, Z is -CONH-. In some forms, Z is -NH-.

[0055] As defined above and described in this document, Ring A is a ring selected from phenylenyl, pyridinylenyl, (R2)m,-Nd (R2)m-fEQr4-O N.

[0056] In some embodiments, Ring A is phenylenyl. In some embodiments, Ring A is pyridinylenyl. In some embodiments, (R2)m-ÇBJ R4v Ring A is the . In some modalities, Ring A is (R2)m R4 N. In some forms, Ring A is r4'N(R2)m In some disciplines, Ring A is -EQ o n. In some morphologies, Ring A is n Petition 870250093594, dated 10 / 13 / 2025, pp. 448 / 829 32 / 384

[0057] In some forms, Ring A is selected from those described in Table 1 below.

[0058] As defined above and described herein, Ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0059] In some embodiments, Ring B is benzoic. In some embodiments, Ring B is a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some forms, Ring B is selected from those described in Table 1 below. in some modalities, the Ring A and Ring are

[0061] In modalities, modalities, Ring Rings are Ring Rings are modalities, modalities, Ring Ring Ring Rings are are

[0062] As defined above and described in this document, Petition 870250093594, dated 10 / 13 / 2025, page 449 / 829 33 / 384 to, each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0063] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9 membered heteroaryl ring having 2 nitrogens. In some embodiments, Ring C is a 9 membered heteroaryl ring having 3 nitrogens.

[0064] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is pyridyl. In some embodiments, Ring C is pyrazolyl. In some embodiments, Ring C is indazolyl. In some embodiments, Ring C is benzothiazolyl.

[0065] In some embodiments, the C-ring is (r1^ . In some embodiments, the C-ring is (RK In some embodiments, the Petition 870250093594, dated 10 / 13 / 2025, pp. 450 / 829 34 / 384 Ring C is (Rl)n. In some embodiments, Ring C is In some modalities, Ring C is (RK In some modalities, Ring C is (RV In some modalities, Ring C is OX (R)n. In some modalities, Ring C is (RK In ( In some modes, Ring C is (RV In some modes- In other words, Ring C is In some embodiments, the C0X0X \ N\ ring is (R)n. In some embodiments, the C ring is (R)>>. In some embodiments, the Ring C is lR^n. In some embodiments, __ / NA, the Ring C is (R^n. In some embodiments, the Petition 870250093594, dated 10 / 13 / 2025, pp. 451 / 829 35 / 384 In some disciplines, Ring C is Ring C is In some disciplines, Ring C is In some disciplines, Ring C is In some disciplines, Ring C is In some sports, the n. In some modalities, Ring C is Ring C is In some disciplines, Ring C is In some disciplines, Ring C is n. In some modalities, Ring C is

[0066] In some embodiments, Ring D is phenyl. In some embodiments, Ring D is a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a he ring. Petition 870250093594, dated 10 / 13 / 2025, pp. 452 / 829 36 / 384 is a 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 9-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 9-membered heteroaryl ring having 2 nitrogens. In some embodiments, Ring D is a 9-membered heteroaryl ring having 3 nitrogens.

[0067] In some embodiments, Ring D is phenyl. In some embodiments, Ring D is pyridyl. In some embodiments, Ring D is pyrazyl. In some embodiments, Ring D is pyrazolo[1,5a]pyrimidinyl. In some embodiments, Ring D is pyrrolo[1,2a]pyrimidine.

[0068] In some forms, the D-ring is (R3)q. In some forms, the D-ring is In some disciplines, the D-ring is In some disciplines, the D-ring is In some disciplines, the D-ring is In some disciplines, the D-ring is In some disciplines, the D-ring is

[0069] In some disciplines, the D-ring is Petition 870250093594, dated 10 / 13 / 2025, p. 453 / 829 37 / 384 In some disciplines, the D-ring is In some disciplines, the D-ring is A / N r3 XT

[0070] In some forms, the D-ring is or XXΎϊ n . In some embodiments, the D-ring is . In xy some embodiments, the D-ring is n .

[0071] In some forms, the Ring ,N -XCN or CN. In some modalities, the Ring, N -ynCN In [ζ jrCNalgumas modalas, o Anel D é n In some sports, the Ring CN or

[0072] CN. In some disciplines, the Ring CN In some disciplines, the D-ring is

[0073] In some embodiments, Ring C and Ring D are selected from those described in Table 1 below.

[0074] As defined above and described in this document, each of R1, R2 and R3 independently hydrogen, RA, ha Petition 870250093594, dated 10 / 13 / 2025, page 454 / 829 38 / 384 logênio, -CN, -NO2, oxo, -OR, -SR, -NR2, -S1R3, -S(O)2R, -S(O)2NR2, S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, N(R)P(O)(NR2)2 ou -N(R)S(O)2R.

[0075] In some embodiments, R1 is hydrogen. In some embodiments, R1 is RA. In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments, R1 is -NO2. In some embodiments, R1 is oxo. In some embodiments, R1 is OR. In some embodiments, R3 is -Si(OH)2R. In some embodiments, R1 is -Si(OH)R2. In some embodiments, R1 is -SR. In some embodiments, R1 is -NR2. In some embodiments, R1 is -SiR3. In some embodiments, R1 is -S(O)2R. In some embodiments, R1 is -S(O)2NR2. In some embodiments, R1 is -S(O)R. In some embodiments, R1 is -C(O)R. In some embodiments, R1 is -C(O)OR. In some embodiments, R1 is -C(O)NR2. In some modalities, R1 is -C(O)N(R)OR. In some modalities, R1 is -CR2N(R)C(O)R. In some modalities, R1 is -CR2N(R)C(O)NR2. In some modalities, R1 is -CFR2. In some modalities, R1 is -CF2R. In some modalities, R1 is -CF3. In some modalities, R1 is CR2(OR). In some modalities, R1 is -CR2(NR2). In some modalities, R1 is -OC(O)R.In some modalities, R1 is OC(O)NR2. In some modalities, R1 is -OP(O)R2. In some modalities, R1 is -OP(O)(OR)2. In some modalities, R1 is OP(O)(OR)NR2. In some modalities, R1 is independently OP(O)(NR2)2-. In some modalities, R1 is -N(R)C(O)OR. In some modalities, R1 is -N(R)C(O)R. In some modalities, R1 is -N(R)C(O)NR2. In some modalities, R1 is -N(R)P(O)R2. In al. Petition 870250093594, dated 10 / 13 / 2025, p. 455 / 829 39 / 384 In some modalities, R1 is -N(R)P(O)(OR)2. In some modalities, R1 is -N(R)P(O)(OR)NR2. In some modalities, R1 is N(R)P(O)(NR2)2. In some modalities, R1 is -N(R)S(O)2R.

[0076] In some embodiments, R1 is fluorine. In some embodiments, R1 is chlorine. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is C(OH)Me2. In some embodiments, R1 is -CHF2. In some embodiments, R1 is -CF3. In some embodiments, R1 is -OC1-6 alkyl. In some embodiments, R1 is -OMe. In some embodiments, R1 is x. In some embodiments, R1 is χ. In some embodiments, R1 is .

[0077] In some embodiments, R2 is hydrogen. In some embodiments, R2 is RA. In some embodiments, R2 is halogen. In some embodiments, R2 is -CN. In some embodiments, R2 is -NO2. In some embodiments, R2 is oxo. In some embodiments, R2 is OR. In some embodiments, R2 is -Si(OH)2R. In some embodiments, R2 is -Si(OH)R2. In some embodiments, R2 is -SR. In some embodiments, R2 is -NR2. In some embodiments, R2 is -SiR3. In some embodiments, R2 is -S(O)2R. In some embodiments, R2 is -S(O)2NR2. In some embodiments, R2 is -S(O)R. In some embodiments, R2 is -C(O)R. In some embodiments, R2 is -C(O)OR. In some embodiments, R2 is -C(O)NR2. In some modalities, R2 is -C(O)N(R)OR. In some modalities, R2 is -CR2N(R)C(O)R. In some modalities, R2 is -CR2N(R)C(O)NR2. In some modalities, R2 is -CFR2. In some modalities, R2 is -CF2R. In some modalities, R2 is -CF3. In some modalities, R2 is CR2(OR). In some modalities, R2 is -CR2(NR2). In some modalities, R2 is -OC(O)R.In some sports, R2 is... Petition 870250093594, dated 10 / 13 / 2025, pp. 456 / 829 40 / 384 OC(O)NR2. In some modalities, R2 is -OP(O)R2. In some modalities, R2 is -OP(O)(OR)2. In some modalities, R2 is OP(O)(OR)NR2. In some modalities, R2 is independently OP(O)(NR2)2-. In some modalities, R2 is -N(R)C(O)OR. In some modalities, R2 is -N(R)C(O)R. In some modalities, R2 is -N(R)C(O)NR2. In some modalities, R2 is -N(R)P(O)R2. In some modalities, R2 is -N(R)P(O)(OR)2. In some modalities, R2 is -N(R)P(O)(OR)NR2. In some modalities, R2 is N(R)P(O)(NR2)2. In some forms, R2 is -N(R)S(O)2R.

[0078] In some embodiments, R2 is fluorine. In some embodiments, R2 is chlorine. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is methyl. In some embodiments, R3 is C(OH)Me2. In some embodiments, R2 is -CHF2. In some embodiments, R2 is -CF3. In some embodiments, R2 is -OC1-6 alkyl. In some embodiments, R2 is -OiPr. In some embodiments, R2 is OMe.

[0079] In some embodiments, R3 is hydrogen. In some embodiments, R3 is RA. In some embodiments, R3 is halogen. In some embodiments, R3 is RA. In some embodiments, R3 is -CN. In some embodiments, R3 is -NO2. In some embodiments, R3 is oxo. In some embodiments, R3 is -OR. In some embodiments, R3 is -Si(OH)2R. In some embodiments, R3 is -Si(OH)R2. In some embodiments, R3 is -SR. In some embodiments, R3 is -NR2. In some embodiments, R3 is -SiR3. In some embodiments, R3 is S(O)2R. In some embodiments, R3 is -S(O)2NR2. In some embodiments, R3 is -S(O)R. In some embodiments, R3 is -C(O)R. In some embodiments, R3 is -C(O)OR. In some disciplines, R3 is -C(O)NR2. In some disciplines, R3 is -C(O)N(R)OR. In some disciplines, R3 is -CR2N(R)C(O)R. In some disciplines, R3 is CR2N(R)C(O)NR2. In some disciplines, R3 is -CFR2. In some Petition 870250093594, dated 10 / 13 / 2025, pp. 457 / 829 41 / 384 modalities, R3 is -CF2R. In some modalities, R3 is -CF3. In some modalities, R3 is -CR2(OR). In some modalities, R3 is -CR2(NR2). In some modalities, R3 is -OC(O)R. In some modalities, R3 is -OC(O)NR2. In some modalities, R3 is OP(O)R2. In some modalities, R3 is -OP(O)(OR)2. In some modalities, R3 is -OP(O)(OR)NR2. In some modalities, R2 is independently -OP(O)(NR2)2-. In some modalities, R3 is N(R)C(O)OR. In some modalities, R3 is -N(R)C(O)R. In some modalities, R3 is -N(R)C(O)NR2. In some modalities, R3 is -N(R)P(O)R2. In some modalities, R3 is -N(R)P(O)(OR)2. In some modalities, R3 is -N(R)P(O)(OR)NR2. In some modalities, R3 is -N(R)P(O)(NR2)2. In some modalities, R3 is N(R)S(O)2R.

[0080] In some embodiments, R3 is fluorine. In some embodiments, R3 is chlorine. In some embodiments, R3 is -CN. In some embodiments, R3 is C1-6 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is t-butyl. In some embodiments, R3 is -CH2OMe. In some embodiments, R3 is -C(OMe)Me2. In some embodiments, R3 is -C(CN)Me2. In some embodiments, R3 is C3-6 cycloalkyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is cyclobutyl. In some embodiments, R3 is -CHF2. In some embodiments, R3 is -CF3. In some embodiments, R3 is -OCF3. In some embodiments, R3 is -OCHF2. In some embodiments, R3 is -OC1-6-alkyl. In some embodiments, R3 is OiPr. In some embodiments, R3 is -OC3-6-cycloalkyl. In some embodiments, R3 is V>. In some embodiments, R3 is '—f. In some embodiments, R3 is ^ / . In some embodiments, R3 is -OMe. In some embodiments, R3 is -NMe2. In Petition 870250093594, dated 10 / 13 / 2025, pp. 458 / 829 42 / 384 some modalities, R3é. In some modalities, R3é f. In some modalities, R3é f. In some modalities, R3é f. In some modalities, R3 is f. In some modalities, R3 is zf. In some modalities, R3 is o In some sports, R3 is... In some sports, R3 is... In some sports, R3 is... In some sports, R3 is . In some sports, R3 is ,o . In some modalities, R3 is o . In some modalities, R3 is \ . In some modalities, R3 Vn. In some modalities, R3é * In some modalities, R3 is In some modalities, R3 is the In some modalities, R3 is... In some modalities, R3 is °... In some modalities, R3 is... In some sports, R3 is \ . In some sports, R3 _ . ..... . In some modalities, R3é \ . In some modalities Petition 870250093594, of 10 / 13 / 2025, page 459 / 829 43 / 384 ... . . ..... , VNlidades, R3é \x. In some modalities, R3é \ In some modalities, R3éο. In some modalities, R3é o . In some modalities, R3é o. In some modalities, R3 is —o. In some modalities, R3 / —\0 / . In some modalities, R3 is \ . In some modalities, R3 is In some modalities, R3 is VN. In some modalities, R3 is \ . In some modalities, R3 is In some modalities, R3 is _ . ..... , VN . In some modalities, R3é . In some modalities, R3é f. In some forms, R3 is nh2 -F f . In some forms, R3 is nh2f . In some forms, R3 is nh2 -F f . In some modalities, R3é f. In some modalities, R3 is V ^Έ. In some Petition 870250093594, dated 10 / 13 / 2025, pp. 460 / 829 44 / 384 modalities. In some modalities, R3 is. In some modalities, R3 is. In some modalities, R3éCHF2. In some modalities, R3ézchf2. In some modalities, R3éCHF2. In some modalities, R3éCF3. In some modalities, R3cf3. In some modalities, R3éCF3. In some modalities, R3é V ^E. In some modalities, R3 CHF2t N. In some modalities, R3é ' cf3. In some modalities, R3é In some modalities, R3 is ο-'-χNH. In some modalities, R3 is In some modalities, R3 is HN^ ^0. In some modes, R3 is In some modalities, R3é V ^E . In some modalities, E^ VNX R3é \ . In some modalities, R3éxx. In alguPetition 870250093594, of 10 / 13 / 2025, page 461 / 829 45 / 384 but modalities, R3é In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is Vn^ff . In some modalities, R3é In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modes, R3 In some sports, R3 is CF3. In some sports, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is Petition 870250093594, dated 10 / 13 / 2025, pp. 462 / 829 46 / 384 In some modalities, R3 is In some modalities, R3é In some modalities, R3 is In some modalities, R3 is In some modalities, R3 is _ . ..... , / ° . ..... In some modalities, R3 is x '—'. In some modalities, R3e -SMe. In some modalities, R3e -SCF3. In some modalities, R3e -SOCF3. In some modalities, R3e -SO2CF3.

[0081] In some modalities, R1, R2 and R3 are selected from those described in Table 1 below.

[0082] As defined above and described in this document, R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl.

[0083] In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-5 alkyl. In some embodiments, R4 is C3-6 cycloalkyl.

[0084] In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is cyclopropyl.

[0085] In some modalities, R4 is selected from those described in Table 1 below.

[0086] As defined above and described herein, R5 is hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl, or C3-6 cycloalkyl; two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R5 groups on two different carbon atoms combine to form, with the Petition 870250093594, dated 10 / 13 / 2025, pp. 463 / 829 47 / 384 intervening atoms connecting the two R5 groups, a 37-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments, R5 is hydrogen. In some embodiments, R5 is halo. In some embodiments, R5 is -CN. In some embodiments, R5 is -OR. In some embodiments, R5 is oxo. In some embodiments, R5 is C1-6 alkyl. In some embodiments, R5 is -CR2OR. In some embodiments, R5 is -OC1-6 alkyl. In some embodiments, R5 is C1-6 haloalkyl. In some embodiments, R5 is -OC1-6 haloalkyl. In some embodiments, R5 is C3-6 cycloalkyl. In some embodiments, two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, two R5 groups on two different carbon atoms combine to form, with the intervening atoms connecting the two R5 groups, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring that has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] In some embodiments, R5 is fluorine. In some embodiments, R5 is geminal difluorophosphate. In some embodiments, R5 is methylphosphate. In some embodiments, R5 is -OH. In some embodiments, R5 is OMe. In some embodiments, R5 is -CMe2OH. In some embodiments, R5 is -CF3. In some embodiments, R5 is -CHF2. In some embodiments, R5 is -CH2CF3. In some embodiments, R5 is CH2CHF2.

[0089] In some embodiments, two R5 groups on two atoms Petition 870250093594, dated 10 / 13 / 2025, pp. 464 / 829 48 / 384 different carbon atoms combine to form -R5- of a saturated or partially unsaturated 3-7 membered heterocyclic or carbocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein -R5- is -CH2-, -O-, CH2CH2-, -CH2O-, or -CH2OCH2-. In some embodiments, two R5 groups on two different carbon atoms combine to form -R5- of a bridging bicycle (e.g., |—N R5N—I or ).

[0090] In some modalities, (R5)q KjH is or

[0091] In some modalities, hZh

[0092] In some modalities, R5 is selected from those described in Table 1 below.

[0093] As defined above and described herein, each R is independently hydrogen, or an optionally substituted group selected from aliphatic C1-6, phenyl, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Petition 870250093594, dated 10 / 13 / 2025, pp. 465 / 829 49 / 384 carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic or spirocyclic carbocyclic or heterocyclic ring that has 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur.

