IRAK degrader and its use

Abstract

This provides an IRAK degrader and its use. The present invention provides compounds, compositions thereof, and methods for using them. This application relates to novel bifunctional compounds that function to recruit IRAK kinase to E3 ubiquitin ligase for degradation, and to methods for their preparation and use. In particular, this disclosure provides bifunctional compounds that are useful as modulators of targeted ubiquitination of IRAK kinase, which is subsequently degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they enable a broad range of pharmacological activity consistent with the degradation / inhibition of IRAK kinase. Furthermore, this description provides methods for using effective amounts of the compounds described herein for the treatment or remission of disease conditions, such as cancer or inflammatory disorders.

Description

[Technical Field]

[0001] Reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 510,011 filed on 23 June 2023, U.S. Provisional Patent Application No. 63 / 579,477 filed on 29 August 2023, U.S. Provisional Patent Application No. 63 / 593,445 filed on 26 October 2023, U.S. Provisional Patent Application No. 63 / 604,610 filed on 30 November 2023, U.S. Provisional Patent Application No. 63 / 625,710 filed on 26 January 2024, and U.S. Provisional Patent Application No. 63 / 570,564 filed on 27 March 2024 (the contents of which are incorporated herein by reference).

[0002] The present invention relates to compounds and methods useful for modulating one or more interleukin-1 receptor-related kinases ("IRAKs") via ubiquitination and / or degradation by compounds according to the present invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods for using said compositions in the treatment of various disorders. [Background technology]

[0003] The ubiquitin-proteasome pathway (UPP) or ubiquitin-proteasome system (UPS) is a crucial pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and deficiencies or imbalances can lead to the development of various diseases. The covalent binding of ubiquitin to specific protein substrates is activated through the action of E3 ubiquitin ligases.

[0004] UPP plays a crucial role in the degradation of short-lived regulatory proteins, which are essential for various fundamental cellular processes, including the cell cycle, regulation of cell surface receptors, and control of ion channels and antigen presentation. This pathway is associated with several malignant pathogenesis in the pathogenesis of several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), in immune surveillance / viral pathogenesis, and in the pathogenesis of muscle wasting. Many diseases are associated with abnormal UPP, negatively impacting the cell cycle and division, cellular responses to stress and extracellular regulators, morphogenesis of neuronal networks, regulation of cell surface receptors, ion channels, secretory pathways, DNA repair, and the biogenesis of organelles.

[0005] UPPs are used to induce selective proteolysis, including the use of fusion proteins to artificially ubiquitinate target proteins and synthesize small molecule probes to induce proteasome-dependent degradation. The bifunctional compounds consist of a target protein-binding ligand and an E3 ubiquitin ligase ligand, inducing proteasome-mediated degradation of selected proteins via their recruitment to the E3 ubiquitin ligase, followed by ubiquitination. These drug-like molecules offer the potential for temporal control over protein expression. Such compounds can induce inactivation of proteins of interest upon addition to cells or administration to animals or humans, making them useful as biochemical reagents and potentially leading to a new paradigm for disease treatment by removing pathogenic or oncogenic proteins ((Non-Patent Literature 1); (Non-Patent Literature 2)).

[0006] There is a continuing need in this technology for effective treatments of diseases, particularly inflammatory diseases. However, non-specific effects and the inability to target and modulate certain classes of proteins, such as regulatory proteins, remain obstacles to the development of effective therapeutic agents. Small molecule therapeutic agents that utilize E3 ligase-mediated proteolysis of target proteins, such as interleukin-1 receptor-related kinases ("IRAKs"), hold promise as therapeutic agents. Therefore, it is necessary to find compounds that are useful IRAK degraders as therapeutic agents. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2008 / 118802 Pamphlet [Patent Document 2] U.S. Patent Application Publication No. 2010 / 0197686 [Patent Document 3] U.S. Patent No. 7,390,799 [Patent Document 4] International Publication No. 2004 / 106328 Pamphlet [Patent Document 5] U.S. Patent Application Publication No. 2005 / 0014802 [Patent Document 6] International Publication No. 2008 / 039218 Pamphlet [Patent Document 7] U.S. Patent Application Publication No. 2008 / 0108636 [Patent Document 8] International Publication No. 2011 / 090760 Pamphlet [Patent Document 9] U.S. Patent Application Publication No. 2010 / 0249092 Specification [Patent Document 10] International Publication No. 2003 / 063794 Pamphlet [Patent Document 11] U.S. Patent Application Publication No. 2004 / 0029902 Specification [Patent Document 12] International Publication No. WO2005 / 007623 Pamphlet [Patent Document 13] U.S. Patent Application Publication No. US2005 / 0075306 Specification [Patent Document 14] International Publication No. WO2006 / 078846 Pamphlet [Patent Document 15] U.S. Patent Application Publication No. US2006 / 0211657 Specification [Patent Document 16] International Publication No. WO2004 / 019973 Pamphlet [Patent Document 17] U.S. Patent Application Publication No. US2004 / 0106569 Specification [Patent Document 18] International Publication No. WO2004 / 089925 Pamphlet [Patent Document 19] U.S. Patent Application Publication No. US2004 / 0242631 Specification [Patent Document 20] U.S. Patent No. 8,138,347 Specification [Patent Document 21] International Publication No. WO2002 / 088112 Pamphlet [Patent Document 22] U.S. Patent Application Publication No. US2004 / 0116421 Specification [Patent Document 23] International Publication No. WO2007 / 084786 Pamphlet [Patent Document 24] U.S. Patent Application Publication No. US2010 / 0249126 Specification [Patent Document 25] International Publication No. WO2007 / 129161 Pamphlet [Patent Document 26] U.S. Patent Application Publication No. US2008 / 0076768 Specification [Patent Document 27] International Publication No. WO2006 / 122806 Pamphlet [Patent Document 28] U.S. Patent Application Publication No. US2008 / 0194579 Specification [Patent Document 29] International Publication No. 2005 / 113554 Pamphlet [Patent Document 30] U.S. Patent Application Publication No. 2008 / 0275067 [Patent Document 31] International Publication No. 2007 / 044729 Pamphlet [Patent Document 32] U.S. Patent Application Publication No. 2010 / 0087440 [Patent Document 33] International Publication No. 2009 / 114512 brochure [Patent Document 34] U.S. Patent Application Publication No. 2009 / 0233903 Specification [Patent Document 35] International Publication No. 2008 / 109943 Pamphlet [Patent Document 36] U.S. Patent Application Publication No. 2010 / 0197671 [Patent Document 37] International Publication No. 2007 / 053452 Brochure [Patent Document 38] U.S. Patent Application Publication No. 2007 / 0191405 Specification [Patent Document 39] International Publication No. 2001 / 0142246 Pamphlet [Patent Document 40] U.S. Patent Application Publication No. 2001 / 0053782 [Patent Document 41] International Publication No. 2007 / 070514 Pamphlet [Patent Document 42] U.S. Patent Application Publication No. 2007 / 0135461 [Patent Document 43] U.S. Patent No. 6,552,065 [Patent Document 44] International Publication No. 2011 / 070024 Brochure [Patent Document 45] U.S. Patent Application Publication No. 2011 / 0165156 [Patent Document 46] International Publication No. 2011 / 0107553 Pamphlet [Patent Document 47] U.S. Patent Application Publication No. 2012 / 0329997 Specification [Patent Document 48] International Publication No. 2011 / 131407 Pamphlet [Patent Document 49] U.S. Patent Application Publication No. 2013 / 0005949 Specification [Patent Document 50] International Publication No. 2013 / 087699 Pamphlet [Patent Document 51] U.S. Patent Application Publication No. 2014 / 0336363 Specification [Patent Document 52] International Publication No. 2013 / 119716 Pamphlet [Patent Document 53] International Publication No. 2013 / 132044 Pamphlet [Patent Document 54] U.S. Patent Application Publication No. 2014 / 0079706 Specification [Patent Document 55] International Publication No. 2011 / 140249 Pamphlet [Patent Document 56] U.S. Patent Application Publication No. 2011 / 0274683 Specification [Patent Document 57] International Publication No. 2013 / 169264 Pamphlet [Patent Document 58] International Publication No. 2014 / 036357 Pamphlet [Patent Document 59] U.S. Patent Application Publication No. 2014 / 0079699 Specification [Patent Document 60] International Publication No. 2012 / 145493 Pamphlet [Patent Document 61] International Publication No. 2010 / 077634 Pamphlet [Patent Document 62] U.S. Patent Application Publication No. 2010 / 0203056 Specification [Patent Document 63] International Publication No. 2007 / 005874 Brochure [Patent Document 64] U.S. Patent Application Publication No. 2009 / 0055944 [Patent Document 65] International Publication No. 2013 / 079174 Brochure [Patent 66] U.S. Patent Application Publication No. 2014 / 0341917 [Patent Document 67] International Publication No. 2010 / 019570 Pamphlet [Patent Document 68] U.S. Patent Application Publication No. 2010 / 0150892 [Patent Document 69] International Publication No. 2014 / 008218 Brochure [Patent Document 70] U.S. Patent Application Publication No. 2014 / 0093511 [Patent Document 71] International Publication No. 2008 / 132601 Pamphlet [Patent Document 72] U.S. Patent Application Publication No. 2010 / 0233183 [Patent Document 73] International Publication No. 2009 / 044273 brochure [Patent Document 74] U.S. Patent Application Publication No. 2011 / 0008331 [Patent Document 75] International Publication No. 12 / 32433 brochure [Patent Document 76] International Publication No. 2006 / 105021 Pamphlet [Patent Document 77] U.S. Patent Application Publication No. 2007 / 0098719 [Patent Document 78] International Publication No. 2009 / 009116 Brochure [Patent Document 79] U.S. Patent Application Publication No. 2009 / 0136494 [Patent Document 80] International Publication No. 2011 / 028683 Pamphlet [Patent Document 81] U.S. Patent Application Publication No. 2012 / 0189639 [Patent Document 82] International Publication No. 2009 / 073620 Pamphlet [Patent Document 83] U.S. Patent Application Publication No. 2011 / 053941 [Patent Document 84] International Publication No. 2009 / 132238 Brochure [Patent Document 85] U.S. Patent Application Publication No. 2011 / 136796 [Patent Document 86] International Publication No. 2011 / 056652 Brochure [Patent Document 87] U.S. Patent Application Publication No. 2012 / 277217 [Patent Document 88] International Publication No. 2012 / 142237 Brochure [Patent Document 89] U.S. Patent Application Publication No. 2014 / 066625 [Patent Document 90] International Publication No. 2006 / 029879 Pamphlet [Patent Document 91] U.S. Patent Application Publication No. 7,501,496 [Patent Document 92] International Publication No. 2011 / 109400 brochure [Patent Document 93] U.S. Patent Application Publication No. 2013 / 0149236 [Patent Document 94] U.S. Patent No. 8,906,682 [Non-patent literature]

[0008] [Non-Patent Document 1] Crews C,Chemistry & Biology,2010,17(6):551-555 [Non-Patent Document 2] Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 [Non-licensed document 3] Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed

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[0009] This application relates to novel bifunctional compounds that function to recruit IRAK kinase to E3 ubiquitin ligase for degradation, and to methods for their preparation and use. In particular, this disclosure provides bifunctional compounds that are useful as modulators of targeted ubiquitination of IRAK kinase, which is subsequently degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they enable a broad range of pharmacological activity consistent with the degradation / inhibition of IRAK kinase. Furthermore, this description provides methods for using effective amounts of the compounds described herein for the treatment or remission of disease conditions, such as cancer or inflammatory disorders.

[0010] This study revealed that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective in regulating targeted ubiquitination. Such compounds are represented by formulas Ia-Ii: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, each variable element as defined and described herein.

[0011] The compounds and pharmaceutically acceptable compositions thereof of the present invention are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signaling pathways involving IRAK kinase. Such diseases, disorders, or conditions include those described herein.

[0012] The compounds provided by the present invention are also useful for studying IRAK enzymes in biological and pathological phenomena; for studying intracellular signaling pathways occurring in body tissues; and for comparative evaluation of novel IRAK inhibitors or IRAK degraders or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo. [Modes for carrying out the invention]

[0013] 1. General description of specific embodiments of the present invention: The compounds and compositions of the present invention are useful as degraders and / or inhibitors of one or more IRAK protein kinases. In some embodiments, the provided compounds degrade and / or inhibit IRAK4.

[0014] 2. Compounds and Definitions: The compounds of the present invention generally include those described herein, and are further illustrated by the classes, subclasses and species disclosed herein. Where used herein, unless otherwise indicated, the following definitions apply. For the purposes of the present invention, chemical elements are identified in accordance with (Non-Patent Document 3). Furthermore, general principles of organic chemistry are described in (Non-Patent Document 4) and (Non-Patent Document 5), the entirety of which is incorporated herein by reference.

[0015] The terms “aliphatic” or “aliphatic group,” as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”), and has a single linkage point to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, is not aromatic, and has one linkage point with the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0016] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system having at least one bridge, i.e., a carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a “bridge” is a non-branched chain of multiple or one atom or monovalent bond connecting two bridgeheads, and a “bridgehead” is any skeletal atom of a ring system to which three or more skeletal atoms (excluding hydrogen) are bonded. In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, in which each group is linked to the rest of its molecule by any of the substituteable carbon or nitrogen atoms. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as shown for aliphatic groups. Furthermore or or, any substituteable nitrogen of a bridged bicyclic group is optionally substituted. Typical examples of double-ring bridges include the following: [ka]

[0017] The term "lower alkyl" is C 1-4 This refers to linear or branched alkyl groups. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0018] The term "lower haloalkyl" refers to a carbon atom substituted with one or more halogen atoms. 1-4 This refers to linear or branched alkyl groups.

[0019] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidation form of nitrogen, sulfur, phosphorus, or silicon; any quaternation form of any basic nitrogen or; a substituteable nitrogen in a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR) + This means (including those found in N-substituted pyrrolidinyls).

[0020] As used herein, the term "unsaturated" means that a part has one or more unsaturated units.

[0021] When used herein, "divalent C" 1-8 (or C 1-6 The term "saturated or unsaturated, linear or branched, hydrocarbon chain" refers to a divalent alkylene, alkenylene, and alkynylene chain that is linear or branched as defined herein.

[0022] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n - where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents for the substituted aliphatic group are listed below.

[0023] 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 substituents. Suitable substituents for the substituted aliphatic group are listed below.

[0024] As used herein, the term "cyclopropyrenyl" refers to the following structure: [ka] This refers to the divalent cyclopropyl group.

[0025] The term "halogen" refers to F, Cl, Br, or I.

[0026] The term “aryl,” used alone or as part of a larger phrase such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In particular embodiments of the present invention, “aryl” refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthranyl, and which may have one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, also fall within the scope of the term “aryl.”

[0027] "Heteroaryl" and "heteroaryl-", used alone or as part of a larger part, e.g., "heteroarylkyl" or "heteroarylcoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; or having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes all oxidation forms of nitrogen or sulfur and all quaternization forms of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms "heteroaryl" and "hetero-" as used herein also include groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or linkage is located on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. A heteroaryl ring may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "aromatic heterocycle," any of which may include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently and optionally substituted.

[0028] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic” are interchangeable and refer to a stable 5-7 member monocyclic or 7-10 member bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has one or more, preferably 1-4, heteroatoms in addition to the carbon atom, as defined above. When used in reference to the ring atoms of a heterocyclic ring, the term “nitrogen” includes the substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N(3,4-dihydro-2H-pyrrolyl), NH(pyrrolidinyl), or + It may be NR (in the case of N-substituted pyrrolidinyl).

[0029] The heterocycle may be linked to its pendant group by any heteroatom or carbon atom that can produce a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, 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 herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl. The heterocyclyl group may be monocyclic, bicyclic, bridging bicyclic, or spirocycle. The heterocycle may contain one or more oxo (=O) or thioxo (=S) substituents. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties are independently and optionally substituted.

[0030] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation as defined herein, but is not intended to include aryl or heteroaryl moieties.

[0031] As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when a plurality of positions in a given structure may be substituted with a plurality of substituents selected from the designated group, the substituents may be the same or different at all positions. The combinations of substituents envisioned by the present invention preferably give rise to the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are not substantially altered when subjected to the processes of their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0032] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0-4 SR°; -(CH2) that may be substituted with R° 0-4 Ph; -(CH2) that may be substituted with R° 0-4 O(CH2) 0-1 Ph; -CH=CHPh that may be substituted with R°; -(CH2) that may be substituted with R° 0-4 O(CH2) 0-1-Pyridyl;-NO2;-CN;-N3;-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-, SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1-4 Linear or branched alkylene) ON(R°)2; or -(C 1-4 The linear or branched alkylene is C(O)ON(R°)2, where each R° may be substituted as defined below, and independently of hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or an aryl ring having 5-6 membered saturated, partially unsaturated, or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, together with their intercalating atoms, may form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, as defined below.

[0033] Suitable monovalent substituents on R° (or the ring formed by the two independent occurrences of R° together with their intercalating atoms) are, independently, halogens, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● 、 -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And here, each R ● If it is unsubstituted or preceded by "halo", it is substituted by only one or more halogens, independently, C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 It is selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from Ph, or nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R° include =O and =S.

[0034] Suitable divalent substituents on the saturated carbon atoms of an "optionally substituted" group are as follows: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to an adjacent substitutable carbon of an "optionally substituted" group include the following: -O(CR * 2) 2-3 O- (where each independent occurrence of R * is hydrogen, C 1-6 aliphatic which may be substituted as defined below or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur).