[0094] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C1-6 aliphatic. In some embodiments, R is a C1-6 alkyl (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is a C1-6 haloalkyl (e.g., -CF3, CHF2, etc.). In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 37 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments, two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, optionally substituted bicyclic, bridging bicyclic or spirocyclic carbocyclic or heterocyclic ring that has 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur.

[0095] In some modalities, R is selected from those described in Table 1 below. Petition 870250093594, dated 10 / 13 / 2025, pp. 466 / 829 50 / 384

[0096] As defined above and described in this document, each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0097] In some embodiments, RA is an optionally substituted C1-6 aliphatic. In some embodiments, RA is a C1-6 alkyl (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, RA is a C1-6 haloalkyl (e.g., -CF3, CHF2, etc.). In some embodiments, RA is an optionally substituted phenyl. In some embodiments, RA is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, RA is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RA is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some modalities, RA is selected from those described in Table 1 below.

[0099] As defined above and described in this document, each of m, n, peq is independently 0, 1, 2, 3, or 4.

[00100] In some modalities, m is 0. In some modalities, m is 1. In some modalities, m is 2. In some modalities, m is 3. In some modalities, m is 4. In some modalities, m is 0 or 1. In some modalities, m is 1 or 2.

[00101] In some modalities, n is 0. In some modalities, Petition 870250093594, dated 10 / 13 / 2025, p. 467 / 829 51 / 384 n is 1. In some modalities, n is 2. In some modalities, n is 3. In some modalities, n is 4. In some modalities, n is 0 or 1. In some modalities, n is 1 or 2.

[00102] In some modalities, p is 0. In some modalities, p is 1. In some modalities, p is 2. In some modalities, p is 3. In some modalities, p is 4. In some modalities, p is 0 or 1. In some modalities, p is 1 or 2.

[00103] In some modalities, q is 0. In some modalities, q is 1. In some modalities, q is 2. In some modalities, q is 3. In some modalities, q is 4. In some modalities, q is 0 or 1. In some modalities, q is 1 or 2.

[00104] In some modalities, m, n, peq are selected from those described in Table 1 below.

[00105] In some embodiments, the present invention provides a compound of formula Ib or Ib' as a compound of formula Ib-1: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00106] In some embodiments, the present invention provides a compound of formula Ib or Ib' as a compound of formula Ib-2: (R2)m , (R1)n Ib-2 Petition 870250093594, dated 10 / 13 / 2025, pp. 468 / 829 52 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00107] In some embodiments, the present invention provides a compound of formula Ic or Ic' as a compound of formula Ic-1: Ic-1 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00108] In some embodiments, the present invention provides a compound of formula Ic or Ic' as a compound of formula Ic-2: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00109] In some embodiments, the present invention provides a compound of formula Ie or Ie' as a compound of formula Ie-1: Petition 870250093594, dated 10 / 13 / 2025, pp. 469 / 829 53 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00110] In some embodiments, the present invention provides a compound of formula Ie or Ie' as a compound of formula Ie-2: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00111] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-1: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00112] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-2: Petition 870250093594, dated 10 / 13 / 2025, pp. 470 / 829 54 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00113] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-3: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00114] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-4: (R2)m If-4 Petition 870250093594, dated 10 / 13 / 2025, pp. 471 / 829 55 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00115] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-5: (R2)m (Rbn If-5 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00116] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-6: (R2)m (Rbn If-6 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00117] In some embodiments, the present invention provides a compound of formula -f' as a compound of formula If-7: Petition 870250093594, dated 10 / 13 / 2025, pp. 472 / 829 56 / 384 If-7 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00118] In some embodiments, the present invention provides a compound of formula If' as a compound of formula If-8: If-8 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00119] In some embodiments, the present invention provides a compound of formula If' as a compound of formula If-9: Petition 870250093594, dated 10 / 13 / 2025, pp. 473 / 829 57 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00120] In some embodiments, the present invention provides a compound of formula If' as a compound of formula If-10: (R1)n If-10 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00121] In some embodiments, the present invention provides a compound of formula If' as a compound of formula If-11: (Rjn If-11 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00122] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-12: Petition 870250093594, dated 10 / 13 / 2025, p. 474 / 829 58 / 384 If-12 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00123] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-13: If-13 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00124] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-14: Petition 870250093594, dated 10 / 13 / 2025, pp. 475 / 829 59 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00125] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-15: (R1)n If-15 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00126] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-16: (R')n If-16 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00127] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-17: Petition 870250093594, dated 10 / 13 / 2025, pp. 476 / 829 60 / 384 If-17 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00128] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-18: If-18 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00129] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-19: Petition 870250093594, dated 10 / 13 / 2025, pp. 477 / 829 61 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00130] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-20: (R1)n If-20 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00131] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-21: If-21 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00132] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-22: Petition 870250093594, dated 10 / 13 / 2025, pp. 478 / 829 62 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00133] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-23: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00134] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-24: (R1)n If-24 Petition 870250093594, dated 10 / 13 / 2025, pp. 479 / 829 63 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00135] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-25: If-25 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00136] In some embodiments, the present invention provides a compound of formula If' as a compound of formula If-26: If-26 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00137] In some embodiments, the present invention provides a compound of formula If or If' as a compound of formula If-27: Petition 870250093594, dated 10 / 13 / 2025, pp. 480 / 829 64 / 384 If-27 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00138] In some embodiments, the present invention provides a compound of formula Ig or Ig' as a compound of formula Ig-1: Ig-1 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00139] In some embodiments, the present invention provides a compound of formula Ig or Ig' as a compound of formula Ig-2: or a pharmaceutically acceptable salt thereof, wherein each varies Petition 870250093594, dated 10 / 13 / 2025, pp. 481 / 829 65 / 384 vel is as defined above and described in modalities in this document, both individually and in combination.

[00140] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-1: Ij-1 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00141] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-2: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00142] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-3: Petition 870250093594, dated 10 / 13 / 2025, pp. 482 / 829 66 / 384 (Rjn Ij-3 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00143] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-4: Ij-4 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00144] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-5: Ij-5 Petition 870250093594, dated 10 / 13 / 2025, pp. 483 / 829 67 / 384

[00145] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00146] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-6: Ij-6 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00147] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-7: (Rhn Ij-7 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00148] In some embodiments, the present invention provides a Petition 870250093594, dated 10 / 13 / 2025, pp. 484 / 829 68 / 384 compound of formula Ij as a compound of formula Ij-8: (Rjn Ij-8 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00149] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-9: Ij-9 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00150] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-10: Petition 870250093594, dated 10 / 13 / 2025, pp. 485 / 829 69 / 384 (RQn Ij-10 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00151] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-11: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00152] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-12: Ij-12 Petition 870250093594, dated 10 / 13 / 2025, pp. 486 / 829 70 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00153] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-13: Ij-13 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00154] In some embodiments, the present invention provides a compound of formula Ij as a compound of formula Ij-14: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00155] In some embodiments, the present invention provides a Petition 870250093594, dated 10 / 13 / 2025, pp. 487 / 829 71 / 384 compound of formula Ij as a compound of formula Ij-15: Ij-15 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00156] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-1: Ik-1 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00157] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-2: Petition 870250093594, dated 10 / 13 / 2025, pp. 488 / 829 72 / 384 Ik-2 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00158] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-3: Ik-3 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00159] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-4: Ik-4 Petition 870250093594, dated 10 / 13 / 2025, pp. 489 / 829 73 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00160] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-5: (R)n Ik-5 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00161] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-6: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00162] In some embodiments, the present invention provides a Petition 870250093594, dated 10 / 13 / 2025, pp. 490 / 829 74 / 384 compound of formula Ik as compound of formula Ik-7: Ik-7 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00163] In some embodiments, the present invention provides a compound of formula Ik as a compound of formula Ik-8: (Rbn Ik-8 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00164] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-1: Petition 870250093594, dated 10 / 13 / 2025, pp. 491 / 829 75 / 384 II-1 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00165] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-2: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00166] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-3: II-3 Petition 870250093594, dated 10 / 13 / 2025, pp. 492 / 829 76 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00167] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-4: II-4 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00168] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-5: II-5 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00169] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-6: Petition 870250093594, dated 10 / 13 / 2025, pp. 493 / 829 77 / 384 II-6 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00170] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-7: II-7 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00171] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-8: Petition 870250093594, dated 10 / 13 / 2025, pp. 494 / 829 78 / 384 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00172] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-9: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00173] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-10: 1-1-10 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00174] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-11: Petition 870250093594, dated 10 / 13 / 2025, pp. 495 / 829 79 / 384 II-11 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00175] In some embodiments, the present invention provides a compound of formula II as a compound of formula II-12: II-12 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both individually and in combination.

[00176] Exemplary compounds of the invention are presented in Table 1 below. Petition 870250093594, dated 10 / 13 / 2025, pp. 496 / 829 80 / 384 Table 1. Exemplary Compounds Petition 870250093594, dated 10 / 13 / 2025, pp. 497 / 829 81 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 498 / 829 82 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 499 / 829 83 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 500 / 829 84 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 501 / 829 85 / 384 I-27 I-28 I-29 I-30 Petition 870250093594, dated 10 / 13 / 2025, pp. 502 / 829 86 / 384 I-32 I-33 I-34 I-35 I-36 I-37 I-38 Petition 870250093594, dated 10 / 13 / 2025, pp. 503 / 829 87 / 384 I-39 I-40 I-41 I-42 I-43 O Petition 870250093594, dated 10 / 13 / 2025, pp. 504 / 829 88 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 505 / 829 89 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 506 / 829 90 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 507 / 829 91 / 384 I-60 I-61 I-62 I-63 I-64 Petition 870250093594, dated 10 / 13 / 2025, pp. 508 / 829 92 / 384 I-65 I-66 I-67 I-68 I-69 Petition 870250093594, dated 10 / 13 / 2025, pp. 509 / 829 93 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 510 / 829 94 / 384 I-75 I-76 I-77 I-78 I-79 I-80 Petition 870250093594, dated 10 / 13 / 2025, pp. 511 / 829 95 / 384 I-81 I-82 I-83 I-84 I-85 I-86 Petition 870250093594, dated 10 / 13 / 2025, pp. 512 / 829 96 / 384 I-87 I-88 I-89 I-90 I-91 Petition 870250093594, dated 10 / 13 / 2025, pp. 513 / 829 97 / 384 I-92 I-93 I-94 I-95 I-96 I-97 Petition 870250093594, dated 10 / 13 / 2025, pp. 514 / 829 98 / 384 I-98 I-99 I-100 I-101 I-102 I-103 I-104 Petition 870250093594, dated 10 / 13 / 2025, pp. 515 / 829 99 / 384 I-105 I-106 I-107 I-108 I-109 I-110 Petition 870250093594, dated 10 / 13 / 2025, pp. 516 / 829 100 / 384 I-111 I-112 I-113 I-114 I-115 Petition 870250093594, dated 10 / 13 / 2025, pp. 517 / 829 101 / 384 I-116 I-117 I-118 I-120 I-121 Petition 870250093594, dated 10 / 13 / 2025, pp. 518 / 829 102 / 384 I-122 I-123 I-124 I-125 I-126 I-127 Petition 870250093594, dated 10 / 13 / 2025, pp. 519 / 829 103 / 384 I-128 I-129 I-130 I-131 I-132 Petition 870250093594, dated 10 / 13 / 2025, pp. 520 / 829 104 / 384 I-133 I-134 I-135 I-136 I-137 Petition 870250093594, dated 10 / 13 / 2025, pp. 521 / 829 105 / 384 I-138 I-139 I-140 I-141 I-142 I-143 Petition 870250093594, dated 10 / 13 / 2025, pp. 522 / 829 106 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 523 / 829 107 / 384 I-149 I-150 I-151 I-152 I-153 I-154 Petition 870250093594, dated 10 / 13 / 2025, pp. 524 / 829 108 / 384 I-155 I-156 I-157 I-158 ° H I-159 HNO I-160 HO Petition 870250093594, dated 10 / 13 / 2025, pp. 525 / 829 109 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 526 / 829 110 / 384 I-167 I-168 I-169 I-170 I-171 Petition 870250093594, dated 10 / 13 / 2025, pp. 527 / 829 111 / 384 I-172 I-173 I-174 I-175 I-176 I-177 Petition 870250093594, dated 10 / 13 / 2025, pp. 528 / 829 112 / 384 I-178 I-179 I-180 I-181 I-182 N, N'' O HN Petition 870250093594, dated 10 / 13 / 2025, pp. 529 / 829 113 / 384 I-183 I-184 I-185 I-186 HN NH NH 0 HN NH Petition 870250093594, dated 10 / 13 / 2025, pp. 530 / 829 114 / 384 I-187 I-188 I-189 I-190 I-191 I-192 Petition 870250093594, dated 10 / 13 / 2025, pp. 531 / 829 115 / 384 I-193 o o H N I-194 I-195 I-196 I-197 I-198 Petition 870250093594, dated 10 / 13 / 2025, pp. 532 / 829 116 / 384 I-199 I-200 I-201 I-202 I-203 Petition 870250093594, dated 10 / 13 / 2025, pp. 533 / 829 117 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 534 / 829 118 / 384 I-211 I-212 I-213 I-214 I-215 I-216 Petition 870250093594, dated 10 / 13 / 2025, pp. 535 / 829 119 / 384 I-217 I-218 I-219 I-220 I-221 Petition 870250093594, dated 10 / 13 / 2025, pp. 536 / 829 120 / 384 I-222 I-223 I-224 I-225 I-226 I-227 Petition 870250093594, dated 10 / 13 / 2025, pp. 537 / 829 121 / 384 I-228 I-229 I-230 I-231 I-232 I-233 Petition 870250093594, dated 10 / 13 / 2025, pp. 538 / 829 122 / 384 I-234 I-235 I-236 I-237 I-238 I-239 Petition 870250093594, dated 10 / 13 / 2025, pp. 539 / 829 123 / 384 I-240 I-241 I-242 I-243 I-244 I-245 I-246 Petition 870250093594, dated 10 / 13 / 2025, pp. 540 / 829 124 / 384 I-247 I-248 NI N I-249 I-250 I-251 the I-252 I-253 Petition 870250093594, dated 10 / 13 / 2025, pp. 541 / 829 125 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 542 / 829 126 / 384 I-261 —N I-262 O I-263 I-264 I-266 I-267 Petition 870250093594, dated 10 / 13 / 2025, pp. 543 / 829 127 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 544 / 829 128 / 384 I-275 I-276 I-277 I-278 I-279 I-280 Petition 870250093594, dated 10 / 13 / 2025, pp. 545 / 829 129 / 384 I-281 I-282 I-283 I-284 I-285 I-286 Petition 870250093594, dated 10 / 13 / 2025, pp. 546 / 829 130 / 384 I-287 I-288 I-289 I-290 I-291 I-292 Petition 870250093594, dated 10 / 13 / 2025, pp. 547 / 829 131 / 384 I-293 I-294 I-295 I-296 I-297 I-298 I-299 Petition 870250093594, dated 10 / 13 / 2025, pp. 548 / 829 132 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 549 / 829 133 / 384 I-305 I-306 I-307 I-308 I-309 I-310 I-311 Petition 870250093594, dated 10 / 13 / 2025, pp. 550 / 829 134 / 384 I-312 I-313 I-314 I-315 o I-316 I-317 Petition 870250093594, dated 10 / 13 / 2025, pp. 551 / 829 135 / 384 I-318 I-319 I-320 I-321 I-322 I-323 o HN F HN aja Petition 870250093594, dated 10 / 13 / 2025, pp. 552 / 829 136 / 384 I-324 I-325 I-326 ^ρ0-ß·'>ν. HN Lfi cr N ο ​​H I-327 I-328 I-329 Petition 870250093594, dated 10 / 13 / 2025, pp. 553 / 829 137 / 384 I-330 I-331 I-332 I-333 I-334 Petition 870250093594, dated 10 / 13 / 2025, pp. 554 / 829 138 / 384 I-335 I-336 I-337 I-338 I-339 I-340 I-341 Petition 870250093594, dated 10 / 13 / 2025, pp. 555 / 829 139 / 384 I-342 I-343 I-344 I-345 ,S 0 ' I-346 N N FF o I-347 Petition 870250093594, dated 10 / 13 / 2025, pp. 556 / 829 140 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 557 / 829 141 / 384 I-355 I-356 I-357 I-358 I-359 I-360 I-361 Petition 870250093594, dated 10 / 13 / 2025, pp. 558 / 829 142 / 384 I-362 I-363 I-364 o HO I-365 I-366 I-367 Petition 870250093594, dated 10 / 13 / 2025, pp. 559 / 829 143 / 384 I-368 I-369 I-370 I-371 I-372 I-373 Petition 870250093594, dated 10 / 13 / 2025, pp. 560 / 829 144 / 384 I-374 I-375 I-376 I-377 I-378 I-379 I-380 Petition 870250093594, dated 10 / 13 / 2025, pp. 561 / 829 145 / 384 I-381 ΖΫ / VF\ .0 0 L 7^ Ό 0 L z^7 yN^f 'Hf's C I-386 H0YYn^'>Yp yu xy° ^ΝΛ N oAnAo H I-387 ”>CÍ-O''CK . „ HN. Ln ,N~f Ύ tí^IX NH Petition 870250093594, dated 10 / 13 / 2025, pp. 562 / 829 146 / 384 I-388 I-389 I-390 I-391 I-392 I-393 Petition 870250093594, dated 10 / 13 / 2025, p. 563 / 829 147 / 384 I-394 I-395 I-396 I-397 I-398 I-399 Petition 870250093594, dated 10 / 13 / 2025, pp. 564 / 829 148 / 384 I-400 I-401 I-402 I-403 I-404 I-405 Petition 870250093594, dated 10 / 13 / 2025, pp. 565 / 829 149 / 384 Petition 870250093594, dated 10 / 13 / 2025, pp. 566 / 829 150 / 384

[00177] In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof.