[0035] R * Suitable substituents on the aliphatic group of are halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ●, -NR ● 2 or -NO2, where each R ● is unsubstituted or, if "halo" comes before, is substituted only with one or more halogens, and independently, C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0036] Suitable substituents on the nitrogen of the "optionally substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2 or -N(R † )S(O)2R † are included; here, each R † is independently hydrogen, C 1-6 aliphatic (which may be substituted as defined below), unsubstituted -OPh or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent occurrences of R † together with their intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0037] R † Suitable substituents on the aliphatic group of are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR● -NH2, -NHR ● , -NR ● It is 2 or -NO2, where each R ● If it is unsubstituted, or if "halo" precedes it, it is substituted by only one or more halogens, and independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 The pH is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] As used herein, the term “Provided Compounds” refers to any genus, subgenus, and / or species shown herein.

[0039] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is within the bounds of sound medical judgment, free from unwanted toxicity, irritation, or allergic reactions, suitable for use in contact with human and lower animal tissues, and balanced by a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in Non-Patent Literature 6, incorporated herein by reference. pharmaceutically acceptable salts of the compounds of the present invention include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malic acid, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleic acid, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.

[0040] Suitable base-derived salts include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates formed using counterions such as halides.

[0041] Unless otherwise specified, the structures shown herein also mean all isomers of the structure (e.g., enantiomers, diastereomers, and geometric (or stereostructural) forms); for example, R and S stereoconfigurations for each chiral center, Z and E double bond isomers, and Z and E stereostructural isomers. Therefore, single stereochemical isomers of the compound, as well as mixtures of enantiomers, diastereomers, and geometric (or stereostructural) forms, are within the scope of the present invention. Unless otherwise specified, all tautomer forms of the compound of the present invention are within the scope of the present invention. Furthermore, unless otherwise specified, the structures shown herein also mean compounds that differ only in the presence of one or more isotopically enriched atoms; for example, the substitution of hydrogen with deuterium or tritium or 13 C- or 14 Compounds having this structure, including carbon substitution with carbon-rich carbon, fall within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0042] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits IRAK kinase having a measurable affinity. In certain embodiments, the inhibitor is an IC50 with an IC50 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. 50 It has and / or coupling constants.

[0043] As used herein, the term “degrader” is defined as a heterobifunctional or monovalent compound that binds to and / or inhibits both IRAK kinase and E3 ligase with a measurable affinity that causes ubiquitination and subsequent degradation of IRAK kinase. In certain embodiments, the degrader is a DC compound with a concentration 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. 50 It has.

[0044] When used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in IRAK protein kinase activity between a sample containing the compound or composition thereof and IRAK protein kinase of the present invention and an equivalent sample containing IRAK protein kinase in the absence of the compound or composition thereof.

[0045] 3. Description of a typical embodiment: As described above, in a particular embodiment, the present invention relates to one compound of the following formula: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is a divalent moiety selected from -CH2- or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR-, or -O-; Ring A is phenylenyl, pyridinyl, [ka] It is a ring selected from; Ring B is a fused ring selected from benzo or 5-6 membered heteroaryls containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 is hydrogen, C 1-5 Alkyl or C 3-6 It is a cycloalkyl; R 1 , R 2 and R 3 Each of them independently contains hydrogen and R A , 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 either hydrogen or C 1-6 A group that is optionally substituted, selected from an aliphatic, phenyl, nitrogen, oxygen, and sulfur-independently saturated or partially unsaturated 3-7 membered carbon ring having 1-2 heteroatoms, or a heterocycle and a 5-6 membered heteroaryl ring having 1-4 heteroatoms, or: Two R groups on the same carbon or nitrogen can optionally combine with their intervening atoms to form a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which these two R groups are linked; Each R A Independently, C 1-6An optionally substituted group selected from a 4-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 These are hydrogen, halo, -CN, -OR, oxo, and C. 1-6 Alkyl, -CR2OR, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl or C 3-6 It is either cycloalkyl or: 2R on the same carbon atom 5 The base, when combined, consists of these two R 5 Together with the carbon atom to which the group is linked, it forms a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two Rs on two different carbon atoms 5 The base, when combined, consists of these two R 5 Together with intervening atoms that link the groups, they form 3-7 membered saturated or partially unsaturated carbon rings or heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings C and D is independently selected from a phenyl or 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each of m, n, p, and q independently provides (0, 1, 2, 3, or 4).

[0046] As described above, in a particular embodiment, the present invention relates to one compound of any of the following formulas: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is a divalent moiety selected from -CH2- or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR-, or -O-; Ring A is phenylenyl, pyridinyl, [ka] It is a ring selected from; Ring B is a fused ring selected from benzo or 5-6 membered heteroaryls containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 is hydrogen, C 1-5 Alkyl or C 3-6 It is a cycloalkyl; R 1 , R 2 and R 3 Each of them independently contains hydrogen and R A , 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 either hydrogen or C 1-6A group that is optionally substituted, selected from an aliphatic, phenyl, nitrogen, oxygen, and sulfur-independently saturated or partially unsaturated 3-7 membered carbon ring having 1-2 heteroatoms, or a heterocycle and a 5-6 membered heteroaryl ring having 1-4 heteroatoms, or: Two R groups on the same carbon or nitrogen can optionally combine with their intervening atoms to form a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which these two R groups are linked; Each R A Independently, C 1-6 An optionally substituted group selected from a 4-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 5 These are hydrogen, halo, -CN, -OR, oxo, and C. 1-6 Alkyl, -CR2OR, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl or C 3-6 It is either cycloalkyl or: 2R on the same carbon atom 5 The base, when combined, consists of these two R 5 Together with the carbon atom to which the group is linked, it forms a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two Rs on two different carbon atoms 5 The base, when combined, consists of these two R 5 Together with intervening atoms that link the groups, they form 3-7 membered saturated or partially unsaturated carbon rings or heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings C and D is independently selected from a phenyl or 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each of m, n, p, and q independently provides (0, 1, 2, 3, or 4).

[0047] In some embodiments of the compounds of the formulas described herein, X is a divalent moiety selected from -CH2- or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR2-, -CONR-, -NR-, or -O-; Ring A is phenylenyl, pyridinyl, [ka] It is a ring selected from; Ring B is a fused ring selected from benzo or 5-6 membered heteroaryls containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 4 is hydrogen, C 1-5 Alkyl or C 3-6 It is a cycloalkyl; R 1 , R 2 and R 3 Each of them independently contains hydrogen and R A, 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 either hydrogen or C 1-6 A group that is optionally substituted, selected from an aliphatic, phenyl, nitrogen, oxygen, and sulfur-independently saturated or partially unsaturated 3-7 membered carbon ring having 1-2 heteroatoms, or a heterocycle and a 5-6 membered heteroaryl ring having 1-4 heteroatoms, or: Two R groups on the same carbon or nitrogen can optionally combine with their intervening atoms to form a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which these two R groups are linked; Each R A Independently, C 1-6 An optionally substituted group selected from a 4-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R 5 These are independently hydrogen, halo, -CN, -OR, oxo, and C. 1-6 Alkyl, -CR2OR, -OC 1-6 Alkyl, C1-6 Haloalkyl, -OC 1-6 Haloalkyl, or C 3-6 It is cycloalkyl, or 2R on the same carbon atom 5 The base, when combined, consists of these two R 5 Together with the carbon atom to which the group is linked, it forms a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two Rs on two different carbon atoms 5 The base, when combined, consists of these two R 5 Together with intervening atoms that link the groups, they form 3-7 membered saturated or partially unsaturated carbon rings or heterocycles having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings C and D is independently selected from a phenyl or 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.

[0048] As defined above and as described herein, X is a divalent moiety selected from -CH2- and -C(O)-.

[0049] In some embodiments, X is -CH2-. In some embodiments, X is -C(O)-.

[0050] In some embodiments, X is selected from those shown in Table 1 below.

[0051] As defined above and as described herein, Y is a nitrogen atom or CH.

[0052] In some embodiments, Y is a nitrogen atom. In some embodiments, Y is CH.

[0053] In some embodiments, Y is selected from those shown in Table 1 below.

[0054] As defined above and as described herein, Z is a covalent bond, -CR2-, -CONR, -NR-, or -O-.

[0055] 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-.

[0056] In some embodiments, Z is -CH2-. In some embodiments, Z is -CONH-. In some embodiments, Z is -NH-.

[0057] As defined above and as described herein, ring A is phenylenyl, pyridinyl, [ka] It is a ring selected from.

[0058] In some embodiments, ring A is phenylenyl. In some embodiments, ring A is pyridinyl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] That is the case.

[0059] In some embodiments, ring A is selected from those shown in Table 1 below.

[0060] As defined above and as described herein, ring B is a fused ring selected from benzo or 5-6 membered heteroaryls containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0061] In some embodiments, ring B is benzo. In some embodiments, ring B is a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] In some embodiments, ring B is selected from those shown in Table 1 below.

[0063] In some embodiments, ring A and ring B are [ka] In some embodiments, ring A and ring B are [ka] In some embodiments, ring A and ring B are [ka] In some embodiments, ring A and ring B are [ka] In some embodiments, ring A and ring B are [ka] That is the case.

[0064] As defined above and as described herein, each of ring C and ring D is independently a ring selected from phenyl or a 5- to 9-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, ring C is phenyl. In some embodiments, ring C is a 5- to 9-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered heteroaryl ring having 2 nitrogen atoms. In some embodiments, ring C is a 9-membered heteroaryl ring having 3 nitrogen atoms.

[0066] 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.

[0067] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] That is the case.

[0068] 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 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 nitrogen atoms. In some embodiments, ring D is a 9 membered heteroaryl ring having 3 nitrogen atoms.

[0069] In some embodiments, ring D is phenyl. In some embodiments, ring D is pyridyl. In some embodiments, ring D is pyrazinyl. In some embodiments, ring D is pyrazolo[1,5-a]pyrimidinyl. In some embodiments, ring D is pyrolo[1,2-a]pyrimidine.

[0070] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] That is the case.

[0071] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] That is the case.

[0072] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] That is the case.

[0073] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] That is the case.

[0074] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] In some embodiments, ring D is [ka] That is the case.

[0075] In some embodiments, rings C and D are selected from those shown in Table 1 below.

[0076] As set forth above and as described herein, R 1 , R 2 , and R 3 Each of them independently contains hydrogen and R A , 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, -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.

[0077] In some embodiments, R 1is hydrogen. In some embodiments, R 1 R A In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -NO2. In some embodiments, R 1 is an oxo. In some embodiments, R 1 is -OR. In some embodiments, R 3 is -Si(OH)2R. In some embodiments, R 1 is -Si(OH)R2. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is -SiR3. In some embodiments, R 1 is -S(O)2R. In some embodiments, R 1 is -S(O)2NR2. In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -C(O)R. In some embodiments, R 1 is -C(O)OR. In some embodiments, R 1 is -C(O)NR2. In some embodiments, R 1 is -C(O)N(R)OR. In some embodiments, R 1 is -CR2N(R)C(O)R. In some embodiments, R 1 This is -CR2N(R)C(O)NR2. In some embodiments, R 1 is -CFR2. In some embodiments, R 1 is -CF2R. In some embodiments, R 1 is -CF3. In some embodiments, R 1 is -CR2(OR). In some embodiments, R 1 This is -CR2(NR2). In some embodiments, R1 is -OC(O)R. In some embodiments, R 1 is -OC(O)NR2. In some embodiments, R 1 is -OP(O)R2. In some embodiments, R 1 is -OP(O)(OR)2. In some embodiments, R 1 is -OP(O)(OR)NR2. In some embodiments, R 1 Independently, is -OP(O)(NR2)2-. In some embodiments, R 1 is -N(R)C(O)OR. In some embodiments, R 1 is -N(R)C(O)R. In some embodiments, R 1 is -N(R)C(O)NR2. In some embodiments, R 1 is -N(R)P(O)R2. In some embodiments, R 1 is -N(R)P(O)(OR)2. In some embodiments, R 1 is -N(R)P(O)(OR)NR2. In some embodiments, R 1 is -N(R)P(O)(NR2)2. In some embodiments, R 1 This is -N(R)S(O)2R.

[0078] In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 C 1-6 It is alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is -C(OH)Me2. In some embodiments, R 1 is -CHF2. In some embodiments, R 1 is -CF3. In some embodiments, R 1 is, -OC 1-6 It is alkyl. In some embodiments, R 1is -OMe. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0079] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 R A In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NO2. In some embodiments, R 2 is an oxo. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -Si(OH)2R. In some embodiments, R 2 is -Si(OH)R2. In some embodiments, R 2 is -SR. In some embodiments, R 2 is -NR2. In some embodiments, R 2 is -SiR3. In some embodiments, R 2 is -S(O)2R. In some embodiments, R 2 is -S(O)2NR2. In some embodiments, R 2 is -S(O)R. In some embodiments, R 2 is -C(O)R. In some embodiments, R 2 is -C(O)OR. In some embodiments, R2 is -C(O)NR2. In some embodiments, R 2 is -C(O)N(R)OR. In some embodiments, R 2 is -CR2N(R)C(O)R. In some embodiments, R 2 This is -CR2N(R)C(O)NR2. In some embodiments, R 2 is -CFR2. In some embodiments, R 2 is -CF2R. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is -CR2(OR). In some embodiments, R 2 This is -CR2(NR2). In some embodiments, R 2 is -OC(O)R. In some embodiments, R 2 is -OC(O)NR2. In some embodiments, R 2 is -OP(O)R2. In some embodiments, R 2 is -OP(O)(OR)2. In some embodiments, R 2 is -OP(O)(OR)NR2. In some embodiments, R 2 In some embodiments, R 2 is -N(R)C(O)OR. In some embodiments, R 2 is -N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)NR2. In some embodiments, R 2 is -N(R)P(O)R2. In some embodiments, R 2 is -N(R)P(O)(OR)2. In some embodiments, R 2 is -N(R)P(O)(OR)NR2. In some embodiments, R 2 is -N(R)P(O)(NR2)2. In some embodiments, R 2 This is -N(R)S(O)2R.

[0080] In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 C 1-6 It is alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 3 is -C(OH)Me2. In some embodiments, R 2 is -CHF2. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is, -OC 1-6 It is alkyl. In some embodiments, R 2 is -OiPr. In some embodiments, R 2 It is -OMe.

[0081] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 R A In some embodiments, R 3 is hydrogen. In some embodiments, R 3 R A In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NO2. In some embodiments, R 3 is an oxo. In some embodiments, R 3 is -OR. In some embodiments, R 3 is -Si(OH)2R. In some embodiments, R 3 is -Si(OH)R2. In some embodiments, R 3 is -SR. In some embodiments, R 3 is -NR2. In some embodiments, R 3 is -SiR3. In some embodiments, R 3 is -S(O)2R. In some embodiments, R 3is -S(O)2NR2. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -C(O)R. In some embodiments, R 3 is -C(O)OR. In some embodiments, R 3 is -C(O)NR2. In some embodiments, R 3 is -C(O)N(R)OR. In some embodiments, R 3 is -CR2N(R)C(O)R. In some embodiments, R 3 This is -CR2N(R)C(O)NR2. In some embodiments, R 3 is -CFR2. In some embodiments, R 3 is -CF2R. In some embodiments, R 3 is -CF3. In some embodiments, R 3 is -CR2(OR). In some embodiments, R 3 This is -CR2(NR2). In some embodiments, R 3 is -OC(O)R. In some embodiments, R 3 is -OC(O)NR2. In some embodiments, R 3 is -OP(O)R2. In some embodiments, R 3 is -OP(O)(OR)2. In some embodiments, R 3 is -OP(O)(OR)NR2. In some embodiments, R 2 In some embodiments, R 3 is -N(R)C(O)OR. In some embodiments, R 3 is -N(R)C(O)R. In some embodiments, R 3 is -N(R)C(O)NR2. In some embodiments, R 3 is -N(R)P(O)R2. In some embodiments, R 3 is -N(R)P(O)(OR)2. In some embodiments, R 3is -N(R)P(O)(OR)NR2. In some embodiments, R 3 is -N(R)P(O)(NR2)2. In some embodiments, R 3 This is -N(R)S(O)2R.

[0082] In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is -CN. In some embodiments, R 3 C 1-6 It is alkyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is t-butyl. In some embodiments, R 3 is -CH2OMe. In some embodiments, R 3 is -C(OMe)Me2. In some embodiments, R 3 is -C(CN)Me2. In some embodiments, R 3 C 3-6 It is cycloalkyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is -CHF2. In some embodiments, R 3 is -CF3. In some embodiments, R 3 is -OCF3. In some embodiments, R 3 is -OCHF2. In some embodiments, R 3 is, -OC 1-6 It is alkyl. In some embodiments, R 3 is -OiPr. In some embodiments, R 3 is, -OC 3-6It is cycloalkyl. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 is -OMe. In some embodiments, R 3 is -NMe2. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 is -SMe. In some embodiments, R 3 This is SCF3. In some embodiments, R 3 is -SOCF3. In some embodiments, R 3 It is -SO2CF3.

[0083] In some embodiments, R 1 , R 2 , and R 3 The following selection is made from the options shown in Table 1.

[0084] As set forth above and as described herein, R 4 is hydrogen, C 1-5 Alkyl, or C 3-6 It is a cycloalkyl group.

[0085] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 C 1-5 It is alkyl. In some embodiments, R 4 C 3-6 It is a cycloalkyl group.

[0086] In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 It is cyclopropyl.

[0087] In some embodiments, R 4 The following selection is made from the options shown in Table 1.