[00178] In some embodiments, the invention also provides a compound described herein (as a compound of any one or more of the formulas described herein or presented in Table 1), or pharmaceutical compositions thereof, for use in a method for degrading IRAK4 as described herein and / or in a method for treating a disorder of Petition 870250093594, dated 10 / 13 / 2025, pp. 567 / 829 151 / 384 dependent on IRAK4 as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of any one or more of the formulas described herein or presented in Table 1), or pharmaceutical compositions thereof, for use in a method of degrading IRAK4 as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of any one or more of the formulas described herein or presented in Table 1), or pharmaceutical compositions thereof, for use in a method of treating an IRAK4-dependent disorder as described herein.

[00179] In some embodiments, the present invention provides a compound of any one or more of the formulas described herein or set forth in Table 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of any one or more of the formulas described herein or set forth in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle for use as a medicament, such as for degrading IRAK4 as described herein and / or for treating an IRAK4-dependent disorder as described herein. 4. General Methods of Supplying the Compounds Present

[00180] The compounds of this invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples described in this document. 5. Uses, Formulation and Administration Petition 870250093594, dated 10 / 13 / 2025, pp. 568 / 829 152 / 384 Pharmaceutically acceptable compositions

[00181] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in compositions of this invention is such that it is effective in measurably degrading and / or inhibiting an IRAK protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that it is effective in measurably degrading and / or inhibiting an IRAK protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such a composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[00182] The term patient, as used in this document, means an animal, preferably a mammal and most preferably a human being.

[00183] The term pharmaceutically acceptable carrier, adjuvant or vehicle refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial mixtures of glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, Petition 870250093594, dated 10 / 13 / 2025, pp. 569 / 829 153 / 384 zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease.

[00184] A pharmaceutically acceptable derivative means any salt, ester, salt of an ester or other non-toxic derivative of a compound of this invention that, after administration to a recipient, is capable of delivering, directly or indirectly, a compound of this invention or a metabolite or residue that inhibits or degrades it.

[00185] As used in this document, the term inhibitoryly active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of an IRAK protein kinase, or a mutant thereof.

[00186] As used in this document, the term degradatively active metabolite or residue thereof means that a metabolite or residue thereof is also a degradator of an IRAK protein kinase, or a mutant thereof.

[00187] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art, using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also Petition 870250093594, dated 10 / 13 / 2025, pp. 570 / 829 154 / 384 be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable parenterally, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium.

[00188] For this purpose, any mild fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying or bioavailability-enhancing agents that are commonly used in the manufacture of solid, liquid, or other pharmaceutically acceptable dosage forms may also be used for formulation purposes.

[00189] The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions, or aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and corn starch. Petition 870250093594, dated 10 / 13 / 2025, pp. 571 / 829 155 / 384 dried corn. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavorings, or colorings may also be added.

[00190] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the medication. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[00191] The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the treatment target includes areas or organs easily accessible by topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs.

[00192] Topical application to the lower intestinal tract can be done using a rectal suppository formulation (see above) or a suitable enema formulation. Topically transdermal patches can also be used.

[00193] For topical applications, the pharmaceutically acceptable compositions provided may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated in a suitable lotion or cream containing the components. Petition 870250093594, dated 10 / 13 / 2025, pp. 572 / 829 156 / 384 active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[00194] For ophthalmic use, the pharmaceutically acceptable compositions provided may be formulated as micronized suspensions in sterile isotonic saline solution with adjusted pH or, preferably, as solutions in sterile isotonic saline solution with adjusted pH, with or without a preservative such as benzylkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[00195] The pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in saline solution, employing benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[00196] Preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[00197] The number of compounds of the present invention that can be combined with carrier materials to produce a Petition 870250093594, dated 10 / 13 / 2025, pp. 573 / 829 157 / 384 composition in a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[00198] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combinations, the attending physician's judgment, and the severity of the specific disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition. Uses of Pharmaceutically Acceptable Compounds and Compositions

[00199] The compounds and compositions described in this document are generally useful for the degradation and / or inhibition of the kinase activity of one or more enzymes.

[00200] Examples of kinases that are degraded and / or inhibited by the compounds and compositions described in this document and against which the methods described in this document are useful include those of the interleukin-1 receptor-associated kinase (IRAK) family of kinases, whose members include IRAK-1, IRAK-2, and IRAK-4, or a mutant thereof. Li et al., IRAK-4: A novel member of the IRAK family with the properties of an IRAK kinase, PNAS 2002, 99(8), 5567-5572, Flannery et al., Interleukin-1 receptor-associated kinases: critical regulators of innate immune signaling Biochem Pharm 2010, 80(12), 1981-1991 incorporated Petition 870250093594, dated 10 / 13 / 2025, pp. 574 / 829 158 / 384 to this document in its entirety by way of reference.

[00201] The activity of a compound used in this invention as a degrader and / or inhibitor of IRAK-1, IRAK-2 and / or IRAK-4, or a mutant thereof, can be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of phosphorylation activity and / or subsequent functional consequences, or of the ATPase activity of activated IRAK-1, IRAK-2 and / or IRAK-4, or a mutant thereof. Alternative in vitro assays quantify the inhibitor's ability to bind to IRAK-1, IRAK-2 and / or IRAK-4. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, isolating the inhibitor / IRAK-1, inhibitor / IRAK-2 or inhibitor / IRAK-4 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by conducting a competition experiment where new inhibitors are incubated with IRAK-1, IRAK-2, and / or IRAK-4 bound to known radioligands.Representative in vitro and in vivo assays useful in the assay of an IRAK-4 inhibitor include those described and disclosed in, for example, Kim et al., A critical role for IRAK4 kinase activity in Toll-like receptor-mediated inonate immunity, J. Exp. Med. 2007 204(5), 1025-1036; Lebakken et al., A fluorescence life-based binding assay to characterize kinase inhibitors, J. Biomol. Tela. 2007, 12(6), 828-841; Maschera et al., Overexpression of an enzymatically activated interleukin-1 receptor-associated kinase activates nuclear factor-KB, Biochem. J. 1999, 339, 227-231; Song et al., Interleukin receptor-associated kinase (IRAK)-1 and 4 kinase activities are reductive in controlling the expression of inflammatory cytokines in human cells, Mol. Immunol. 2009, 46, 1458-1466, the entirety of each of which is incorporated herein by reference. Detailed conditions for testing a compound used in this invention as a degrader. Petition 870250093594, dated 10 / 13 / 2025, pp. 575 / 829 159 / 384 and / or inhibitor of IRAK-1, IRAK-2 and / or IRAK-4, or a mutant thereof, are presented in the Examples below.

[00202] The best characterized member of the IRAK family is the serine / threonine kinase IRAK-4. IRAK-4 is implicated in signaling innate immune responses of Toll-like receptors (TLRs) and Toll / IL-1 receptors (TIRs).

[00203] Innate immunity detects pathogens through the recognition of pathogen-associated molecular patterns by TLRs, which then links to the adaptive immune response. TLRs recognize conserved microbial structures and endogenous molecules. TLRs that recognize bacterial and fungal components are located on the cell surface, while TLRs that recognize viral or microbial nucleic acids are located in intracellular membranes, such as endosomes and phagosomes. Cell surface TLRs can be targeted by small molecules and antibodies, while intracellular TLRs require targeting with oligonucleotides.

[00204] TLRs mediate the innate immune response by positively regulating the expression of inflammatory genes in multiple target cells. See, for example, Sen et al., Transcriptional signaling by double-stranded RNA: role of TLR3, Cytokine & Growth Factor Rev. 2005, 16, 1-14, incorporated by reference in its entirety. Although the TLR-mediated inflammatory response is critical for innate immunity and host defense against infections, uncontrolled inflammation is detrimental to the host, leading to sepsis and chronic inflammatory diseases such as chronic arthritis, atherosclerosis, multiple sclerosis, cancer, autoimmune diseases such as rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel diseases.

[00205] After ligand binding, most TLRs recruit the MyD88 adapter molecule via the TIR domain, mediating the pathway Petition 870250093594, dated 10 / 13 / 2025, pp. 576 / 829 160 / 384 dependent on MyD88. MyD88 then recruits IRAK-4, which interacts with nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAP) cascades, and interferon regulatory factor, leading to the induction of pro-inflammatory cytokines. NF-κB activation results in the induction of inflammatory cytokines and chemokines such as TNF-α, IL-1α, IL-6, and IL-8. IRAK-4 kinase activity has been shown to play a critical role in TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of the innate immune response orchestrated by the interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs). It has been shown that inactivation of IRAK-1 and / or IRAK-4 activity results in decreased production of cytokines and chemokines in response to stimulation by IL-1 and TLR ligands. See, for example, Picard et al., Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency, Medicine (Baltimore), 2010, 89(6), 043-25; Li, IRAK4 in TLR / IL-1R signaling: Possible clinical applications, Eur. J. Immunology 2008, 38:614-618; Cohen et al., Targeting protein kinases for the development of anti-inflammatory drugs, Curr. Opin. Cell Bio. 2009, 21:317-324; Flannery et al., The interleukin-1 receptorassociated kinases: Critical regulators of innate immune signalling, Biochem. Pharm. 2010, 80(12), 1981-1991; Gottipati et al., IRAK1: A critical signaling mediator of innate immunity, Cellular Signaling 2008, 20, 269-276; Kim et al., A critical role for IRAK4 kinase activity in Tolllike receptor-mediated innate immunity, J. Exp. Med. 2007 204(5), 1025-1036; Koziczak-Holbro et al., IRAK-4 Kinase Activity Is Required for Interleukin-1 (IL-1) Receptor- and Toll-like Receptor 7-mediated Signaling and Gene Expression, J. Biol. Chem. 2007, 282(18), 1355213560; Kubo-Murai et al.IRAK-4-dependent degradation of IRAK-1 is a negative feedback signal for TLR-mediated NF-κB activation, J. Biochem. 2008, 143, 295-302; Maschera et al., Overexpression of an. Petition 870250093594, dated 10 / 13 / 2025, pp. 577 / 829 161 / 384 enzymatically inactive interleukin-1-receptor-associated kinase activates nuclear factor-KB, Biochem. J. 1999, 339, 227-231; Lin et al., Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR / IL-1R signalling, Nature 2010, 465(17), 885-891; Suzuki et al., IRAK-4 as the central TIR signaling mediator in innate immunity, TRENDS in Immunol . 2002, 23(10), 503-506; Suzuki et al., Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4, Nature 2002, 416, 750-754; Swantek et al., IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin, J. Immunol. 2000, 164, 4301-4306; Hennessy, E., et al., Targeting Toll-like receptors: emerging therapeutics? Nature Reviews, vol. 9, pp: 293-307 (2010); Dinarello, C. Interleukin-18 and the Pathogenesis of Inflammatory Diseases, Seminars in Nephrology, vol. 27, n° 1, pp: 98-114 (2007), a totalidade de cada um dos quais é incorporada no presente documento a título de referência.In fact, knockdown mice expressing a catalytically inactive mutant IRAK-4 protein are completely resistant to septic shock and exhibit impaired IL-1 activity. Furthermore, these mice are resistant to joint and bone inflammation / destruction in an arthritis model, suggesting that IRAK-4 could be targeted to treat chronic inflammation. Additionally, while IRAK-4 appears to be vital for childhood immunity against some pyogenic bacteria, it has been shown to play a redundant role in protective immunity against most infections in adults, as demonstrated by a study in which patients over 14 years of age without IRAK-4 activity did not exhibit invasive infections. Cohen et al., Targeting protein kinases for the development of antiinflammatory drugs, Curr. Opin. Cell Bio. 2009, 21:317-324; Ku et al., Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective. Petição 870250093594, de 13 / 10 / 2025, pág. 578 / 829 162 / 384 immunity, J. Exp. Med. 2007, 204(10), 2407-2422; Picard et al., Inherited human IRAK-4 deficiency: an update, Immunol. Res. 2007, 38, 347-352; Song et al., The kinase activities of interleukin-e receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells, Mol. Immunol. 2009, 46, 1458-1466; Rokosz, L. et al., Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges, Expert Opinions on Therapeutic Targets, 12(7), pp: 883-903 (2008); Gearing, A. Targeting toll-like receptors for drug development: a summary of commercial approaches, Immunology and Cell Biology, 85, pp: 490-494 (2007); Dinarello, C. IL-1: Discoveries, controversies and future directions, European Journal of Immunology, 40, pp: 595-653 (2010), a totalidade de cada um dos quais é incorporada no presente documento a título de referência.Because TLR activation triggers IRAK-4 kinase activity, IRAK-4 inhibition presents an attractive target for treating the underlying causes of inflammation in numerous diseases.

[00206] Representative IRAK-4 inhibitors include those described and disclosed, for example, in Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3211-3214; Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3291-3295; Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3656-3660; Powers et al., Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4, Bioorg. Med. Chem. Lett. 2006, 16, 2842-2845; Wng et al., IRAK-4 Inhibitors for Inflammation, Curr. Topics in Med. Chem. 2009, 9, 724-737, the entirety of each of which is incorporated herein by reference.

[00207] As used in this document, the terms treatment, treat, and treating refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more Petition 870250093594, dated 10 / 13 / 2025, pp. 579 / 829 163 / 384 symptoms thereof, as described in this document. In some modalities, treatment may be administered after the development of one or more symptoms. In other modalities, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after resolution of symptoms, for example, to prevent or delay their recurrence.

[00208] The compounds provided are degraders and / or inhibitors of one or more of IRAK-1, IRAK-2 and / or IRAK-4 and are therefore useful for treating one or more disorders associated with the activity of one or more of IRAK-1, IRAK-2 and / or IRAK-4. Thus, in certain embodiments, the present invention provides a method for treating an IRAK-1 mediated, IRAK-2 mediated and / or IRAK-4 mediated disorder comprising the step of administering to a patient in need a compound of the present invention or its pharmaceutically acceptable composition.

[00209] As used herein, the terms IRAK-1-mediated, IRAK-2-mediated, and / or IRAK-4-mediated disorders, diseases, and / or conditions, as used herein, mean any disease or other deleterious condition in which one or more of IRAK-1, IRAK-2, and / or IRAK-4, or a mutant thereof, are known to play a role. Consequently, another embodiment of the present invention relates to the treatment or reduction of the severity of one or more diseases in which one or more of IRAK-1, IRAK-2, and / or IRAK-4, or a mutant thereof, are known to play a role.

[00210] In some embodiments, the present invention provides a method for treating one or more disorders, diseases and / or conditions in Petition 870250093594, dated 10 / 13 / 2025, pp. 580 / 829 164 / 384 that the disorder, disease or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathological immunological conditions involving T-cell activation, a cardiovascular disorder or a CNS disorder.

[00211] Diseases and conditions treatable according to the methods of this invention include, but are not limited to, cancer (see, for example, Ngo, V. et al., Oncogenically active MYD88 mutations in human lymphoma, Nature, vol. 000, pp: 1-7 (2010); Lust, J. et al., Induction of a Chronic Disease State in patients With Smoldering of Indolent Multiple Myeloma by Targeting Interleukin 1B-Induced Interleukin 6 Production and the Myeloma Proliferative Component, Mayo Clinic Proceedings, 84(2), pp: 114-122 (2009)), diabetes, cardiovascular disease, viral disease, autoimmune diseases such as lupus (see, for example, Dinarello, C. Interleukin-18 and the Pathogenesis of Inflammatory Diseases, Seminars in Nephrology, vol. 27, no. 1, pp: 98114 (2007); Cohen et al., Targeting protein kinases for the development of anti-inflammatory drugs, Curr. 21:317-324) and rheumatoid arthritis (see, for example, Geyer, M. et al., Actual status of antiinterleukin-1 therapies in rheumatic diseases, Current Opinion in Rheumatology, 22, pp: 246-251 (2010)), autoinflammatory syndromes (see, for example, Hoffman, H. et al., Efficacy and Safety of Rilonacept (Interleukin-1 Trap) in Patients with CryopyrinAssociated Periodic Syndromes, Arthritis & Rheumatism, vol. 58, n° 8, pp: 2443-2452 (2008)), atherosclerosis, psoriasis, allergic disorders, Petition 870250093594, dated 10 / 13 / 2025, pp. 581 / 829 165 / 384 doença inflamatória intestinal (consultar, por exemplo, Cario, E. Therapeutic Impact of Toll-like Receptors on Inflammatory Bowel Diseases: A Multiple-edged Sword, Inflamm. Bowel Dis., 14, pp: 411-421 (2008)), inflamação (consultar, por exemplo, Dinarello, C. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process, The American Journal of Clinical Nutrition, 83, pp: 447S-455S (2006)), gota aguda e crônica e artrite gotosa (consultar, por exemplo, Terkeltaub, R. Update on gout: new therapeutic strategies and options, Nature, vol. 6, pp: 30-38 (2010); Weaver, A. Epidemiology of gout, Cleveland Clinic Journal of Medicine, vol. 75, supl. 5, pp: S9-S12 (2008); Dalbeth, N. et al., Hyperuricaemia and gout: state of the art and future perspectives, Annals of Rheumatic Diseases, 69, pp: 1738-1743 (2010); Martinon, F. et al., Gout-associated uric acid crystals activate the NALP3 inflammasome, Nature, vol. 440, pp: 237-241 (2006); So, A. et al., A pilot study of IL-1 inhibition by anakinra in acute gout, Arthritis Research & Therapy, vol. 9, no. 2, pp: 1-6 (2007); Terkeltaub, R. et al., The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomized, single-blind pilot study, Annals of Rheumatic Diseases, 68, pp: 1613-1617 (2009); Torres, R. et al., Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis, Annals of Rheumatic Diseases, 68, pp: 1602-1608 (2009)), distúrbios neurológicos, síndrome metabólica (consultar, por exemplo, Troseid, M. The role of interleukin-18 in the metabolic syndrome, Cardiovascular Diabetology, 9:11, pp:1-8 (2010)), distúrbios de imunodeficiência, como AIDS e HIV (consultar, por exemplo, Iannello, A. et al., Role of Interleukin-18 in the Development and Pathogenesis of AIDS, AIDS Reviews, 11, pp: 115-125 (2009)), destructive bone disorders (see, for example, Hennessy, E., et al., Targeting Toll-like receptors:. Petition 870250093594, dated 10 / 13 / 2025, pp. 582 / 829 166 / 384 emerging therapeutics? Nature Reviews, vol. 9, pp: 293-307 (2010)), osteoartrite, distúrbios proliferativos, Macroglobulinemia de Waldenstrom (consultar, por exemplo, Treon, et al., Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenstrom’s Macroglobulinemia 53aReunião Anual da ASH; Xu, et al., A somatic variant in MYD88 (L256P) revealed by whole genome sequencing differentiates lymphoplasmacytic lymphoma from marginal zone lymphomas 53aReunião Anual da ASH; Yang et al., Disruption of MYD88 pathway signaling leads to loss of constitutive IRAKI, NK-kB and JAK / STAT signaling and induces apoptosis of cells expressing the MYD88 L265P mutation in Waldenstrom’s Macroglobulinemia 53aReunião Anual da ASH; Iriyama et al.Clinical significance of genetic mutations of CD79B, CARD11, MYD88, and EZH2 genes in diffuse large B-cell lymphoma patients. 53rd Annual Meeting of ASH; infectious diseases, conditions associated with cell death, pathological immunological conditions involving T-cell activation, and CNS disorders in a patient. In one embodiment, a human patient is treated with a compound of the present invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to degrade and / or inhibit IRAK4 kinase activity.

[00212] The compounds of the present invention are useful in the treatment of a proliferative disease selected from among a benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testicles, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, epidermal hyperproliferation, psoriasis, Petition 870250093594, dated 10 / 13 / 2025, pp. 583 / 829 167 / 384 prostate hyperplasia, a neoplasm, a neoplasm of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas, Hodgkin's and non-Hodgkin's, a breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, a disorder caused by IL-1, a disorder caused by MyD88, slow-burning indolent multiple myeloma or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, myeloma Multiple lymphoma, plasmacytoma, large B-cell intravascular lymphoma, AML, MDS).

[00213] In some embodiments, the proliferative disease that can be treated according to the methods of this invention is a disorder caused by MyD88. In some embodiments, the disorder caused by MyD88 that can be treated according to the methods of this invention is selected from ABC DLBCL, primary CNS lymphomas, primary extranodal lymphomas, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

[00214] In some embodiments, the proliferative disease that can be treated according to the methods of this invention is a disorder caused by IL-1. In some embodiments, the IL-1-triggered disorder is indolent multiple myeloma latency.

[00215] The compounds according to the invention are useful in the treatment of inflammatory or obstructive airway diseases, resulting, for example, in the reduction of tissue damage and inflammation. Petition 870250093594, dated 10 / 13 / 2025, pp. 584 / 829 168 / 384 of the airways, bronchial hyperreactivity, remodeling or progression of the disease. The inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. The treatment of asthma should also be understood as encompassing the treatment of individuals, for example, under 4 or 5 years of age, who present with wheezing symptoms and are diagnosed or diagnosable as wheezing infants, an established patient category of great medical concern and now frequently identified as incipient or early-stage asthmatics.

[00216] The compounds according to the invention are useful in the treatment of heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect venoms, animal dander, animal hair, dust mites or cockroach exterminations), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

[00217] Prophylactic efficacy in the treatment of asthma will be evidenced by a reduction in the frequency or severity of symptomatic attacks, for example, acute asthma attacks or bronchoconstrictors, improvement in lung function or improvement in airway hyperreactivity. It may be further evidenced by a reduced need for other symptomatic therapy, such as therapy to restrict or abort a symptomatic attack when it occurs, for example, anti-inflammatory or bronchodilator. The prophylactic benefit in asthma may be particularly apparent in individuals prone to Petition 870250093594, dated 10 / 13 / 2025, pp. 585 / 829 169 / 384 Morning dip. Morning dip is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by an asthma attack, for example, between 4 and 6 a.m., that is, at a time normally substantially distant from any previously administered symptomatic asthma therapy.

[00218] The compounds of the present invention can be used for other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), acute / adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airway hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of any type or origin including, but not limited to, acute, arachnoid, catarrhal, croupus, chronic or phthinoid bronchitis.Additional inflammatory or obstructive airway diseases to which the present invention is applicable include pneumoconiosis (an inflammatory disease, commonly occupational, of the lungs, frequently accompanied by airway obstruction, whether chronic or acute, and caused by repeated inhalation of dusts) of any type or origin, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tabacosis, and byssinosis.

[00219] With regard to their anti-inflammatory activity, in particular with respect to the inhibition of eosinophil activation, the compounds of the invention are also useful in the treatment of eosinophil-related disorders, for example, eosinophilia, in particular eosinophil-related airway disorders (e.g., Petition 870250093594, dated 13 / 10 / 2025, p. 586 / 829 170 / 384 involving morbid eosinophilic infiltration of lung tissues), including hypereosinophilia, as it affects the airways and / or lungs, as well as, for example, eosinophil-related airway disorders, consequent to or concomitant with Löffler's syndrome, eosinophilic pneumonia, parasitic infestation (in particular metazoans) (including eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD and eosinophil-related disorders affecting the airways caused by a drug reaction.

[00220] The compounds of the invention are also useful in the treatment of inflammatory or allergic skin conditions, for example, psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, hidradenitis suppurativa, Sweet's syndrome, pyoderma gangrenosum and other inflammatory or allergic skin conditions.

[00221] The compounds of the invention can also be used for the treatment of other diseases or conditions, such as diseases or conditions that have an inflammatory component, for example, treatment of eye diseases and conditions such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases in which autoimmune reactions are implicated or have an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, Petition 870250093594, dated 10 / 13 / 2025, pp. 587 / 829 171 / 384 rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, for example,including idiopathic nephrotic syndrome or nephropathy due to mental alteration), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica-induced diseases, COPD (damage reduction, airway inflammation, bronchial hyperreactivity, disease remodeling or progression), lung disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in, Petition 870250093594, dated 10 / 13 / 2025, pp. 588 / 829 172 / 384 associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitistonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[00222] In some embodiments, the inflammatory disease that can be treated according to the methods of this invention is a skin disease. In some embodiments, the inflammatory skin disease is selected from among contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, hidradenitis suppurativa, and other inflammatory or allergic skin conditions.

[00223] In some embodiments, the inflammatory disease that can be treated according to the methods of this invention is selected from among acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndrome (CAPS), adult-onset Still's disease, active syndrome Petition 870250093594, dated 10 / 13 / 2025, pp. 589 / 829 173 / 384 macrophage infection (MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH), familial Mediterranean fever, NLRP12 autoinflammatory syndrome, and osteoarthritis.

[00224] In some embodiments, the inflammatory disease that can be treated according to the methods of this invention is a TH17-mediated disease. In some embodiments, the TH17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[00225] In some embodiments, the inflammatory disease that can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

[00226] In some embodiments, the present invention provides a method of treating hidradenitis suppurativa in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[00227] In some embodiments, the present invention provides a method of treating atopic dermatitis in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[00228] In some embodiments, the present invention provides a method of treating rheumatoid arthritis in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[00229] Cardiovascular diseases that can be treated according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, stroke Petition 870250093594, dated 10 / 13 / 2025, pp. 590 / 829 174 / 384 ischemic cerebrovascular disease, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, stroke, transient ischemic attack, peripheral arterial occlusive disorder, pulmonary embolism, and deep vein thrombosis.

[00230] In some embodiments, the neurodegenerative disease that can be treated according to the methods of this invention includes, but is not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, organ transplantation and graft-versus-host disease.

[00231] Loss of IRAK4 function results in decreased Aβ levels in an in vivo murine model of Alzheimer's disease and has been associated with decreased microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from the brain of adult mice revealed an altered pattern of gene expression associated with changes in the microglial phenotype that were associated with the expression of IRF transcription factors governing the microglial phenotype. Furthermore, loss of IRAK4 function also promoted amyloid clearance mechanisms, including elevated expression of the enzyme that degrades insulin. Finally, blocking IRAK function restored olfactory behavior (Cameron et al. Loss of Interleukin Receptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer's Disease Journal of Neuroscience (2012) 32(43), 15112-15123).

[00232] In some embodiments, the invention provides a method for treating, preventing, or reducing the severity of Alzheimer's disease, Petition 870250093594, dated 10 / 13 / 2025, pp. 591 / 829 175 / 384 which comprises administering to a patient in need thereof, a supplied compound or a pharmaceutically acceptable salt or composition thereof.

[00233] In some embodiments, the invention provides a method of treating a disease condition that commonly occurs in conjunction with transplantation. In some embodiments, the disease or condition that commonly occurs in conjunction with transplantation is selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[00234] In some embodiments, the invention provides a method of treating a metabolic disease. In some embodiments, the metabolic disease is selected from among type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[00235] In some embodiments, the invention provides a method of treating a viral disease. In some embodiments, the viral infection is HIV infection.

[00236] The present invention encompasses the recognition that the compounds provided may have improved properties compared to certain other IRAK4 degraders, for example, improved bioavailability and / or improved clearance. In some embodiments, a compound of the present invention has improved bioavailability compared to another IRAK4 degrader (for example, as measured by rodent pharmacokinetics according to Example 9). In some embodiments, a compound of the present invention has higher (for example, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% more) bioavailability compared to another IRAK4 degrader (for example, as measured by rodent pharmacokinetics according to Example 9). In some embodiments, a compound of the present invention has improved clearance compared to Petition 870250093594, dated 10 / 13 / 2025, pp. 592 / 829 176 / 384 another IRAK4 degrader (e.g., as measured by rodent pharmacokinetics according to Example 9). In some embodiments, a compound of the present invention has lower (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% less) clearance compared with another IRAK4 degrader (e.g., as measured by rodent pharmacokinetics according to Example 9). In some embodiments, a compound of the present invention has improved protein degrader selectivity for IRAK4 compared with other proteins (e.g., SIRT2, GAK, ADK), compared with another IRAK4 degrader (e.g., as determined by the procedure in Example 10).

[00237] Additionally, the invention provides the use of a compound according to the definitions in this document, or a pharmaceutically acceptable salt, or a hydrate, or solvate thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease or a disorder that commonly occurs in conjunction with transplantation. Combination Therapies

[00238] Depending on the particular condition or disease to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, the additional therapeutic agents that are normally administered to treat a specific disease or condition are known as appropriate for the disease or condition to be treated.

[00239] In certain modalities, a combination provided or Petition 870250093594, dated 10 / 13 / 2025, pp. 593 / 829 177 / 384 of the same composition, is administered in combination with another therapeutic agent.

[00240] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[00241] Examples of agents with which combinations of this invention may also be combined include, without limitation: treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for HIV, such as ritonavir; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrol, pramipexole, bromocriptine, pergolide, trihexefendil and amantadine; agents to treat multiple sclerosis (MS), such as beta-interferon (e.g., Avonex® and Rebif®), Copaxone® and mitoxantrone; treatments for asthma, such as albuterol and Singulair®; agents to treat schizophrenia, such as zyprexa, risperdal, seroquel and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide and sulfasalazine.Immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, and calcium channel blockers. Petition 870250093594, dated 10 / 13 / 2025, pp. 594 / 829 178 / 384 Ionic agents, riluzole and antiparkinsonian agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood disorders, such as corticosteroids, antileukemic agents and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) and agents to treat immunodeficiency disorders, such as gamma globulin.

[00242] In certain embodiments, the combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or a therapeutic siRNA.

[00243] These additional agents may be administered separately from a provided combination therapy as part of a multiple dosing regimen. Alternatively, these agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be given simultaneously, sequentially, or within a time period of each other, typically within five hours of each other.

[00244] As used in this document, the terms combination, combined, and related terms refer to the simultaneous or sequential administration of therapeutic agents according to this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or in combination. Petition 870250093594, dated 10 / 13 / 2025, pp. 595 / 829 179 / 384 together in a single unit dosage form.

[00245] The amount of additional therapeutic agent present in the compositions of this invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions presently disclosed will range between about 50% and 100% of the amount normally present in a composition comprising that agent as the sole therapeutically active agent.

[00246] One or more other therapeutic agents may be administered separately from a compound or composition of the invention as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents may form part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosing regimen, one or more other therapeutic agents and a compound or composition of the invention may be administered simultaneously, sequentially, or within a period of time of each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, or 24 hours of each other. In some embodiments, one or more other therapeutic agents and a compound or composition of the invention are administered as a multiple-dose regimen over more than 24 hours per person.

[00247] In one embodiment, the present invention provides a composition comprising a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agent may be administered in conjunction with a supplied compound or a pharmaceutically acceptable salt thereof, or may be administered before or after the administration of a supplied compound or a pharmaceutically acceptable salt thereof. Petition 870250093594, dated 10 / 13 / 2025, pp. 596 / 829 180 / 384 same. Suitable therapeutic agents are described in more detail below. In certain embodiments, a supplied compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a supplied compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours. hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours after the therapeutic agent.

[00248] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof, a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents.These additional therapeutic agents may be small molecules or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and similar drugs, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmu. Petition 870250093594, dated 10 / 13 / 2025, pp. 597 / 829 181 / 384 ne®), leflunomide (Arava®) and anti-TNF agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), anti-IL1 agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), anti-T cell agents such as abatacept (Orencia®), anti-IL-6 agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®,Beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®) and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, sodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine / zidovudine (Combivir®), Petition 870250093594, dated 10 / 13 / 2025, pp. 598 / 829 182 / 384 stavudine (Zerit®) and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®) and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®) or any combination thereof.

[00249] In another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, probenecid, allopurinol and febuxostat (Uloric®).

[00250] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and similar. Petition 870250093594, dated 10 / 13 / 2025, pp. 599 / 829 183 / 384 res, sulfassalazine (Azulfidine®), antimalaria drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), ouro drugs such as ouro thioglycoses (Solganal®), ouro thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicilamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and anti-TNF agents such as etanercept (Enbrel®), infliximabe (Remicade®), golimumabe (Simponi®), certolizumab pegol (Cimzia®) and adalimumabe (Humira®), anti-IL-1 agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximabe (Rituxan®), anti-T cell agents such as abatacept (Orencia®), and anti-IL6 agents such as tocilizumabe (Actemra®).

[00251] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[00252] In some embodiments, the present invention provides a method of treating lupus comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Ara Petition 870250093594, dated 10 / 13 / 2025, pp. 600 / 829 184 / 384 len®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[00253] In some embodiments, the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids and antibiotics such as Flagyl or ciprofloxacin.

[00254] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies, such as REGN3500 (SAR440340) or CNTO 7160, Singulair®, beta2 agonists, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), corticosteroids Inhaled medications such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera®, cromolyn sodium (Intal®), me Petition 870250093594, of 13 / 10 / 2025, p. 601 / 829 185 / 384 tilxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline and IgE antibodies such as omalizumabe (Xolair®).

[00255] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (TheoDur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera®.In some embodiments, the present invention provides a method of treating eosinophilic COPD comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an anti-IL-33 antibody, such as REGN3500 (SAR440340) or CNTO 7160. In some embodiments, the present invention provides a method of treating eosinophilic asthma comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an anti-IL-33 antibody, such as REGN3500 (SAR440340) or CNTO 7160. Petition 870250093594, dated 10 / 13 / 2025, pp. 602 / 829 186 / 384

[00256] In some embodiments, the present invention provides a method of treating HIV comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among nucleoside reverse transcriptase inhibitors, such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®) and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors, such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®),Lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®) and combinations thereof.

[00257] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor and combinations thereof. Petition 870250093594, dated 10 / 13 / 2025, pp. 603 / 829 187 / 384

[00258] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor and combinations thereof.

[00259] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and an inhibitor of the Hedgehog (Hh) signaling pathway. In some modalities, hematological malignancy is DLBCL (Ramirez et al.Defining causative factors that contribute to the activation of hedgehog signaling in diffuse large B-cell lymphoma (Leuk. Res. 2012, published online July 17 and incorporated herein by reference in its entirety).

[00260] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor and combinations thereof.

[00261] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a salt. Petition 870250093594, dated 10 / 13 / 2025, pp. 604 / 829 188 / 384 pharmaceutically acceptable of the same and a chemotherapy regimen of CHOP (cyclophosphamide, Hydrodaunorubicin®, Oncovin® and prednisone or prednisolone) or R-CHOP (rituximab, cyclophosphamide, Hydrodaunorubicin®, Oncovin® and prednisone or prednisolone).

[00262] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof, a supplied compound or a pharmaceutically acceptable salt thereof and a rituximab / bendamustine chemotherapy regimen.

[00263] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor (e.g., ibrutinib).

[00264] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and an anti-CD20 antibody (e.g. rituximab).

[00265] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and an anti-CD79B ADC (e.g., polatuzumab).

[00266] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor (e.g., venetoclax).

[00267] In some embodiments, the present invention provides a Petition 870250093594, dated 10 / 13 / 2025, pp. 605 / 829 189 / 384 method of treatment of DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and lenalidomide or pomalidomide

[00268] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[00269] In some embodiments, the present invention provides a method of treating a cell disease or deficiency described herein comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[00270] In some embodiments, the present invention provides a method of treating DLBCL comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (e.g., bortezomib).