[0088] As set forth above and as described herein, R 5 These are hydrogen, halo, -CN, -OR, oxo, and C. 1-6 Alkyl, -CR2OR, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, or C 3-6 It is a cycloalkyl group, and has two R atoms on the same carbon atom. 5 The two bases combine to form these two R 5 Together with the carbon atom to which the group is linked, it forms a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on two different carbon atoms 5 However, these two R5 groups combine with intervening atoms to form a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0089] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halo. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -OR. In some embodiments, R 5 is an oxo. In some embodiments, R 5 C 1-6 It is alkyl. In some embodiments, R 5 is -CR2OR. In some embodiments, R 5is, -OC 1-6 It is alkyl. In some embodiments, R 5 C 1-6 In some embodiments, R 5 is, -OC 1-6 In some embodiments, R 5 C 3-6 It is a cycloalkyl. In some embodiments, two R atoms are located on the same carbon atom. 5 The two bases combine to form these two R 5 Together with the carbon atom to which the group is linked, it forms a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups are located on two different carbon atoms. 5 The base, when combined, consists of these two R 5 Together with intervening atoms that link the groups, it forms a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, R 5 is fluoro. In some embodiments, R 5 is a geminal difluoro. In some embodiments, R 5 is methyl. In some embodiments, R 5 is -OH. In some embodiments, R 5 is -OMe. In some embodiments, R 5 is -CMe2OH. In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF2. In some embodiments, R 5 is -CH2CF3. In some embodiments, R 5 It is -CH2CHF2.

[0091] In some embodiments, two R on two different carbon atoms 5The group combines to form a 3-7 membered rated or partially unsaturated carbon ring or heterocycle -R having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5 - forms, where -R 5 - is -CH2-, -O-, -CH2CH2-, -CH2O-, or -CH2OCH2-. In some embodiments, two R on two different carbon atoms. 5 The bases combine to form a bridged biring ring (for example) [ka] ) of -R 5 -forms

[0092] In some embodiments, [ka] teeth, [ka] That is the case.

[0093] In some embodiments, [ka] teeth, [ka] That is the case.

[0094] In some embodiments, R 5 The following selection is made from the options shown in Table 1.

[0095] As defined above and as described herein, each R is independently hydrogen or C 1-6The R group is optionally substituted by a 3-7 member saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, or by an optionally substituted group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or by two R groups on the same carbon or nitrogen optionally together with their intervening atoms to form a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which these two R groups are linked.

[0096] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted with C. 1-6 It is aliphatic. In some embodiments, R is C 1-6 It is an alkyl group (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is C 1-6 The R group is a haloalkyl group (e.g., -CF3, CHF2, etc.). In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted 3-7 member saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 member 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 member 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 combined with their intervening atoms to form an optionally substituted 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which these two R groups are linked.

[0097] In some embodiments, R is selected from those shown in Table 1 below.

[0098] As set forth above and as described herein, each R A Independently, C 1-6 The group is optionally substituted, selected from a 4-7 member saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, R A C is a C that is optionally substituted. 1-6 It is aliphatic. In some embodiments, R A C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R A C 1-6 It is a haloalkyl (e.g., -CF3, CHF2, etc.). In some embodiments, R A is a phenyl compound that is optionally substituted. In some embodiments, R A R is a 3- to 7-membered saturated or partially unsaturated carbon ring that is optionally substituted. In some embodiments, R A R is an optionally substituted 4-7 member saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R A This is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, R A The following selection is made from the options shown in Table 1.

[0101] As defined above and as described herein, each of m, n, p, and q is independently 0, 1, 2, 3, or 4.

[0102] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2.

[0103] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2.

[0104] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2.

[0105] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2.

[0106] In some embodiments, m, n, p, and q are selected from those shown in Table 1 below.

[0107] In some embodiments, the present invention relates to compounds of formula Ib or I-b' as compounds of formula Ib-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0108] In some embodiments, the present invention relates to compounds of formula Ib or I-b' as compounds of formula Ib-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0109] In some embodiments, the present invention relates to compounds of formula Ic or I-c' as compounds of formula Ic-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0110] In some embodiments, the present invention relates to compounds of formula Ic or I-c' as compounds of formula Ic-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0111] In some embodiments, the present invention relates to compounds of formula Ie or I-e' as compounds of formula Ie-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0112] In some embodiments, the present invention relates to compounds of formula Ie or I-e' as compounds of formula Ie-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0113] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0114] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0115] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-3: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0116] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-4: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0117] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-5: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0118] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-6: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0119] In some embodiments, the present invention relates to a compound of formula -f' as a compound of formula If-7: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0120] In some embodiments, the present invention relates to compounds of formula I-f' as compounds of formula If-8: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0121] In some embodiments, the present invention relates to compounds of formula I-f' as compounds of formula If-9: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0122] In some embodiments, the present invention relates to compounds of formula I-f' as compounds of formula If-10: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0123] In some embodiments, the present invention relates to compounds of formula I-f' as compounds of formula If-11: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0124] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-12: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0125] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-13: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0126] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-14: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0127] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-15: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0128] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-16: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0129] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-17: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0130] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-18: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0131] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-19: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0132] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-20: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0133] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-21: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0134] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-22: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0135] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-23: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0136] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-24: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0137] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-25: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0138] In some embodiments, the present invention relates to compounds of formula I-f' as compounds of formula If-26: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0139] In some embodiments, the present invention relates to compounds of formula If or I-f' as compounds of formula If-27: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0140] In some embodiments, the present invention relates to compounds of formula Ig or I-g' as compounds of formula Ig-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0141] In some embodiments, the present invention relates to compounds of formula Ig or I-g' as compounds of formula Ig-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0142] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0143] In some embodiments, the present invention relates to a compound of formula Ij as a compound of formula Ij-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0144] In some embodiments, the present invention relates to a compound of formula Ij as a compound of formula Ij-3: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0145] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-4: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0146] In some embodiments, the present invention relates to a compound of formula Ij as a compound of formula Ij-5: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0147] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-6: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0148] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-7: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0149] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-8: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0150] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-9: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0151] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-10: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0152] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-11: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0153] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-12: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0154] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-13: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0155] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-14: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0156] In some embodiments, the present invention relates to compounds of formula Ij as compounds of formula Ij-15: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0157] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0158] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0159] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-3: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0160] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-4: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0161] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-5: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0162] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-6: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0163] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-7: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0164] In some embodiments, the present invention relates to compounds of formula Ik as compounds of formula Ik-8: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0165] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-1: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0166] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-2: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0167] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-3: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0168] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-4: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0169] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-5: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0170] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-6: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0171] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-7: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0172] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-8: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0173] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-9: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0174] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-10: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0175] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-11: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0176] In some embodiments, the present invention relates to a compound of formula Il as a compound of formula Il-12: [ka] Alternatively, a pharmaceutically acceptable salt thereof is provided, where each variable element is defined above and as described in the embodiments herein, both individually and in combination.

[0177] Representative compounds of the present invention are shown in Table 1 below.

[0178] [ka] [ka] [ka] [ka] [ka]

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[0179] In some embodiments, the present invention provides compounds shown in Table 1 above, or pharmaceutically acceptable salts thereof.

[0180] In some embodiments, the present invention also provides compounds described herein (such as any one of the compounds of the formulas described herein or shown in Table 1) or pharmaceutical compositions thereof for use in methods for degrading IRAK4 as described herein and / or methods for treating IRAK4-dependent disorders as described herein. In some embodiments, the present invention also provides compounds described herein (such as any one of the compounds of the formulas described herein or shown in Table 1) or pharmaceutical compositions thereof for use in methods for degrading IRAK4 as described herein. In some embodiments, the present invention also provides compounds described herein (such as any one of the compounds of the formulas described herein or shown in Table 1) or pharmaceutical compositions thereof for use in methods for treating IRAK4-dependent disorders as described herein.

[0181] In some embodiments, the present invention provides a pharmaceutical composition for pharmaceutically acceptable use, such as for degrading IRAK4 as described herein and / or treating IRAK4-dependent disorders as described herein, comprising any compound of any of the formulas described herein or shown in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0182] 4. General method for providing the compound The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods described in detail in the examples herein.

[0183] 5. Use, prescriptions and administration Pharmacologically acceptable composition In another embodiment, the present invention provides compositions comprising the compound of the present invention or pharmaceutically acceptable derivatives thereof and pharmaceutically acceptable carriers, adjuvants, or vehicles. The amount of the compound in the composition of the present invention is such that it is effective in measurably degrading and / or inhibiting IRAK protein kinase or its mutants in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it is effective in measurably degrading and / or inhibiting IRAK protein kinase or its mutants in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0184] Where used herein, the term “patient” means an animal, preferably a mammal, and most preferably a human.

[0185] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological properties of the compound it is formulated with. Examples of pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partially glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolin.

[0186] "Pharmacologically acceptable derivatives" means any non-toxic salts, esters, ester salts, or other derivatives of the compounds of the present invention that, when administered to a recipient, can directly or indirectly provide the compounds of the present invention or metabolites or residues thereof that are inhibitory or degradatively active.

[0187] As used herein, the term “inhibitoryly active metabolite or residue thereof” means that the metabolite or residue thereof is also an inhibitor or mutant of IRAK protein kinase.

[0188] As used herein, the term “degradably active metabolite or residue thereof” means that the metabolite or residue thereof is also a degrader or mutant of the IRAK protein kinase.

[0189] The compositions of the present invention may be administered orally, parenterally, or by inhalation spray topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intraarachnoid, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art, using appropriate dispersing or wetting and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils have been conventionally used as solvents or suspension media.

[0190] For this purpose, any sterile, non-volatile oil, including synthetic mono- or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable formulations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersions, such as carboxymethylcellulose or similar dispersants, which are commonly used in formulations of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens®, Spans®, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0191] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, a useful diluent contains lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or colorings may also be added as needed.

[0192] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0193] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Appropriate topical formulations can be readily prepared for each of these areas or organs.

[0194] Topical application to the lower intestinal tract can be appropriately performed with rectal suppository formulations (see above) or with appropriate enema formulations. Topical transdermal patches may also be used.

[0195] For topical application, the pharmaceutically acceptable compositions provided may be formulated in a suitable ointment containing an active component suspended or dissolved in one or more carriers. Examples of carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated in a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Examples of 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.

[0196] For ocular use, the pharmaceutically acceptable composition provided may be formulated as an atomized suspension in isotonic pH-adjusted sterile saline, or, preferably, as a solution in isotonic pH-adjusted sterile saline with or without a preservative such as benzylalkonium chloride. Alternatively, for ocular use, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

[0197] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared in accordance with techniques well known in the art of pharmaceutical formulations, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solvents or dispersants, and may be prepared as solutions in physiological saline.

[0198] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0199] The amount of the compound of the present invention that can be combined with a carrier material to produce a composition in single-dose form varies depending on the host being treated and the specific method of administration. Preferably, the provided compositions should be formulated so that a dosage of the compound between 0.01 and 100 mg / kg body weight / day can be administered to the patient receiving these compositions.

[0200] It should be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0201] Use of compounds and pharmaceutically acceptable compositions The compounds and compositions described herein are generally useful for the degradation and / or inhibition of the kinase activity of one or more enzymes.

[0202] Examples of kinases that are degraded and / or inhibited by the compounds and compositions described herein, and for which the methods described herein are useful, include members of the interleukin-1 receptor-associated kinase (IRAK) family of kinases, including IRAK-1, IRAK-2, and IRAK-4 or their mutants. (Non-Patent Literature 7), (Non-Patent Literature 8) (incorporated by reference in their entirety).

[0203] The activity of compounds used in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4 or their mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays to determine phosphorylation activity and / or subsequent functional consequences or inhibition of any of the ATPase activity of activated IRAK-1, IRAK-2, and / or IRAK-4 or their mutants. Alternative in vitro assays quantify the ability of inhibitors 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 complexes, and determining the amount of radiolabeled binding. Alternatively, inhibitor binding can be determined by performing competitive experiments in which novel inhibitors are incubated with IRAK-1, IRAK-2, and / or IRAK-4 bound to known radioligands. Representative in vitro and in vivo assays useful for assaying IRAK-4 inhibitors include, for example, those described and disclosed in (Non-Patent Document 9); (Non-Patent Document 10); (Non-Patent Document 11); (Non-Patent Document 12) (each incorporated in its entirety herein by reference). Detailed conditions for assaying the compounds used in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2 and / or IRAK-4 or their mutants are shown in the following examples.

[0204] The most well-defined member of the IRAK family is the serine / threonine kinase IRAK-4. IRAK-4 is involved in the signaling of innate immune responses from Toll-like receptors (TLRs) and Toll / IL-1 receptors (TIRs).

[0205] Innate immunity detects pathogens through the recognition of pathogen-associated molecular patterns by TLRs, which then link to an adaptive immune response. TLRs recognize conserved structures of both microbial 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.

[0206] TLRs intervene in innate immune responses by upregulating the expression of inflammatory genes in multiple target cells. See, for example, (Non-Patent Literature 13) (the whole is incorporated herein by reference). While TLR-mediated inflammatory responses are crucial for innate immunity and host defense against infection, uncontrolled inflammation is detrimental to the host and can lead to sepsis and chronic inflammatory diseases, such as chronic arthritis, atherosclerosis, multiple sclerosis, cancer, and autoimmune disorders, such as rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel disease.

[0207] Upon ligand binding, most TLRs recruit the adapter molecule MyD88 through their TIR domain, which mediates a MyD88-dependent pathway. MyD88 then recruits IRAK-4, which is involved in the nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinase, and interferon-regulatory cascade, leading to the induction of pro-inflammatory cytokines. Activation of NF-κB results in the induction of inflammatory cytokines and chemokines, such as TNF-α, IL-1α, IL-6, and IL-8. The kinase activity of IRAK-4 has been shown to play a crucial role in TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of innate immune responses organized by interleukin-1 receptors (IL-1R), interleukin-18 receptors (IL-18R), IL-33 receptors (IL-33R), and Toll-like receptors (TLRs). Inactivation of IRAK-1 and / or IRAK-4 activity has been shown to lead to decreased production of cytokines and chemokines in response to stimulation of IL-1 and TLR ligands. See, for example, (Non-Patent Literature 14); (Non-Patent Literature 15); (Non-Patent Literature 16); (Non-Patent Literature 8); (Non-Patent Literature 17); (Non-Patent Literature 9); (Non-Patent Literature 18); (Non-Patent Literature 19); (Non-Patent Literature 11); (Non-Patent Literature 20); (Non-Patent Literature 21); (Non-Patent Literature 22); (Non-Patent Literature 23); (Non-Patent Literature 24); (Non-Patent Literature 25) (each whole incorporated herein by reference). Indeed, knockdown mice expressing catalytically inactive mutant IRAK-4 protein are completely resistant to septic shock and exhibit poor IL-1 activity. Furthermore, these mice are resistant to joint and bone inflammation / destruction in arthritis models, suggesting that IRAK-4 can be targeted to treat chronic inflammation. Furthermore, while IRAK-4 appears to be important for childhood immunity against some pyogenic bacteria, as demonstrated by one study in which patients over 14 years of age lacking IRAK-4 activity did not show invasive infections, it has been shown to play an overlapping role in protective immunity against most infections in adults.(Non-Patent Document 16); (Non-Patent Document 26); (Non-Patent Document 27); (Non-Patent Document 12); (Non-Patent Document 28); (Non-Patent Document 29); (Non-Patent Document 30) (each in its entirety incorporated herein by reference). Since TLR activation induces IRAK-4 kinase activity, IRAK-4 inhibition provides an attractive target for addressing the underlying causes of inflammation in countless diseases.

[0208] Representative IRAK-4 inhibitors include, for example, those described and disclosed in (Non-Patent Document 31); (Non-Patent Document 32); (Non-Patent Document 33); (Non-Patent Document 34); (Non-Patent Document 35) (each in whole being incorporated herein by reference).

[0209] As used herein, the terms “treatment,” “to treat,” and “to treat” mean reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more of its symptoms, as described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered when there are no symptoms. For example, treatment may be administered to individuals who are susceptible to the disease before the onset of symptoms (e.g., in light of the disease history of the symptoms and / or in light of genetic or other susceptibility factors). Treatment may be continued after the symptoms have resolved, for example, to prevent or delay their recurrence.

[0210] The compounds provided are one or more degraders and / or inhibitors 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. Accordingly, in certain embodiments, the present invention provides a method for treating IRAK-1-mediated, IRAK-2-mediated, and / or IRAK-4-mediated disorders, comprising the step of administering the compounds of the present invention or pharmaceutically acceptable compositions thereof to a patient in need thereof.

[0211] As used herein, the terms “IRAK-1-mediated,” “IRAK-2-mediated,” and / or “IRAK-4-mediated” disorders, diseases, and / or conditions mean, as used herein, any disease or other adverse condition known to involve one or more of IRAK-1, IRAK-2, and / or IRAK-4 or their mutants. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases known to involve one or more of IRAK-1, IRAK-2, and / or IRAK-4 or their mutants.

[0212] In some embodiments, the present invention provides methods for treating one or more disorders, diseases and / or conditions, the disorders, diseases or conditions being cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related disorders, metabolic disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions including T cell activation, cardiovascular disorders, or CNS disorders.

[0213] Diseases and conditions treatable according to the method of the present invention include cancer (see, e.g., Non-Patent Document 36; Non-Patent Document 37), diabetes, cardiovascular disease, viral diseases, autoimmune diseases such as lupus (see, e.g., Non-Patent Document 38; Non-Patent Document 16), rheumatoid arthritis (see, e.g., Non-Patent Document 39), autoinflammatory syndromes (see, e.g., Non-Patent Document 40), atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease (see, e.g., Non-Patent Document 41), inflammation (see, e.g., Non-Patent Document 42), acute and chronic gout and gouty arthritis (see, e.g., Non-Patent Document 43; Non-Patent Document 44; Non-Patent Document 4 5); (See Non-Patent Document 46); (See Non-Patent Document 47); (See Non-Patent Document 48); (See Non-Patent Document 49)); neuropathy, metabolic syndrome (e.g., see Non-Patent Document 50); immunodeficiency disorders, e.g., AIDS and HIV (e.g., see Non-Patent Document 51); destructive bone disorders (e.g., see Non-Patent Document 24); osteoarthritis; proliferative disorders; Waldenström macroglobulinemia (e.g., see Non-Patent Document 52); (See Non-Patent Document 53); (See Non-Patent Document 54); (See Non-Patent Document 55)); infectious diseases, conditions related to cell death, pathological immune conditions including T cell activation, and CNS disorders in patients. In one embodiment, a human patient is treated with the compound of the present invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound is present in an amount that measurably degrades and / or inhibits IRAK4 kinase activity.

[0214] The compounds of the present invention are used to treat benign or malignant tumors, solid tumors, carcinomas, sarcomas, glioblastomas, neuroblastomas, multiple myelomas, gastrointestinal cancers, especially colon cancers or colorectal adenomas, tumors of the head and neck, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplastic syndromes, and neoplastic syndromes of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, stomach, stomach tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland, solid tumors, carcinomas, sarcomas, glioblastomas, neuroblastomas, multiple myelomas, gastrointestinal cancers, especially colon cancers or colorectal adenomas, tumors of the head and neck, epidermal hyperplasia, psoriasis, prostatic hyperplasia, and neoplastic syndromes of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, stomach tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland. Neoplasms of epithelial morphology, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin and non-Hodgkin's lymphoma, breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, MyD88-driven disorders, smoldering low-grade multiple myeloma or hematological malignancies (leukemia, diffuse large B-cell lymphoma (DLBCL), ABC) It is useful in the treatment of proliferative disorders selected from DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), perisplenic zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, and MDS.

[0215] In some embodiments, the proliferative disorders that can be treated according to the methods of the present invention are disorders promoted by MyD88. In some embodiments, the disorders promoted by MyD88 that can be treated according to the methods of the present invention are selected from ABC DLBCL, primary CNS lymphoma, primary extranodal lymphoma, Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

[0216] In some embodiments, the proliferative disorder that can be treated according to the method of the present invention is an IL-1-driven disorder. In some embodiments, the IL-1-driven disorder is a smoldering, low-grade multiple myeloma.

[0217] The compounds according to the present invention are useful in the treatment of inflammatory or obstructive airway diseases, resulting in, for example, reduction of tissue damage, airway inflammation, bronchial hypersensitivity, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present invention is applicable include all types and origins of asthma, including both endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis-induced asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Treatment of asthma is also understood to include treatment of subjects, for example, subjects under 4 or 5 years of age who present with wheezing symptoms and have been diagnosed or can be diagnosed as “wheezing infants,” and are now often identified as first-onset or early-phase asthma, which is an established patient category of primary medical interest.

[0218] The compounds according to the present 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, blood transfusion, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect toxins, animal hair, animal scales, house dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0219] The prophylactic effectiveness in treating asthma will be demonstrated by a reduction in the frequency or severity of symptomatic attacks, such as acute asthma or bronchoconstrictor-induced attacks, or by an improvement in lung function or increased airway responsiveness. This may be further demonstrated by a reduction in the need for other symptomatic treatments, such as treatments to limit or interrupt symptomatic attacks when they occur, or treatments aimed at doing so, such as anti-inflammatory or bronchodilation therapies. The prophylactic benefits in asthma may be particularly evident in individuals prone to the “morning dip.” The “morning dip” is a recognized asthmatic syndrome common to a significant percentage of asthmatic attacks and those characterized by asthmatic attacks, typically occurring between 4 and 6 a.m., that is, a time when the individual is generally free from virtually all previously administered symptomatic asthma treatment.

[0220] The compounds of the present invention may be used for other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung diseases (COPD, COAD, or COLD), including chronic bronchitis or associated dyspnea, emphysema, and exacerbations resulting from increased airway response to other drug therapies, particularly other inhaled drug therapies. The present invention is also applicable to the treatment of bronchitis of any type or origin, including but not limited to acute, arachidic, catarrhal, croupus, chronic, or phthinoid bronchitis. Further inflammatory or obstructive airway diseases to which the present invention can be applied include pneumoconiosis of any type or origin (inflammatory diseases of the lungs, usually occupational diseases, frequently accompanied by airway obstruction, whether chronic or acute, caused by repeated inhalation of dust), such as aluminum lung disease, anthracnose disease, asbestos disease, copper deposition disease, feather lung (ptilosis), iron deposition disease, silicosis, tobacco poisoning disease, and cotyledonosis.

[0221] With respect to their anti-inflammatory activity, and particularly with respect to the inhibition of eosinophil activation, the compounds of the present invention are also useful in treating eosinophil-related disorders, such as eosinophilia, particularly those affecting the airways and / or lungs, including eosinophil-related disorders of the airways (e.g., including pathological eosinophilic infiltration of lung tissue), as well as eosinophil-related disorders of the airways resulting from or contemporaneously with Loeffler's syndrome, such as eosinophilic pneumonia, parasitic (especially metazoan) parasitism (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD, and eosinophil-related disorders affecting the airways caused by drug reactions.

[0222] The compounds of the present invention are also useful in treating inflammatory or allergic conditions of the skin, such as psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, 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 conditions of the skin.

[0223] The compounds of the present invention also have the potential to treat other diseases or conditions, such as diseases or conditions having inflammatory components, such as eye diseases and conditions including allergic ophthalmia, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases associated with autoimmune reactions or having autoimmune components or etiologies, such as autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood 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), irritable bowel syndrome, celiac disease, periodontitis, hyalin 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 (pre- and post-), ​​Sjögren's syndrome, psoriatic keratoconjunctivitis and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-related periphery Periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minor change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth restriction, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhydrous epithelial dysplasia, Behçet's disease, incontinence pigmentation, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic) Acid-induced lung injury, bronchitis (mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, eye allergies, silica-induced diseases, COPD (damage reduction, airway inflammation, bronchial hypersensitivity, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis,Bronchitis, synovitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease It may be used to treat laryngitis, mastitis, meningitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, amniotic membrane inflammation, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0224] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present invention are skin diseases. In some embodiments, the inflammatory skin diseases are selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, hidradenitis suppurativa, and other inflammatory or allergic conditions of the skin.

[0225] In some embodiments, inflammatory diseases that can be treated according to the methods of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), adult-onset Still's disease, macrophage activation syndrome (MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH), familial Mediterranean fever, NLRP12 autoinflammatory syndrome, and osteoarthritis.

[0226] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present invention are TH17-mediated diseases. In some embodiments, the TH17-mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0227] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present invention are selected from ocular conditions such as Sjögren's syndrome, allergic disorders, osteoarthritis, ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic sinusitis with nasal polyps (CRSwNP).

[0228] In some embodiments, the present invention provides a method for treating hidradenitis suppurativa in a patient requiring treatment for the condition, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the present invention provides a method for treating atopic dermatitis in a patient requiring treatment for atopic dermatitis, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the present invention provides a method for treating rheumatoid arthritis in a patient requiring treatment for rheumatoid arthritis, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0231] Cardiovascular diseases that can be treated according to the method of the present invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, stroke, transient ischemia, peripheral artery occlusive disorder, pulmonary embolism, and deep vein thrombosis.

[0232] In some embodiments, neurodegenerative diseases that can be treated according to the methods of the present invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases caused by cerebral ischemia and traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0233] Loss of IRAK4 function resulted in decreased Aβ levels in an in vivo mouse model of Alzheimer's disease, accompanied by reduced microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from adult mouse brains revealed changes in microglial phenotype and associated gene expression patterns linked to the expression of IRF transcription factors that govern the microglial phenotype. Furthermore, loss of IRAK4 function, including increased expression of insulin-degrading enzymes, also promoted amyloid clearance mechanisms. Finally, inhibition of IRAK function restored olfactory behavior (Non-Patent Literature 56).

[0234] In some embodiments, the present invention provides methods for treating, preventing, and reducing the severity of Alzheimer's disease, which include administering a compound or a pharmaceutically acceptable salt or composition thereof to a patient in need.

[0235] In some embodiments, the present invention provides methods for treating disease conditions that commonly occur in connection with transplantation. In some embodiments, the disease or condition that commonly occurs in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[0236] In some embodiments, the present invention provides a method for treating metabolic diseases. In some embodiments, the metabolic disease is selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0237] In some embodiments, the present invention provides a method for treating a viral disease. In some embodiments, the viral infection is HIV infection.

[0238] The present invention encompasses the recognition that the compounds provided may have improved properties compared to certain other IRAK4 degraders, such as improved bioavailability and / or improved clearance. In some embodiments, the compounds of the present invention have improved bioavailability compared to another IRAK4 degrader (e.g., as measured by rodent pharmacokinetics according to Example 9). In some embodiments, the compounds of the present invention have higher bioavailability (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more) compared to another IRAK4 degrader (e.g., as measured by rodent pharmacokinetics according to Example 9). In some embodiments, the compounds of the present invention have improved clearance compared to another IRAK4 degrader (e.g., as measured by rodent pharmacokinetics according to Example 9). In some embodiments, the compounds of the present invention have lower clearances (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%) compared to other IRAK4 degraders (e.g., as measured by rodent pharmacokinetics according to Example 9). In some embodiments, the compounds of the present invention have improved protein degrader selectivity for IRAK4 compared to other IRAK4 degraders (e.g., as determined by the procedure of Example 10).

[0239] Furthermore, the present invention provides the use of compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for the preparation of drugs for the treatment of proliferative disorders, inflammatory disorders, obstructive ventilatory disorders, cardiovascular disorders, metabolic disorders, neurological disorders, neurodegenerative disorders, viral disorders, or disorders commonly associated with transplantation.

[0240] Combination therapy Depending on the specific condition or disease to be treated, further therapeutic agents commonly administered to treat that condition are administered in combination with the compounds and compositions of the present invention. Where used herein, further therapeutic agents commonly administered to treat a particular disease or condition are known as those "appropriate for the disease or condition being treated."

[0241] In certain embodiments, the combination or composition provided is administered in combination with another therapeutic agent.

[0242] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, the method comprising administering to a patient in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof and an effective amount of one or more further therapeutic agents, such as those described herein, simultaneously or sequentially. In some embodiments, the method comprises the simultaneous administration of one further therapeutic agent. In some embodiments, the method comprises the simultaneous administration of two further therapeutic agents. In some embodiments, the combination of the disclosed compound and further therapeutic agents or drugs acts synergistically.

[0243] Examples of combinations of agents of the present invention include, but are not limited to, the following: treatments for Alzheimer's disease, e.g., Aricept® and Excelon®; treatments for HIV, e.g., ritonavir; treatments for Parkinson's disease, e.g., L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl and amantadine; agents for treating multiple sclerosis (MS), e.g., β-interferon (e.g., Avonex® and Rebif®), Copaxone® and mitoxantrone; treatments for asthma, e.g., albuterol and Singulair®; agents for treating schizophrenia, e.g., Zyprexa, Risperdal, Seroquel and haloperidol; anti-inflammatory agents, e.g., corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressant agents, e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinson's disease-like agents; agents for treating cardiovascular diseases, e.g., β-blockers, ACE inhibitors Inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons and antivirals; agents for treating hematological disorders, such as corticosteroids, antileukemia 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 for treating immunodeficiency disorders, such as gamma globulin.

[0244] In certain embodiments, the combination therapy or pharmaceutically acceptable composition thereof of the present invention is administered in combination with monoclonal antibody or siRNA therapy.

[0245] These additional agents may be administered individually from a combination therapy provided, as part of a multi-dose regimen. Alternatively, these agents may be part of a single-dose formulation, mixed with the compounds of the present invention in a single composition. When administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain time interval from each other, typically within 5 hours from each other.

[0246] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combinations of the present invention may be administered together, simultaneously or sequentially, with other therapeutic agents, either in individual unit dosage forms or in single-dose unit dosage forms.

[0247] The amount of further therapeutic agents present in the composition of the present invention does not exceed the amount typically administered in a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of further therapeutic agents in the composition disclosed herein is in the range of about 50% to 100% of the amount typically present in a composition containing the agent as the sole therapeutic agent.

[0248] One or more other therapeutic agents may be administered individually from the compounds or compositions of the present invention as part of a multi-dosing regimen. Alternatively, one or more other therapeutic agents may be part of a single-dose formulation mixed with the compounds of the present invention in a single composition. When administered as a multi-dosing regimen, one or more other therapeutic agents and the compounds or compositions of the present invention may be administered simultaneously, sequentially, or from each other within a certain time frame, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from each other. In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention may be administered as a multi-dosing regimen with each part exceeding 24 hours.

[0249] In one embodiment, the present invention provides a composition comprising a compound or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents. The therapeutic agents may be administered together with the compound or a pharmaceutically acceptable salt thereof, or may be administered before or after the administration of the compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In certain embodiments, the 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, the compound provided 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 after the therapeutic agent.

[0250] In another embodiment, the present invention provides a method for treating an inflammatory disease, disorder, or condition in a patient requiring treatment of an inflammatory disease, disorder, or condition by administering the compound provided or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologics, and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, cortisin (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat (U loric®), sulfasalazine (Azulfidine®), antimalarial drugs, e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts, e.g., gold thioglucose (Solganal®), gold thiomalic acid (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (D epen(registered trademark) or Cuprimine(registered trademark), azathioprine (Imuran(registered trademark)), cyclophosphamide (Cytoxan(registered trademark)), chlorambucil (Leukeran(registered trademark)), cyclosporine (Sandimmune(registered trademark)), leflunomide (Arava(registered trademark)), and "anti-TNF" agents, such as etanercept (Enbrel(registered trademark)), infliximab (Remicade(registered trademark)), golimumab (Simponi( (Registered Trademark), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents, such as anakinra (Kineret®) and lilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors, such as tofacitinib and rituximab (Rituxan®), antibodies, "anti-T cell" agents, such as abatacept (Orencia®), "anti-IL-6" agents,For example, monoclonal antibodies such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®), and warfarin (Coumadin®), antidiarrheal drugs such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine and alosetron (Lo tronex(registered trademark), lubiprostone (Amitiza(registered trademark)), laxatives, e.g., magnesia milk, polyethylene glycol (MiraLax(registered trademark)), Dulcolax(registered trademark), Correctol(registered trademark) and Senokot(registered trademark), anticholinergics or antispasmodics, e.g., dicyclomine (Bentyl(registered trademark)), Singulair(registered trademark), beta-2 agonists, e.g., albuterol (Ventolin(registered trademark) HFA, Proventil(registered trademark) HFA), revalbuterol (Xope nex(registered trademark), metaproterenol (Alupent(registered trademark)), pirbuterol acetate (Maxair(registered trademark)), terbutaline sulfate (Brethaire(registered trademark)), salmeterol xinafoate (Serevent(registered trademark)) and formoterol (Foradil(registered trademark)), anticholinergics, such as ipratropium bromide (Atrovent(registered trademark)) and tiotropium (Spiriva(registered trademark)), inhaled corticosteroids, such as beclomethasone dipropionate (Beclovent( (Registered Trademark), Qvar (Registered Trademark) and Vanceril (Registered Trademark), Triamcinolone acetonide (Azmacort (Registered Trademark)), Mometasone (Asthmanex (Registered Trademark)), Budesonide (Pulmocort (Registered Trademark)) and Flunisolide (Aerobid (Registered Trademark)), Afviar (Registered Trademark), Symbicort (Registered Trademark), Dulera (Registered Trademark), Cromolyn sodium (Intal (Registered Trademark)), Methylxanthine, e.g., Theophylline (Theo-Dur (Registered Trademark), Theolair (Registered Trademark)),Slo-bid(registered trademark), Uniphyl(registered trademark), Theo-24(registered trademark) and aminophylline, IgE antibodies, e.g., omalizumab (Xolair(registered trademark)), nucleoside reverse transcriptase inhibitors, e.g., zidovudine (Retrovir(registered trademark)), abacavir (Ziagen(registered trademark)), abacavir / lamivudine (Epzicom(registered trademark)), abacavir / lamivudine / zidovudine (Trizivir(registered trademark)), didanosine (Videx(registered trademark)), emtricitabine (Emtriva(registered trademark)), Lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stabudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors, such as delavirudine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors, such as tenofovir (Viread( (Registered Trademark), 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 The following are examples of drugs: tiplanavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®).Or it may include any combination(s) of them.

[0251] In another embodiment, the present invention provides a method for treating gout, which comprises administering to a patient in need one or more further therapeutic agents selected from the provided compound or a pharmaceutically acceptable salt thereof and nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, colchicine (Colcrys®), etc., corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, and febuxostat (Uloric®), etc.

[0252] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, which, to a patient in need, provides a compound or pharmaceutically acceptable salt thereof, and nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; corticosteroids, such as prednisone, prednisolone, methylprednisolone, and hydrocortisone; sulfasalazine (Azulfidine®); antimalarial drugs, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®); gold salts, such as gold thioglucose (Solganal®), gold thiomalic acid (Myochrysine®), and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®); Azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), etc., and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia The treatment involves administering one or more additional therapeutic agents selected from "anti-IL-1" agents such as anakinra (Kineret®) and lilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0253] In some embodiments, the present invention provides a method for treating osteoarthritis, which comprises administering to a patient in need of it one or more further 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.

[0254] In some embodiments, the present invention provides a method for treating lupus, which comprises administering to a patient in need of it one or more further therapeutic agents selected from the compound provided or a pharmaceutically acceptable salt thereof, and one or more further 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, and hydrocortisone, antimalarial drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0255] In some embodiments, the present invention provides a method for treating inflammatory bowel disease, which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as magnesia milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergic or antispasmodic agents such as dicyclomine (Bentyl®), anti-TNF therapeutic agents, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0256] In some embodiments, the present invention provides a method for treating asthma, which, to a patient in need, provides a compound or a pharmaceutically acceptable salt thereof, and an anti-IL-33 antibody, e.g., REGN3500 (SAR440340) or CNTO7160, such as Singulair®; a beta-2 agonist, e.g., albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); an anticholinergic agent, e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); and an inhaled corticosteroid. The treatment involves administering one or more additional therapeutic agents selected from the theroids, 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®), etc., methylxanthines, such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, etc., and IgE antibodies, such as omalizumab (Xolair®).