[00271] In some embodiments, the present invention provides a method of treating a T-cell disease or deficiency described herein comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (e.g., bortezomib).

[00272] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more agents Petition 870250093594, dated 10 / 13 / 2025, pp. 606 / 829 190 / 384 additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[00273] In another embodiment, the present invention provides a method of treating Waldenstrom's macroglobulinemia comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor and a SYK inhibitor.

[00274] In some embodiments, one or more other therapeutic agents are an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for the treatment of basal cell carcinoma.

[00275] In some embodiments, one or more therapeutic agents are a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[00276] In some modalities, one or more therapeutic agents are a histone deacetylase (HDAC) inhibitor. In some moPetição 870250093594, dated 13 / 10 / 2025, p. 607 / 829 191 / 384 dalidades, an HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[00277] In some embodiments, one or more therapeutic agents are a CDK inhibitor, such as a CDK4 / CDK6 inhibitor. In some embodiments, a CDK 4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[00278] In some embodiments, one or more therapeutic agents are folic acid inhibitors. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[00279] In some embodiments, one or more therapeutic agents are a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors under study that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[00280] In some embodiments, one or more therapeutic agents are an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors under study that may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[00281] In some embodiments, one or more other therapeutic agents are an arginase inhibitor. Arginase inhibitors under study that may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for myeloid leukemia. Petition 870250093594, dated 10 / 13 / 2025, pp. 608 / 829 192 / 384 acute and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[00282] In some embodiments, one or more other therapeutic agents are a glutaminase inhibitor. The glutaminase inhibitors under study that may be used in the present invention include CB839 (Calithera Biosciences).

[00283] In some embodiments, one or more therapeutic agents are an antibody that binds to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech); ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech); dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused with emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30 conjugate, Adcetris®, Seattle Genetics).

[00284] In some embodiments, one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors under study and which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[00285] In some embodiments, one or more therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention Petition 870250093594, dated 10 / 13 / 2025, pp. 609 / 829 193 / 384 include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins that have undergone clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[00286] In some embodiments, one or more therapeutic agents are an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation); approved androgen synthesis inhibitors include abiraterone (Zytiga®, Centocor / Ortho); and an approved gonadotropin-releasing hormone (GnRH) receptor antagonist (Degaralix, Firmagon®, Ferring Pharmaceuticals).

[00287] In some embodiments, one or more therapeutic agents are a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[00288] In some modalities, one or more therapeutic agents are a bone resorption inhibitor. An approved therapy that inhibits bone resorption is Denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, preventing binding to its RANK receptor, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediate bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[00289] In some embodiments, one or more therapeutic agents are an inhibitor of the interaction between the two primary p53 suppressor proteins, MDMX and MDM2. The p53 suppressor protein inhibitors under study that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that binds Petition 870250093594, dated 10 / 13 / 2025, pp. 610 / 829 194 / 384 equipotently and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[00290] In some embodiments, one or more other therapeutic agents are a transforming growth factor beta (TGF-beta or TGFB) inhibitor. Studyable TGF-beta protein inhibitors that may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody that is being clinically tested for the treatment of several types of cancer, including breast, lung, hepatocellular, colorectal, pancreatic, prostate, and renal cancer (NCT 02947165). In some embodiments, the TGF-beta protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some modalities, the additional therapeutic agent is a TGF-beta trap, as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978.A therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck KGaA - formerly MSB0011459X), which is a bispecific anti-PD-L1 / TGFB compound (NCT02699515); and (NCT02517398). M7824 comprises a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFB trap.

[00291] In some embodiments, one or more other therapeutic agents are selected from among glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-NMB glycoprotein antibody (gpNMB) (CR011) linked to cytotoxic MMAE. gpNMB is a protein Petition 870250093594, dated 10 / 13 / 2025, pp. 611 / 829 195 / 384 overexpressed by multiple tumor types associated with the metastatic capacity of cancer cells.

[00292] In some embodiments, one or more other therapeutic agents are an antiproliferative compound. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubular active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target / decrease the activity of a protein or lipid kinase and other antiangiogenic compounds; compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadotropins; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors;Inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, or inhibit Flt-3 activity; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17DMAG (17-dimethylaminoethylamino-17-desmethoxygeldanamycin); NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); spindle protein kinesin inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[00293] In some embodiments, the present invention provides a method of treating Alzheimer's disease comprising ad Petition 870250093594, dated 10 / 13 / 2025, pp. 612 / 829 196 / 384 administer to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[00294] In some embodiments, one or more therapeutic agents are a taxane compound, which causes microtubule disruption, which is essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[00295] In some embodiments, one or more therapeutic agents are a nucleoside inhibitor or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[00296] In some embodiments, a nucleoside inhibitor is selected from trabectedine (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug for 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) alkylating agent Temodar®, Merck); cytarabine injection (ara-C, cytidine antimetabolite analogue, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (cytidine pyrimidine nucleoside analogue, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxin ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysantemi (enzyme for...) Petition 870250093594, dated 10 / 13 / 2025, pp. 613 / 829 197 / 384 supplementation of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional derivative of mechlorethamine, believed to form cross-links between DNA strands, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analogue of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of a deoxyguanosine analogue, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of a ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analogue and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

[00297] In some embodiments, one or more other therapeutic agents are a VEGF-R kinase inhibitor or antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron / Sanofi). VEGFR inhibitors include regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); Petition 870250093594, dated 10 / 13 / 2025, pp. 614 / 829 198 / 384 bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (which targets activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); Pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[00298] Other kinase inhibitors and VEGF-R antagonists that are under development and may be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, South Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP547632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[00299] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among a steroid, cyclosporine, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, Petition 870250093594, dated 10 / 13 / 2025, pp. 615 / 829 199 / 384 a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor and a SYK inhibitor.

[00300] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, comprising administering to a patient in need of the compound provided or a pharmaceutically acceptable salt thereof and a BTK inhibitor, wherein the disease is selected from among inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease,Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferative disease, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, medications, foods, insect venoms, animal dander, animal dander, dust mites, or excrement) (cockroach), type I hypersensitivity, conjunctivitis, Petition 870250093594, dated 10 / 13 / 2025, pp. 616 / 829 200 / 384 allergic, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorder,For example, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, prolymphocytic B-cell leukemia, Waldenstrom's lymphoplasmacytic lymphoma / macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bones and joints, including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behçet's disease, Petition 870250093594, dated 10 / 13 / 2025, pp. 617 / 829 201 / 384 Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolic disease (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, stroke, transient ischemic attack, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, disease of Sjögren's syndrome, tissue graft rejection, hyperacute organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD).autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as syndrome acute respiratory distress and ischemia / reperfusion injury) and Graves' disease.

[00301] In another embodiment, the present invention provides a method of treating or reducing the severity of a disease comprising administering to a patient in need thereof a Petition 870250093594, dated 10 / 13 / 2025, pp. 618 / 829 202 / 384 compound supplied or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from among a cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immunological conditions involving T-cell activation, a cardiovascular disorder and a CNS disorder.

[00302] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, comprising administering to a patient in need of the compound provided or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testicle, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasm, a neoplasm of epithelial character, adenoma, adenocarcinoma, keratoacanthoma,squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also called Hodgkin's disease), Petition 870250093594, dated 10 / 13 / 2025, pp. 619 / 829 203 / 384 or Hodgkin's disease), breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia, diseases including Cowden syndrome, Lhermitte-Duclos disease and Bannayan-Zonana syndrome or diseases in which the PI3K / PKB pathway is aberrantly activated, asthma of any type or origin, including intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), acute respiratory distress syndrome / adult (ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COPD or FRIC), including chronic bronchitis or associated dyspnea, emphysema, as well as exacerbation of airway hyperreactivity consequent to other Drug therapy, in particular other inhaled drug therapy, bronchitis of any type or origin, including,but without limitation, acute bronchitis, archidic bronchitis, catarrhal bronchitis, croup, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory disease, commonly occupational, of the lungs, often accompanied by chronic or acute airway obstruction and caused by repeated inhalation of dusts) of any type or origin, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptiloxosis, siderosis, silicosis, tabacosis and byssinosis, Löffler's syndrome, eosinophilic pneumonia, parasitic infestation (in particular metazoan) (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, Dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus.pemphigus, acquired epidermolysis bullosa, Petition 870250093594, dated 10 / 13 / 2025, pp. 620 / 829 204 / 384 rhinitis, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis and inflammatory disease in which autoimmune reactions are implicated or have an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and later), dry keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis,Psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or nephropathy due to mental alteration, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

[00303] In some embodiments, one or more other therapeutic agents are a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics). Petition 870250093594, dated 10 / 13 / 2025, pp. 621 / 829 205 / 384

[00304] In some embodiments, the present invention provides a method of treating AML comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from among: FLT3 inhibitors; targeted agents such as IDH inhibitors, anti-CD33 ADCs (e.g., Mylotarg), BCL2 inhibitors and Hedgehog inhibitors; and chemotherapy such as AraC, daunarubicin, etoposide, methotrexate, fludarabine, mitozanthrone, azacitidine and corticosteroids.

[00305] In some embodiments, the present invention provides a method of treating MDS comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from azacitidine, decitabine and revlimid.

[00306] In some embodiments, the present invention provides a method of treating inflammatory skin conditions, such as hidradenitis suppurativa, comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-TNF drugs.

[00307] In some embodiments, the present invention provides a method of treating inflammatory skin conditions such as atopic dermatitis, comprising administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from IL-4 / IL-13 targeted agents such as dupilumab.

[00308] In some embodiments, the present invention provides a method of treating inflammatory skin conditions such as psoriasis. Petition 870250093594, dated 10 / 13 / 2025, pp. 622 / 829 206 / 384 riasis, which comprises administering to a patient in need thereof a supplied compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-17 and anti-IL-23 antibodies.

[00309] The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective to treat or reduce the severity of cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative disease or neurological disorder, schizophrenia, bone disorder, liver disease, or heart disorder. The exact amount required will vary from individual to individual, depending on the species, age, and general condition of the individual, the severity of the infection, the specific agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease of administration and dosage uniformity. The term unit dosage form, as used herein, refers to a physically distinct unit of agent appropriate for the patient to be treated.It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any given patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition employed; the age, body weight, general health status, sex, and diet of the patient; the timing of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in medical techniques. Petition 870250093594, dated 10 / 13 / 2025, pp. 623 / 829 207 / 384

[00310] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), buccally, as an oral or nasal spray, or similarly, depending on the severity of the infection to be treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg of the individual's body weight per day, once or more times a day, to obtain the desired therapeutic effect.

[00311] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavorings and fragrances.

[00312] Injectable preparations, for example, sterile aqueous or oily injectable suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation Petition 870250093594, dated 10 / 13 / 2025, pp. 624 / 829 208 / 384 can also be a sterile injectable solution, suspension, or emulsion in a parenterally acceptable non-toxic diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Furthermore, fatty acids such as oleic acid are used in the preparation of injectables.

[00313] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[00314] In order to prolong the effect of a compound of the present invention, it is often desirable to delay the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved through the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are produced by forming microcapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include Petition 870250093594, dated 10 / 13 / 2025, pp. 625 / 829 209 / 384 poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by trapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00315] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax that are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00316] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.In such solid dosage forms, the active compound is mixed with at least one inert and pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants such as Talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the pharmaceutical form may also include buffering agents.

[00317] Solid compositions of a similar type may also be Petition 870250093594, dated 10 / 13 / 2025, pp. 626 / 829 210 / 384 used as fillers in soft and hard gelatin capsules, with the use of excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferably, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, with the use of excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00318] The active compounds may also be in microencapsulated form with one or more excipients, as noted above. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings, release-control coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed by addition with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tablet-forming lubricants and other tablet-forming aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also Petition 870250093594, dated 10 / 13 / 2025, pp. 627 / 829 211 / 384 comprise buffering agents. These may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferably, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[00319] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is mixed by addition under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this invention.Additionally, the present invention contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be achieved by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate-control membrane or by dispersing the compound in a polymeric matrix or gel.

[00320] According to one embodiment, the invention relates to a method of inhibiting protein kinase activity or degradation of a protein kinase in a biological sample comprising the step of bringing said biological sample into contact with a compound of this invention or a composition comprising said compound.

[00321] According to another embodiment, the invention relates to a method of inhibiting or degrading the activity of IRAK-1, IRAK-2 Petition 870250093594, dated 10 / 13 / 2025, pp. 628 / 829 212 / 384 and / or IRAK-4 or a mutant thereof in a biological sample comprising the step of bringing said biological sample into contact with a compound of this invention or a composition comprising said compound.

[00322] The term biological sample, as used in this document, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[00323] The inhibition and / or degradation of a protein kinase activity or a protein kinase selected from IRAK-1, IRAK-2 and / or IRAK-4 or a mutant thereof in a biological sample is useful for a variety of purposes known to one skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage and biological assays.

[00324] Another embodiment of the present invention relates to a method of degrading a protein kinase and / or inhibiting protein kinase activity in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.

[00325] According to another embodiment, the invention relates to a method of degrading and / or inhibiting the activity of one or more of IRAK-1, IRAK-2 and / or IRAK-4 or a mutant thereof in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by one or more of IRAK-1, IRAK-2 and / or IRAK-4 or a mutant thereof in a patient in need thereof, comprising the step of administering Petition 870250093594, dated 10 / 13 / 2025, pp. 629 / 829 213 / 384 to said patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail in the present document.

[00326] Depending on the particular condition or disease to be treated, the additional therapeutic agents normally administered to treat that condition may also be present in the compositions of this invention. As used herein, the additional therapeutic agents that are normally administered to treat a specific disease or condition are known as appropriate for the disease or condition to be treated.

[00327] A compound of the present invention can also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubular active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target / decrease the activity of a protein or lipid kinase and other antiangiogenic compounds; compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadotropins; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies;Heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, or inhibit Flt-3 activity; Hsp90 inhibitors, such as 17AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17; Petition 870250093594, dated 10 / 13 / 2025, pp. 630 / 829 214 / 384 dimethylaminoethylamino-17-desmethoxygeldanamycin, NSC707545), IPI504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); spindle protein kinesin inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[00328] The term aromatase inhibitor as used herein refers to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atemestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™.A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor-positive tumors, such as breast tumors.

[00329] In some embodiments, one or more other therapeutic agents are an mTOR inhibitor that inhibits cell proliferation, angiogenesis, and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[00330] In some modalities, one or more other agents will have Petition 870250093594, dated 10 / 13 / 2025, pp. 631 / 829 215 / 384 pharmaceuticals are an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[00331] The term antiestrogen as used in this document refers to a compound that antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant may be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent that is an antiestrogen is particularly useful for the treatment of estrogen receptor-positive tumors, such as breast tumors.

[00332] The term antiandrogen as used herein refers to any substance that has the ability to inhibit the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term gonadorelin agonist as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[00333] The term topoisomerase I inhibitor as used in this document includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecan and their analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan may be administered, for example, in the form in which it is marketed, for example under the trade name Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[00334] The term topoisomerase II inhibitor as used in Petition 870250093594, dated 10 / 13 / 2025, pp. 632 / 829 216 / 384 This document includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade names Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[00335] The term microtubular active agent refers to microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubule polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin RP™. Vincristine sulfate is marketed under the trade name Farmistin™.

[00336] The term alkylating agent as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[00337] The term histone deacetylase inhibitors or HDAC inhibitors refers to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, Petition 870250093594, dated 10 / 13 / 2025, pp. 633 / 829 217 / 384 suberoylanilide hydroxamic acid (SAHA).

[00338] The term antineoplastic antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacitidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[00339] The term platinum compound as used in this document includes, but is not limited to, carboplatin, cisplatin and oxaliplatin. Carboplatin may be administered, for example, in the form in which it is marketed, for example under the trade name Carboplat™. Oxaliplatin may be administered, for example, in the form in which it is marketed, for example under the trade name Eloxatin™.

[00340] The term Bcl-2 inhibitor as used herein includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma protein 2 (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO 2008 / 118802, US 2010 / 0197686), navitoclax (and analogs thereof, see US 7,390,799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO documents). 2004 / 106328, US 2005 / 0014802), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan) and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic component. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic component.

[00341] The term compounds that target / reduce activity Petition 870250093594, of 10 / 13 / 2025, page 634 / 829 218 / 384 activity of a protein or lipid kinase; or a protein or lipid phosphatase activity; or other antiangiogenic compounds, as used herein, includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor receptors (PDGFR), such as compounds that target, decrease or inhibit PDGFR activity, especially compounds that inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit the activity of fibroblast growth factor receptors (FGFR);c) compounds that target, decrease, or inhibit the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds that target, decrease, or inhibit IGF-IR activity, especially compounds that inhibit IGF-I receptor kinase activity or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, decrease, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, decrease, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, decrease, or inhibit Ret receptor tyrosine kinase activity; g) compounds that target, decrease, or inhibit Kit / SCFR receptor tyrosine kinase activity, such as imatinib;h) compounds that target, decrease, or inhibit the activity of C-Kit receptor tyrosine kinases that are part of the PDGFR family, such as compounds that target, decrease, or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that; Petition 870250093594, dated 10 / 13 / 2025, pp. 635 / 829 219 / 384 target, decrease, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, such as compounds that target the decrease or inhibit activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds that target, decrease, or inhibit the activity of members of the serine / threonine kinase (PKC) and Raf families, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK, and TEC families, and / or members of the cyclin-dependent kinase (CDK) family, including staurosporine derivatives such as midostaurin; examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (a CDK inhibitor); k) compounds that target, decrease, or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, decrease, or inhibit the activity of protein tyrosine kinase inhibitors, including imatinib mesylate (Gleevec™) or tirfostine, such as Tyrphostin A23 / RG50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adafostine (adamantil ester of 4-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid; NSC 680410, adafostine); l) compounds that target, diminish or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds that target, diminish or inhibit the activity of the receptor family of Petition 870250093594, dated 10 / 13 / 2025, pp. 636 / 829 220 / 384 epidermal growth factor, are especially compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3d]pyrimidine derivatives;m) compounds that target, decrease, or inhibit the activity of the c-Met receptor, such as compounds that target, decrease, or inhibit c-Met activity, especially compounds that inhibit c-Met receptor kinase activity, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, decrease, or inhibit the kinase activity of one or more members of the JAK family (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including, but not limited to, PRT-062070, SB1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG101348, tofacitinib, and ruxolitinib; (o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K), including, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL719, dactolisib, XL-147, XL-765, and idelalisib; and;eq) compounds that target, decrease, or inhibit the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[00342] Compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1, phosphatase 2A, or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[00343] In some modalities, one or more other agents will have Petition 870250093594, dated 10 / 13 / 2025, pp. 637 / 829 221 / 384 pharmaceuticals are growth factor antagonists, such as platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) antagonists or their receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly); panitumumab (Vectibix®, Amgen); and osimertinib (which targets activated EGFR, Tagrisso®, AstraZeneca).