[0257] In some embodiments, the present invention provides a method for treating COPD, which, to patients in need, provides a compound or pharmaceutically acceptable salt thereof, and beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo The present invention includes administering one or more additional therapeutic agents selected from inhaled corticosteroids such as -24(registered trademark) and aminophylline, e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent(registered trademark), Qvar(registered trademark) and Vanceril(registered trademark)), triamcinolone acetonide (Azmacort(registered trademark)), mometasone (Asthmanex(registered trademark)), budesonide (Pulmocort(registered trademark)), flunisolide (Aerobid(registered trademark)), Afviar(registered trademark), Symbicort(registered trademark) and Dulera(registered trademark), and in some embodiments, the present invention provides a method for treating eosinophilic COPD, which includes administering to a patient in need the provided 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 CNTO7160.In some embodiments, the present invention provides a method for treating eosinophilic asthma, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents selected from anti-IL-33 antibodies, such as REGN3500 (SAR440340) or CNTO7160.

[0258] In some embodiments, the present invention provides a method for treating HIV, which, to a patient in need, provides a compound or a pharmaceutically acceptable salt thereof, and a nucleoside reverse transcriptase inhibitor, such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Em Non-nucleoside reverse transcriptase inhibitors such as triva(registered trademark), lamivudine (Epivir(registered trademark)), lamivudine / zidovudine (Combivir(registered trademark)), stabudine (Zerit(registered trademark)), and zalcitabine (Hivid(registered trademark)), such as delavirudine (Rescriptor(registered trademark)), efavirenz (Sustiva(registered trademark)), nevairapine (Viramune(registered trademark)), and etravirine (Intelence(registered trademark)). Nucleotide reverse transcriptase inhibitors, such as tenofovir (Viread(registered trademark)), protease inhibitors, such as amprenavir (Agenerase(registered trademark)), atazanavir (Reyataz(registered trademark)), darunavir (Prezista(registered trademark)), fosamprenavir (Lexiva(registered trademark)), indinavir (Crixivan(registered trademark)), lopinavir and ritonavir (Kaletra(registered trademark)), nelfinavir (Viracept(registered trademark)), etc. The treatment involves administering one or more additional therapeutic agents selected from entry inhibitors such as ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), integrase inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), raltegravir (Isentress®), and combinations thereof.

[0259] In another embodiment, the present invention provides a method for treating hematological malignancies, which comprises administering to a patient in need a compound provided or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0260] In another embodiment, the present invention provides a method for treating a solid tumor, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0261] In another embodiment, the present invention provides a method for treating hematological malignancies, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Non-Patent Literature 57, published online on July 17 and incorporated herein by reference in its entirety).

[0262] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0263] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need of it a compound provided or a pharmaceutically acceptable salt thereof and a CHOP (cyclophosphamide, hydroxydaunorubicin®, Oncovin®, and prednisone or prednisolone) or R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin®, Oncovin®, and prednisone or prednisolone) chemotherapy regimen.

[0264] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need of it a compound provided or a pharmaceutically acceptable salt thereof, and a rituximab / bendamustine chemotherapy regimen.

[0265] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor (e.g., ibrutinib).

[0266] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and an anti-CD20 antibody (e.g., rituximab).

[0267] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need of it a compound or a pharmaceutically acceptable salt thereof and an anti-CD79B ADC (e.g., polatuzumab).

[0268] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor (e.g., venetoclax).

[0269] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need of it a compound or a pharmaceutically acceptable salt thereof, and lenalidomide or pomalidomide.

[0270] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need of it a compound provided or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralicib).

[0271] In some embodiments, the present invention provides a method for treating T-cell disorders or deficiencies described herein, which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralicib).

[0272] In some embodiments, the present invention provides a method for treating DLBCL, which comprises administering to a patient in need of it a compound provided or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (e.g., bortezomib).

[0273] In some embodiments, the present invention provides a method for treating T-cell disorders or deficiencies described herein, which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (e.g., bortezomib).

[0274] In another embodiment, the present invention provides a method for treating multiple myeloma, which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors (in combination with lenalidomide (Rebrimid®)).

[0275] In another embodiment, the present invention provides a method for treating Waldenström macroglobulinemia, which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0276] In some embodiments, one or more other therapeutic agents are Hedgehog pathway antagonists. Approved Hedgehog pathway inhibitors that may be used in the present invention include soni-degib (Odomzo®, Sun Pharmaceuticals) and bismodegib (Erivedge®, Genentech), both of which are used for the treatment of basal cell carcinoma.

[0277] In some embodiments, one or more other therapeutic agents are poly-ADP-ribose polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); lucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0278] In some embodiments, one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitors are 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).

[0279] In some embodiments, one or more other therapeutic agents are CDK inhibitors, such as CDK4 / CDK6 inhibitors. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0280] In some embodiments, one or more other therapeutic agents are folate inhibitors. An approved folate inhibitor useful in the present invention is pemetrexed (Alimta®, Eli Lilly).

[0281] In some embodiments, one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. An example of a CCR4 inhibitor that may be useful in the present invention that has been tested is mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0282] In some embodiments, one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors that may be useful in the present invention and have been tested include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); and IDH305 (Novartis, NCT02987010).

[0283] In some embodiments, one or more other therapeutic agents are arginase inhibitors. Examples of arginase inhibitors that may be used in the present invention that have been tested include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which has been tested in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234), and CB-1158 (Calithera Biosciences).

[0284] In some embodiments, one or more other therapeutic agents are glutaminase inhibitors. An example of a glutaminase inhibitor tested and potentially used in this invention is CB-839 (Calithera Biosciences).

[0285] In some embodiments, one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens and 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 Examples include Therapeutics; trastuzumab (anti-HER2, Herceptin®, Genentech); ad-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0286] 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) and topotecan (Hycamtin®, GlaxoSmithKline). A topoisomerase inhibitor that may be useful in the present invention and has been tested is picantron (Pixuvri®, CTI Biopharma).

[0287] In some embodiments, one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that may be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech) and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins and are currently undergoing clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott) and the BCL-2 inhibitor (NCT02079740).

[0288] In some embodiments, one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation); approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor / Ortho); and approved antagonists of the gonadotropin-releasing hormone (GnRH) receptor include degaralix (Firmagon®, Ferring Pharmaceuticals).

[0289] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modifiers (SERMs) that interfere with estrogen synthesis or activity. An approved SERM useful in the present invention is raloxifene (Evista®, Eli Lilly).

[0290] In some embodiments, one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, which interferes with the binding of osteoclasts, their precursors, and their receptor RANK found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, mediating bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0291] In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between two major p53 suppressor proteins, MDMX and MDM2. Among the p53 suppressor protein inhibitors tested and potentially used in this invention is ALRN-6924 (Aileron), a major peptide that isodynamically binds and disrupts the interaction between MDMX and MDM2 and p53. ALRN-6924 is currently being evaluated in clinical trials (NCT02909972;NCT02264613) for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL).

[0292] In some embodiments, one or more other therapeutic agents are inhibitors of transforming growth factor beta (TGF-beta or TGFβ). Tested TGF-beta protein inhibitors that may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody, which has been clinically tested for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer (NCT02947165). In some embodiments, the TGF-beta protein inhibitor is fresolimmab (GC1008; Sanofi-Genzyme), which has been tested for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Furthermore, in some embodiments, additional therapeutic agents include TGF-beta traps, such as those described in Non-Patent Literature 58. One 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 / TGFβ trapping compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of the human TGF-beta receptor II, which functions as a TGFβ "trap".

[0293] In some embodiments, one or more other therapeutic agents are selected from grembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to cytotoxic MMAE. gpNMB is a protein overexpressed by several tumor types associated with the metastatic potential of cancer cells.

[0294] In some embodiments, one or more other therapeutic agents are antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor anti-metabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and further anti-angiogenic compounds; compounds that target, reduce, or inhibit protein or lipid phosphatase activity; gonadrelin agonists; anti-androgens; methionine aminopeptidase inhibitors Matrix metalloproteinase inhibitors; bisphosphonates; biological reaction modifiers; anti-proliferative antibodies; heparanase inhibitors; Ras carcinogenic isoform inhibitors; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors, e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma From Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, e.g., SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, e.g., ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer and leucovorin, but not limited to these.

[0295] In some embodiments, the present invention provides a method for treating Alzheimer's disease, which comprises administering to a patient in need the compound provided or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0296] In some embodiments, one or more other therapeutic agents are taxane compounds, which cause the disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-conjugated paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0297] In some embodiments, one or more other therapeutic agents are nucleoside inhibitors or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, or cell replication, or otherwise inhibit rapidly proliferating cells.

[0298] In some embodiments, the nucleoside inhibitors include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechloretamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (alkylating agent, prodrug for 5-(3-methyltriazeno-1-yl)-imidazole-4-carboxamide (MTIC), Temodar®, Merck); cytarabine injection (ara-C, anti-metabolized cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); and azacitidine (pyrimidine nucleoside of cytidine). Analogues, Vidaza®, Celgene); Omasetaxin mepesuccinate (cephalotaxin ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); Asparaginase Erwinia chrysanthemi (enzyme for asparagine deficiency, Elspar®, Lundbeck; Erwinaze®, EUSA) Pharma); Eribulin mesylate (microtubule inhibitor, tubulin-based mitotic inhibitor, Halaven®, Eisai); Cabazitaxel (microtubule inhibitor, tubulin-based mitotic inhibitor, Jevtana®, Sanofi-Aventis); Capasetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); Bendamustine (bifunctional mechloretamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); Ixabepirone (semisynthetic analog of epothyron B, microtubule inhibitor, tubulin-based mitotic inhibitor, Ixempra®, Bristol-Myers Squibb);The following are selected: nelarabine (a prodrug of deoxyguanosine analog, a nucleoside metabolism inhibitor, Arranon®, Novartis); chlorafabine (a prodrug of ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (a thymidine-based nucleoside analog and a thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

[0299] In some embodiments, one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF and kinase inhibitors useful in the present invention include bevacizumab (Avastin®, Genentech / Roche) anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly) anti-VEGFR-2 antibody; and ziv-aflibercept, also known as VEGF trap (Zaltrap®; Regeneron / Sanofi). Other VEGFR inhibitors include regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); and Raf inhibitors, such as sorafenib (Nexavar®, Bayer). AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, e.g., cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, e.g., imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariadnex). Pharmaceuticals); Her2 and EGFR inhibitors, e.g., gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim);Osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, e.g., cabozanitib (Cometriq®, Exelexis); and multi-kinase inhibitors, e.g., sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, e.g., crizotinib (Xalkori®, Pfizer); certinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, e.g., ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, e.g., midostaurin (Rydapt®, Novartis).

[0300] Other kinase inhibitors and VEGF-R antagonists currently under development and potentially usable in this invention include: tivozanib (Aveo Pharmaceuticals); batalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovinitib (TKI258, Novartis); thiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Examples include Therapeutics; CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo Co., Ltd.) and motesanib (Amgen / Takeda Pharmaceutical).

[0301] In another embodiment, the present invention provides a method for treating organ transplant rejection or graft-versus-host disease, which comprises administering to a patient in need a compound provided or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0302] In another embodiment, the present invention comprises administering a compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor to a patient in need of treatment for or reduction of the severity of a disease, the disease being inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, Oldo's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroboroliosis, 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's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia areata, Behçet's disease, chronic fatigue, autonomic nervous system disorders, membranous glomerulonephropathy, endometriosis, interstitial cystitis , pemphigus vulgaris, bullous pemphigoid, neuromuscular tonicity, scleroderma, vulvodysia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect toxins, animal hair, animal dander, mites or cockroaches), type 1 hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis Synovitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibroitis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,Sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasmacytoma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodular marginal zone B-cell lymphoma Bolar lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary humoral lymphoma, Burkitt lymphoma / leukemia, or lymphomatous 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 bone and joints including but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone Cancer, bone metastases, thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, restenosis after aortic bypass, restenosis after coronary artery bypass, stroke, transient ischemia, peripheral artery occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's disease, tissue graft rejection, Excessive acute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polygland disease (also known as autoimmune polygland syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,The following conditions are selected: Waldenström 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 reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0303] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, the disease being selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions including T-cell activation, cardiovascular disorders, and CNS disorders.

[0304] 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, the disease being a benign or malignant tumor, carcinoma or solid tumor, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer, of the brain, kidneys (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, or other gastrointestinal cancers. This includes colorectal adenoma or tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasms, neoplasms with epithelial characteristics, adenoma, adenocarcinoma, corneal cell tumor, epidermal carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (e.g., non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lermite-Dudos disease and Bannayan-Zonana syndrome, or diseases including diseases in which the PI3K / PKB pathway is abnormally activated, endogenous (non-allergic) asthma and exogenous (allergic) Asthma of any type or origin, including allergistic asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced following bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD, or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and worsening of airway hyperresponsiveness as a result of other drug therapies, in particular, all types including but not limited to acute, arachidic, catarrhal, croup, chronic, or tuberculous bronchitis. This includes bronchitis of origin, such as aluminum deposition disease, anthrax, asbestosis, stone lung, eyelash alopecia, iron deposition disease, silicosis, tobacco poisoning and pneumonosis, all types or origins of pneumoconiosis (inflammatory, general occupational, lung disease, chronic or acute, frequently accompanied by airway obstruction and repeated inhalation of dust), Loeffler's syndrome, eosinophilic, pneumonia, parasitic (especially metazoan) infections (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 multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases involving autoimmune reactions or autoimmune components or etiologies, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood 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 The following conditions are selected: 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 posterior), psoriatic keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (e.g., with and without nephrotic syndrome, including idiopathic nephropathy or mild change nephropathy), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0305] In some embodiments, one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselicib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlicib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0306] In some embodiments, the present invention provides a method for treating AML, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof provided, and one or more further therapeutic agents selected from a range of chemotherapeutic agents, such as AraC, daunorubicin, etoposide, methotrexate, fludarabine, mitozantrone, azacitidine, and corticosteroids.

[0307] In some embodiments, the present invention provides a method for treating MDS, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents selected from azacitidine, decitabine, and revlimid.

[0308] In some embodiments, the present invention provides a method for treating an inflammatory skin condition such as hidradenitis suppurativa, which comprises administering to a patient in need one or more further therapeutic agents selected from the compound provided or a pharmaceutically acceptable salt thereof and anti-TNF drugs.

[0309] In some embodiments, the present invention provides a method for treating an inflammatory skin condition such as atopic dermatitis, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents selected from IL-4 / IL-13-targeted agents, such as dupilumab.

[0310] In some embodiments, the present invention provides a method for treating an inflammatory skin condition such as psoriasis, which comprises administering to a patient in need a compound or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents selected from anti-IL-17 and anti-IL-23 antibodies.

[0311] The compounds and compositions produced by the methods of the present invention may be administered in any amount and by any route of administration that is effective in treating or reducing the severity of cancer, autoimmune disorders, proliferative disorders, inflammatory disorders, neurodegenerative or neurological disorders, schizophrenia, bone-related disorders, liver disease, or cardiac disorders. The exact amount required will vary from subject to subject, depending on the species, age, and overall condition of the subject, the severity of the infection, the specific drug, and the method of administration. The compounds of the present invention are preferably formulated in dosage units for ease of administration and for dosage uniformity. Where used herein, the term "dosage unit" refers to a physically separated unit of the drug appropriate for the patient to be treated. However, it should be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of sound medical judgment. The specific effective dose level for any particular patient or organism depends on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; and factors well known in the field of pharmacologics and medicine that are used in combination with or simultaneously with the specific compound used.

[0312] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals, depending on the severity of the infection being treated, by means of oral, rectal, parenteral, intracisional, vaginal, intraperitoneal, topical (such as in powder, ointment, or drops), buccal, or as an oral or nasal spray. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at dose levels of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg of body weight / day, once or more per day, to obtain the desired therapeutic effect.

[0313] 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 compound, the liquid dosage form may contain, for example, water or other solvents, solubilizers and emulsifiers, and inert diluents commonly used in the art, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters and mixtures thereof. In addition to inert diluents, the oral composition may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavorings, and fragrances.

[0314] Injectable preparations, such as sterile aqueous or oily suspensions for injection, may be formulated according to known techniques using appropriate dispersants or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions, such as solutions in non-toxic, parenterally acceptable diluents or solvents, for example, in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils have conventionally been used as solvents or suspension media. For this purpose, any sterile non-volatile oil, including synthetic mono or diglycerides, may be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0315] Injectable formulations can be sterilized, for example, by filtration through a bacterial capture filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection medium before use.

[0316] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low solubility in water. The absorption rate of the compound then depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, the absorption delay of parenterally administered compound forms can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot formulations are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The compound release rate can be controlled depending on the polymer formation rate of the compound and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injectable formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0317] The composition for rectal or vaginal administration is a suppository that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is preferably solid at ambient temperature but liquid at body temperature, and thus melts in the rectum or vaginal cavity and releases the active compound.

[0318] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is provided with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) water-retaining agents, such as glycerol; and d) disintegrants, such as agar, calcium carbonate, and jasper. e) a solubility retarder, such as potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; f) an absorption enhancer, such as quaternary ammonium compounds; g) a wetting agent, such as cetyl alcohol and glycerol monostearate; h) an absorbent, such as kaolin and bentonite clay; and i) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include a buffer.

[0319] Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other coatings, which are well known in the art of pharmaceutical formulation. These may optionally contain opacifiers, which may release only the active ingredient, or preferentially, selectively, and delayedly, in a specific part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0320] The active compound may also be in the form of microencapsulation with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings, which are well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also, as is common practice, include further substances other than inert diluents, such as tableting agents, lubricants, and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include buffers. These may optionally contain opacifiers, and may be compositions that release only the active ingredient, or preferentially, optionally, in a delayed manner, in a specific part of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0321] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active components are mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ocular formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. Furthermore, the present invention intends to utilize transdermal patches, which have the added advantage of providing controlled delivery of the compounds to the body. Such dosage forms can be made by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers may also be used to increase the flow of the compounds across the skin. The rate can be controlled by either providing a membrane that controls the rate or by dispersing the compounds in a polymer matrix or gel.

[0322] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity or degrading protein kinase in a biological sample, which includes the step of contacting the biological sample with a compound of the present invention or a composition containing said compound.

[0323] According to another embodiment, the present invention relates to a method for inhibiting or degrading the activity of IRAK-1, IRAK-2, and / or IRAK-4 or their mutants in a biological sample, which includes the step of bringing the biological sample into contact with the compound of the present invention or a composition containing the compound.

[0324] The term “biological sample” as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0325] The inhibition and / or degradation of protein kinases, or the activity of protein kinases selected from IRAK-1, IRAK-2, and / or IRAK-4 or their mutants, in biological samples, is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens, and biological assays.

[0326] Another embodiment of the present invention relates to a method for degrading a protein kinase and / or inhibiting protein kinase activity in a patient, which includes the step of administering a compound of the present invention or a composition containing said compound to said patient.

[0327] In another embodiment, the present invention relates to a method for degrading and / or inhibiting the activity of one or more IRAK-1, IRAK-2, and / or IRAK-4 or their mutants in a patient, comprising the step of administering the compound of the present invention or a composition comprising the compound to the patient. In yet another embodiment, 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 their mutants in a patient in need thereof, comprising the step of administering the compound of the present invention or a pharmaceutically acceptable composition thereof to the patient. Such disorders are described in detail herein.

[0328] Depending on the specific condition or disease to be treated, further therapeutic agents that are typically administered to treat that condition may also be present in the composition of the present invention. As used herein, further therapeutic agents that are typically administered to treat a particular disease or condition are known as “appropriate for the disease or condition being treated.”

[0329] The compounds of the present invention may also be used in combination with other antiproliferative compounds for further benefit. Such antiproliferative compounds include aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylated compounds; histone deacetylase inhibitors; compounds that induce cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and further anti-angiogenic compounds; compounds that target, reduce, or inhibit protein or lipid phosphatase activity; gonadrelin agonists; anti-androgens; methionine aminopeptidase inhibitors. Agents; matrix metalloproteinase inhibitors; bisphosphonates; biological reaction modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras carcinogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce, or inhibit Flt-3 activity; Hsp90 inhibitors, e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, Conforma From Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, e.g., SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, e.g., ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin, among others.

[0330] The term “aromatase inhibitor,” as used herein, refers to compounds that inhibit estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane and formestan, and nonsteroids, particularly aminoglutethimide, logretimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, volozol, fadrozol, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin®. Formestan is marketed under the trade name Lentaron®. Fadrozol 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®. The present invention, which includes a chemotherapeutic agent that is an aromatase inhibitor, is particularly useful for the treatment of hormone receptor-positive tumors, such as breast tumors.

[0331] In some embodiments, one or more other therapeutic agents are mTOR inhibitors, which inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitors are everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0332] In some embodiments, one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitors are selected from exemestane (Aromasin®, Pfizer); anastazol (Arimidex®, AstraZeneca); and letrozole (Femara®, Novartis).

[0333] When used herein, the term “anti-estrogen” refers to compounds that weaken the effects of estrogen at the estrogen receptor level. This 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®. The combination of anti-estrogen chemotherapeutic agents of the present invention is particularly useful for the treatment of estrogen receptor-positive tumors, such as breast tumors.

[0334] The term “anti-androgen,” as used herein, refers to any substance capable of inhibiting the biological effects of androgenic hormones, including but not limited to bicalutamide (Casodex®). The term “gonadrelin agonist,” as used herein, includes but not limited to abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex®.

[0335] The term “topoisomerase I inhibitor” as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecule camptothecin complex PNU-166148. Irinotecan is marketed, for example, under the trade name Camptosar® and can be administered in that form. Topotecan is marketed under the trade name Hycamptin®.

[0336] The term "topoisomerase II inhibitor," as used herein, 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.

[0337] The term "microtubule activators" refers to microtubule stabilizing, microtubule destabilizing compounds and microtubule phosphate 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; discodermold; cochicine and epotilone and their derivatives. 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®.

[0338] 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®.

[0339] The terms "histone deacetylase inhibitor" or "HDAC inhibitor" refer to compounds that inhibit histone deacetylase and retain antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0340] The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation 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®.

[0341] The term "platin compounds," as used herein, includes, but is not limited to, carboplatin, cis-platin, cis-platin, and oxaliplatin. Carboplatin may be administered in a form such as that which is marketed under the trade name Carboplat®. Oxaliplatin may be administered in a form such as that which is marketed under the trade name Eloxatin®.

[0342] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but is not limited to, ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogues), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genacens (G3139), HA14-1 (and its analogues; see Patent Document 1, Patent Document 2), navitoclax (and its analogues; see Patent Document 3), NH-1 (Shenayng Pharmaceutical University), ovatoclax (and its analogues; see Patent Document 4, Patent Document 5), S-001 (Gloria Pharmaceuticals), compounds in the TW series (Univ. of Michigan), and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutic agents. In some embodiments, Bcl-2 inhibitors are peptide mimes.

[0343] The term "protein or lipid kinase activity; or compounds that target / decrease protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein means protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, for example, a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor receptor (PDGFR), for example, compounds that target, decrease or inhibit the activity of PDGFR, in particular compounds that inhibit the PDGF receptor, for example, N-phenyl-2-pyrimidine-amine derivatives, for example, imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, decrease or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example, compounds that target the activity of IGF-IR d) Compounds that target, reduce, or inhibit the activity of the IGF-I receptor, particularly compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; e) Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; f) Compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; g) Compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; h) Compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g., imatinib; h) Compounds that target, reduce, or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, e.g., compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit the c-Kit receptor, e.g., imatinib;i) Compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825); j) Compounds that target, reduce, or inhibit the activity of members of the Raf family of protein kinase C (PKC) and serine / threonine kinases, 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 family (CDK), e.g., staurosporine derivatives, e.g., midostaurin; further examples of compounds include UCN-01, safingol, BAY43-9006, bryostatin 1, perifosin; rimofosin; RO318220 and RO320432; GO 6976; lsis 3521;LY333531 / LY379196;Isoquinoline compounds;FTI;PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor);k)Compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, for example, compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec®) or thyrophostine For example, thyrofostin A23 / RG-50810; AG99; thyrofostin AG213; thyrofostin AG1748; thyrofostin AG490; thyrofostin B44; thyrofostin B44(+) enantiomer; thyrofostin AG555; AG494; thyrofostin AG556, AG957 and adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC680410, adafostin);l) Compounds that target, reduce, or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, for example, compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, in particular inhibiting members of the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3, and ErbB4, or EGF or EGF-related ligands, CP 358774, ZD 1839, ZM Compounds, proteins, or antibodies that bind to 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-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce, or inhibit the activity of the c-Met receptor, for example, compounds that target, reduce, or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) PRT-062070, SB-157 8) Compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to baricitinib, pacritinib, momerotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) Compounds that target, reduce, 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, BYL-719, dactricib, XL-147, XL-765, and idelalisib;Furthermore, q) includes, but is not limited to, compounds that target, reduce, or inhibit the signaling effect of the hedgehog protein (Hh) or smoothed receptor (SMO) pathway, including, cyclopamine, bismodegib, itraconazole, erythmodegib, and IPI-926 (salidegib).

[0344] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases include, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0345] In some embodiments, one or more other therapeutic agents are growth factor antagonists, such as platelet-inducible growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR) antagonists. Approved PDGF antagonists that may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that may be used in the present invention include cetuximab (Erbitux®; Eli Lilly); nesitumumab (Portrazza®; Eli Lilly); panitumumab (Vectibix®; Amgen); and osimertinib (targeting activated EGFR; Tagrisso®; AstraZeneca).

[0346] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present 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, dactricib, XL-147, XL-765, and idelalisib.

[0347] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0348] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and hostamatinib.

[0349] Further examples of BTK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in (Patent Document 6), (Patent Document 7), and (Patent Document 8) and (Patent Document 9), each of which is incorporated herein by reference.

[0350] Further examples of SYK inhibitory compounds and conditions treatable with such compounds in combination with the compounds of the present invention can be found in (Patent Document 110), (Patent Document 11), (Patent Document 12), (Patent Document 13), and (Patent Document 14) and (Patent Document 15), each of which is incorporated herein by reference.

[0351] Further examples of PI3K inhibitory compounds and conditions treatable with such compounds in combination with the compounds of the present invention can be found in (Patent Document 16), (Patent Document 17), (Patent Document 18), (Patent Document 19), (Patent Document 20), (Patent Document 21), (Patent Document 22), (Patent Document 23), (Patent Document 24), (Patent Document 25), (Patent Document 26), (Patent Document 27), (Patent Document 28), (Patent Document 29), (Patent Document 30), and (Patent Document 31) and (Patent Document 32), each of which is incorporated by reference herein.

[0352] Further examples of JAK inhibitory compounds and conditions treatable with such compounds in combination with the compounds of the present invention can be found in (Patent Document 33), (Patent Document 34), (Patent Document 35), (Patent Document 36), (Patent Document 37), (Patent Document 38), (Patent Document 39), (Patent Document 40), and (Patent Document 41) and (Patent Document 42), each of which is incorporated herein by reference.

[0353] Further anti-angiogenic compounds include those with different mechanisms of activity, such as those unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid®) and TNP-470.

[0354] Examples of proteasome inhibitors useful for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0355] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases include, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0356] Examples of compounds that induce cell differentiation include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0357] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and its derivatives, such as celecoxib (Celebrex®), rofecoxib (Vioxx®), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0358] The term "bisphosphonate," as used herein, includes, but is not limited to, etidronic acid, clodronic acid, dydronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel®. Clodronic acid is marketed under the trade name Bonefos®. Dydronic 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 Zometa®. The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and retain antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican®), CCI-779, and ABT578.

[0359] The term "heparanase inhibitor," as used herein, refers to a compound that targets, reduces, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological reaction modifier," as used herein, refers to a lymphokine or interferon.

[0360] The term “inhibitor of Ras oncogenic isoforms,” such as H-Ras, K-Ras, or N-Ras, as used herein, refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, “farnesyltransferase inhibitors,” such as L-744832, DK8G557, or R115777 (Zarnestra®). The term “telomerase inhibitor,” as used herein, refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0361] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamides and their derivatives.

[0362] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces, or inhibits the activity of the proteasome. Examples of compounds that target, reduce, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade®); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda); and MLN341.

[0363] The terms “matrix metalloproteinase inhibitor” or (“MMP” inhibitor), as used herein, include, but are not limited to, collagen peptide mimes and non-peptide mimetics, tetracycline derivatives, such as the hydroxymato peptide mimetics bacistat and its orally bioavailable analogs maristat (BB-2516), prinomast (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B, or AAJ996.

[0364] The term “compounds used in the treatment of hematological malignancies” as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranosilcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase.

[0365] Compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) include, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0366] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90; or compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90 include, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radisicol, and HDAC inhibitors.

[0367] The term "antiproliferative antibody," as used herein, includes, but is not limited to, trastuzumab (Herceptin®), trastuzumab-DM1, Erbitux, bevacizumab (Avastin®), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibodies mean intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments insofar as they exhibit the desired biological activity.

[0368] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention may be used in combination with standard leukemia treatments, and in particular with treatments used for the treatment of AML. In particular, the compounds of the present invention may 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, carboplatinum, and PKC412.

[0369] Other anti-leukemia compounds include, for example, Ara-C and pyrimidine analogs, which are 2'-alpha-hydroxyribose (arabinoside) derivatives of deoxycytidine. Purine analogs of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate are also included. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors, 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 (Patent Document 43), including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indole-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indole-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or pharmaceutically acceptable salts thereof, particularly lactates. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage approaches refer to approaches such as ionizing radiation. As used herein, the term “ionizing radiation” above and thereafter means ionizing radiation occurring as any electromagnetic radiation (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiotherapy and is known in the art. See Non-Patent Document 59.

[0370] This also includes EDG conjugates and ribonucleotide reductase inhibitors. The term "EDG conjugate," as used herein, refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" 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 (particularly in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyureas or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0371] The range also particularly includes compounds, proteins, or monoclonal antibodies of VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or pharmaceutically acceptable salts thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin®; Endostatin®; Anthranilamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g., rhuMAb and RHUFab; VEGF aptamers, e.g., Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozymes (RPI4610) and bevacizumab (Avastin®).

[0372] Photodynamic therapy, as used herein, refers to treatments that use certain chemical substances known as photosensitive compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne® and porfimer sodium.

[0373] When used herein, anti-angiogenic steroids refer to compounds that block or inhibit angiogenesis, such as anecoltab, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0374] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0375] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological reaction modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or various other compounds or compounds with unknown mechanisms of action.

[0376] The compounds of the present invention are also useful as concurrent therapeutic compounds for use in combination with other active pharmaceutical ingredients (APIs), such as anti-inflammatory, bronchodilated, or antihistamine APIs, particularly in the treatment of obstructive or inflammatory airway diseases, such as those previously mentioned herein, for example, as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dose or mitigating the potential side effects of such drugs. The compounds of the present invention can be mixed with other APIs in an immobilized pharmaceutical composition, or they can be administered separately, before, simultaneously with, or after other APIs. Accordingly, the present invention includes combinations of the compounds of the present invention, as previously described herein, with anti-inflammatory, bronchodilated, antihistamine, or anti-cough syncope APIs, wherein the compounds of the present invention and the APIs are in the same or different pharmaceutical compositions.

[0377] Appropriate anti-inflammatory drugs include steroids, especially glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247, etc.; LTD4 antagonists, such as montelukast and zafirlukast, etc.; PDE4 inhibitors, such as siromirist (Ariflo® GlaxoSmithKline), roflumirist (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Alophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Examples include 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. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts, and CHF4226 (Chiesi) and glycopyrrolates.

[0378] Suitable antihistamine active pharmaceutical ingredients include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0379] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs include antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4 and 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-benzo-cyclohepten-8-yl]carbonyl]aminophenyl]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0380] The structures of active compounds identified by code number, generic name, or trade name can be obtained from the actual edition of the standard list "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications).

[0381] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, the provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiotherapy.

[0382] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of fixed combinations, or the administration of the compounds of the present invention and one or more other therapeutic compounds may be staggered or given independently of each other, or a combination of fixed combinations and one or more other therapeutic compounds. The compounds of the present invention may also be administered, or further, in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for the treatment of tumors. Long-term treatment is equally possible as adjuvant therapy in terms of other treatment strategies, as described above. Other possible treatments include, for example, treatment to maintain the patient's condition after tumor regression or further after chemopreventive therapy in patients at risk.

[0383] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single-dose formulation mixed with the compound of the present invention in a single composition. When administered as part of a multi-dose regimen, the two active agents may be presented simultaneously, sequentially, or within a certain time interval from each other, usually within 5 hours from each other.

[0384] As used herein, the terms “combined,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present invention provides unit dosage forms comprising the compounds of the present invention, further therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0385] The amounts of both the compound of the present invention and any further therapeutic agents (in a composition containing such further therapeutic agents) that can be combined with a carrier material to produce a single-dose formulation vary depending on the host being treated and the specific administration method. Preferably, the composition of the present invention should be formulated so that a dose of 0.01 to 100 mg / kg body weight / day of the compound of the present invention can be administered.

[0386] In a composition containing further therapeutic agents, the further therapeutic agents and the compounds of the present invention may act synergistically. Therefore, the amount of further therapeutic agent in such a composition is less than the amount required in monotherapy using only that therapeutic agent. In such a composition, a dosage of 0.01 to 1,000 μg / kg body weight / day of the further therapeutic agent may be administered.

[0387] The amount of one or more other therapeutic agents present in the composition of the present invention may not exceed the amount typically administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the composition disclosed herein is in the range of about 50% to 100% of the amount typically present in a composition containing that agent as the sole therapeutic active agent. In some embodiments, one or more other therapeutic agents are administered at doses of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount typically administered for that agent. As used herein, the phrase “typically administered” means the amount approved for administration of an FDA-approved therapeutic agent in accordance with the FDA label insert.

[0388] The compounds of the present invention or their pharmaceutical compositions are also incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents have been used, for example, to overcome restenosis (narrowing of the blood vessel wall again after injury). However, patients using stents or other implantable devices are at risk of thrombosis or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention.

[0389] Representative tumor immunotherapy drugs In some embodiments, one or more other therapeutic agents are oncological immunotherapy agents. As used herein, the term “oncological immunotherapy agent” refers to an agent that is effective in enhancing, stimulating, and / or upregulating the immune response in a subject. In some embodiments, administration of an oncological immunotherapy agent with the compounds of the present invention has a synergistic effect in the treatment of cancer.

[0390] Oncology immunotherapy agents may be, for example, small molecule drugs, antibodies, or biological or small molecule drugs. Examples of biological oncology immunotherapy agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0391] In some embodiments, the tumor immunotherapy agent is (i) an agonist of a stimulating (including co-stimulation) receptor or (ii) an antagonist of an inhibitory (including co-inhibition) signal in T cells, both of which result in amplification of an antigen-specific T cell response.