[00344] The term PI3K inhibitor as used herein includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3 kinase family, including, but not limited to, PI3Ka, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2a, PI3K-C2e, PI3K-C2Y, Vps34, ρ110-α, ρ110-β, ρ110-γ, p110δ, ρ85-α, ρ85-β, ρ55-γ, p150, p101 and p87. Examples of PI3K inhibitors useful in this invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[00345] The term BTK inhibitor as used herein includes, but is not limited to, compounds that have inhibitory activity against Bruton Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[00346] The term SYK inhibitor as used herein includes, but is not limited to, compounds that have inhibitory activity against splenic tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607 and fostamatinib.

[00347] Additional examples of BTK inhibitory compounds and conditions treatable by such compounds in combination with those with Petition 870250093594, dated 10 / 13 / 2025, pp. 638 / 829 222 / 384 applications of this invention can be found in documents WO 2008 / 039218, US 2008 / 0108636 and WO 2011 / 090760, US 2010 / 0249092, the entirety of which is incorporated by reference herein.

[00348] Additional examples of SYK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in documents WO 2003 / 063794, US 2004 / 0029902, WO 2005 / 007623, US 2005 / 0075306 and WO 2006 / 078846, US 2006 / 0211657, the entirety of which is incorporated by reference herein.

[00349] Additional examples of PI3K inhibitory compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in documents WO 2004 / 019973, US 2004 / 0106569, WO 2004 / 089925, US 2004 / 0242631, US 8,138,347, WO 2002 / 088112, US 2004 / 0116421, WO 2007 / 084786, US 2010 / 0249126, WO 2007 / 129161, US 2008 / 0076768, WO 2006 / 122806, US 2008 / 0194579, WO 2005 / 113554, US 2008 / 0275067 and WO 2007 / 044729, US 2010 / 0087440, the entirety of which is incorporated by reference herein.

[00350] Additional examples of JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in documents WO 2009 / 114512, US 2009 / 0233903, WO 2008 / 109943, US 2010 / 0197671, WO 2007 / 053452, US 2007 / 0191405, WO 2001 / 0142246, US 2001 / 0053782 and WO 2007 / 070514, US 2007 / 0135461, the entirety of which is incorporated by reference herein.

[00351] Additional antiangiogenic compounds include compounds that have another mechanism for their activity, for example, not Petition 870250093594, dated 10 / 13 / 2025, pp. 639 / 829 223 / 384 related to the inhibition of protein or lipid kinase, for example, thalidomide (Thalomid™) and TNP-470.

[00352] Examples of proteasome inhibitors useful for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770 and MLN9708.

[00353] Compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1, phosphatase 2A, or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[00354] Compounds involved in cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[00355] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[00356] The term bisphosphonates as used herein includes, but is not limited to, etidronic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acids. Etidronic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Petition 870250093594, dated 10 / 13 / 2025, pp. 640 / 829 224 / 384 al Zometa™. The term mTOR inhibitors refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779, and ABT578.

[00357] The term heparanase inhibitor as used herein refers to compounds that target, decrease, or inhibit the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. The term biological response modifier as used herein refers to a lymphokine or interferons.

[00358] The term inhibitor of oncogenic Ras isoforms, such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds that target, decrease, or inhibit the oncogenic activity of Ras; for example, a farnesyltransferase inhibitor, such as L-744832, DK8G557, or R115777 (Zarnestra™). The term telomerase inhibitor as used herein refers to compounds that target, decrease, or inhibit telomerase activity. Compounds that target, decrease, or inhibit telomerase activity are especially compounds that inhibit the telomerase receptor, such as telostatin.

[00359] The term methionine aminopeptidase inhibitor as used herein refers to compounds that target, decrease, or inhibit the activity of methionine aminopeptidase. Compounds that target, decrease, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[00360] The term proteasome inhibitor as used herein refers to compounds that target, decrease, or inhibit proteasome activity. Compounds that target, decrease, or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade™); carfilzomib (Kyprolis®, Amgen); and Petition 870250093594, dated 10 / 13 / 2025, pp. 641 / 829 225 / 384 ixazomib (Ninlaro®, Takeda) and MLN 341.

[00361] The term matrix metalloproteinase inhibitor or (MMP inhibitor) as used herein includes, but is not limited to, peptidomimetic collagen and non-peptidomimetic inhibitors, tetracycline derivatives, for example, peptidomimetic hydroxamate inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[00362] The term compounds used in the treatment of hematologic malignancies as used in this document includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease, or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-βD-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds that target, decrease, or inhibit anaplastic lymphoma kinase.

[00363] Compounds that target, decrease, or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins, or antibodies that inhibit members of the Flt-3R kinase receptor family, such as PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.

[00364] The term HSP90 inhibitors as used herein includes, but is not limited to, compounds that target, diminish, or inhibit the intrinsic ATPase activity of HSP90; degrade, target, diminish, or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, diminish, or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit HSP90 ATPase activity, such as 17-allylamino,17-desmethoxygeldanamycin (17AAG), a geldanamycin derivative; or Petition 870250093594, dated 10 / 13 / 2025, pp. 642 / 829 226 / 384 compounds related to geldanamycin; radicicol and HDAC inhibitors.

[00365] The term antiproliferative antibodies as used in this document includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibody. By antibodies, we mean intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies and antibody fragments provided they exhibit the desired biological activity.

[00366] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin and PKC412.

[00367] Other antileukemic compounds include, for example, Ara-C, a pyrimidine analog that is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included are the purine analog of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, decrease, or inhibit the activity of histone deacetylase inhibitors (HDACs), such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in US patent 6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl) Petition 870250093594, dated 10 / 13 / 2025, pp. 643 / 829 227 / 384 ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds that target, treat, or inhibit the somatostatin receptor, such as octreotide and SOM230. Approaches that damage tumor cells refer to approaches such as ionizing radiation. The term ionizing radiation referred to above and herein means ionizing radiation that occurs as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided, but without limitation, in radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Volume 1, pages 248 to 275 (1993).

[00368] Also included are EDG binders and ribonucleotide reductase inhibitors. The term EDG binders as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with araC against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1-Hisoindol-1,3-dione derivatives.

[00369] Also included in particular are those VEGF monoclonal compounds, proteins or antibodies, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically available salt. Petition 870250093594, dated 10 / 13 / 2025, pp. 644 / 829 228 / 384 acceptable of the same, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

[00370] Photodynamic therapy as used herein refers to therapy that uses certain chemicals known as photosensitive compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and sodium porfimer.

[00371] Angiostatic steroids as used herein refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[00372] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[00373] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with another mechanism of action or unknown mechanism of action.

[00374] The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases, such as those Petition 870250093594, dated 10 / 13 / 2025, pp. 645 / 829 229 / 384 as previously mentioned, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or the potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or may be administered separately, before, simultaneously with, or after the drug substance. Consequently, the invention includes a combination of a compound of the invention as described herein with an anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substance, wherein said compound of the invention and said drug substance are in the same pharmaceutical composition or in different pharmaceutical compositions.

[00375] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (ScheringPlough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists;and beta-2 adrenergic receptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and pharmaceutically acceptable salts thereof. Bronchodilator drugs include anti-adrenergic compounds; Petition 870250093594, dated 10 / 13 / 2025, pp. 646 / 829 230 / 384 cholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate.

[00376] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, ativastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[00377] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, for example CCR-1, CCR-2, CCR-3, CCR-4, CCR5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amino chloride (TAK-770).

[00378] The structure of active compounds identified by code numbers, generic or trade names may be taken from the current edition of the standard compendium The Merck Index or from databases, for example, Patents International (e.g., IMS World Publications).

[00379] A compound of the present invention can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a given compound is used as a radiosensitizer, especially for the treatment of tumors that exhibit little sensitivity to radiotherapy.

[00380] A compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Petition 870250093594, dated 10 / 13 / 2025, pp. 647 / 829 231 / 384 cos, wherein the possible combination therapy considers the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds is staggered or given independently of another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the present invention may, in addition, be administered specifically for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term therapy is also possible, as it is adjuvant therapy in the context of other treatment strategies as described above. Other possible treatments are therapy to maintain the patient's condition after tumor regression or even chemopreventive therapy, for example, in at-risk patients.

[00381] These additional agents may be administered separately from a composition containing the inventive compound, as part of a multiple dosing regimen. Alternatively, these agents may form part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be administered simultaneously, sequentially, or within a time period of each other, typically within five hours of each other.

[00382] As used in this document, the terms combination, combined, and related terms refer to the simultaneous or sequential administration of therapeutic agents according to this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Consequently, the pre Petition 870250093594, dated 10 / 13 / 2025, pp. 648 / 829 232 / 384 present invention provides a unique unit dosage form comprising a compound of the present invention, an additional therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[00383] The amount of both an inventive compound and an additional therapeutic agent (in those compositions comprising an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered.

[00384] In those compositions comprising an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in monotherapy using only that therapeutic agent. In such compositions, a dosage between 0.01 and 1000 μg / kg body weight / day of the additional therapeutic agent may be administered.

[00385] The amount of one or more other therapeutic agents present in the compositions of this invention may be no more than an amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the compositions disclosed herein will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the sole therapeutically effective agent. In some embodiments, one or more other therapeutic agents Petition 870250093594, dated 10 / 13 / 2025, pp. 649 / 829 233 / 384 Therapeutic agents are administered at a dosage of approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% of the amount normally administered for that agent. As used herein, the term "normally administered" means that the amount of an FDA-approved therapeutic agent is approved for dosage as per the FDA label insert.

[00386] The compounds of this invention or pharmaceutical compositions thereof can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents have, for example, been used to overcome restenosis (narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. Examples of Immuno-oncological Agents

[00387] In some embodiments, one or more other therapeutic agents are an immuno-oncological agent. As used herein, the term an immuno-oncological agent refers to an agent that is effective in enhancing, stimulating, and / or positively regulating immune responses in an individual. In some embodiments, the administration of an immuno-oncological agent with a compound of the invention has a synergistic effect in the treatment of cancer.

[00388] An immuno-oncological agent can be, for example, a Petition 870250093594, dated 10 / 13 / 2025, pp. 650 / 829 234 / 384 small molecule drug, an antibody or a biological or small molecule. Examples of biological immuno-oncologic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.

[00389] In some embodiments, an immuno-oncologic agent is (i) an agonist of a stimulatory receptor (including a co-stimulatory receptor) or (ii) an antagonist of an inhibitory signal (including a coininhibitory signal) on T cells, both of which result in the amplification of antigen-specific T cell responses.

[00390] Certain stimulatory and inhibitory molecules are members of the immunoglobulin (IgSF) superfamily. An important family of membrane-bound ligands that bind to co-stimulatory or coinhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PDL1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor members, which include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTeR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, α / TNFe, TNFR2, TNFa, LTeR, Lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[00391] In some modalities, an immuno-oncologic agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate a response. Petition 870250093594, dated 10 / 13 / 2025, pp. 651 / 829 235 / 384 is immune.

[00392] In some embodiments, a combination of a compound of the invention and an immuno-oncological agent can stimulate a T cell response. In some embodiments, an immuno-oncological agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[00393] In some modalities, an immuno-oncological agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells. In some modalities, an immuno-oncological agent is a KIR antagonist, such as lirilumab.

[00394] In some embodiments, an immuno-oncologic agent is an agent that inhibits or depletes macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as CSF-1R antagonist antibodies including RG7155 (documents WO 2011 / 070024, US 2011 / 0165156, WO 2011 / 0107553, US 2012 / 0329997, WO 2011 / 131407, US 2013 / 0005949, WO 2013 / 087699, US 2014 / 0336363, WO 2013 / 119716, WO 2013 / 132044, US 2014 / 0079706) or FPA-008 (documents WO 2011 / 140249, US 2011 / 0274683; WO 2013 / 169264; WO 2014 / 036357, US 2014 / 0079699).

[00395] In some modalities, an immuno-oncological agent is selected from among agonistic agents that bind to positive costimulatory receptors, blocking agents that attenuate signaling. Petition 870250093594, dated 10 / 13 / 2025, pp. 652 / 829 236 / 384 through inhibitory receptors, antagonists and one or more agents that systemically increase the frequency of antitumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor involvement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo depletion of anti-CD25 beads), inhibit metabolic enzymes such as IDO or reverse / prevent T cell energy or exhaustion) and agents that trigger innate immune activation and / or inflammation at tumor sites.

[00396] In some embodiments, an immuno-oncologic agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is a CTLA-4 antagonist antibody. In some embodiments, a CTLA-4 antagonist antibody is YERVOY (ipilimumab) or tremelimumab.

[00397] In some embodiments, an immuno-oncologic agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immuno-oncologic agent is an antibody or an antigen-binding moiety thereof that specifically binds to a Programmed Death 1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is a PD-1 antagonist antibody. In some embodiments, a PD-1 antagonist antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI0680 (AMP-514; WO2012 / 145493 document). In some embodiments, an immuno-oncologic agent may be pidilizumab (CT-011). In some modalities, an immuno-oncological agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224. Petition 870250093594, dated 10 / 13 / 2025, pp. 653 / 829 237 / 384

[00398] In some embodiments, an immuno-oncologic agent is a PD-L1 antagonist. In some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; documents WO 2010 / 077634, US 2010 / 0203056), durvalumab (MEDI4736), BMS-936559 (documents WO 2007 / 005874, US 2009 / 0055944) and MSB0010718C (documents WO 2013 / 079174, US 2014 / 0341917).

[00399] In some embodiments, an immuno-oncologic agent is an LAG-3 antagonist. In some embodiments, an LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, an LAG3 antibody is BMS-986016 (WO documents). 2010 / 019570, US 2010 / 0150892, WO 2014 / 008218, US 2014 / 0093511) or IMP-731 or IMP-321 (documents WO 2008 / 132601, US 2010 / 0233183, WO 2009 / 044273, US 2011 / 0008331).

[00400] In some embodiments, an immuno-oncologic agent is a CD137 (4-1BB) agonist. In some embodiments, a CD137 (4-1BB) agonist is a CD137 agonist antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO12 / 32433 document).

[00401] In some embodiments, an immuno-oncologic agent is a GITR agonist. In some embodiments, a GITR agonist is a GITR agonist antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (documents WO 2006 / 105021, US 2007 / 0098719, WO 2009 / 009116, US 2009 / 0136494) or MK-4166 (documents WO 2011 / 028683, US 2012 / 0189639).

[00402] In some embodiments, an immuno-oncologic agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from among the Petition 870250093594, dated 10 / 13 / 2025, pp. 654 / 829 238 / 384 tat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO 2009 / 073620, US 2011 / 053941, WO 2009 / 132238, US 2011 / 136796, WO 2011 / 056652, US 2012 / 277217, WO 2012 / 142237, US 2014 / 066625).

[00403] In some embodiments, an immuno-oncologic agent is an OX40 agonist. In some embodiments, an OX40 agonist is an OX40 agonist antibody. In some embodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

[00404] In some embodiments, an immuno-oncologic agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (documents WO 2006 / 029879, US 7,501,496).

[00405] In some embodiments, an immuno-oncological agent is a CD40 agonist. In some embodiments, a CD40 agonist is a CD40 agonist antibody. In some embodiments, an immuno-oncological agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is a CD40 antagonist antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab.

[00406] In some embodiments, an immuno-oncologic agent is a CD27 antagonist. In some embodiments, a CD27 agonist is a CD27 agonist antibody. In some embodiments, a CD27 antibody is varlilumab.

[00407] In some modalities, an immuno-oncologic agent is MGA271 (for B7H3) (documents WO 2011 / 109400, US Petition 870250093594, dated 10 / 13 / 2025, pp. 655 / 829 239 / 384 2013 / 0149236).

[00408] In some embodiments, an immuno-oncologic agent is abagovomabe, adecatumumabe, afutuzumabe, alemtuzumabe, anatumomabe mafenatox, apolizumabe, atezolimabe, avelumabe, blinatumomabe, BMS-936559, catumaxomabe, durvalumabe, epacadostat, epratuzumabe, indoximod, inotuzumabe ozogamicin, intelumumabe, ilimumabe, isatuximabe, lambrolizumabe, MED14736, MPDL3280A, nivolumabe, obinutuzumabe, ocaratuzumabe, ofatumumabe, olatatumabe, pembrolizumabe, pidilizumabe, rituximabe, ticilimumabe, samalizumabe or tremelimumabe.