[0392] Certain stimulating and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulating or co-inhibiting receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), 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 co-stimulating or co-inhibiting receptors is the TNF family of molecules that bind to members of the congeneral TNF receptor family, including 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, R ANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, Includes EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0393] In some embodiments, the tumor immunotherapy 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 an immune response.

[0394] In some embodiments, combinations of the compounds of the present invention and tumor immunotherapy agents can stimulate a T-cell response. In some embodiments, the oncological immunotherapy 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, etc.; 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, etc.

[0395] In some embodiments, the tumor immunotherapy agent is an antagonist of an inhibitory receptor on NK cells or an agonist that activates a receptor on NK cells. In some embodiments, the tumor immunotherapy agent is an antagonist of KIRs, such as lirirumab.

[0396] In some embodiments, the tumor immunotherapy agent is a drug that inhibits or depletes macrophages or monocytes, and includes, but is not limited to, a CSF-1R antagonist antibody, such as RG7155 ((Patent Documents 44), (Patent Documents 45), (Patent Documents 46), (Patent Documents 47), (Patent Documents 48), (Patent Documents 49), (Patent Documents 50), (Patent Documents 51), (Patent Documents 52), (Patent Documents 53), (Patent Documents 54)) or FPA-008 ((Patent Documents 55), (Patent Documents 56); (Patent Documents 57); (Patent Documents 58), (Patent Documents 59)).

[0397] In some embodiments, the oncological immunotherapy agent is selected from agonist agents that link positive co-stimulatory receptors, blockers that attenuate signaling 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., involvement of block inhibitory receptors (e.g., PD-L1 / PD-1 interaction)), deplete or inhibit Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell energy or depletion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0398] In some embodiments, the tumor immunotherapy agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is Yervoy (ipilimumab) or tremelimumab.

[0399] In some embodiments, the oncology immunotherapy agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by intravenous infusion. In some embodiments, the oncology immunotherapy agent is an antibody or its antigen-binding moiety that specifically binds to the Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; (Patent Document 60)). In some embodiments, the oncology immunotherapy agent may be pizilizumab (CT-011). In some embodiments, the oncology immunotherapy agent is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0400] In some embodiments, the tumor immunotherapy agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; (Patent Document 61), (Patent Document 62)), durvalumab (MEDI4736), BMS-936559 ((Patent Document 63), (Patent Document 64)), and MSB0010718C ((Patent Document 65), (Patent Document 66)).

[0401] In some embodiments, the tumor immunotherapy agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 ((Patent Document 67), (Patent Document 68), (Patent Document 69), (Patent Document 70)) or IMP-731 or IMP-321 ((Patent Document 71), (Patent Document 72), (Patent Document 73), (Patent Document 74)).

[0402] In some embodiments, the tumor immunotherapy agent is a CD137(4-1BB) agonist. In some embodiments, the CD137(4-1BB) agonist is an agonist-like CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 ((Patent Document 75)).

[0403] In some embodiments, the tumor immunotherapy agent is a GITR agonist. In some embodiments, the GITR agonist is an agonist-like GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 ((Patent Document 76), (Patent Document 77), (Patent Document 78), (Patent Document 79)) or MK-4166 ((Patent Document 80), (Patent Document 81)).

[0404] In some embodiments, the tumor immunotherapy agent is an indreamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (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); kynurenine-degrading enzyme (Kynase, Kyn Therapeutics); and NLG-919 ((Patent Documents 82), (Patent Documents 83), (Patent Documents 84), (Patent Documents 85), (Patent Documents 86), (Patent Documents 87), (Patent Documents 88), (Patent Documents 89)).

[0405] In some embodiments, the tumor immunotherapy agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonist-like OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0406] In some embodiments, the tumor immunotherapy agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 ((Patent Document 90), (Patent Document 91)).

[0407] In some embodiments, the tumor immunotherapy agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist-like CD40 antibody. In some embodiments, the tumor immunotherapy agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0408] In some embodiments, the tumor immunotherapy agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonist-like CD27 antibody. In some embodiments, the CD27 antibody is varylumab.

[0409] In some embodiments, the tumor immunotherapy drug is MGA271 (against B7H3) ((Patent Document 92), (Patent Document 93)).

[0410] In some embodiments, the oncology immunotherapy agent is avagovomab, adecatumumab, aftuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimmab, avelumab, blinatumomab, BMS-936559, catumakisomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intermumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, okalatuzumab, ofatumumab, aratazumab, pembrolizumab, pizilizumab, rituximab, tisilimmab, samarizumab, or tremelimumab.

[0411] In some embodiments, tumor immunotherapy agents are immunostimulants. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes have been shown in clinical trials to deregulate activated tumor-reactive T cells and induce a durable antitumor response, improving the histology of many tumor types, including some tumor types not conventionally considered immunotherapy-sensitive. See, for example, (Non-Patent Literature 60); (Non-Patent Literature 61). The anti-PD-1 antibody nivolumab (also known as ONO-4538, MDX1106, and BMS-936558, Opdivo®, Bristol-Myers Squibb) has shown potential to improve overall survival in RCC patients who experience disease progression during or after preliminary anti-angiogenic therapy.

[0412] In some embodiments, immunomodulatory therapies specifically induce apoptosis in tumor cells. Approved immunomodulatory therapies that may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Rebrimid®, Celgene); and ingenol mevate (Picato®, LEO Pharma).

[0413] In some embodiments, the oncological immunotherapy agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from ciproisel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-resistant) prostate cancer; and tarimodine-laharpalebeck (formerly known as T-VEC, Imlygic®, BioVex / Amgen), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions in melanoma. In some embodiments, the oncolytic immunotherapy agent is pexastymodin debasilepvec (JX-594, SillaJen / formerly Jennerex Biotherapeutics) modified to express thymidine kinase-(TK-) deficient vaccinia virus for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics) for many cancers including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627). Biotech; variants of respiratory enteric orphan virus (reovirus) that do not replicate in RAS-unactivated cells; enadenotucirev (NG-348, PsiOxus, ColoAd1), an adenovirus modified to express antibody fragments specific to full-length CD80 and T cell receptor CD3 proteins in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); melanoma (NCT03003676);The following are selected for peritoneal diseases, colorectal cancer, or ovarian cancer (NCT02963831): ONCOS-102 (Targovax / formerly Oncos), an adenovirus modified to express GM-CSF; GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus modified to express beta-galactosidase (beta-gal) / beta-glucoronidase (glucoronidase) or beta-gal / human sodium iodide cotransporter (hNIS), respectively; tested in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT02759588); or for bladder cancer (NCT02365818): CG0070 (Cold Genesys), an adenovirus modified to express GM-CSF.

[0414] In some embodiments, the oncology immunotherapy agents include JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a modified TK- and vaccinia growth factor-deficient vaccinia virus that expresses cytosine deaminase, capable of converting the prodrug 5-fluorocytosine to the cytotoxic agent 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapies targeted against difficult-to-treat RAS mutations; TILT-123 (TILT Biotherapeutics), a modified adenovirus called Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a modified vesicular stomatitis virus (VSV) (antigen-specific CD8) that expresses the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV). + Selected from (which can be further modified to express antigens designed to elicit a T cell response).

[0415] In some embodiments, the tumor immunotherapy agent is a T cell modified to express a chimeric antigen receptor or CAR. Such a T cell modified to express a chimeric antigen receptor is called a CAR-T cell.

[0416] CARs are constructed from a binding domain that may be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific to the cell surface antigen, which is fused to the endodomain, the functional end of the T cell receptor (TCR), and, for example, a CD3-zeta signaling domain from the TCR that can generate an activation signal in T lymphocytes. Upon antigen binding, such CARs link to an endogenous signaling pathway in effector cells, generating an activation signal similar to that initiated by the TCR complex.

[0417] For example, in some embodiments, CAR-T cells are one of those described in Patent Document 94, each of which is incorporated by reference herein, which discloses CAR-T cells modified to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) and which is fused to the intracellular signaling domain of a T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed on T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. More than 200 clinical trials using CAR-Ts in a wide range of applications are currently underway. [(Non-Patent Document 62)]

[0418] In some embodiments, the immunostimulant is an activator of retinoic acid receptor-associated orphan receptor γ (RORγt). RORγt is a transcription factor that plays a crucial role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation and maintenance of IL-17-expressing innate immune cell subpopulations such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0419] In some embodiments, the immunostimulant is an agonist or activator of Toll-like receptors (TLRs). Suitable TLR activators include TLR9 agonists or activators such as SD-101 (Dynavax). SD-101 is an immunostimulant CpG that has been tested against B-cell, follicular, and other lymphomas (NCT02254772). An example of a TLR8 agonist or activator that may be used in the present invention is motlimod (VTX-2337, VentiRx Pharmaceuticals), which has been tested against squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0420] Other tumor immunotherapy agents that may be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; valrirumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirirumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; anddecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0421] In some embodiments, the immunostimulant is selected from elotuzumab, mifamultide, Toll-like receptor agonists or activators, and RORγt activators.

[0422] In some embodiments, the immunostimulator is recombinant human interleukin-15 (rhIL-15). rhIL-15 has been tested in clinical settings as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulator is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapy agent is a fusion complex consisting of heterodimer IL-15 (hetIL-15, Novartis / Admune) and a synthetic form of endogenous IL-15 compounded with the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0423] In some embodiments, the oncological immunotherapy agent is selected from those described in Non-Patent Literature 63, the contents of which are incorporated herein by reference in whole. In some embodiments, the oncological immunotherapy agent is selected from the examples listed in Table 1 of Non-Patent Literature 63. In some embodiments, the oncological immunotherapy agent is a small molecule targeting an immune-cancer target selected from those listed in Table 2 of Non-Patent Literature 63. In some embodiments, the oncological immunotherapy agent is a small molecule drug selected from those listed in Table 2 of Non-Patent Literature 63.

[0424] In some embodiments, the oncological immunotherapy agent is selected from the small molecule oncological immunotherapy agents described in (Non-Patent Literature 64), the contents of which are incorporated herein by reference in whole. In some embodiments, the oncological immunotherapy agent is a drug that targets a pathway as described in (Non-Patent Literature 64).

[0425] In some embodiments, the tumor immunotherapy agent is selected from those described in (Non-Patent Literature 65), the contents of which are incorporated herein by reference in whole. In some embodiments, the tumor immunotherapy agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, and the released cytokines induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, a bispecific T cell engager (BiTE®) antibody construct activates T cells, resulting in the induction of bystander cell lysis. In some embodiments, the bystander cells are solid tumor cells. In some embodiments, the lysed bystander cells are in close proximity to BiTE®-activated T cells. In some embodiments, the bystander cells include tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells include EGFR-negative cancer cells. In some embodiments, the oncological immunotherapy agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the oncological immunotherapy agent is ex vivo expanded cultured tumor-infiltrating T cells. In some embodiments, the oncological immunotherapy agent is a bispecific antibody construct or chimeric antigen receptor (CAR) that directly binds tumor-associated surface antigens (TAAs) to T cells.

[0426] Representative immune checkpoint inhibitors In some embodiments, the tumor immunotherapy agent is an immune checkpoint inhibitor as described herein.

[0427] When used herein, the term “checkpoint inhibitor” refers to drugs that are useful in preventing cancer cells from evading a patient’s immune system. One of the main mechanisms of antitumor immune disruption is also known as “T cell depletion,” which occurs as a result of chronic exposure to antigens that lead to the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0428] PD-1 and its co-inhibitory receptors, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuators (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activator gene-3 (Lag-3; CD223), are often called checkpoint regulators. They act as "gatekeepers," molecules that enable extracellular information to direct whether or not cell cycle progression and other intracellular signaling processes should proceed.

[0429] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1), preventing the receptor from binding to the inhibitory ligand PD-1, and thus rendering the tumor unable to suppress the host antitumor immune response.

[0430] In one embodiment, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In another embodiment, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further embodiment, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In further embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In one embodiment, the checkpoint inhibitor is an immunostimulant, T cell growth factor, interleukin, antibody, vaccine, or combination thereof. In further embodiments, the interleukin is IL-7 or IL-15. In specific embodiments, the interleukin is glycosylated IL-7. In further embodiments, the vaccine is a dendritic cell (DC) vaccine.

[0431] Checkpoint inhibitors include any drug that statistically significantly blocks or inhibits an inhibitory pathway of the immune system. Such inhibitors may include small molecule inhibitors, antibodies or their antigen-binding fragments that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted for blockade or inhibition include CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, and 2B4 (all NK, γδ, and memory CD8 molecules belonging to the CD2 family). +Examples of B7 family ligands include, but are not limited to, CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands (expressed on αβ T cells). Examples of B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Examples of checkpoint inhibitors include antibodies or their antigen-binding fragments, other binding proteins, biological agents, or small molecules that bind to one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049 and block or inhibit their activity. Examples of immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-Ll monoclonal antibody (anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS-936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Examples of checkpoint protein ligands include, but are not limited to, PD-Ll, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0432] In certain embodiments, the immune checkpoint inhibitor is selected from PD-1 antagonists, PD-L1 antagonists, and CTLA-4 antagonists. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the 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, Tecentriq®, Genentech).

[0433] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pizilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, rilurumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[0434] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pizilizumab (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; and avelumab (Bavencio®, Pfizer / Merck), also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer. KGaA); or PDR001 (Novartis), a PD-1-binding inhibitor antibody 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 is being tested in clinical trials for several indications, including: mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell carcinoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer of the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic non-histoplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being tested in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0435] In some embodiments, the checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin-containing protein-3 (TIM-3). Examples of TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody that has been tested in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody that has been tested in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody that has been tested in advanced malignant tumors (NCT02608268).

[0436] In some embodiments, the checkpoint inhibitor is an inhibitor of a T cell immune receptor having Ig and ITIM domains, or an inhibitor of TIGIT, which is an immune receptor on certain T cells and NK cells. Examples of TIGIT inhibitors that may 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).

[0437] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte-activating gene-3 (LAG-3). Examples of LAG-3 inhibitors that may be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, has been tested in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and has been tested in malignant tumors (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein and has been tested in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0438] The checkpoint inhibitors that may be used in the present invention include OX40 agonists. OX40 agonists tested in clinical trials include: PF-04518600 / PF-8600 (Pfizer), an agonist-type anti-OX40 antibody, in metastatic renal cell carcinoma (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist-type anti-OX40 antibody, in a Phase 1 cancer trial (NCT02528357); and M in advanced solid tumors (NCT02318394 and NCT02705482). Examples include EDI0562 (Medimmune / AstraZeneca), an agonist-type anti-OX40 antibody; MEDI6469, an agonist-type anti-OX40 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 agonist-type anti-OX40 antibody, in patients with advanced cancer (NCT02737475).

[0439] The checkpoint inhibitors that may be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists that have been tested in clinical trials include utomirumab (PF-05082566, Pfizer), an agonist-type anti-CD137 antibody, for diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); and urelumab (BMS-663513, Bristol-Myers Squibb), an agonist-type anti-CD137 antibody, for melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0440] Examples of checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists that have been tested in clinical trials include valrirumab (CDX-1127, Celldex Therapeutics) and agonist-type anti-CD27 antibodies in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0441] Examples of checkpoint inhibitors that may be used in the present invention include glucocorticoid-inducible tumor necrosis factor receptor (GITR) agonists. GITR agonists tested in clinical trials include TRX518 (Leap Therapeutics), an agonist-type anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); solid tumors and lymphomas (NCT Examples include GWN323 (Novartis), an agonist-type anti-GITR antibody, in 02740270; INCAGN01876 (Incyte / Agenus), an agonist-type anti-GITR antibody, in advanced cancer (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist-type anti-GITR antibody, in solid tumor (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonist-type hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumor (NCT02583165).

[0442] Checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulatory factor (ICOS, also known as CD278) agonists. ICOS agonists that have been tested in clinical trials include MEDI-570 (Medimmune), an agonist-type anti-ICOS antibody, in lymphoma (NCT02520791); GSK3359609 (Merck), an agonist-type anti-ICOS antibody, in Phase 1 trial (NCT02723955); and JTX-2011 (Jounce Therapeutics), an agonist-type anti-ICOS antibody, in Phase 1 trial (NCT02904226).

[0443] Examples of checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being tested in clinical trials include ririrumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, for leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) for myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma) for lymphoma (NCT02593045), an anti-KIR antibody that binds to the three domains of the long cytoplasmic tail (KIR3DL2).

[0444] Examples of checkpoint inhibitors that may be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors tested in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and interferes with CD47 / SIRPa-mediated signaling, and TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein produced by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1 (which binds to human CD47 and inhibits its "do not" effect on macrophages). Examples include CC-90002 (Celgene), an anti-CD47 antibody, which works by preventing it from delivering the "eat" signal and is currently in Phase 1 clinical trials (NCT02890368 and NCT02663518); and Hu5F9-G4 (Forty Seven, Inc.), which works in leukemia (NCT02641002); and in colon neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0445] Examples of checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors that have been tested in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody for solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody for solid tumors (NCT02754141).

[0446] Examples of checkpoint inhibitors that may be used in the present invention include agonists of interferon gene protein stimulants (STING, also known as transmembrane protein 173 or TMEM173). STING agonists that have been tested in clinical trials include MK-1454 (Merck), an agonist synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide, in Phase 1 trials (NCT02675439 and NCT03172936).

[0447] Examples of checkpoint inhibitors that may be used in the present invention include CSF1R inhibitors. CSF1R inhibitors that have been tested in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule 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 pancreatic cancer (NCT03153410), melanoma (NCT03101254) and Examples include IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, for solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazole-6-yloxyl]pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, for advanced solid tumors (NCT02829723).

[0448] Examples of checkpoint inhibitors that may be used in the present invention include NKG2A receptor inhibitors. Examples of NKG2A receptor inhibitors that have been tested in clinical trials include monalizumab (IPH2201, Innate Pharma) and anti-NKG2A antibodies for head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0449] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pizilizumab. [Examples]

[0450] Example Synthesis method The following examples are illustrative of the present invention and should not be construed as limiting the invention. Temperatures are given in Celsius. Unless otherwise noted, evaporation was carried out under reduced pressure, preferably at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final product, intermediates, and starting materials were confirmed by standard analytical methods, such as microanalysis and spectroscopic features, such as MS, IR, and NMR. Abbreviations used are conventional in the art.

[0451] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention were either commercially available or could be prepared by organic synthesis methods known to those skilled in the art (Non-Patent Literature 66). Furthermore, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the following examples.

[0452] Unless otherwise specified, all reactions are carried out under nitrogen or argon conditions.

[0453] Proton NMR 1 The 1H NMR spectrum is performed in a deuterated solvent. In certain compounds disclosed herein, one or more 1 The H shift overlaps with the residual proteosolvent signal; these signals are not reported in the experiments provided below.

[0454] [Table 2]

[0455] Regarding acidic LCMS data: LCMS was recorded on an Agilent 1200 series LC / MSD or Shimadzu LCMS2020 equipped with electrospray ionization and a quadruple MS detector [ES+ve for obtaining MH+], and a Chromolith Flash RP-18e 25*2.0 mm column, eluted with 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). Other LCMS data was recorded on an Agilent 1290 Infinity RRLC fitted with an Agilent 6120 mass detector. The column used was BEH C18 50*2.1 mm, 1.7 microns. The column flow rate was 0.55 ml / min, and the mobile phases used were (A) 2 mM ammonium acetate in 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile.

[0456] Basic LC-MS data: LC-MS was recorded on an Agilent 1200 series LC / MSD or Shimadzu LCMS 2020 equipped with electrospray ionization and a quadruple MS detector [ES+ve for obtaining MH+], with either an Xbridge C18 2.1×50mm column packed with 5mm C18-coated silica or a Kinetex EVO C18 2.1×30mm column packed with 5mm C18-coated silica, eluted with 0.05 vol% NH3·H2O in water (solvent A) and acetonitrile (solvent B).

[0457] HPLC analysis method: HPLC was performed on an X Bridge C18 150*4.6 mm, 5 micron column. The column flow rate was 1.0 ml / min, and the mobile phases used were (A) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile.

[0458] Preparative HPLC analysis: The compound was purified on a Shimadzu LC-20AP and UV detector. The column used was 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 was (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.

[0459] NMR method: 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400 MHz / 5 mm probe (BBFO). Chemical shifts are reported in parts per million.

[0460] In some examples, the intermediates and compounds described in the examples contained one or more stereocenters, resulting in the production of two or more enantiomers / diastereomers. In some embodiments, these enantiomers / diastereomers were separated and isolated, but their stereochemistry was not degraded. Unless otherwise specified, stereochemistry is arbitrarily assigned. For intermediates, each enantiomer / diastereomer with arbitrarily assigned stereochemistry may yield a final compound (e.g., assigned the number "I-"), which also retains the arbitrarily assigned stereochemistry. Thus, any compound having or produced from an intermediate having arbitrarily assigned stereochemistry may be indicated herein as a specific stereoisomer, although it is understood that such a compound may be other stereoisomers (i.e., enantiomers or diastereomers).

[0461] As shown in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While the general method illustrates the synthesis of specific compounds of the present invention, it will be understood that the following general method and other methods known to those skilled in the art may be applied to all compounds and their respective subclasses and species as described herein.

[0462] intermediate 5,5-difluoro-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl (intermediate A) [ka] Step 1 - 5,5-difluoro-3,9-diazaspiro[5.5]undecane-3,9-dicarboxylic acid O3-benzyl O9-tert-butyl. To a solution of 11,11-difluoro-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl (1.8 g, 6.2 mmol, CAS#1784848-04-9) in ACN (9 mL) and H2O (9 mL), NaHCO3 (677 mg, 8.06 mmol) and CbzCl (1.48 g, 8.68 mmol) were added. The mixture was then stirred at 25°C for 12 hours. Upon completion, the mixture was quenched with water (20 mL) at 0°C and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 10:1 to 8:1) to obtain the title compound (2.4 g, yield 87%) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)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=11.6Hz,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) + .

[0463] Step 2 - 5,5-difluoro-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl. To a solution of 5,5-difluoro-3,9-diazaspiro[5.5]undecane-3,9-dicarboxylic acid O3-benzyl O9-tert-butyl (1 g, 2 mmol) in DCM (10 mL), TFA (3.84 g, 33.6 mmol) was added. The mixture was then stirred at 25°C for 1 hour. Upon completion, the mixture was quenched at 0°C with NaHCO3 aq. (50 mL) and extracted with DCM (25 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated to obtain the title compound (760 mg, yield 95%) as a yellow oily substance. LC-MS (ESI + ) m / z 325.2 (M+H) + .

[0464] 5,5-difluoro-9-(3-methyl-2-oxo-1H-benzimidazole-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl (intermediate B) [ka] Step 1 - 5,5-difluoro-9-(3-methoxycarbonyl-2-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl. To a solution of 5,5-difluoro-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl (760 mg, 2.34 mmol, intermediate A) in DMF (3 mL), methyl 3-fluoro-2-nitrobenzoate (606 mg, 3.05 mmol, CAS#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. Upon completion, the reaction mixture was added to ice water (10 mL), and the precipitate was collected by filtration. The residue was purified by column chromatography (SiO2, PE / EA = 10:1 to 6:1) to obtain the title compound (1.13 g, 95% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 7.69(dd,J=3.6,5.6Hz,1H),7.47-7.38(m,2H),7.27(s,4H),5.06(s,2H),3.80(d,J=1.6Hz,3H),3.63(t,J=11.2Hz,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) + .

[0465] Step 2-9-(2-amino-3-methoxycarbonyl-phenyl)-5,5-difluoro-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl. To a solution of 5,5-difluoro-9-(3-methoxycarbonyl-2-nitro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl (1 g, 1.99 mmol) in THF (15 mL), Pt / V / C (500 mg, 1.92 mmol) was added under Ar. The suspension was then degassed under vacuum and purged multiple times with H2 (15 psi). The mixture was then stirred at 25°C for 4 hours under H2 (15 psi). At completion, the mixture was filtered. The filtrate was then concentrated under vacuum to obtain the title compound (833 mg, yield 88%) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=8.0Hz,1H),7.46-7.31(m,4H),7.13(d,J=7.2Hz,1H),6.61(t,J=7.6Hz,1H),6.22(s,2H),5.17(s,2H),3.87(s,3H),3.7 5(t,J=11.6Hz,2H),3.60(s,2H),3.04-2.93(m,2H),2.75(s,2H),2.06(d,J=6.4Hz,2H),1.91(s,2H),1.81-1.61(m,3H);LC-MS(ESI + )m / z 474.6(M+H) + .

[0466] Step 3-5,5-difluoro-9-[3-methoxycarbonyl-2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate benzyl. To a solution of 9-(2-amino-3-methoxycarbonyl-phenyl)-5,5-difluoro-3,9-diazaspiro[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. Upon completion, the mixture was quenched with water (10 mL) at 0°C and extracted with ethyl acetate (15 mL x 3). The combined organic ...

Claims

1. One of the following compounds: 【Transformation 356】 【Chemistry 357】 【Chemical 358】 【Chemistry 359】 or a pharmaceutically acceptable salt thereof (in the formula, X is -CH ２ It is a divalent part selected from - or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR ２ -, -CONR-, -NR-, or -O-; Ring A is phenylenyl, pyridinyl, 【Chemical 360】 It is a ring selected from; Ring B is a fused ring selected from benzo or 5-6 membered heteroaryls containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ４ is hydrogen, C １－５ Alkyl or C ３－６ It is cycloalkyl; R １ 、R ２ and R ３ each is, independently, hydrogen, R Ａ , halogen, -CN, -NO ２ , oxo, -OR, -SR, -NR ２ , -SiR ３ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -CR ２ N(R)C(O)R, -CR ２ N(R)C(O)NR ２ , -CFR ２ , -CF ２ R, -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -OC(O)R, -OC(O)NR ２ , -OP(O)R ２ , -OP(O)(OR) ２ , -OP(O)(OR)NR ２ , -OP(O)(NR ２ ) ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)S(O) ２ R, -N(R)P(O)R ２ , -N(R)P(O)(OR) ２ , -N(R)P(O)(OR)NR ２ , -N(R)P(O)(NR ２ ) ２ , or -N(R)S(O) ２ R; Each R is independently either hydrogen or C １－６ A group that is optionally substituted, selected from an aliphatic, phenyl, nitrogen, oxygen, and sulfur-independently saturated or partially unsaturated 3-7 membered carbon ring having 1-2 heteroatoms, or a heterocycle and a 5-6 membered heteroaryl ring having 1-4 heteroatoms, or: Two R groups on the same carbon or nitrogen can optionally combine with their intervening atoms to form a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which the two R groups are linked; Each R Ａ Independently, C １－６ An optionally substituted group selected from a 4-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R ５ These are independently hydrogen, halo, -CN, -OR, oxo, and C. １－６ Alkyl, -CR ２ OR, -OC １－６ Alkyl, C １－６ Haloalkyl, -OC １－６ Haloalkyl, or C ３－６ It is cycloalkyl, or Two R atoms on the same carbon atom ５ The base, when combined, forms the two R components. ５ Together with the carbon atom to which the group is linked, it forms a 3- to 7-membered saturated or partially unsaturated carbon ring or heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two Rs on two different carbon atoms ５ The base, when combined, forms the two R components. ５ Together with intervening atoms that link the groups, they form a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings C and D is independently selected from a 5- to 9-membered heteroaryl ring having phenyl or 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and (Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.)

2. One of the following compounds: 【Chemical 361】 【Chemical 362】 【Chemical 363】 or a pharmaceutically acceptable salt thereof (in the formula, X is -CH ２ It is a divalent part selected from - or -C(O)-; Y is nitrogen or CH; Z is a covalent bond, -CR ２ -, -CONR-, -NR-, or -O-; Ring A is phenylenyl, pyridinyl, 【Chemical 364】 It is a ring selected from; Ring B is a fused ring selected from benzo or 5-6 membered heteroaryls containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ４ is hydrogen, C １－５ Alkyl or C ３－６ It is cycloalkyl; R １ 、R ２ and R ３ each is, independently, hydrogen, R Ａ 、halogen, -CN, -NO ２ 、-OR, -SR, -NR ２ 、-SiR ３ 、-S(O) ２ R, -S(O) ２ NR ２、 -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ２ 、-C(O)N(R)OR, -C(R) ２ N(R)C(O)R, -C(R) ２ N(R)C(O)NR ２ and -CFR ２ 、-CF ２ R, -CF ３ 、-CR ２ (OR), -CR ２ (NR ２ ), -OC(O)R, -OC(O)NR ２ 、-OP(O)R ２ 、-OP(O)(OR) ２ 、-OP(O)(OR)NR ２ 、-OP(O)(NR ２ ) ２ 、-N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ 、-N(R)S(O) ２ R, -N(R)P(O)R ２ 、-N(R)P(O)(OR) ２ 、-N(R)P(O)(OR)NR ２ 、-N(R)P(O)(NR ２ ) ２ or -N(R)S(O) ２ R; Each R is independently either hydrogen or C １－６ An optionally substituted group selected from a 3-7 member saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two R groups on the same carbon or nitrogen can optionally combine with their intervening atoms to form a 4-11 member saturated or partially unsaturated monocyclic, bicyclic, bridging bicyclic, or spirocyclic carbocyclic or heterocyclic ring, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the carbon or nitrogen to which the two R groups are linked; Each R Ａ Independently, C １－６ An optionally substituted group selected from a 4-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R ５ is, independently, hydrogen, halo, -CN, -OR, oxo, C １－６ alkyl, -CR ２ OR, -OC １－６ alkyl, C １－６ haloalkyl, -OC １－６ haloalkyl, or C ３－６ cycloalkyl, or Two R atoms on the same carbon atom ５ The base, when combined, forms the two R components. ５ Together with the carbon atom to which the group is linked, it forms a 3- to 7-membered saturated or partially unsaturated carbon ring or heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two Rs on two different carbon atoms ５ The base, when combined, forms the two R components. ５ Together with intervening atoms that link the groups, they form a 3-7 member saturated or partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings C and D is independently selected from a 5- to 9-membered heteroaryl ring having phenyl or 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and (Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.)

3. The compound is selected from one of the following formulas: 【Chemical 365】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. The compound is selected from one of the following formulas: 【Chemical 366】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. The compound is selected from one of the following formulas: 【Chemical 367】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. The compound is selected from one of the following formulas: 【Chemical 368】 【Chemical 369】 【Chemistry 370】 【Chemistry 371】 【Chemistry 372】 【Chemistry 373】 【Chemistry 374】 【Chemistry 375】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. The compound is selected from one of the following formulas: 【Transformation 376】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. The compound is selected from one of the following formulas: 【Chemical 377】 【Chemistry 378】 【Chemistry 379】 【Chemical 380】 【Chemistry 381】 【Chemistry 382】 【Chemistry 383】 【Chemical 384】 【Chem.385】 【Chemical 386】 【Chemistry 387】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. Ring A is phenylenyl, 【Chemical 388】 The compound according to any one of claims 1 to 8.

10. Ring A and Ring B are 【Chem.389】 The compound according to any one of claims 1 to 9.

11. Ring A and Ring B are 【Chemical 390】 The compound according to any one of claims 1 to 10.

12. Ring A and Ring B are 【Chemistry 391】 The compound according to any one of claims 1 to 10.

13. Ring A and Ring B are 【Chemistry 392】 The compound according to any one of claims 1 to 10.

14. Ring A and Ring B are 【Chemistry 393】 The compound according to any one of claims 1 to 10.

15. The compound according to any one of claims 1 to 14, wherein ring C and ring D are rings selected from 5- to 9-membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

16. Ring C is 【Chem. 394】 The compound according to any one of claims 1 to 15.

17. Ring C is 【Chemical 395】 The compound according to any one of claims 1 to 16.

18. Ring C is 【Chemistry 396】 The compound according to any one of claims 1 to 16.

19. Ring C is 【Chemistry 397】 The compound according to any one of claims 1 to 16.

20. Ring C is 【Chem.398】 The compound according to any one of claims 1 to 16.

21. Ring C is 【Chem.399】 The compound according to any one of claims 1 to 16.

22. The compound according to any one of claims 1 to 21, wherein ring D is phenyl, pyridyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, or pyrrolo[1,2-a]pyrimidine.

23. n is 1 and R １ However, hydrogen, R Ａ , halogen, -CN, -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -CFR ２ , -CF ２ R, -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(S)NR ２ -C(O)N(R)OR, -OC(O)R, or -OC(O)NR ２ The compound according to any one of claims 1 to 22.

24. m is 1 and R ２ However, hydrogen, R Ａ , halogen, -CN, -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -CFR ２ , -CF ２ R, -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(S)NR ２ -C(O)N(R)OR, -OC(O)R, or -OC(O)NR ２ The compound according to any one of claims 1 to 23.

25. p is 1 and R ３ However, hydrogen, R Ａ , halogen, -CN, -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -CFR ２ , -CF ２ R, -CF ３ , -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(S)NR ２ -C(O)N(R)OR, -OC(O)R, or -OC(O)NR ２ The compound according to any one of claims 1 to 24.

26. R ４ However, C １－５ A compound according to any one of claims 1 to 25, wherein the compound is alkyl.

27. The compound according to any one of claims 1 to 26, wherein the compound is selected from any one of the compounds shown in Table 1 or from pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

29. A method for degrading IRAK4 protein kinase in a patient or biological sample, comprising administering a compound or pharmaceutical composition thereof according to any one of claims 1 to 27 to the patient, or bringing the biological sample into contact with it.

30. A method for treating a disorder, disease, or condition involving IRAK4 in a patient, comprising administering to the patient a compound or pharmaceutical composition thereof according to any one of claims 1 to 27.

31. A method for treating an autoimmune disease, inflammatory disorder, or immunodeficiency disorder in a patient, comprising administering to the patient a compound or pharmaceutical composition thereof according to any one of claims 1 to 27.

32. The aforementioned diseases or disorders include 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, hyalin membrane disease, renal disease, glomerular disease, alcoholic liver disease, endocrine ophthalmology, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and systemic juvenile disease. Arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis, chronic granulomatous disease, endometriosis, leptospirosis, nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth restriction, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhydrous epithelial dysplasia, Behçet's disease, incontinence pigmentation, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, COPD, lung disease, cystic fibrosis, acid-induced Lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, blepharitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, Interstitial lung disease, laryngitis, mastitis, meningitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, herpetihormis dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis,The method according to claim 31, wherein the condition is 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.

33. The aforementioned diseases or disorders include: allergies to the eyes, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, chronic sinusitis with nasal polyps (CRSwNP), hemolytic anemia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenia, eosinophilia, hypereosinophilia, Loeffler's syndrome, eosinophilic pneumonia, tropical eosinophilia, bronchopulmonary aspergillosis, polyarteritis nodosa, Churg-Strauss syndrome, eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD, psoriasis, generalized pustular psoriasis, psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis, herpes-like symptoms, scleroderma, vitiligo, and hyper The method according to claim 31, wherein the condition is irritable vasculitis, urticaria, bullous pemphigoid, lupus, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, hidradenitis suppurativa, Sweet's syndrome, pyoderma gangrenosum, allergic conditions of the skin, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes, adult-onset Still's disease, macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis, familial Mediterranean fever, or NLRP12 autoinflammatory syndrome.

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