[00409] In some modalities, an immuno-oncologic agent is an immunostimulatory agent. For example, antibodies that block the geometric axis inhibitory of PD-1 and PD-L1 can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable antitumor responses in a growing number of tumor histologies, including some tumor types that have not been conventionally considered responsive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558) has shown potential to improve overall survival in patients with RCC who experienced disease progression during or after prior antiangiogenic therapy.

[00410] In some embodiments, the immunomodulatory therapeutic component specifically induces apoptosis of tumor cells. Approved therapeutic components that can be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[00411] In some modalities, an immuno-oncological agent is Petition 870250093594, dated 10 / 13 / 2025, pp. 656 / 829 240 / 384 a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which has been approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic viral therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma. In some modalities, an immuno-oncological agent is selected from among an oncolytic viral therapy, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of the enteric respiratory orphan virus (reovirus) that does not replicate in cells that are not activated by RAS, in several types of cancer, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); squamous cell carcinoma of the head and neck (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express a full CD80 and a fragment of antibody specific to the CD3 T-cell receptor protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, squamous cell carcinoma of the head and neck, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676);and peritoneal disease, colorectal cancer or; Petition 870250093594, dated 10 / 13 / 2025, pp. 657 / 829 241 / 384 ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucuronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[00412] In some embodiments, an immuno-oncologic agent is selected from among JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which has the ability to convert the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-delta24-hTNFa-IREShIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), which can be further modified to express engineered antigens to generate an antigen-specific CD8+ T cell response.

[00413] In some embodiments, an immuno-oncologic agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are termed CAR-T cells.

[00414] CARs were constructed consisting of binding domains that can be derived from natural ligands, single-strand variable fragments (scFv) derived from monoclonal antibodies specific for cell surface antigens, fused to endodo Petition 870250093594, dated 10 / 13 / 2025, pp. 658 / 829 242 / 384 minima that are the functional end of the T cell receptor (TCR), such as the CD3-zeta signaling domain of TCRs, which has the ability to generate an activation signal in T lymphocytes. After antigen binding, these CARs bind to endogenous signaling pathways in the effector cell and generate activation signals similar to those initiated by the TCR complex.

[00415] For example, in some embodiments, the CAR-T cell is one of those described in U.S. Patent 8,906,682, the entirety of each of which is incorporated by reference herein, which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen-binding domain (such as a CD19-binding domain), fused to an intracellular signaling domain of the zeta chain of the T cell antigen receptor complex (such as CD3 zeta). When expressed on the T cell, the CAR has the ability to redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. There are currently about 200 clinical trials underway employing CAR-T in a wide range of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors& pg=1].

[00416] In some embodiments, an immunostimulatory agent is an activator of retinoic acid-related orphan receptor γ (RORYt). RORYt is a transcription factor with key roles in the differentiation and maintenance of effector subsets of Type 17 CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subpopulations, such as NK cells. In some embodiments, an activator of RORYt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862). Petition 870250093594, dated 10 / 13 / 2025, pp. 659 / 829 243 / 384

[00417] In some embodiments, an immunostimulatory agent is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include a TLR9 agonist or activator, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for B-cell, follicular, and other lymphomas (NCT02254772). TLR8 agonists or activators that may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[00418] Other immuno-oncological agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[00419] In some embodiments, an immunostimulatory agent is selected from among elotuzumab, mifamurtide, a receptor-like agonist or activator, and a RORYt activator.

[00420] In some embodiments, an immunostimulatory therapeutic component is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically tested as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL-15-based immunotherapeutic component is Petition 870250093594, dated 10 / 13 / 2025, pp. 660 / 829 244 / 384 Heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed with the alpha chain of the IL-15 receptor soluble IL-15 binding protein (IL15:sIL-15RA) that has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and squamous cell carcinoma of the head and neck (NCT02452268). In some embodiments, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724 or NCT02542124.

[00421] In some embodiments, an immuno-oncological agent is selected from those described in Jerry L. Adams et al., Great opportunities for small molecules in immuno-oncology, Cancer Therapy 2015, Volume 14, pages 603-622, the content of which is incorporated by reference in its entirety in this document. In some embodiments, an immuno-oncological agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, an immuno-oncological agent is a small molecule that targets an immuno-oncological target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, an immuno-oncological agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[00422] In some embodiments, an immuno-oncological agent is selected from among the small molecule immuno-oncological agents described in Peter L. Toogood, Small molecule immuno-oncology therapeutic agents, Bioorganic & Medicinal Chemistry Letters 2018, Volume 28, pages 319-329, the content of which is incorporated by reference in its entirety in this document. In some embodiments, an immuno-oncological agent is an agent that targets the pathways as described in Peter L. Toogood. Petition 870250093594, dated 10 / 13 / 2025, pp. 661 / 829 245 / 384

[00423] In some embodiments, an immuno-oncological agent is selected from those described in Sandra L. Ross et al. Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing, PLoS ONE 12(8): e0183390, the content of which is incorporated herein in its entirety by reference. In some embodiments, an immuno-oncological agent is a bispecific T cell engager antibody construct (BiTE®). In some embodiments, a bispecific T cell engager antibody construct (BiTE®) is a bispecific CD19 / CD3 antibody construct. In some embodiments, a bispecific T cell engager antibody construct (BiTE®) is a bispecific EGFR / CD3 antibody construct. In some modalities, a bispecific T-cell-enabled antibody construct (BiTE®) activates T cells.In some embodiments, a bispecific T-cell hitch antibody construct (BiTE®) activates T cells that release cytokines that induce upregulation of intracellular adhesion molecule 1 (ICAM-1) and FAS in bystander cells. In some embodiments, a bispecific T-cell hitch antibody construct (BiTE®) activates T cells resulting in induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, the bystander cells that are lysed are in the vicinity of BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immuno-oncologic agent is an antibody that blocks the geometric axis of PD-L1 / PD1 and / or CTLA4.In some modalities, an immuno-oncologic agent is an ex vivo expanded tumor-infiltrating T cell. In some modalities, an immuno-infiltrating agent... Petition 870250093594, dated 10 / 13 / 2025, pp. 662 / 829 246 / 384 oncological is a construct of bispecific antibodies or chimeric antigen receptors (CARs) that directly connect T cells to tumor-associated surface antigens (TAAs). Exemplary Immune Checkpoint Inhibitors

[00424] In some embodiments, an immuno-oncologic agent is an immune checkpoint inhibitor as described in this document.

[00425] The term checkpoint inhibitor as used in this document refers to agents useful in preventing cancer cells from evading the patient's immune system. One of the main mechanisms of subverting antitumor immunity is known as T-cell exhaustion, which results from chronic exposure to antigens that has led to the upregulation of inhibitory receptors. These inhibitory receptors serve as an immune checkpoint in order to prevent uncontrolled immune reactions.

[00426] PD-1 and coinhibitory receptors, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), Lymphocyte Activator Gene-3 (Lag-3; CD223), and others are often referred to as checkpoint regulators. They act as molecular gatekeepers that allow extracellular information to determine whether cell cycle progression and other intracellular signaling processes should proceed.

[00427] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to programmed cell death receptor 1 (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby nullifying the ability of tumors to suppress the host antitumor immune response.

[00428] In one aspect, the checkpoint inhibitor is a biological therapeutic component or a small molecule. In Petition 870250093594, dated 10 / 13 / 2025, p. 663 / 829 247 / 384 In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PD1L, PD1L2, PD1L, B7H3, B7H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In a further aspect, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PD1L, PD1L2, PD1L, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In one aspect, the checkpoint inhibitor is an immunostimulatory agent, a T-cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In one specific aspect, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[00429] Checkpoint inhibitors include any agent that blocks or inhibits, in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK T cells, Petition 870250093594, dated 10 / 13 / 2025, pp. 664 / 829 248 / 384 γδ and memory CD8+ (αβ)), CD160 (also called BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B71, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments, other binding proteins, biological therapeutic components, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049.Immune checkpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody), antiOX40, PD-L1 monoclonal antibody (Anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PD1 antibody), BMS-936559 (anti-PD1 antibody), MPLDL3280A (anti-PD1 antibody), MSB0010718C (anti-PD1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7H3, B7H4, CD28, CD86, and TIM-3.

[00430] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the immune checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Petition 870250093594, dated 10 / 13 / 2025, pp. 665 / 829 249 / 384 Tecentriq®, Genentech).

[00431] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®) and tremelimumab.

[00432] In some modalities, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; Avelumab (Bavencio®, Pfizer / Merck KGaA), also known as MSB0010718C), a fully human anti-PD-L1 IgG1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer;or PDR001 (Novartis), an inhibitor antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; AstraZeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for various indications, including: mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer; Petition 870250093594, dated 10 / 13 / 2025, pp. 666 / 829 250 / 384 endometrial, metastatic liver cancer, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[00433] In some embodiments, a checkpoint inhibitor is a T-cell immunoglobulin mucin-containing protein-3 (TIM-3) inhibitor. TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being studied in solid tumors (NCT02608268).

[00434] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoreceptors with Ig and ITIM or TIGIT domains, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and an anti-TIGIT monoclonal antibody (NCT03119428).

[00435] In some embodiments, an inhibitory checkpoint is a Lymphocyte Activation Gene-3 (LAG-3) inhibitor. LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), also an anti-LAG-3 antibody, is being studied in malignancy. Petition 870250093594, dated 10 / 13 / 2025, pp. 667 / 829 251 / 384 des (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein that is studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[00436] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include PF04518600 / PF-8600 (Pfizer), an anti-OX40 agonist antibody, in metastatic renal cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an anti-OX40 agonist antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an anti-OX40 agonist antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an anti-OX40 agonist antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an anti-OX40 agonist antibody, in advanced cancers (NCT02737475).

[00437] Checkpoint inhibitors that can be used in the present invention include CD137 agonists (also called 4-1BB). CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an anti-CD137 agonist antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, BristolMyers Squibb), an anti-CD137 agonist antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[00438] Checkpoint inhibitors that can be used Petition 870250093594, dated 10 / 13 / 2025, pp. 668 / 829 252 / 384 of the present invention include CD27 agonists. The CD27 agonists being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics), an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[00439] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor (GITR) receptor agonists. GITR agonists being studied in clinical trials include TRX518 (Leap Therapeutics), an anti-GITR agonist antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an anti-GITR agonist antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte / Agenus), an anti-GITR agonist antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune / AstraZeneca), a hexameric GITR agonist-binding molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).

[00440] Checkpoint inhibitors that can be used in the present invention include inducible T-cell co-stimulatory agonists (ICOs, also known as CD278). ICOS agonists being studied in clinical trials include MEDI570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).

[00441] Checkpoint inhibitors that can be used Petition 870250093594, dated 10 / 13 / 2025, page 669 / 829 253 / 384 of the present invention include inhibitors of the IgG killer-like receptor (KIR). KIR inhibitors being studied in clinical trials include lirilumab (IPH2102 / BMS986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three long cytoplasmic tail domains (KIR3DL2), in lymphoma (NCT02593045).

[00442] Checkpoint inhibitors that can be used in the present invention include CD47, inhibitors of the interaction between CD47 and signaling regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling, in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by binding the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, acts by binding to human CD47 and preventing delivery of its no-eat signal to macrophages, is in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

[00443] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors. Petition 870250093594, dated 10 / 13 / 2025, pp. 670 / 829 254 / 384 (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[00444] Checkpoint inhibitors that can be used in the present invention include interferon gene stimulator protein (STING) agonists (also known as transmembrane protein 173 or TMEM173). STING agonists being studied in clinical trials include MK-1454 (Merck), a synthetic cyclic dinucleotide agonist, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), a synthetic cyclic dinucleotide agonist, in Phase 1 (NCT02675439 and NCT03172936).

[00445] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a small molecule CSF1R inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available CSF1R inhibitor, in advanced solid tumors (NCT02829723).

[00446] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516). Petition 870250093594, dated 10 / 13 / 2025, pp. 671 / 829 255 / 384

[00447] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. EXEMPLIFICATION Synthetic Methods

[00448] The following examples are intended to illustrate the invention and should not be interpreted as limitations thereof. Temperatures are given in degrees Celsius. Unless otherwise mentioned, all evaporations were carried out under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20133 mbar). The structure of final products, intermediates and starting materials was confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. The abbreviations used are those conventional in the art.

[00449] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention were commercially available or can be produced by organic synthesis methods known to a person skilled in the art (Houben-Weyl 4a Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the compounds of the present invention can be produced by organic synthesis methods known to a person of ordinary skill in the art, as shown in the following examples.

[00450] All reactions are carried out under nitrogen or argon, unless otherwise indicated.

[00451] Proton NMR (1H NMR) is conducted in deuterated solvent. In certain compounds disclosed in this document, one or more 1H shifts overlap with the residual signals of Petition 870250093594, dated 10 / 13 / 2025, pp. 672 / 829 256 / 384 protein solvent; these signals were not reported in the experiment provided below. Table 2: Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 Agilent Technologies 1200 series MS: Agilent Technologies 6110 Agilent Technologies 1200 series MS: LC / MSD VL NMR BRUKER AVANCE III / 400; Frequency (MHz) 400.13; Core: 1H; Number of Transients: 8 Prep-HPLC Gilson GX-281 Systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F, GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra cSFC analytical Agilent Technologies 1290 Infinity Prep-cSFC Waters SFC Prep 80

[00452] For acidic LCMS data: The LCMS was registered in a An Agilent 1200 series or Shimadzu LCMS2020 LC / MSD equipped with electrospray ionization and a quad MS detector [ES+ve to generate MH+] and fitted with a 25*2.0 mm RP-18e Chromolith Flash, eluting with 0.0375 vol % TFA in water (solvent A) and 0.01875 vol % TFA in acetonitrile (solvent B). Other LCMS were recorded on an Agilent 1290 Infinity RRLC connected to an Agilent 6120 mass detector. The column used was a 50*2.1 mm, 1.7 micron BEH C18. The column flow rate was 0.55 ml / min and the mobile phase used was (A) 2 mM ammonium acetate in 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile.

[00453] For basic LCMS data: The LCMS was recorded on an Agilent 1200 series LC / MSD or Shimadzu LCMS 2020 equipped with electrospray ionization and a quad MS detector [ES+ve to generate MH+] and fitted with Xbridge C18 columns, 2.1X50 mm, packed with 5 mm C18 coated silica or Kinetex EVO C18 columns 2.1X30 mm, packed with 5 mm C18 coated silica, eluting with 0.05 vol % NH3·H2O in water (solvent A) and acetonitrile (solvent B).

[00454] HPLC analytical method: HPLC was performed on X Petition 870250093594, dated 10 / 13 / 2025, pp. 673 / 829 257 / 384 Bridge C18 150*4.6 mm, 5 microns. The column flow rate was 1.0 ml / min and the mobile phase used was (A) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile.

[00455] Preparative HPLC Analytical Method: The compound was purified using a Shimadzu LC-20AP and a UV detector. The column used was an X-BRIDGE C18 (250*19) mm, 5 μm. The column flow rate was 16.0 ml / min. The mobile phase used was (A) 0.1% formic acid in water and (B) acetonitrile. The basic method used (A) 5 mM ammonium bicarbonate and 0.1% NH3 in water and (B) acetonitrile or (A) 0.1% ammonium hydroxide in water and (B) acetonitrile. UV spectra were recorded at 202 nm and 254 nm.

[00456] NMR Method: 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400 MHz / 5 mm (BBFO) probe. Chemical changes are reported in parts per million.

[00457] In some cases, the intermediates and compounds described in the examples comprise one or more stereocenters, and more than one enantiomer / diastereomer has been produced. In some embodiments, these enantiomers / diastereomers have been separated and isolated, although the stereochemistry has not been resolved. Unless otherwise indicated, stereochemistry has been arbitrarily assigned. For intermediates, each enantiomer / diastereomer with arbitrarily assigned stereochemistry may result in a final compound (e.g., assigned an I- number) that also retains the arbitrarily assigned stereochemistry. Consequently, any compound with arbitrarily assigned stereochemistry or produced from an intermediate with arbitrarily assigned stereochemistry may be described herein as a certain stereoisomer, but it is understood that such a compound may be the other stereoisomer (i.e., enantiomer or diastereomer).

[00458] As described in the Examples below, in certain modalities Petition 870250093594, dated 10 / 13 / 2025, pp. 674 / 829 258 / 384 exemplary compounds, the compounds are prepared in accordance with the general procedures to be followed. It will be understood that, although the general methods describe the synthesis of certain compounds of the present invention, the general methods to be followed and other methods known to a person of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described in this document. Intermediaries 5,5-difluoro-3,9-diazaspiro[5,5]undecane-3-benzyl carboxylate (Intermediate A) TFA THE

[00459] Step 1 - O3-benzyl 9-tert-butyl 5,5-difluoro-3,9-diazaespiro[5.5]undecane-3,9-dicarboxylate. To a solution of tert-butyl 11,11-difluoro-3,9-diazaespiro[5.5]undecane-3-carboxylate (1.8 g, 6.2 mmol, CAS No. 1784848-04-9) in ACN (9 ml) and H2O (9 ml) were added NaHCO3 (677 mg, 8.06 mmol) and CbzCl (1.48 g, 8.68 mmol). The mixture was then stirred at 25 °C for 12 hours. After completion, the mixture was rapidly cooled with water (20 ml) to 0 °C and extracted with ethyl acetate (20 ml x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated to generate a residue. The residue was purified by column chromatography (SiO2, PE / EA=10:1 to 8:1) to generate the title compound (2.4 g, 87% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 7.39 7.33 (m, 5H), 5.16 (s, 2H), 3.99 - 3.83 (m, 2H), 3.73 - 3.32 (m, 2H), 3.56 (s, 2H), 2.99 (t, J = 11.6 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.68 - 1.51 (m, 4H), 1.47 (s, 9H); LC-MS (ESI+) m / z 447.2 (M+Na)+.

[00460] Step 2 - 5,5-difluoro-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl. To a solution of O9-tert-butyl 5,5-difluoro-3,9 Petition 870250093594, dated 10 / 13 / 2025, pp. 675 / 829 259 / 384 diazaespiro[5.5]undecane-3,9-dicarboxylate of O3-benzyl (1 g, 2 mmol) in DCM (10 ml) was added to TFA (3.84 g, 33.6 mmol). The mixture was then stirred at 25 °C for 1 h. After completion, the mixture was rapidly cooled with aqueous NaHCO3 (50 ml) to 0 °C and extracted with DCM (25 ml χ 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated to yield the title compound (760 mg, 95% yield) as a yellow oil. LC-MS (ESI+) m / z 325.2 (M+H)+. Benzyl 5,5-difluoro-9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9diazaspiro[5.5] undecane-3-carboxylate (Intermediate B) DIEA, DMF MeOTf HFIP Pt / V / C, H2 THF LiOH MeOH / H2O DPPA, DIEA t-BuOH

[00461] Step 1 - 5,5-difluoro-9-(3-methoxycarbonyl-2-nitrophenyl)-3,9-diazaespiro[5.5]undecane-3-carboxylate benzyl. To a solution of 5,5-difluoro-3,9-diazaespiro[5.5]undecane-3-carboxylate benzyl (760 mg, 2.34 mmol, Intermediate A) in DMF (3 ml), 3-fluoro-2-nitrobenzoate methyl (606 mg, 3.05 mmol, CAS No. 1214353-57-7) and K2CO3 (971 mg, 7.03 mmol) were added at 0°C. The mixture was then stirred at 80°C for 5 hours. After completion, the reaction mixture was added to ice-cold water (10 ml) and the precipitate was collected by filtration. The residue was purified by column chromatography. Petition 870250093594, dated 10 / 13 / 2025, pp. 676 / 829 260 / 384 (SÍO2, PE / EA = 10:1 to 6:1) for a larger volume (1.13 g, 95% of rendimento) with the same volume.1H RMN (400 MHz, CDCh) δ 7.69 (dd, J = 3.6, 5.6 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.27 (s, 4H), 5.06 (s, 2H), 3.80 (d, J = 1.6 Hz, 3H), 3.63 (t, J = 11.2 Hz, 2H), 3.47 (s, 2H), 3.24 - 2.98 (m, 2H), 2.87 (s, 1H), 2.85 - 2.77 (m, 3H), 2.07 - 1.90 (m, 2H), 1.72 (s, 2H), 1.58 (s, 1H); LC-MS (ESI+) m / z 504.1 (M+H)+.

[00462] Step 2 - 9-(2-amino-3-methoxycarbonylphenyl)-5,5-difluoro-3,9-diazaspiro[5.5]undecane-3-benzyl carboxylate. To a solution of 5,5-difluoro-9-(3-methoxycarbonyl-2-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-benzyl carboxylate (1 g, 1.99 mmol) in THF (15 ml) was added Pt / V / C (500 mg, 1.92 mmol) under Ar. The suspension was then degassed under vacuum and purged with H2 (0.10 MPa (15 psi)) several times. The mixture was then stirred under H2 (0.10 MPa (15 psi)) at 25°C for 4 hours. After completion, the mixture was filtered. The filtrate was then concentrated under vacuum to provide the title compound (833 mg, 88% yield) as yellow oil.1H NMR (400 MHz, CDCls) δ 7.66 (d, J = 8.0 Hz, 1H), 7.46 - 7.31 (m, 4H), 7.13 (d, J = 7.2 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H), 6.22 (s, 2H), 5.17 (s, 2H) 1.81 - 1.61 (m, 3H); LCMS (ESI+) m / z 474.6 (M+H)+.

[00463] Step 3 - 5,5-difluoro-9-[3-methoxycarbonyl-2-(methylamino)phenyl]-3,9-diazaespiro[5.5]undecane-3-carboxylate benzyl. To a solution of 9-(2-amino-3-methoxycarbonylphenyl)-5,5-difluoro3,9-diazaespiro[5.5]undecane-3-carboxylate benzyl (820 mg, 1.73 mmol) in HFIP (8 ml), methyl trifluoromethanesulfonate (341 mg, 2.08 mmol) was added at 0 °C. The mixture was then stirred at 25 °C for 3 hours. After completion, the mixture was rapidly cooled with water (10 ml) to 0 °C and extracted with ethyl acetate (15 ml x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated. Petition 870250093594, dated 10 / 13 / 2025, pp. 677 / 829 261 / 384 treated to generate the title compound (840 mg, 99% yield) as yellow oil. LC-MS (ESI+) m / z 488.1 (M+H)+.

[00464] Step 4 - 3-(3-Benzyloxycarbonyl-5,5-difluoro-3,9-diazaspiro[5.5]undecan-9-yl)-2-(methylamino)benzoic acid. To a solution of 5,5-difluoro-9-[3-methoxycarbonyl-2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl (840 mg, 1.72 mmol) in H2O (1 ml) and MeOH (6 ml) was added LiOH.H2O (216 mg, 5.17 mmol) in MeOH (6 ml). The mixture was then stirred at 60 °C for 8 hours. After completion, the mixture was concentrated under vacuum. The mixture was diluted with H2O (15 ...

Claims

1. Compound, characterized in that it has the formula: (R1)n If-11 or a pharmaceutically acceptable salt thereof, wherein: X is a divalent chemical moiety selected from -CH2 or -C(O)-; Y is a nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; each of R1, R2 and R3 is independently hydrogen, RA, halogen, -CN, -NO2, oxo, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, CR2N(R)C(O)R, -CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R;each R is independently hydrogen or an optionally substituted group selected from aliphatic C1-6, phenyl, a saturated or partially unsaturated carbocyclic or heterocyclic ring of 3-7 members having 1-2 heteroatoms selected independently from nitrogen, oxygen and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms selected independently. Petition 870250093594, of 10 / 13 / 2025, p. 802 / 829 2 / 24 among nitrogen, oxygen and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 4-11 membered carbocyclic or heterocyclic monocyclic, bicyclic, bridging bicyclic or spirocyclic ring having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from among nitrogen, oxygen and sulfur;Each RA is independently an optionally substituted group selected from an aliphatic C1-6 phenyl group, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring D is selected from a phenyl or 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each of men is independently 0, 1, 2, or 3; ep is 0, 1, 2, 3, or 4.

2. Compound, characterized in that it has the Formula: or a pharmaceutically acceptable salt thereof, wherein: Petition 870250093594, dated 10 / 13 / 2025, page 803 / 829 3 / 24 X is a divalent chemical moiety selected from -CH2 or -C(O)-; Y is a nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; each of R1, R2 and R3 is independently hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, - N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R;each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 3-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 4-11 membered carbocyclic or monocyclic, bicyclic, bridging bicyclic or spirocyclic heterocycle ring having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur;Each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring (Petition 870250093594, 10 / 13 / 2025, page 804 / 829 4 / 24) having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C is independently selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; in is 0, 1, 2 or 3; en is 0, 1, 2, 3 or 4.

3. Compound according to claim 2, characterized in that Ring C is a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

4. Compound, according to claim 3, characterized by the fact that Ring C is (R, (R, (R, Petition 870250093594, of 10 / 13 / 2025, page 805 / 829 5 / 24 HXÍ' hcQ (R')„, (R')„ or (RV 5. Compound according to claim 4, characterized in that Ring C is (R)n.

6. Compound according to claim 1, characterized in that Ring D is phenyl, pyridyl, pyrazinyl, pyrazol[1,5a]pyrimidinyl or pyrrolo[1,2-a]pyrimidine.

7. Compound according to claim 6, characterized in that Ring D is pyridyl or pyrazinyl.

8. Compound according to any one of claims 1 to 7, characterized in that n is 1 and R1 is hydrogen, RA, halogen, -CN, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R or -OC(O)NR2.

9. Compound, according to any one of claims 1 to 8, characterized in that n is 1 and R1 is -OR or CR2(OR).

10. Compound, according to any one of claims 1 to 9, characterized in that m is 1 and R2 is hydrogen, RA, halogen, -CN, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R or -OC(O)NR2.

11. Compound, according to any one of claims 1 to 10, characterized in that m is 1 and R2 is hydrogen.

12. Compound, according to any of claims 1 to 11, characterized in that R3 is hydrogen, RA is halogen, -CN, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, C(S)NR2, -C(O)N(R)OR, -OC(O)R or -OC(O)NR2.

13. Compound, according to any one of claims 1 to 12, characterized in that R3 is either -CN or -CF3.

14. Compound according to any one of claims 1 to 13, characterized in that R4 is C1-5 alkyl.

15. Compound according to any one of claims 1 to 14, characterized in that X is -C(O)-.

16. Compound according to any one of claims 1 to 15, characterized in that Y is CH.

17. A compound according to any one of claims 1 to 16, characterized in that Z is a covalent bond.

18. Compound according to claim 1, characterized in that the compound is: I-222 I-223 I-230 Petition 870250093594, dated 10 / 13 / 2025, p. 807 / 829 7 / 24 I-231 I-379 I-380 I-416 I-417 or a pharmaceutically acceptable salt thereof.

19. Compound, according to claim 2, characterized by Petition 870250093594, dated 10 / 13 / 2025, page 808 / 829 8 / 24 Petition 870250093594, dated 10 / 13 / 2025, page 809 / 829 9 / 24 or a pharmaceutically acceptable salt thereof.

20. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 19, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

21. Use of a compound, as defined in any one of claims 1 to 19, characterized in that it is for the preparation of a medicament, pharmaceutical composition and / or product for the degradation of the IRAK4 protein kinase in a patient or biological sample.

22. Use of a compound, as defined in any one of claims 1 to 19, characterized in that it is for the preparation of a medicament, pharmaceutical composition and / or product to treat an IRAK4-mediated disorder, disease or condition in a patient.

23. Use of a compound, as defined in any of claims 1 to 19, characterized in that it is for the preparation of a medicine, pharmaceutical composition and / or product to treat an autoimmune disease, an inflammatory disorder or an immunodeficiency disorder in a patient.

24. Use according to claim 23, characterized in that the disease or disorder is systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis, chronic granulomatosis, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain.Complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, silica-induced diseases, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, Petition 870250093594, dated 10 / 13 / 2025, p. 811 / 829 11 / 24 lichen planus, Type 1 diabetes, Type 2 diabetes, appendicitis, atopic dermatitis, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acute and chronic gout,Chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome, adult-onset Still's disease, macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis, familial Mediterranean fever, NLRP12 autoinflammatory syndrome, or osteoarthritis.

25. Use, according to claim 23, characterized in that the disease or disorder is ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRScPN), hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, eosinophilia, hypereosinophilia, Löffler's syndrome, eosinophilic pneumonia, tropical eosinophilia, bronchopulmonary aspergillosis, polyarteritis nodosa, Churg-Strauss syndrome, eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD, psoriasis, generalized pustular psoriasis. Petition 870250093594, dated 10 / 13 / 2025, p.812 / 829 12 / 24 zada, psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, hidradenitis suppurativa, Sweet's syndrome, pyoderma gangrenosum, allergic skin conditions, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome, adult-onset Still's disease, macrophage activation syndrome, primary hemophagocytic lymphohistiocytosis and secondary, familial Mediterranean fever or NLRP12 autoinflammatory syndrome.

26. In vitro / ex vivo method for degrading the IRAK4 protein kinase in a biological sample, characterized in that it comprises bringing said biological sample into contact with a compound, as defined in any of claims 1 to 19, or with a pharmaceutical composition thereof.

27. Invention, characterized by any form of its embodiments or by any applicable category of claim encompassed by the subject matter initially described, disclosed or illustrated in this patent application or in examples presented herein, including: (A) Compound exhibiting any of the following Formulas: I-a' Petition 870250093594, dated 10 / 13 / 2025, p. 813 / 829 13 / 24 I-b' (Rjn I-e' Petition 870250093594, of 10 / 13 / 2025, p. 814 / 829 14 / 24 ι-g' I-h' Ik Petition 870250093594, of 10 / 13 / 2025, p. 815 / 829 15 / 24 Ι-o or a pharmaceutically acceptable salt thereof, Petition 870250093594, of 10 / 13 / 2025, p. 816 / 829 16 / 24 wherein: X is a divalent chemical moiety selected from -CH2 or -C(O)-; -CONR-, -NR- or -O-;Ring A is a ring selected from phenylenyl, pyridinylene; Ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; each of R1, R2 and R3 is independently hydrogen, RA, halogen, -CN, -NO2, oxo, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, CR2N(R)C(O)R, -CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R;each R is independently hydrogen or an optionally substituted group selected from aliphatic C1-6, phenyl, a saturated or partially unsaturated carbocyclic or heterocyclic ring of 3-7 members having 1-2 heteroatoms selected independently from nitrogen, oxygen and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms selected independently. Petition 870250093594, of 10 / 13 / 2025, p. 817 / 829 17 / 24 among nitrogen, oxygen and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated 4-11 membered carbocyclic or heterocyclic monocyclic, bicyclic, bridging bicyclic or spirocyclic ring, having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from among nitrogen, oxygen and sulfur;Each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Each R5 is independently hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl, or: two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R5 groups on two different carbon atoms combine to form, with the intervening atoms connecting the two R5 groups, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;Each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring (Petition 870250093594, 10 / 13 / 2025, pp. 818 / 829 18 / 24) having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each of m, n, p, and q are independently 0, 1, 2, 3, or 4. (B) Compound that presents any of the following Formulas: Ia Ib (Rjn Ic (Rbn Id Petition 870250093594, of 10 / 13 / 2025, page 819 / 829 19 / 24 (R2)m 0=^ / -Z-( A Ί HN-X r \ ) / -Z-( A Yn^-(CH2 HN-X N' (R2)m Q=(\~Z \ A ) HN-X (R2)m (Rhn Ie zp5\ / ^~^\ q H ( D ) ΓC ) 0 (R3)p (R1)n If :)oi / H ( D ) -N \ / --\ f \ Π \ q (CHzJtM-M-í C ) 0 (R )p (R1)n ig O ~T^7 H ( D ) / / __ A y ( c ) 0 (R3)p (R1)n Ih Petition 870250093594, of 10 / 13 / 2025, page. which: X is a divalent chemical portion selected from -CH2 or -C(O)-; Y is a nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR- or -O-;Ring A is a ring selected from phenylenyl, pyridinyl elyl, ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; each of R1, R2 and R3 is independently hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, - N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R;Each R is independently hydrogen or an optional group. Petition 870250093594, dated 10 / 13 / 2025, page 1. 821 / 829 21 / 24 individually substituted selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated heterocyclic ring of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a saturated or partially unsaturated carbocyclic or heterocyclic ring of 4-11 members, having 1-3 heteroatoms, in addition to the carbon or nitrogen to which the two R groups are attached, independently selected from nitrogen, oxygen and sulfur;Each RA is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a saturated or partially unsaturated 4-7 membered carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Each R5 is independently hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or Cs-6 cycloalkyl, or: two R5 groups on the same carbon atom combine to form, with the carbon atom to which the two R5 groups are attached, a saturated or partially unsaturated 3-7 membered carbocyclic or heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R5 groups on two different carbon atoms combine to form, with the intervening atoms connecting the Petition 870250093594, of 10 / 13 / 2025, p. 822 / 829 22 / 24 two R5 groups, a saturated or partially unsaturated carbocyclic or heterocyclic ring of 3-7 members having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;Each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of m, n, peq are independently 0, 1, 2, 3 or 4; (C) Pharmaceutical composition comprising a compound, as defined in (A) or (B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle; (D) Combination comprising a compound and / or pharmaceutical composition, as defined in any of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents; (E) Use of a compound, as defined in (A) or (B), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament, pharmaceutical composition and / or product for: (i) degradation of IRAK4 protein kinase in a patient or biological sample;and / or (ii) treat or prevent an IRAK4-mediated disorder, disease or condition in a patient; and / or (iii) treat or prevent an autoimmune disease, an inflammatory disorder or an immunodeficiency disorder in a patient; and / or (iv) treat or prevent a disease, disorder or health condition in a patient; (F) Use of a compound, as defined in any of the preceding claims, or a pharmaceutically acceptable salt thereof, and of one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, for the preparation of a single or separate medicament, a single or separate pharmaceutical composition, a single or separate combination and / or a single or separate product for: (i) degradation of IRAK4 protein kinase in a patient or biological sample; and / or (ii) treat or prevent an IRAK4-mediated disorder, disease, or condition in a patient;and / or (iii) treat or prevent an autoimmune disease, an inflammatory disorder, or an immunodeficiency disorder in a patient; and / or (iv) treat or prevent a disease, disorder, or health condition in a patient; (G) Use of a compound, as defined in any of the preceding claims, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament, pharmaceutical composition, and / or product, in combination with one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, to: (ii) treat or prevent an IRAK4-mediated disorder, disease, or condition in a patient; and / or (iii) treat an autoimmune disease, an inflammatory disorder, or an immunodeficiency disorder in a patient; and / or (iv) treat or prevent a disease, disorder, or health condition in a patient;(H) Compound, medicine, pharmaceutical composition, combination and / or product, according to any of the preceding claims, for use in: (ii) treating or preventing an IRAK4-mediated disorder, disease or condition in a patient; and / or Petition 870250093594, dated 10 / 13 / 2025, p. 824 / 829 24 / 24 (iii) treating or preventing an autoimmune disease, an inflammatory disorder or an immunodeficiency disorder in a patient; and / or (iv) treating or preventing a disease, disorder or health condition in a patient; and / or (I) In vitro / ex vivo method for degrading IRAK4 protein kinase in a biological sample, said method comprising placing said biological sample in contact with a compound, as defined in (A) or (B), or with a pharmaceutical composition thereof.